0001
 1       IN THE UNITED STATES DISTRICT COURT
            FOR THE DISTRICT OF WYOMING
 2   
                            _ _ _
 3   
     TOBIN, et al,            :  NO. 00CV0025
 4           Plaintiffs       :
                              :
 5           vs.              :
                              :
 6   SMITHKLINE BEECHAM,      :
            Defendant         :
 7   
                            _ _ _
 8   
                  Videotaped Deposition of DAVID
 9   
     WHEADON, M.D., taken pursuant to notice, at
10   
     One Commerce Square, Suite 2600, Philadelphia,
11   
     Pennsylvania, on Wednesday, October 18, 2000,
12   
     beginning at approximately 9:00 a.m., before
13   
     Jeanne Hoyt_Christian, Court Reporter_Notary
14   
     Public, there being present.
15   
                                _ _ _
16   
     APPEARANCES:
17   
                  VICKERY & WALDNER, LLP
18                BY:  ANDY VICKERY, ESQUIRE
                  2929 Allen Parkway, Suite 2410
19                Houston, Texas 77019
                  Phone: (713) 526_1100
20                Representing the Plaintiffs
21                LAW OFFICE OF VINCE D. NGUYEN
                  BY:  DONALD J. FARBER, ESQUIRE
22                2858 Stevens Creek Boulevard
                  San Jose, California 95128
23                Phone: (408) 296_1881
                  Representing the Plaintiffs
24   
25   
0002
 1   APPEARANCES CONTINUED:
 2                PREUSS SHANAGHER ZVOLEFF &
                  ZIMMER
 3                BY:  CHARLES F. PREUSS,
                  ESQUIRE
 4                AND THOMAS W. PULLIAM, JR.,
                  ESQUIRE
 5                225 Bush Street, 15th Floor
                  San Francisco, California
 6                94104
                  Phone: (415) 397_1730
 7                Representing SmithKline
                  Beecham Company
 8   
                  STOEL, RIVES, LLP
 9                BY:  JOHN A. ANDERSON, ESQUIRE
                  201 S. Main Street, Suite 1100
10                Salt Lake City, Utah 84111
                  Phone: (801) 578_6930
11                Representing SmithKline
                  Beecham Company
12   
                  SMITHKLINE BEECHAM
13                BY:  ANDREA L. PARRY, ESQUIRE
                  Senior Counsel
14                One Franklin Plaza
                  Philadelphia, Pennsylvania
15                19101
                  Phone: (215) 751_7022
16                Representing SmithKline
                  Beecham Company
17   
18   
19   
20   
21   
22   
23   
24   
25   
0003
 1                            I N D E X
 2                             _ _ _
 3   WITNESS                        EXAMINATION
 4   DAVID WHEADON, M.D.
 5                BY MR. VICKERY      4
 6                BY MR. FARBER      213
 7   
 8   
 9                     E X H I B I T S
10                           _ _ _
11   
12   NUMBER       DESCRIPTION     PAGE MARKED
13   1            Notice of Deposition. . .  6
14   2            Curriculum Vitae. . . . . 30
15   3            3/29/91 Letter. . . . . . 46
16   4            5/15/91 Letter. . . . . . 60
17   5            Beasley, et al Article. . 81
18   6            9/14/90 Memo. . . . . . . 107
19   7            Ballenger, et al Article. 121
20   8            Summary of Visits. . . .  159
21   9            Notice of Deposition. . . 215
22   10           Appendix V.1. . . . . . . 331
23   
24   
25   
0004
 1                      THE VIDEO TAPE OPERATOR:
 2   We're on the video record.  Today's date is
 3   October 18, 2000.  The deponent for today is
 4   David Wheadon, M.D.  The time is 9:15.
 5                      The court reporter will now
 6   swear in the witness.
 7                            _ _ _
 8                      DAVID WHEADON, M.D., after
 9   having been first duly sworn, was examined and
10   testified as follows:
11                            _ _ _
12                         EXAMINATION
13                            _ _ _
14   BY MR. VICKERY:
15   Q.    State your name, please, sir.
16   A.    David E. Wheadon, M.D.
17   Q.    Doctor Wheadon, where are you employed?
18   A.    I am employed by SmithKline Beecham.
19   Q.    What is your title?
20   A.    Vice_President Regulatory Affairs and
21   Product Professional Services.
22   Q.    Can you give me an idea of the sort of
23   range of functional responsibilities you have
24   in that job?
25   A.    In my present job, I am responsible for
0005
 1   interactions between the company and the US
 2   Food and Drug Administration.  My group
 3   negotiates with the FDA for drug approval.  We
 4   negotiate with the FDA around labeling.  We
 5   interact with R&D concerning what we call the
 6   New Drug Application, NDA, so we work closely
 7   with R&D in collating data from clinical
 8   trials, putting that into a systematic fashion
 9   that's called the NDA, filing that with the
10   FDA, and then negotiating with the FDA for
11   ultimate drug approval.
12   Q.    Is that just for Paxil or for the full
13   range of SmithKline Beecham products?
14   A.    My responsibility covers the full
15   portfolio of SmithKline Beecham products.
16   Q.    All right, sir.  We introduced ourselves
17   before the deposition.  For the record, my
18   name is Andy Vickery.  I am a lawyer from
19   Houston, Texas, and I represent some folks
20   that have a lawsuit against your company.
21                      You understand that, don't
22   you?
23   A.    Yes, I do.
24   Q.    We are here today because I issued a
25   notice pursuant to the Federal Rules for the
0006
 1   person at Pfizer most knowledgeable about
 2   certain items, and they chose you.
 3                      Are you aware of that?
 4   A.    Actually, I'm not at Pfizer.
 5   Q.    I'm sorry.  I have spent so much time
 6   fighting with Pfizer, it just comes out of my
 7    __ it just rolls off my tongue.  SmithKline
 8   Beecham.  Please forgive me, Ms. Parry and
 9   Doctor Wheadon, at SmithKline Beecham.
10                      Are you, indeed, the person
11   at SmithKline Beecham that is most
12   knowledgeable about the matters covered by my
13   notice with the exception of Item 4_B and Item
14   5?
15                      MR. PREUSS:  And 4_D.
16                      MR. VICKERY:  And 4_D?
17                      THE WITNESS:  Well, I don't
18   have the items committed to memory, but __
19   BY MR. VICKERY:
20   Q.    Let me hand that to you there.  That's
21   Exhibit 1.
22   A.    And your question is again?
23   Q.    My question is, with the exception of
24   Items 4_B and D and Item 5, are you the person
25   at SmithKline Beecham that is most
0007
 1   knowledgeable about the other topics that are
 2   listed on the notice?
 3   A.    As you mentioned, I'm the person that's
 4   been designated as someone that has knowledge
 5   concerning the topics that you have listed,
 6   with the exceptions of the ones you have
 7   noted, yes.
 8   Q.    Well, I know that probably humility
 9   plays a role, but would it be fair to say that
10   you are the person there that is most
11   knowledgeable about these __
12   A.    I have been designated as the person to
13   appear for this deposition.  I have knowledge
14   concerning those topics, yes.
15                      MR. PREUSS:  Just, Andy,
16   for the record, Doctor Blumhardt has specific
17   knowledge of the earlier stage of the product,
18   which was set forth in Vern's letter to you.
19                      MR. VICKERY:  Yes, I
20   understand that.
21   BY MR. VICKERY:
22   Q.    You didn't join SmithKline Beecham until
23   the spring of '92, right?
24   A.    That's correct, February of 1992.
25   Q.    So in terms of your personal knowledge,
0008
 1   it begins from that point forward at
 2   SmithKline Beecham?
 3   A.    That is correct.
 4   Q.    But I presume that you have acquired
 5   some institutional knowledge, if you will, by
 6   reviewing files and things and learning what
 7   went on before you got there?
 8   A.    I reviewed documents and files that were
 9   done prior to my joining SmithKline, that is
10   correct.
11   Q.    Okay, sir, now, my notice requested a
12   current CV, and I understand that that's going
13   to be faxed over in a few minutes, so we will
14   talk about that when it gets here.
15                      It also asks for any file
16   that you have maintained in the regular course
17   of business which relates to any of these
18   topics.
19                      Have you maintained files
20   specifically related to any of these topics in
21   the regular course of your business at
22   SmithKline Beecham?
23   A.    Any and all files that I have concerning
24   those topics have been turned over to counsel,
25   and my understanding is that those have been
0009
 1   provided to you.
 2   Q.    Now, the same question with regard to
 3   e_mails.
 4                      Has an effort been made to
 5   retrieve any e_mails that you may have sent or
 6   received that relate to any of these topics?
 7   A.    Any e_mail that I have sent or received
 8   concerning these topics have been turned over
 9   to counsel, and those have been made available
10   to you.
11                      MR. PREUSS:  Again, Mr.
12   Vickery, just for the record, the letter of
13   October 11th __ I believe it was October 11th
14    __ to you from Vern, third paragraph, deals
15   with those issues.
16                      MR. VICKERY:  I know.  I
17   just want to get it from the witness on the
18   record here.
19                      MR. PREUSS:  That's fine.
20   BY MR. VICKERY:
21   Q.    Now, Item C asks for any materials that
22   you reviewed in preparation for your
23   deposition.
24                      Have you reviewed materials
25   within the last month or so in order to
0010
 1   refresh your recollection and prepare yourself
 2   for this deposition?
 3   A.    Yes, I have.
 4   Q.    What have you reviewed?
 5   A.    I have looked at transcripts, for
 6   example, of the advisory committee on a
 7   meeting of the FDA concerning the approval of
 8   Paxil, at which I was one of the presenters.
 9   Q.    Is that the October '92 meeting?
10   A.    That is correct.  I have looked at
11   literature, for example, the Teicher article
12   of 1990, the Beasley article, other articles
13   in the literature.
14                      I have also reviewed
15   internal documents that have been made
16   available to you, and it is my understanding
17   that all the things that I reviewed in
18   preparation for this deposition have been made
19   available to you and are known to you.
20   Q.    Now, since we don't have your CV, would
21   you give me just sort of a brief thumbnail
22   sketch?  First of all, how old of a gentleman
23   are you?
24   A.    I am 43 years old.
25   Q.    And what is your educational background?
0011
 1   A.    I am a physician, an M.D., trained at
 2   Johns Hopkins Medical School.  Prior to
 3   getting my M.D. Degree, I went to Harvard
 4   University, where I graduated with an AB in
 5   biology.
 6                      Following medical school, I
 7   did my residency in surgery at Tufts New
 8   England Medical Center.  That was preceded by
 9   an internship in surgery at Tufts New England
10   Medical Center.
11                      At the end of my residency,
12   I served as chief resident at the Boston VA
13   Medical Center in psychiatry, and I ran an
14   inpatient unit there for a year.  And
15   following that, I took a decision to join Eli
16   Lilly and Company, where I was employed from
17   1987 to 1992.
18   Q.    And then you have been employed for
19   SmithKline Beecham from '92 to the present?
20   A.    That is correct.
21   Q.    All right, sir.  Now, did you complete a
22   residency in psychiatry?
23   A.    Yes, I did.
24   Q.    Are you Board_certified by the Board of
25   Neurology and Psychiatry?
0012
 1   A.    No.  I am Board_eligible, but not
 2   Board_certified.
 3   Q.    Do you intend to sit for those boards or
 4   not?
 5   A.    No, I do not.
 6   Q.    Just not something you need to do in
 7   your job with a pharmaceutical company?
 8   A.    Well, certainly, Board_certification is
 9   primarily driven by the need for those who are
10   practicing and seeing patients on a daily
11   basis.
12                      As I mentioned, I am
13   Board_eligible.  I have the full candidacy to
14   sit for the boards, but in light of my
15   employment in the industry, I have elected not
16   to get further certification.
17   Q.    Doctor Wheadon, with the exception of
18   your training, have you ever actually
19   practiced medicine?
20   A.    Outside of the training situation I have
21   described to you, no, I have not had a private
22   practice, no.
23   Q.    So you have never had occasion to
24   diagnose or treat someone with depression?
25   A.    That is not correct.
0013
 1   Q.    Did you do that as part of your
 2   residency training?
 3   A.    Yes.
 4   Q.    Have you ever had occasion to prescribe
 5   antidepressant medications?
 6   A.    Yes, I have.
 7   Q.    Have you ever prescribed Paxil?
 8   A.    Paxil was not available on the market
 9   when I was in my training and running an
10   inpatient unit.
11   Q.    Of course.  If I had stopped to think of
12   that.  Neither was Prozac, for that matter,
13   was it?
14   A.    That is correct.
15   Q.    So what did you describe, TCA's?
16   A.    Primarily, tricyclic antidepressants,
17   that's correct, in terms of antidepressants.
18   Q.    Let's, if we can, get some of the buzz
19   words out, sort of make a little glossary,
20   because I just made a boo_boo, in that I used
21   a term, which, thankfully, you explained.
22                      TCA means tricyclic
23   antidepressants, right?
24   A.    That is correct, yes.
25   Q.    Let's see if we can kind of get some of
0014
 1   the buzz words or shorthands out, so we can
 2   then use them, and this will be meaningful to
 3   anyone who reads or hears this deposition.
 4                      First of all, Paxil, what
 5   is the chemical name for Paxil?
 6   A.    The chemical name is Paroxetine, and the
 7   trade name is Paxil, as you have mentioned.
 8   Q.    So any time in a document or a medical
 9   article or something that we see, Paroxetine
10   __ it is actually Paroxetine Hydrochloride,
11   right?
12   A.    Paroxetine Hydrochloride is the
13   formulation that's available on the market,
14   that's correct.
15   Q.    So if we see Paroxetine or Paroxetine
16   Hydrochloride, we know that means Paxil?
17   A.    Yes.
18   Q.    So for the purpose of this deposition,
19   is it all right with you if we just use the
20   trade name Paxil?
21   A.    That is fine with me.
22   Q.    Now, same question with regard to
23   Prozac.  What is the chemical name for Prozac?
24   A.    The chemical name for Prozac is
25   Fluoxetine.  And again, I think that is a
0015
 1   hydrochloride as well, Fluoxetine
 2   Hydrochloride, and the trade name is Prozac.
 3   Q.    So let's use Prozac for that, okay?
 4   A.    That's fine.
 5   Q.    Now, that was a drug that was launched
 6   while you were at Eli Lilly by your company,
 7   Eli Lilly; correct?
 8   A.    That is correct.
 9   Q.    And I believe you had a fair amount to
10   do with that drug while you were employed for
11   about four and a half years with Lilly, didn't
12   you?
13   A.    That is correct.
14   Q.    All right, sir.
15                      Another drug in that class
16   of drugs is one called Sertraline
17   Hydrochloride, isn't it?
18   A.    Yes, Sertraline Hydrochloride is the
19   third SSRI or at least one of the first three,
20   I should put it, and the trade name is Zoloft.
21   Q.    So let's just use Zoloft for that one.
22                      More recently, there is
23   another SSRI on the market.  The trade name is
24   Selexa?
25   A.    That is correct.
0016
 1   Q.    And what's that called?
 2   A.    Quite frankly, I'm blanking on the
 3   generic name for Selexa.
 4   Q.    Citalopram?
 5   A.    I think it is Citalopram, yes.
 6   Q.    And prior to that, there was another
 7   one, which never had an indication for
 8   depression in this country, but does for OCD
 9   called Luvox, right?
10   A.    Right, that is Fluvoxamine.
11   Q.    Fluvoxamine?
12   A.    Right.
13   Q.    Now, you and I, I think, both have used
14   the term SSRI, but we haven't really defined
15   it yet in the deposition.
16                      Would you tell us what an
17   SSRI is?
18   A.    SSRI stands for Selective Serotonin
19   Reuptake Inhibitor, and that essentially is
20   intended to describe the mode of action of
21   these drugs.  They act by inhibiting or
22   preventing the reuptake of serotonin, which is
23   a neurotransmitter in the central nervous
24   system.
25   Q.    So all of them presumably work by
0017
 1   inhibiting the reuptake of serotonin in the
 2   brain; correct?
 3   A.    Our best understanding is that the mode
 4   of action that underlies the therapeutic
 5   improvement that's seen is by inhibiting
 6   serotonin reuptake, yes.
 7   Q.    Let me see if I can say that a little
 8   more in the vernacular.
 9                      When these drugs work, when
10   they help people, the way you think they help
11   people is by blocking the reuptake of
12   serotonin in the brain, right?
13   A.    That is the best understanding, that
14   that is the mode of action of the drugs, yes.
15   Q.    Which increases the amount of serotonin
16   in the synaptic cleft?
17   A.    I wouldn't necessarily say that, no.
18   Q.    What would you say about it?
19   A.    These drugs are used primarily in
20   situations where there is at least an
21   assumption that there is a deficit of
22   serotonin in the synaptic cleft, and as a
23   result, by blocking the reuptake of serotonin
24   within the cleft, it is not necessarily
25   increasing the amount in the cleft.  It is
0018
 1   allowing the amount that is present in the
 2   cleft to bind to the appropriate receptors for
 3   a longer period of time.
 4                      So you are not technically
 5   increasing serotonin, per se, but you are
 6   allowing the serotonin that is available more
 7   time to do the activities that it is there to
 8   do.
 9   Q.    Now, you have been very careful in your
10   selection of words to describe that this is
11   presumably how they work.
12                      The truth is that none of
13   the manufacturers of the SSRI drugs really
14   know why it is that the blocking of the
15   reuptake receptor alleviates depression in
16   some people, do they?
17   A.    I wouldn't say that we don't really
18   know.  We have a lot of evidence that, pieced
19   together, gives us a very good sense of how
20   these drugs work and why they work.
21                      There is a lot of
22   literature that outlines the evidence that in
23   depressed patients, there tends to be __ at
24   least a component of depressed patients __ a
25   diminished level of serotonin.  And when that
0019
 1   level is corrected, or in the case of
 2   serotonin reuptake inhibitors, sort of
 3   modified by their longevity in the cleft, you
 4   see an improvement in depressive symptoms.
 5   Q.    Part of my job is to make sure that when
 6   you and I ask questions and answers, that we
 7   put it in terms that folks can understand.  So
 8   pardon me, if sometimes I ask you to sort of
 9   rephrase something in the vernacular.
10                      Doctor Wheadon, are you
11   familiar with the theoretical basis which gave
12   rise to the development of the SSRI drugs as a
13   class to treat depression?
14   A.    Yes.
15   Q.    Tell me whether or not suicide, and
16   particularly, autopsies on suicide patients
17   who had committed suicide, had anything to do
18   with the development of these drugs.
19   A.    Well, I have to ask you to specify what
20   you mean by suicide or autopsies on patients
21   who committed suicide.
22   Q.    Isn't it true that the whole reason that
23   the pharmaceutical community thought that a
24   drug which blocked the reuptake of serotonin
25   might help treat depression is because when
0020
 1   some autopsies were done on people who had
 2   committed suicide, it was found that they had
 3   a low level of the metabolite of serotonin;
 4   isn't that true?
 5   A.    That is not correct.  That is not
 6   absolutely correct.  Do you want me to
 7   finish?
 8   Q.    Sure.  Straighten me out.
 9   A.    The scenario is as follows.  A number of
10   studies have been done to look at the
11   situation around neurotransmitters and the
12   role they may or may not play in depression.
13   Studies have been done in depressed patients,
14   using peripheral surrogates, so markers that
15   we can tap into to see what's going on in
16   terms of the central nervous system.
17                      So, for example, we have
18   looked at serotonin levels in platelets of
19   depressed patients, and there is some
20   correlation between what you may see in terms
21   of serotonin level available to you in the
22   blood and what may be going on in the central
23   nervous system.
24                      In depressed patients, it
25   has been seen that serotonin tends to be at
0021
 1   lower levels by this peripheral assay than
 2   what we call normal controls, people that are
 3   not depressed.
 4   Q.    May I stop you there just for a minute?
 5   I don't mean to interrupt you, but is it true
 6   that the only way we can tell the level of
 7   serotonin in a person's brain is by autopsy,
 8   after they are dead?
 9   A.    In terms of presently available assays,
10   the only way you can definitively know what a
11   serotonin level is in the central nervous
12   system is, as you say, by assaying following a
13   person's demise, yes.
14   Q.    So you can't do it on a live human
15   being, can you?
16   A.    We don't have ways of assaying central
17   nervous system serotonin levels in the brain,
18   no.
19   Q.    I apologize to you for interrupting
20   you.  You were giving us an excellent history
21   of the background of these drugs.
22   A.    Additionally, as I was outlining, we
23   have also __ or investigators have done
24   studies where patients were treated or given
25   meals that were depleted, lacking in
0022
 1   tryptophan.  Tryptophan is an aminoacid that's
 2   a precursor of serotonin, and without that
 3   precursor, you cannot make serotonin.
 4                      What was seen in these
 5   individuals given these meals that were low in
 6   tryptophan or absent of tryptophan is that
 7   they developed depressive symptoms, so another
 8   very strong indicator that at least in some
 9   subset of depressed patients, serotonin must
10   be playing a role.
11                      And as you point out,
12   additionally, there have been some very
13   interesting and very elegant studies that were
14   done in patients that committed suicide,
15   where, as you say, their central nervous
16   system or their brains were assayed for the
17   level of serotonin, and it has also been shown
18   in those situations, that patients that have
19   committed suicide where the assays were done
20   in their brain, serotonin was at a lower level
21   than in the brains of individuals that died of
22   other causes, not of depression.
23   Q.    Now, you have used the word assay
24   several times.  Is that really a synonym for
25   test?  When you say assay, do you mean they
0023
 1   have been tested?
 2   A.    Well, tested is such a general word.
 3   Assay is the more specific way of looking at
 4   or measuring the level of a substance, in this
 5   case, serotonin, in the blood, or in the
 6   brain, obviously.
 7   Q.    Let's get back, if I may, to our
 8   glossary building.  You and I have used the
 9   term serotonin, and that term is becoming more
10   and more familiar to people in the general
11   populus, but would you just tell us, sort of
12   in plain English terms, what serotonin is?
13   A.    Serotonin is a chemical, which is
14   present throughout the body, both in the
15   blood, or, as I mentioned, in platelets, but
16   more specifically, in terms of what we're
17   talking about, it is present in the brain and
18   in the central nervous system.
19                      It is what we call a
20   neurotransmitter.  That means that it acts on
21   certain sites in the brain and the central
22   nervous system to do a host of things, like it
23   is involved in cognition to some __ is an
24   example.  It is obviously involved in emotions
25   and how you modulate or sort of tailor your
0024
 1   emotions from a chemical balance standpoint.
 2   Q.    How about inhibitions?  Is serotonin
 3   involved in controlling inhibitions?
 4   A.    When you say inhibitions, what do you
 5   mean?
 6   Q.    Those things that keep us from doing
 7   socially inappropriate things, those things
 8   that make us act in a civil and reasonable way
 9   towards one another?
10   A.    I don't think there is any literature
11   that boils down our abilities to control our
12   actions to one chemical.  So there are studies
13   that indicate that there are a host of
14   chemicals involved in our ability to control
15   our behavior, our actions, how we interact
16   with one another, and yes, serotonin is one of
17   those, but it is not the sole determinant of
18   how we control ourselves.
19   Q.    Nor, indeed, is it the sole determinant
20   of when people are depressed, is it?
21   A.    No, there are __ other neuro chemicals
22   have been implicated as well.  Norepinephrine
23   is another one, for example.
24   Q.    Norepinephrine.  Now, we are glossary
25   building still.  Norepinephrine is another of
0025
 1   these neurotransmitters, isn't it?
 2   A.    That is correct.
 3   Q.    And is another one called dopamine?
 4   A.    That is correct.
 5   Q.    And do both of those neurotransmitters
 6   also affect human emotion?
 7   A.    Yes, they are also involved in human
 8   emotion, dopamine and norepinephrine, yes.
 9   Q.    Are there antidepressants that are
10   marketed in this country that focus on those
11   neurotransmitter systems?  In other words, the
12   norepinephrine __ that's called the
13   noradrenergic system, right?
14   A.    That's correct.
15   Q.    So are there systems that affect the
16   noradrenergic or dopaminergic systems __ I'm
17   sorry.  Let me start that over.
18                      Are there medicines
19   marketed in this country as antidepressants
20   which affect dopamine or norepinephrine,
21   rather than serotonin?
22   A.    Actually, in answering your question,
23   there are medicines that affect norepinephrine
24   that are used as antidepressants.  Dopamine,
25   however, is not a primary neurotransmitter
0026
 1   that most antidepressants are intended to
 2   impact upon.  Dopamine is really indicated in
 3   other psychiatric disorders, schizophrenia
 4   being an example.
 5   Q.    Doctor Wheadon, is it fair, just sort of
 6   in general lay terms, to think of
 7   neurotransmitters as chemical messengers?
 8   A.    That is one way of describing it, yes.
 9   Q.    So they tell the brain or the body, feel
10   this way or do this?  In other words, they
11   send messages throughout the body, don't they?
12   A.    I wouldn't describe it that they tell
13   the body to feel this way or do this.  They
14   are a mechanism for the body to carry out the
15   sort of signals, if you will, that the brain
16   is sending.  So if the brain is sending a
17   signal to lift your right arm, obviously,
18   there is an elaborate pathway that goes from
19   that desire to your right arm going up.
20   Q.    And neurotransmitters, these chemicals,
21   are the little messengers that take that
22   message down to the muscles that make your
23   right arm lift, aren't they?
24   A.    That's correct.
25   Q.    How many neurotransmitters are there in
0027
 1   the body?
 2   A.    Quite frankly, I can't give you an exact
 3   number.  There are a number of different
 4   neurotransmitters.
 5   Q.    How many different receptor sites are
 6   there for the neurotransmitter serotonin?
 7   A.    That number changes on a daily basis, so
 8   we are finding out different receptor sites
 9   for serotonin as we speak.  Generally, we say
10   there is, on average, about eight, nine
11   different __ for example, 5HT1 has several
12   subsets of serotonin receptors that are called
13   5HT1.  So there are several different types.
14   Q.    Let's glossary_build again.  5HT, what
15   is that?
16   A.    5HT is scientific shorthand for
17   serotonin.
18   Q.    Thank you.  And when you say 5HT1 or
19   5HT2, what you are talking about is a cell in
20   the body that is specifically designed to
21   receive the message from that little chemical
22   messenger that we have called serotonin,
23   right?
24   A.    Well, actually, the __ a more correct
25   characterization would be it is a limb, if you
0028
 1   will, of a cell that's designed to receive
 2   these chemicals.
 3   Q.    So in other words, it is a tangible
 4   portion of the body that God has designed to
 5   receive the serotonin?
 6   A.    It is a site that is designed to receive
 7   the serotonin, yes.
 8   Q.    Now, what is the reuptake site or
 9   receptor?  Is there a receptor that's the
10   reuptake receptor for serotonin?
11   A.    Well, it is what we actually call a
12   reuptake pump or mechanism, and what that does
13   essentially is similar to a __ almost like a
14   paddle on a ferry boat, where the serotonin
15   will bind to the appropriate site, it is then
16   rotated into the cell, where it is metabolized
17   down to its basic component.  So it is a
18   reuptake mechanism.
19   Q.    And to use that metaphor, that paddle
20   wheel metaphor, is the function of the SSRI,
21   like Paxil, basically like putting a stick in
22   the paddle wheel?  In other words, something
23   that stops that pump from causing the
24   serotonin to go back into wherever it was that
25   it started?
0029
 1   A.    Well, it doesn't stop the pump
 2   completely, so it is not exactly like putting
 3   a stick in the paddle wheel, as you say.  What
 4   it does is, it binds in a competitive way.  So
 5   Paxil or Prozac or Zoloft will bind to the
 6   reuptake pump competitively with serotonin.
 7   So the more of the drug that binds to those
 8   sites, the less serotonin is able to get to
 9   those sites.  But it doesn't disconnect the
10   reuptake mechanism, it doesn't stop it.
11   Serotonin still binds to some sites that are
12   not occupied by Paxil, for example.  So it is
13   not exactly the same analogy as what you have
14   described.
15   Q.    Okay, I think I understand you.  It just
16   competes with the serotonin molecules that are
17   there for the attention of these receptor
18   sites?
19   A.    That's correct.
20   Q.    Kind of like asking a gal to dance.  It
21   is like the Paxil beats you to the gal and
22   says, hey, how about dancing with me, and so
23   now, you can't dance with her if you are
24   serotonin, because she is already dancing with
25   Mr. Paxil, right?
0030
 1   A.    But she can always change her mind.
 2   Q.    Okay, very well.
 3                      I think your CV has
 4   arrived, and let me ask the court reporter to
 5   mark that as Exhibit 2.
 6                            _ _ _
 7                      (Whereupon the court
 8   reporter marked document as Exhibit 2 for
 9   identification.)
10                            _ _ _
11   BY MR. VICKERY:
12   Q.    I just saw you were born in Houston,
13   Texas, my hometown.
14   A.    I knew you were responding to that, yes.
15   Q.    Did you grow up there?
16   A.    Grew up in Houston, family still lives
17   there, yes.
18   Q.    Did you go to high school there?
19   A.    Actually, I went to a boarding school in
20   Austin, Texas, St. Steven's Episcopal School.
21   Q.    Fine school, a very fine school.  I will
22   quibble with you about your choice of
23   colleges, but we will do that off the record.
24                      Doctor Wheadon, help me
25   understand what areas of expertise you have
0031
 1   and what areas you really are not comfortable
 2   in talking about, okay?
 3                      Obviously, you are a
 4   trained physician and have gone through a
 5   residency program in psychiatry, so you have
 6   expertise in psychiatry; correct?
 7   A.    Yes.
 8   Q.    Would you call yourself a
 9   psychopharmacologist?
10   A.    Well, certainly, part of my training at
11   Tufts New England Medical Center was very well
12   grounded in psychopharmacology.  The chairman
13   of the department at the time was Doctor
14   Richard Schader, who is a very well known
15   psychopharmacologist.  It was a strong part of
16   our training.  So I have knowledge in
17   psychopharmacology.  I wouldn't go any further
18   than that.
19   Q.    So that's not a way that you would
20   describe yourself to other people; although,
21   obviously, you have been trained, and plus,
22   have a lot of work experience in it; correct?
23   A.    That is correct.
24   Q.    Now, how about biology or microbiology?
25   Would you consider yourself an expert in those
0032
 1   fields?
 2   A.    Certainly, my undergrad degree is in
 3   biology.  Biology and microbiology are
 4   components of what we do on a daily basis in
 5   doing scientific research.  I have knowledge
 6   of it, and that's all I can say.
 7   Q.    How about suicidology?  Have you devoted
 8   yourself at all to the study of that
 9   phenomenon called suicide?
10   A.    As a psychiatrist, suicide being a core
11   component of a number of psychiatric
12   disorders, not least of which is depression,
13   that is something we are very familiar with,
14   something we deal with on a daily basis.
15   Obviously, in the course of developing drugs
16   to treat depression, you look at suicide as a
17   core symptom, along with other symptoms of
18   depression.
19   Q.    It is one of nine, isn't it?
20   A.    There is actually eight, you look for.
21   So I have knowledge of, I have experience with
22   the issues around suicide, both in terms of
23   treating patients who are suicidal, as well as
24   suicide as a core component of depression.
25   Q.    Would you call yourself a suicidologist?
0033
 1   A.    I wouldn't necessarily call myself a
 2   suicidologist, no.
 3   Q.    There are, you understand, people that
 4   do that that belong to organizations that
 5   focus on suicide, that receive professional
 6   journals regularly that focus on suicide?
 7   A.    I have heard some people characterize
 8   themselves that way, yes.
 9   Q.    Do you belong to any organization or do
10   you regularly read any professional journal
11   that focuses on the phenomenon of suicide?
12   A.    Well, certainly, the American Journal of
13   Psychiatry and all psychiatry journals focus
14   on suicide, because it is a component of
15   psychiatric illness.  So I do read journals
16   that are very focused on suicide, yes.
17   Q.    I was really thinking about the journal
18   Suicide and Life_Threatening Behaviors.  Do
19   you know that journal?
20   A.    I'm not familiar with that journal, no.
21   Q.    All right.
22                      What made you decide, when
23   you completed all of your academic training
24   and your residency, to go into industry?
25   A.    At the time I was finishing, I had
0034
 1   several options, and the industry was one that
 2   I found very interesting.  It allowed me to
 3   continue to be involved in psychiatric
 4   research, which is one of the things I was
 5   definitely interested in.  And it was
 6   something that presented an opportunity that I
 7   had not expected to be presented to me at that
 8   point in my career.  And that is to really be
 9   able to delve into some very interesting
10   research at a time that I found very
11   exciting.
12   Q.    Were you sought out by a headhunter or
13   by the company?  I mean, just how did it
14   happen that you came to go to work for Eli
15   Lilly and Company upon the completion of your
16   residency?
17   A.    A headhunter contacted me.
18   Q.    And what were you hired to do there?
19   A.    I was hired as research physician,
20   responsible for designing clinical trials for
21   various CNS compounds that Lilly was working
22   on, Prozac obviously being one, for evaluating
23   data, for providing medical input to the
24   company on understanding the data and writing
25   reports around the data, what have you.  So
0035
 1   really looking at the overall CNS portfolio of
 2   Lilly and working on projects to which I was
 3   assigned.
 4   Q.    What is CNS?
 5   A.    Central nervous system.
 6   Q.    Thank you.
 7                      Now, when you were first
 8   hired, did you know that you would be spending
 9   a lot of time on this SSRI drug, Prozac?
10   A.    When you said did I know, I certainly
11   was aware that Lilly was working on Prozac,
12   and that, obviously, was one of the reasons
13   why I was hired as a psychiatrist, to assist
14   with the development of Prozac, yes.
15   Q.    How much of the time, of your
16   professional time, while you were employed at
17   Lilly, was spent on Prozac, as opposed to
18   other kinds of products?
19   A.    That's a difficult question to answer,
20   because it is variable.  So you need to be a
21   bit more specific.
22   Q.    Just give us, you know, your best idea
23   as __ I mean, did you spend half of your time
24   on Prozac, generally averaging it out or
25   three_quarters or 90 percent or __
0036
 1   A.    Well, again, it depends on what time
 2   frame you are speaking of.  For example, at
 3   the time I joined Lilly, it was just prior to
 4   Prozac being approved, so, obviously, 80
 5   percent of my time was around Prozac.
 6   Following the approval of Prozac, that
 7   percentage decreased significantly.
 8   Q.    Now, you talked about trials.  Did you
 9   actually at Lilly draft study protocols for
10   clinical trials?
11   A.    Yes, I did.
12   Q.    And some folks use the shorthand RCT to
13   describe clinical trials.
14                      Do you use that?  Is that
15   something you are comfortable with?
16   A.    That's actually not a term I use
17   regularly, but I know what you are referring
18   to, RCT being Randomized Control Trials.
19   Q.    What term would you use to describe
20   those kinds of trials?
21   A.    I tend to not use shorthand quite as
22   much as some people do, so I tend to call them
23   randomized control trials.
24   Q.    And did you, in fact, draft study
25   protocols for a randomized control trials?
0037
 1   A.    At Lilly?
 2   Q.    At Lilly.
 3   A.    Yes.
 4   Q.    And were you then responsible as the
 5   medical director for sort of overseeing the
 6   conduct of those trials?
 7   A.    For the ones that I was responsible for,
 8   yes.
 9   Q.    How many did you do?
10   A.    Quite frankly, I don't remember.
11   Several.  I don't remember exactly how many
12   trials I was responsible for.
13   Q.    Do you remember what the study
14   hypothesis was for the trials that you were
15   responsible for?
16   A.    Well, again, you need to be more
17   specific.  I worked on a number of different
18   compounds at Lilly, and so the hypothesis
19   would have been different depending on the
20   compound.
21   Q.    I'm only interested right now in the
22   SSRI drug Prozac.
23                      Do you remember the
24   hypothesis of any of the randomized control
25   trials that you wrote and supervised that
0038
 1   related to Prozac?
 2   A.    Again, you need to be more specific,
 3   because, as you know, Prozac has a number of
 4   different uses and indications.
 5   Q.    Right, and what I'm really asking is __
 6   well, let's use an example.
 7                      One kind of a trial that
 8   someone might do is to study the hypothesis
 9   that this drug might help people with
10   depression, right?
11   A.    Yes.
12   Q.    And you have seen a number of trials
13   that had been conducted to test that
14   hypothesis, haven't you?
15   A.    That is correct.
16   Q.    And randomized control trials always
17   have a stated hypothesis like that; in other
18   words, something that the study is designed to
19   determine; correct?
20   A.    Randomized control trials will have a
21   stated set of primary, and oftentimes,
22   secondary objectives or efficacy or safety
23   assessments, yes.
24   Q.    Is it typical that the primary outcome
25   of measure or the principal thing you are
0039
 1   trying to find out is usually one thing?
 2   A.    That is not necessarily true, no.
 3   Q.    All right, now, I have given you one
 4   example, the hypothesis that this drug might
 5   help treat depression.
 6                      Did you ever draft or
 7   supervise a study to test that hypothesis?
 8   A.    Yes.
 9   Q.    How about the hypothesis that this drug
10   might be useful in treating obsessive
11   compulsive disorders, OCD?
12                      MR. PREUSS:  Again, we are
13   talking Prozac?
14                      MR. VICKERY:  Yes, we are
15   talking about your Lilly experience right
16   now.  Did you ever draft or supervise a
17   protocol to study that hypothesis?
18                      THE WITNESS:  Yes.
19   BY MR. VICKERY:
20   Q.    Did you ever draft or supervise a study
21   where the hypothesis was anything other than a
22   given use for the drug?
23   A.    Well, you have to be more specific.
24   Q.    Okay.  We have just talked about two
25   things; in other words, depression and OCD
0040
 1   that you did draft and supervise studies to
 2   determine, right?
 3   A.    That's correct.
 4   Q.    Now, both of those things are uses for
 5   which Prozac and Paxil are marketed in this
 6   country, aren't they?
 7   A.    That is correct.
 8   Q.    And so typically, when a drug company
 9   formulates a randomized control trial, it does
10   so to test something like that; in other
11   words, a use that this drug might be put to;
12   isn't that true?
13   A.    Well, again, I think you are boiling it
14   down to far too simple an equation.  Drug
15   companies design randomized control trials to
16   answer several questions, efficacy being one,
17   but always safety as well.
18   Q.    I know, I know.
19                      Have you ever seen a
20   randomized control trial, either in your days
21   at Lilly or your days at SmithKline Beecham,
22   where the stated principal or primary
23   hypothesis being tested was anything other
24   than a use to which this drug could be put?
25   A.    Yes.
0041
 1   Q.    Give me an example of one.
 2   A.    Well, certainly, there are situations in
 3   what we call Phase I studies.
 4   Q.    Animal studies?
 5   A.    No, Phase I studies are studies in
 6   normal volunteers, where the intent is to see
 7   what the effect of the drug is on humans.  So
 8   it is the first introduction in the humans.
 9   So it is not intended, oftentimes, in Phase I
10   to ask any question concerning the effect the
11   drug may have in terms of a targeted disease
12   entity, just looking at the effect the drug
13   has in humans.
14   Q.    Now, you introduced the term Phase I.
15   There are actually four phases of clinical
16   trials that are involved in the FDA regulatory
17   process, aren't there?
18   A.    Well, there are more trials, but in
19   terms of clinical trials in humans, yes, there
20   is actually three phases in terms of the
21   initial approval.
22   Q.    Right, and Phase IV typically describes
23   that period of time when the drug has been
24   approved, and it is out there on the market,
25   and everyone, including the drug manufacturer
0042
 1   and the FDA, are now learning, once it is
 2   being used in the population, more about how
 3   the drug affects people, right?
 4   A.    Well, Phase IV typically refers to
 5   studies that are done post_approval.  They may
 6   be looking at a host of subjects.  It is not
 7   simply learning more about the drug.  You
 8   could be looking at a number of different
 9   issues.
10   Q.    With the exception of Phase I studies,
11   where you give it to healthy volunteers just
12   to see how it affects them, have you ever seen
13   any study done at Lilly or at SmithKline
14   Beecham, where the primary measure of outcome
15   was anything other than some disease or
16   condition that this drug could be marketed to
17   treat?
18   A.    Not that I can think of, no.
19   Q.    So neither of these companies, to your
20   knowledge, has ever conducted a prospective
21   randomized control trial to determine whether
22   or not those drugs cause some patients to
23   become violent or suicidal; isn't that true?
24   A.    I'm not aware of such, no.
25   Q.    Now, Doctor Wheadon, have you ever had
0043
 1   occasion to see a study protocol that was
 2   drafted to test that hypothesis?
 3   A.    You need to be more specific.
 4   Q.    The hypothesis being that an SSRI drug
 5   causes some people to become suicidal or
 6   commit suicide?  Have you ever seen a
 7   document, a draft study protocol, to test that
 8   hypothesis?
 9   A.    I have seen protocols that have been
10   proposed by individuals not necessarily either
11   affiliated with Lilly or SmithKline, yes.
12   Q.    What individuals?
13   A.    Well, both companies, and again, I need
14   to be very careful, because I am here for
15   SmithKline, and not for Lilly.
16   Q.    Sure.
17   A.    So I will look to my counsel to make
18   sure I stay in the correct path, but both
19   companies receive requests from physicians all
20   over the place with ideas of study, and
21   sometimes, a protocol may come in, saying they
22   want to use the drug, Paxil, in the case of
23   SmithKline, in a host of different scenarios.
24   Q.    I see.
25                      Now, if you were going to
0044
 1   design a study protocol to prospectively study
 2   the question of whether Paxil causes some
 3   patients to become violent or suicidal, how
 4   would you design that study?
 5   A.    Well, that's such a general question.  I
 6   need to give a little bit of background before
 7   I can answer that question.
 8   Q.    Okay.
 9   A.    Studies are generally designed based on
10   some knowledge of what you are looking for.
11   So it would be difficult to design a study if
12   what you are proposing has not been shown to
13   exist.  A study cannot be designed in terms of
14   adequate numbers, in terms of how you would
15   assess, how you would insure that it is
16   blinded appropriately, how you would control.
17   So there are a lot of difficulties in just
18   designing a study for something that has not
19   been shown to exist.  So I am not quite sure
20   how I can answer your question beyond that.
21   Q.    Well, let me ask you this.
22                      Have you ever seen a study
23   protocol drafted by someone at a major
24   pharmaceutical company to study in a
25   prospective way the question of whether or not
0045
 1   an SSRI drug causes some patients to become
 2   violent or suicidal?
 3   A.    I have not seen a protocol such as what
 4   you are describing.
 5   Q.    Let's see if I can jog your
 6   recollection.
 7                      Doctor Wheadon, do you
 8   recall, in the spring of 1991, that Eli Lilly
 9   drafted and submitted a rechallenge protocol
10   to the FDA?
11   A.    Well, you used a very important term, a
12   rechallenge protocol.  That is not a
13   prospective randomized trial.  So you need to
14   be very specific.
15   Q.    Do you recall that Eli Lilly drafted and
16   submitted to the FDA a rechallenge protocol?
17   A.    I recall that there was discussion of a
18   rechallenge protocol, yes.
19   Q.    Do you recall that you, sir, were to be
20   one of the people at Eli Lilly and Company who
21   would be supervising this study, if it was
22   done?
23   A.    That was not one of my responsibilities,
24   no.
25   Q.    Are you sure about that?
0046
 1   A.    Not that I recall.
 2   Q.    Do you recall, in May of 1991, meeting
 3   with folks at the FDA and promising them that
 4   Eli Lilly and Company was going to go forward
 5   with this study?
 6   A.    I do not recall that.
 7   Q.    I want to see if I can jog your
 8   recollection about some of these matters.
 9                      Would you mark that as
10   Exhibit 3, please?
11                            _ _ _
12                      (Whereupon the court
13   reporter marked document as Exhibit 3 for
14   identification.)
15                            _ _ _
16                      MR. PREUSS:  Can we go off
17   the record for a minute?
18                      THE VIDEO TAPE OPERATOR:
19   Going off the video record.  The time is
20   10:03.
21                      THE VIDEO TAPE OPERATOR:
22   Back on the video record.  The time is 10:04.
23   BY MR. VICKERY:
24   Q.    Doctor Wheadon, I have showed you a
25   document that is marked PZ 1339 1061 to 1089.
0047
 1   And we had an off_the_record discussion about
 2   the fact that it was marked Fentress
 3   Confidential, and what I told Mr. Preuss was I
 4   was quite confident that this document has now
 5   been admitted in the public domain in various
 6   depositions, and I believe in the Fentress
 7   trial, and perhaps, even in the Forsythe
 8   trial, so I don't think there are any trade
 9   secrets or anything here that we are violating
10   of Eli Lilly and Company.
11                      Do you remember this
12   document being drafted and submitted to the
13   FDA in the spring of 1991?
14   A.    I recall this document that you put in
15   front of me being discussed.  I don't recall
16   exactly when it was submitted to the FDA, no.
17   Q.    Do you have any reason to doubt the date
18   on the first page of March 29, 1991?
19   A.    That's the date on the front page, yes.
20   Q.    Now, Charles Beasley actually drafted
21   the protocol, didn't he?
22   A.    I don't recall exactly who drafted the
23   protocol, but Doctor Beasley was probably the
24   person __ one of the people responsible in
25   drafting it, yes.
0048
 1   Q.    Were you and he in the same group at
 2   Lilly?
 3   A.    We were both in the same group, yes.
 4   Q.    And how close were your offices to one
 5   another?
 6   A.    I quite frankly don't recall.
 7   Q.    I mean, did you see him on a daily
 8   basis?
 9   A.    Not necessarily.
10   Q.    Did you see him several times a week?
11   A.    It depended on schedules and travel and
12   what have you.
13   Q.    Did you co_author scientific papers
14   together?
15   A.    Doctor Beasley and I have co_authored a
16   few papers, yes.
17   Q.    Did you work together on this issue of
18   whether or not Prozac causes some people to
19   become violent or suicidal?
20   A.    We did work together on this issue, yes.
21   Q.    Now, would you look at Page 3 of this
22   document, kind of right there in the middle,
23   where it says, name and title of the person
24   responsible for monitoring the conduct and
25   progress of the clinical investigations?
0049
 1                      And it lists six people
 2   there.  Are you one of the six people?
 3   A.    There is a typo, but I assume I am who
 4   is referred to as DH Wheadon.
 5   Q.    It is really DE, isn't it?
 6   A.    That's correct.
 7   Q.    But there was no other fellow named
 8   Wheadon that was an M.D. at Lilly that would
 9   have been listed as being a person responsible
10   for monitoring the conduct and progress of
11   this investigation, was there?
12   A.    That is correct.
13   Q.    Now, before this document was submitted
14   by Lilly to the FDA, did you review it?
15   A.    I can't recall if I reviewed the final
16   document.  As I have said, I have seen this
17   document, but I cannot recall if I reviewed
18   the final document that was sent into the FDA
19   as a draft.
20   Q.    Did you discuss with Doctor Beasley,
21   while he was preparing this document, the
22   design of this study?
23   A.    I recall some discussions concerning the
24   design and the pitfalls of the design, yes.
25   Q.    And did you agree with his ultimate
0050
 1   choice of the design of the study?
 2   A.    I quite frankly don't recall whether I
 3   agreed or disagreed with the ultimate choice
 4   of the design.
 5   Q.    Who within your group there at Lilly
 6   would have had the authority and the
 7   responsibility for blessing the final design
 8   of the study?
 9   A.    Well, again, this is a draft, as you
10   see, that went in over the signature of Doctor
11   Max Talbott, who was head of regulatory
12   affairs.  So I really can't tell you who would
13   be the ultimate authority at that time that
14   would have blessed this draft design.
15   Q.    If you had had problems with the design
16   of the study that Doctor Beasley was putting
17   together as you discussed it with him, would
18   you have brought those to the attention of
19   whoever was superior to both you and he there?
20   A.    Certainly.
21   Q.    Were you and he on par with one another
22   when you were there?
23   A.    Yes.
24   Q.    And to whom did you both report?
25   A.    At this time, I think it was Doctor
0051
 1   Daniel Masica.
 2   Q.    And having looked at this third page,
 3   does it refresh your recollection as to
 4   whether you, sir, were going to be one of the
 5   physicians at Lilly responsible for monitoring
 6   the conduct and progress of this study?
 7   A.    Well, what you have shown me is name and
 8   title of persons responsible for monitoring
 9   the conduct, progress of the clinical
10   investigation.
11                      What was done at the time
12   is, all of the individuals in the CNS division
13   were listed as possible responsible
14   individuals, because all physicians are
15   responsible for fielding phone calls from
16   investigators concerning safety issues,
17   adverse events, what have you.
18                      So the procedure was to
19   list everyone.  That does not mean that I was
20   the person responsible for the conduct of the
21   study.
22   Q.    Are the six people whose names are
23   listed there all people who worked for Doctor
24   Masica in the Central Nervous System Division
25   of Lilly?
0052
 1   A.    Actually, no, Doctor Lou Lemberger did
 2   not work for Doctor Masica at the time.
 3   Q.    What division was he in?
 4   A.    Doctor Lemberger was actually head of
 5   the Lilly Clinic, which was the Phase I unit.
 6   Q.    Can you tell me whether the use of
 7   rechallenge as a methodology of study, as
 8   embodied in this protocol, is a proper way, a
 9   proper and scientifically valid, reliable way
10   to determine whether or not an SSRI drug, like
11   Paxil or Prozac, causes some people to become
12   violent or suicidal?
13   A.    No.
14   Q.    You can't tell me one way or the other?
15   A.    I can tell you that I do not think it is
16   a proper way of deciding whether Prozac or
17   Paxil or other SSRI's cause some people to
18   become violent or suicidal.
19   Q.    So you think that this approach that's
20   embodied in this study protocol of using a
21   rechallenge is not scientifically valid?
22   A.    I think it is a __ it has a flawed
23   characteristic to it, yes.
24   Q.    And what is that?
25   A.    Well, again, it depends on the issues
0053
 1   you are looking at.  And as we have discussed,
 2   suicide is a core component of depression,
 3   focusing on suicide, and it is known to be a
 4   waxing and waning symptom.
 5                      So the fact that suicide
 6   may be present at one time, point in time, not
 7   there at another point in time, and then back
 8   again does not necessarily correlate with the
 9   treatment that someone happens to be on at the
10   time that the symptom either was there or was
11   not there.
12   Q.    So you mean because the people involved
13   in the study were depressed and because there
14   is a correlation between depression and
15   suicide, that that's just not a valid
16   methodology?
17   A.    That is a flawed methodology.
18   Q.    And did you tell the folks at Eli Lilly
19   before they submitted it to the FDA that it
20   was a flawed methodology?
21   A.    Yes.
22   Q.    Who did you tell?
23   A.    I don't recall exactly who, but I
24   remember expressing that opinion.
25   Q.    Did you tell the FDA, when Lilly met
0054
 1   with the FDA in May of 1991 and promised to do
 2   this study, that you were promising to do a
 3   study that had a flawed methodology?
 4   A.    Well, first and foremost, I don't recall
 5   meeting with the FDA in May '91 and promising
 6   to do the study.  So I cannot comment on
 7   that.
 8   Q.    I will see if I can refresh your
 9   recollection about that in a minute.
10   A.    I cannot comment on that.
11   Q.    Can you tell us why this study was not
12   done at Lilly while you were there?
13   A.    I have no recollection of any reason why
14   it was or was not done.
15   Q.    Can you tell me whether or not the use
16   of a study design which involves challenge,
17   dechallenge, rechallenge and dechallenge is a
18   valid way, general speaking, to determine
19   side_effects caused by a drug?
20   A.    Could you ask the question again?
21   Q.    Sure.
22                      Is challenge, dechallenge,
23   rechallenge, dechallenge a valid way to
24   determine scientifically if an adverse effect
25   that a human being experiences while on a drug
0055
 1   was caused by that drug?
 2   A.    It depends on the adverse effect you are
 3   studying.
 4   Q.    Well, take one that is __ let's take one
 5   that is not confounded in any way by some
 6   association with an underlying condition.
 7   Let's say it was a healthy volunteer.  It was
 8   one of your Phase I studies.
 9                      If it were a healthy
10   volunteer, and they became suicidal on an SSRI
11   drug, and then you took them off of it, and
12   they weren't suicidal again, but then you
13   rechallenged them with that drug, and they
14   became suicidal again, and then you took them
15   off the drug again, and it went away, is that
16   pretty powerful scientific proof that the drug
17   was causing that healthy person to become
18   suicidal?
19   A.    Not necessarily, no.
20   Q.    Then what explanation would you, as a
21   psychiatrist, give us for the phenomenon that
22   appeared in this completely healthy person?
23   A.    Well, you are using healthy in a very
24   general term.  You have given me no
25   information concerning the environmental
0056
 1   stressors that individual may be undergoing.
 2   I have no idea what the social situation may
 3   be.  Suicide, while it is a core component of
 4   depression, can also be reflective of other
 5   issues in a person's life.  So I cannot in any
 6   way answer in the affirmative to the question
 7   you have given.
 8   Q.    So is it useful or useless information?
 9   A.    What?
10   Q.    The fact that the phenomenon waxes and
11   wanes, whether they are on the drug or not on
12   the drug?
13   A.    That is very tenuous information.  You
14   may use it to build upon a body of
15   information, but it is tenuous.
16   Q.    Doctor, I didn't tell you this at the
17   start, but any time you want a comfort break
18    __
19   A.    I could use some water.
20                      THE VIDEO TAPE OPERATOR:
21   Going off the video record.  The time is
22   10:15.
23                      THE VIDEO TAPE OPERATOR:
24   Back on the video record.  The time is 10:24.
25   BY MR. VICKERY:
0057
 1   Q.    Doctor Wheadon, whatever misgivings you
 2   may have had about the study design and the
 3   rechallenge protocol drafted by Doctor
 4   Beasley, it would be fair to say, would it
 5   not, that the people in higher authority at
 6   Eli Lilly obviously disagreed with that,
 7   because it was, indeed, submitted to the FDA?
 8                      MR. PREUSS:  I object to
 9   the form.
10   BY MR. VICKERY:
11   Q.    You can still answer my question.
12   A.    Would you repeat it?
13   Q.    Yes, sir.  Let me just rephrase it,
14   since he has objected.
15                      Whatever misgivings you had
16   about this study format were, in essence,
17   trumped by folks higher up at Eli Lilly than
18   you, weren't they?
19                      MR. PREUSS:  I object to
20   the form again.
21   BY MR. VICKERY:
22   Q.    Answer it.
23   A.    Well, again, as the cover letter states,
24   this is a draft protocol.  This isn't a final
25   protocol.  This is not an indication that it
0058
 1   is a decided protocol that was submitted to
 2   the FDA.  So all I can tell you is, this was a
 3   draft, and clearly, there is a discussion of
 4   the issues around the limitations of such
 5   studies and what you have put in front of me.
 6   Q.    Have you ever known any big
 7   pharmaceutical company to submit something to
 8   the FDA, something being a draft study, where
 9   the company hadn't sort of massaged it
10   internally beforehand and decided it was a
11   good idea?
12   A.    Absolutely.  That happens on a regular
13   basis.  Often, protocols are submitted in
14   draft to FDA for their input and guidance.
15   Oftentimes, the FDA will say that they don't
16   agree with the methodology of the protocol.
17   So that happens on a regular basis.
18   Q.    In the eight years you have been at
19   SmithKline Beecham, have you ever submitted to
20   the FDA a draft study protocol that your
21   company considered to be flawed?
22   A.    Absolutely, yes.
23   Q.    Why?
24   A.    Science is not an exact discipline, so
25   there are a lot of issues that we are studying
0059
 1   where there is no clarity and exactness about
 2   what it is we are proposing to do.
 3                      So, yes, we will submit
 4   protocols that we have reservations about that
 5   we know that there are inherent flaws within.
 6   And we submit it to the FDA for their input,
 7   for their guidance and their recommendations
 8   around how to carry out the study, if at all.
 9   Q.    And when you do that, do you tell them,
10   hey, this is __ we think it is flawed, but we
11   are tossing it out to you for your input?
12   A.    Absolutely.
13   Q.    Now, I want to see if I can jog your
14   recollection about the May 1991 meeting.  And
15   in all fairness, it is not clear to me from
16   the documentation whether you were at the
17   meeting or whether you just received a
18   report.
19                      So let me ask you first, do
20   you recall receiving a report of a meeting
21   that other people at Lilly had with the FDA to
22   discuss this draft protocol?
23   A.    Quite frankly, I recall in a previous
24   deposition being questioned about a report
25   around a meeting with the FDA, but I do not
0060
 1   recall being at the FDA meeting.
 2   Q.    And is the exhibit you were questioned
 3   about the one which we are going to mark now
 4   as Exhibit Number 4?
 5                            _ _ _
 6                      (Whereupon the court
 7   reporter marked document as Exhibit 4 for
 8   identification.)
 9                            _ _ _
10   BY MR. VICKERY:
11   Q.    We have now handed you Exhibit 4, which
12   has the PZ numbers 1057 25 and 26.
13                      Do you recall being
14   questioned about this document before?
15   A.    I recall being questioned about this
16   document, yes.
17   Q.    In a deposition?
18   A.    In a previous deposition.
19   Q.    How many previous depositions have you
20   given, Doctor Wheadon?
21   A.    Fortunately, only one.
22   Q.    And was that deposition given in June of
23   1992, at a point in time when you were
24   employed by SmithKline Beecham?
25   A.    I don't remember the exact date, but I
0061
 1   assume that's when it was.
 2   Q.    Have you kept a copy of the transcript
 3   of that deposition?
 4   A.    I have a copy of the transcript, yes.
 5   Q.    Have you reread it in the last year?
 6   A.    I have reviewed it in preparation for
 7   this deposition.
 8   Q.    All right.
 9                      Now, this shows on the
10   distribution list that this document went to
11   Doctor DE Wheadon at 2128.
12                      Is that you?
13   A.    That is correct.
14   Q.    What is 2128?
15   A.    It is the mail code.
16   Q.    Mail code?
17   A.    The mail, M_A_I_L, code.
18   Q.    Right.  I didn't think it was an M_A_L_E
19   code.
20                      And so whenever we see
21   2128, like by Doctor Beasley's name, by Doctor
22   Zerbe's, does that mean all of you all were in
23   that section of the company together?
24   A.    When you say all of you all, everyone
25   listed on here?
0062
 1   Q.    Everyone that has 2128 by their name?
 2   A.    That's not necessarily true.  For
 3   example, Doctor AJ Weinstein was not in the
 4   CNS group.
 5   Q.    Now, do you see here where this memo
 6   says, at the FDA meeting, Lilly agreed to do
 7   the following projects, proceed with the
 8   rechallenge study?  Do you see where it says
 9   that?
10   A.    I see where it says that, yes.
11   Q.    And do you recall, either by virtue of
12   having received this memorandum or by virtue
13   of having been told by someone, that Lilly
14   agreed, flaws notwithstanding, to proceed with
15   the rechallenge protocol, which is Exhibit 3
16   to your deposition?
17   A.    Well, let me bring to your attention the
18   third bullet under Number 1, where it says, we
19   agreed to have the rechallenge protocol ready
20   to go by September 1st, 1991, and to provide
21   data after the first quarter, which would
22   provide information on six months of
23   experience.  This would allow the FDA and
24   Lilly to determine if the study was feasible
25   or not and to give a feel for the data we were
0063
 1   collecting if patients were enrolled.
 2                      So even within the memo,
 3   there is not very much clarity around whether
 4   or not there was an agreement or not.  I do
 5   not recall an agreement to proceed with the
 6   FDA __ with the FDA to proceed with this
 7   rechallenge protocol.
 8   Q.    Well, do you recall providing data after
 9   the first quarter, which would give
10   information on six months' experience?
11   A.    I do not recall, because at that point,
12   I was not at Lilly.
13   Q.    Well, you were at Lilly until the spring
14   of '92, weren't you?
15   A.    I joined SmithKline in February of
16   1992.  So if, as this says, the rechallenge
17   protocol will be ready to go by September 1st,
18   1991 and provide six months of experience,
19   that transitioned over into my no longer being
20   employed by Lilly.
21   Q.    I understand.
22                      Doctor Wheadon, since
23   coming to SmithKline Beecham, have you ever
24   considered or proposed that your company do
25   any prospective study, whether using the
0064
 1   Beasley rechallenge format or some other study
 2   design, to test the hypothesis of whether
 3   Paxil does or does not cause some people to
 4   commit acts of violence or suicide?
 5   A.    No, I have not.
 6   Q.    Why not?
 7   A.    Because as with all these situations,
 8   where you have a question of a possible
 9   adverse effect, step number one is to go back
10   and verify whether or not that is a true,
11   valid finding or not.
12                      What has happened around
13   this issue of suicidality ideation behavior
14   associated with antidepressant medication,
15   SSRI's in particular, is that three
16   independent large data bases have been
17   analyzed to investigate this question.
18                      The data base for Prozac,
19   the data base Paxil, the data base for Zoloft,
20   all done independently, all done by different
21   individuals, all coming to the same very, very
22   strong conclusion that there is no evidence to
23   support an association between SSRI treatment
24   and the emergence of suicidal ideation or
25   behavior.
0065
 1   Q.    I want to talk to you about that
 2   probably at some length, but what you are
 3   talking about is a meta analysis, right?
 4   A.    What I'm talking about is, in some
 5   instances, a meta analysis, and in other
 6   instances, there are analyses just looking at
 7   rates of occurrence, if you will, yes.
 8   Q.    Let's defer that discussion for a little
 9   later, okay?  Let's kind of go back and put it
10   in historical perspective, if we may.
11                      When did this issue come to
12   public attention?
13   A.    To my knowledge, this issue, as you say,
14   that being the emergence of suicidal ideation
15   associated with SSRI treatment, was brought to
16   public attention with the publication of the
17   Teicher article in 1990.
18   Q.    That was February 1990; correct?
19   A.    That is correct.
20   Q.    And you folks at Lilly had a copy of it
21   before it hit the streets in the journal it
22   was published in, didn't you?
23   A.    I quite frankly don't recall if we got a
24   pre_publication copy.  That might have
25   happened.  I don't recall.
0066
 1   Q.    You keep saying the Teicher article.
 2   There were two other authors on that paper,
 3   were there not?
 4   A.    I recall correctly, Doctor Jonathan Cole
 5   and Ms. Gilad, I don't remember her first
 6   name, who was a study nurse.
 7   Q.    Carol.
 8                      Now, tell me, first of all,
 9   about Jonathan Cole.  Do you know anything
10   about his reputation and statute in the field
11   of psychopharmacology in this country?
12   A.    Doctor Jonathan Cole was, and I think he
13   is now deceased, but I'm not sure __
14   Q.    He is not.  He is very much alive and
15   well.
16   A.    My apologies to Jonathan.  He is or was
17   at the time I was at Lilly at McLean Hospital,
18   which was a Harvard_affiliated psychiatric
19   hospital in Boston, had done a number of
20   studies in psychopharmacology across the board
21   in all sorts of therapeutic modalities.
22   Q.    He has been described to me by expert
23   witnesses hired by Pfizer as a pioneer in the
24   field of psychopharmacology.
25                      Is that the reputation that
0067
 1   this man enjoys, to your knowledge?
 2   A.    Certainly, Doctor Cole was among the
 3   early biologically_based psychiatrists who
 4   were looking into the biological underpinnings
 5   of psychiatry and how you might treat
 6   psychiatric illnesses with medication, yes.
 7   Q.    Now, how about Martin Teicher?  What did
 8   you know about his reputation or credentials
 9   in February of 1990, when this article hit the
10   streets?
11   A.    Prior to the publication of the article
12   or our becoming aware of it, I knew nothing of
13   Doctor Teicher.
14   Q.    And what have you learned since then
15   about Doctor Teicher?
16   A.    He was on faculty at McLean Hospital,
17   again, the Harvard_affiliated psychiatric
18   hospital in Boston.
19   Q.    Did Doctor Teicher __ to your knowledge,
20   was he also a member of the ACNP?
21   A.    I'm not aware of whether or not Doctor
22   Teicher was or was not a member or is or is
23   not a member of ACNP.
24   Q.    Are you a member?
25   A.    I am not.
0068
 1   Q.    What is ACNP?
 2   A.    ACNP is the American College of
 3   Neuropsychopharmacology.
 4   Q.    Is that the most prestigious
 5   organization for neuropsychopharmacologists in
 6   this country?
 7   A.    I think that's debatable, but it is
 8   certainly one of the well_regarded
 9   organizations.  And I actually have to
10   correct, I was a corporate member of the
11   American College of Neuropsychopharmacology.
12   Q.    Is that an invitation_only organization?
13   A.    Yes, it is.
14   Q.    And was the invitation __ when you say
15   you were a corporate member, was the
16   invitation issued to SmithKline to nominate
17   someone to belong, and they nominated you?
18   A.    That's correct.
19   Q.    Now, because Doctor Cole and Doctor
20   Teicher were people who were affiliated with
21   the Harvard affiliate, McLean Hospital, when
22   they published this article, suggesting that
23   for some patients, Prozac might precipitate
24   suicidal thinking or suicidal actions, you all
25   took that very seriously, didn't you?
0069
 1   A.    We take __ we, being Lilly at the time,
 2   take any literature citation outlining adverse
 3   effects on a Lilly drug seriously.
 4   Q.    How many times did you fly from
 5   Indianapolis, Indiana to Boston, Massachusetts
 6   to meet with Doctor Cole to discuss his
 7   hypothesis or concern that this SSRI drug,
 8   Prozac, was causing some people to become
 9   violent or suicidal?
10   A.    Well, first of all, I'm not sure Doctor
11   Cole has expressed his __
12   Q.    I'm sorry, Doctor Teicher.
13   A.    __ his hypothesis or concern, as you
14   outlined it, so do you want to rephrase the
15   question?
16   Q.    Yes.  I misspoke.  I meant Doctor
17   Teicher.
18                      How many times did you fly
19   to Boston to discuss this issue with Doctor
20   Teicher?
21   A.    If I recall correctly, I met with Doctor
22   Teicher on two occasions.
23   Q.    And did other Lilly scientists go with
24   you to meet with Doctor Teicher?
25   A.    If I recall correctly, on one occasion,
0070
 1   Doctor Dan Masica accompanied me, and on
 2   another occasion, Doctor Robert Zerbe
 3   accompanied me.
 4   Q.    And Doctor Zerbe was a pretty high_up
 5   muckety_muck at Lilly, wasn't he?
 6   A.    Doctor Zerbe was head of clinical, all
 7   of clinical research at Lilly.
 8   Q.    Incidentally, who is the top scientific
 9   officer at SmithKline Beecham?
10   A.    It depends on how you define top
11   scientific officer.
12   Q.    I'm talking about the guy that's highest
13   up the corporate ladder that's a scientist or
14   doctor.
15   A.    I imagine that would be Doctor Tachi
16   Yamada, who is the chairman of research and
17   development.
18   Q.    Can you spell that last name for me?
19   A.    Y_A_M_A_D_A; first name, Tachi,
20   T_A_C_H_I.
21   Q.    In your meetings with Doctor Teicher,
22   did he express to you a concern that there is
23   a small subset of patients out there who would
24   be caused or triggered by an SSRI drug, like
25   Paxil or Prozac, to commit acts of violence or
0071
 1   suicide?
 2   A.    In my meetings with Doctor Teicher, he
 3   expressed an interest in the nature of the
 4   cases that he was describing.  And that is
 5   that it wasn't simply that they had suicidal
 6   thoughts on Prozac, but it was the obsessive
 7   sort of quality in terms of these patients
 8   ruminating and thinking about committing
 9   suicide that he found very unusual.
10                      He was quick to point out
11   that he had not seen such before, that he had
12   treated numbers of patients with Prozac, that
13   he was not sure what this was, he could not
14   explain it, and he was also not sure that it
15   was drug related, but it was something that he
16   found interesting, which is why he did the
17   case reports.
18   Q.    And would it be fair to say, Doctor
19   Wheadon, that he believed two things about
20   that?  Number one, that it should be tested;
21   and number two, that there should be warnings
22   about that, until such time as it was either
23   proven or disproven that this phenomenon was
24   caused by the drug?
25                      MR. PREUSS:  I object to
0072
 1   the form.
 2   BY MR. VICKERY:
 3   Q.    You can answer my question.
 4   A.    That is not something that Doctor
 5   Teicher expressed to me, no.
 6   Q.    Did you attend the September 1991 PDAC
 7   hearing?
 8   A.    If you are referring to the advisory
 9   committee hearing on this issue, yes.
10   Q.    And you were there at the behest of Eli
11   Lilly?
12   A.    That is correct.
13   Q.    Were the other SSRI manufacturers
14   invited to attend?
15   A.    It was an open advisory committee, so
16   anybody that had an interest would be able to
17   to attend, yes.
18   Q.    Was anyone from SmithKline Beecham
19   there?
20   A.    I have no idea.  I was not with the
21   company at the time.
22   Q.    Have you subsequently learned, upon
23   coming to the company, whether or not the
24   company was invited to participate and
25   declined to participate?
0073
 1   A.    I have no idea.
 2   Q.    Tell me whether or not you recall at
 3   that hearing that Doctor Teicher wanted to use
 4   some slides to illustrate his remarks and his
 5   concerns and whether he was precluded from
 6   doing so by the chairman of the committee.
 7   A.    I don't recall that specific incident,
 8   no.
 9   Q.    You do recall that the folks at Eli
10   Lilly had quite a dog and pony show, with
11   slides and other things to present, don't you?
12   A.    I recall that Lilly had a prepared
13   presentation, yes.
14   Q.    Do you believe the determinations or
15   decisions made by that committee have anything
16   to do with Paxil or this lawsuit?
17   A.    I'm not quite sure what you are asking.
18   Q.    Do you think that what the PDAC did or
19   didn't do in September of 1991 has anything to
20   do with any issue in this lawsuit?
21                      And the reason I ask you,
22   quite obviously, is, if you think so, I need
23   to ask you some questions about it.  If you
24   don't, then I will leave it alone.
25                      MR. PREUSS:  I object to
0074
 1   the form.
 2                      THE WITNESS:  I really am
 3   having difficulty understanding that
 4   question.
 5   BY MR. VICKERY:
 6   Q.    All right, well, we will come back to
 7   that one.
 8                      Doctor Wheadon, is it
 9   within your authority at SmithKline Beecham to
10   initiate a label change for Paxil?
11   A.    When you say within my authority to
12   initiate, what exactly do you mean?
13   Q.    Well, we all know that the label has to
14   ultimately be blessed by the FDA?
15   A.    That is correct.
16   Q.    But my question is, if there were to be
17   a label change, let's say that we were going
18   to put a warning on the Paxil label about the
19   possibility that it might, through some way or
20   the other, paradoxically, cause some people to
21   act in a violent or suicidal way, are you the
22   person within SmithKline Beecham that would
23   have the authority to make that decision?  In
24   other words, we are going to recommend to the
25   FDA that they let us put this warning in
0075
 1   there?
 2   A.    No, that is not how the process works.
 3   There is a committee that is responsible for
 4   label changes that reviews the data and makes
 5   decisions on a corporate basis around label
 6   changes that would be proposed or not.
 7   Q.    Does that committee operate under the
 8   auspices of your section of the company?
 9   A.    No, it does not.
10   Q.    If you thought that a label change of
11   the kind I have described was appropriate,
12   would that be something that you could __ you
13   could start the ball rolling within SmithKline
14   Beecham to get to that to happen?
15   A.    Anyone within the company in an
16   appropriate level of position can initiate
17   discussion review of potential label changes.
18   Q.    And are you familiar with what the
19   federal regulatory requirements are with
20   respect to when a warning should be put on a
21   label of a drug like Paxil?
22   A.    I know the general requirements in the
23   code of federal regulations, yes.
24   Q.    What are they?
25   A.    Generally speaking, if there is
0076
 1   reasonable evidence of an association, that
 2   might be sufficient to warrant a warning.
 3   Q.    And do the regulations specifically say
 4   you do not have to wait for proof of
 5   causation?
 6   A.    The regulations do say that causation is
 7   not necessary to be established.
 8   Q.    So just if there is reasonable evidence
 9   that the drug might cause this, then a warning
10   is appropriate, right?
11   A.    That would be reason for discussion
12   around adding a warning, yes.
13   Q.    And does that then __ in essence, are we
14   talking about a reasonable possibility?  If
15   there is a reasonable possibility that the
16   drug causes some people to do something bad,
17   then we need to warn about it?
18   A.    The regulations do not use the phrase
19   reasonable possibility, no.
20   Q.    They say reasonable evidence, don't
21   they?
22   A.    Yes.
23   Q.    Of an association?
24   A.    Right.
25   Q.    Now, is an association a term of art?
0077
 1   Is that word association a term of art?
 2   A.    Actually, to reiterate and quite
 3   frankly, I could read it to you directly, but
 4   it is reasonable evidence of a possible
 5   association, I think, is how it is phrased.
 6   Q.    Now, let's talk about the kinds of
 7   things that might constitute reasonable
 8   evidence of an association, okay?
 9                      Is there on the label or
10   package insert for Paxil a bold_face warning
11   or contraindication, today, as we sit here?
12   A.    When you say a bold_face warning or
13   contraindication, what do you mean?
14   Concerning this issue?
15   Q.    No, sir.  Is there on the Paxil label a
16   warning or contraindication in bold_face type?
17   A.    There are both warnings and
18   contraindications in the Paxil label.
19   Q.    Tell me what kind of bold_face warning
20   you know about in the Paxil label.
21   A.    The bold_face warning you are referring
22   to is concerning the concomitant use of Paxil
23   with Monoamine Oxidase Inhibitors.
24   Q.    That's a big ten_penny word, Monoamine
25   Oxidase Inhibitors, sometimes written as
0078
 1   MAOI's, right?
 2   A.    That is correct.
 3   Q.    And when you say concomitant
 4   administration, is what you are saying you are
 5   not supposed to give Paxil at the same time
 6   you give an MAOI?
 7   A.    That's correct.
 8   Q.    Even within 14 days of one another,
 9   right?
10   A.    That is correct.
11   Q.    And that's been on the Paxil label since
12   it was first put on the market, hasn't it?
13   A.    It was in the label at the time of
14   approval in the US, that's correct.
15   Q.    Which was when?
16   A.    If I recall correctly, that was in
17   December of 1992.
18   Q.    Now, that __ a similar warning is on the
19   label for Prozac and Zoloft and the other
20   SSRI's, isn't it?
21   A.    That is correct.
22   Q.    But it wasn't on the Prozac label in
23   January of '88 when this product was first
24   launched, was it?
25   A.    Not that I recall.
0079
 1   Q.    Do you recall the events in May of 1990,
 2   when the FDA required Lilly to put that
 3   bold_face warning on the label?
 4   A.    I recall some of the discussions that
 5   were occurring in May of 1990 concerning that
 6   warning, yes.
 7   Q.    To your knowledge, has any manufacturer
 8   of an SSRI drug, including SmithKline Beecham
 9   and the other manufacturers, ever conducted a
10   prospective randomized control trial to
11   determine what happens to folks that get
12   MAOI's concomitantly with SSRI's?
13   A.    I'm not aware of a prospective
14   randomized control trial looking at that
15   issue, no.
16   Q.    Tell me what a case report is.
17   A.    A case report is a description of what
18   has been observed by a practitioner in the
19   case of medical case reports.
20   Q.    And those are frequently published in
21   medical journals, aren't they?
22   A.    That is correct.
23   Q.    Sometimes, they are peer_reviewed;
24   sometimes, not?
25   A.    That is correct.
0080
 1   Q.    Like a letter to the editor would not be
 2   peer_reviewed, right?
 3   A.    In most journals, a letter to the editor
 4   is not peer_reviewed, right.
 5   Q.    But the Teicher, Cole and Gilad article
 6   was peer_reviewed, wasn't it?
 7   A.    In the case of the Teicher, Cole and
 8   Gilad article, I think it was reviewed by the
 9   editors, yes.
10   Q.    Okay.
11                      Tell me whether or not you,
12   sir, have ever published an article,
13   recommending that the bold_face warning about
14   MAOI's being given at the same time as SSRI's,
15   recommending that that warning be given.
16                      First of all, have you ever
17   published anything making that recommendation?
18   A.    If I recall correctly, I, along with
19   Doctors Beasley and others at Lilly, published
20   information concerning analyses looking at
21   concomitant use of MAOI's and Prozac.
22   Q.    And the conclusion of your article was
23   that this contraindication or warning still
24   needed to be on the label for SSRI drugs;
25   isn't that true?
0081
 1   A.    I don't recall what the conclusion of
 2   that article was.
 3   Q.    Well, I have it, and I will show it to
 4   you in a minute.
 5                      Do you recall that your
 6   conclusion about that warning was based on
 7   eight case reports, out of two and a half
 8   million people who had taken the drug?
 9   A.    I don't recall that, no.
10   Q.    Let me see if I can refresh your
11   recollection here.
12                   We will have to mark __ I only
13   have one copy, so we will mark it, and then we
14   will substitute it, if we can, at the break.
15   This is Exhibit 5.
16                            _ _ _
17                      (Whereupon the court
18   reporter marked document as Exhibit 5 for
19   identification.)
20                            _ _ _
21                      THE WITNESS:  If you don't
22   mind, I would like to refresh my memory.
23   Thank you.
24                      MR. VICKERY:  Absolutely.
25   Go right ahead.
0082
 1                      THE WITNESS:  Okay.
 2   BY MR. VICKERY:
 3   Q.    Doctor Wheadon, if you would first
 4   identify for us what Exhibit 5 is, just give
 5   us the tile of the article and the authors and
 6   the publication in which it appeared.
 7   A.    The title is Possible Monoamine Oxidase
 8   Inhibitor_Serotonin Uptake Inhibitor
 9   Interaction:  Fluoxetine Clinical Data and
10   Preclinical Findings.  The lead author is
11   Doctor Charles Beasley; other authors, Doctor
12   Daniel Masica, John Heiligenstein, M.D., David
13   Wheadon, M.D., and Robert L. Zerbe, M.D. It
14   appears in the Journal of Clinical
15   Psychopharmacology, 1993.
16   Q.    When was that article actually submitted
17   for publication?
18   A.    I don't recall.
19   Q.    I believe it shows you there on the
20   first page.
21   A.    It says, received February 10, 1992 and
22   accepted March 8, 1993.
23   Q.    Can you tell me what the conclusion of
24   that article was?
25   A.    When you say the conclusion, what do you
0083
 1   mean?
 2   Q.    I mean your conclusion.  I don't know
 3   how to say it any different.
 4   A.    Well, the end of the article states, and
 5   I will quote, "The clinical and preclinical
 6   data reviewed here stressed the importance of
 7   adhering to the manufacturer's recommendations
 8   against the administration of MAOI's
 9   concomitantly with or in close temporal
10   proximity to Fluoxetine, which are explicitly
11   stated in the package literature for
12   Fluoxetine (Prozac).  The clinical data
13   reinforced that the administration of an MAOI
14   in close temporal proximity to Fluoxetine is
15   contraindicated."
16   Q.    To put that in plain old English, what
17   you all were saying is, the label needs to
18   continue to have this bold_face warning about
19   giving an SSRI at the same time or within 14
20   days of giving an MAOI, right?
21   A.    No, that is not what we said, and I will
22   read it again, if I need to __
23   Q.    No, put it in plain English for me.
24   A.    What we said is that physicians need to
25   adhere to the already existing warning in the
0084
 1   label that there is reasonable evidence that
 2   prompted the warning going in the label based
 3   on clinical trial data, and these case reports
 4   were further elucidation of that.
 5   Q.    Now, Doctor Wheadon, the reason that you
 6   all submitted that for publication in February
 7   of '92 is because both Paxil and Zoloft were
 8   about to come out of the chute at the FDA and
 9   hit the market, and you wanted to make darn
10   sure that they had to have the same black
11   bold_faced warning on their label that you had
12   on Prozac; isn't that true?
13   A.    That is not correct.
14                      MR. PREUSS:  Objection to
15   the form, argumentative.
16                      THE WITNESS:  And it is not
17   correct.
18   BY MR. VICKERY:
19   Q.    That's not correct?
20   A.    That is not correct.
21   Q.    That had nothing to do with it?
22   A.    Nothing to do with it.
23   Q.    Well, then, why did you all write it?
24   A.    Again, I can read it to you again, it
25   was clear that based on these case reports
0085
 1   that were published, there were some instances
 2   where clinicians were not adhering to the
 3   warning that was in the Prozac label, so we
 4   wanted to further elucidate the need to adhere
 5   to the preexisting warning prior to the
 6   appearance of these cases and this
 7   publication.
 8   Q.    I know.
 9   A.    About this interaction.
10   Q.    The warning had been on there almost two
11   years at that point in time?
12   A.    Yes.
13   Q.    And you are telling me that you think
14   that physicians were ignoring that bold_face
15   warning on the label?
16   A.    I'm saying that there were some
17   instances where, as best we could tell,
18   clinicians were not adhering to the
19   recommendations contained in that warning.
20   Q.    Let's talk about depression and suicide,
21   and I'd like to see if we can isolate our
22   areas of agreement or disagreement.
23                      Can we both agree that
24   there is what you doctors would use the term
25   co_morbidity, there is a co_morbidity between
0086
 1   depression and suicide?
 2   A.    Well, no.  Co_morbidity implies a
 3   similar rate of appearance or occurrence
 4   between two disease entities.
 5   Q.    I should have used correlation.
 6                      There is a correlation
 7   between depression and suicide, right?
 8   A.    Well, I wouldn't agree with that,
 9   either.
10   Q.    What word __ I'm not trying to put words
11   in your mouth.  I'm just trying to get out the
12   testimony.
13                      Tell me what words you
14   would use to describe the relationship, if
15   any, between depression and suicide.
16   A.    Well, we can use DSM_4 or 4R as a
17   template for our discussion.  DSM_4, which is
18   the Diagnostic and Statistical Manual that
19   psychiatrists and other use in diagnosing
20   psychiatric disorders, lists as one of the
21   core symptoms of depression, symptoms,
22   suicide, either in ideation or behavior, or
23   frank attempts.
24   Q.    So in other words, we talked before
25   about these eight items.  There are eight
0087
 1   listed items, sort of like a checklist, in the
 2   DSM_4 that a doctor, as he visits with a
 3   patient and a patient's family, can go down
 4   and check to see if any of these are present,
 5   and if four or more of them are present, then
 6   that person is depressed, right?
 7   A.    That is how the manual reads, yes.
 8   Q.    And if four or more of those things are
 9   checked, then that is an indication for that
10   person to get a drug like Paxil, isn't it?
11   A.    That is not necessarily true, no.
12   Q.    What are the indications for use of
13   Paxil?
14   A.    Well, Paxil is indicated for the
15   treatment of major depressive disorder of
16   depression, among other things.  But that
17   doesn't __ DSM_4 does not dictate that if a
18   patient has four or more of the symptoms, then
19   that Paxil or any antidepressant, for that
20   matter, should be used.
21   Q.    Of course not.  And I wasn't meaning to
22   suggest they were.  I'm saying that to make a
23   diagnosis of depression, you have to check off
24   four or more of the items on that checklist.
25                      Is that true?
0088
 1   A.    By DSM_4, the recommendation __ the
 2   guideline is that four or more of the core
 3   symptoms need to be present for a diagnosis of
 4   major depression, yes.
 5   Q.    And of the eight core symptoms that are
 6   listed, one of those is suicidal ideation or
 7   attempts or __ I guess ideation or attempts,
 8   right?
 9   A.    That is correct, yes.
10   Q.    Now, in terms of the indications for
11   prescribing Paxil for depression, one would
12   have to similarly check off four of those
13   eight items, right?
14   A.    Well, I wouldn't necessarily say that.
15   Clinicians are able to use medications in the
16   way they deem fit.  So within the label for
17   Paxil, there is no requirement that clinicians
18   go through the checklist, as you describe, to
19   check off four of eight symptoms to decide
20   whether or not Paxil or other antidepressants
21   should be used.
22   Q.    Well, isn't that the way that SmithKline
23   Beecham markets Paxil?  I mean, don't you
24   provide those checklists, particularly, to
25   primary care physicians, as a convenient means
0089
 1   for them both to diagnose depression and to
 2   treat it by prescribing Paxil?
 3   A.    We provide educational materials for
 4   physicians in terms of diagnosing depression,
 5   in terms of the symptomatology one may look
 6   for, but it is not a sine qua non requirement
 7   in terms of a physician deciding to prescribe
 8   the drug.
 9   Q.    Do you or do you not provide educational
10   materials to physicians which lists those
11   eight factors from the DSM_4?
12   A.    Yes, we do.
13   Q.    And do you, in providing that material
14   to them, encourage them to prescribe Paxil
15   whenever they make a diagnosis using those
16   eight criteria?
17   A.    That is not correct.
18   Q.    Well, what's correct?  Under what
19   circumstances do you all encourage physicians
20   to use Paxil for depression?
21   A.    We encourage physicians to make a choice
22   concerning treating depression, and we offer
23   that Paxil is a good option in choosing to
24   treat depression.
25                      Your statement was we give
0090
 1   the list of eight, they check off four, and
 2   then we then say, all right, then you use
 3   Paxil for treating depression.
 4                      There are separate
 5   situations.  There is an education effort
 6   around depression and its core symptoms, and
 7   then you also educate the physician concerning
 8   the use of Paxil as an effective
 9   antidepressant.
10   Q.    Well, you are not going to tell me that
11   when a SmithKline Beecham sales rep visits a
12   doctor and provides these educational
13   materials, that their goal is anything other
14   than to encourage that doctor to prescribe
15   Paxil, are you?
16                      MR. PREUSS:  I object to
17   the form.  Argumentative.
18                      THE WITNESS:  Well, the
19   sales rep is there to promote Paxil as an
20   effective antidepressant, that is correct.
21   BY MR. VICKERY:
22   Q.    Now, I started down this discussion with
23   you about depression, because I want to talk
24   about depression and suicide.
25                      Can we both agree that a
0091
 1   person who has a major depressive illness is
 2   at an increased risk for suicide?
 3   A.    Suicide is a morbidity associated with
 4   depression, yes.  So a depressed patient is at
 5   risk of suicide.
 6   Q.    Sometimes, when depressed patients kill
 7   themselves, it is fair for us to say they kill
 8   themselves because they were depressed; isn't
 9   that true?
10   A.    In some instances, that would be true.
11   In some instances, that may not be true.
12   Q.    Can we both also agree that in some
13   patients, Paxil helps to reduce the tendency
14   of that person to kill themselves?  In other
15   words, it helps them?
16   A.    I don't agree with the statement as you
17   have phrased it, no.
18   Q.    Well, how would you phrase it?  If
19   someone asked you the question, instead in
20   sort of this more formal setting, if they ask
21   you informally, hey, does that drug that your
22   company promotes, does that help people who
23   are suicidal, how would you answer that
24   question?
25   A.    My answer to that question is, Paxil, as
0092
 1   an effective antidepressant, is effective in a
 2   number of patients in treating depression, and
 3   as a part of treating depression, you may have
 4   improvement in the symptoms of depression,
 5   such as insomnia, poor appetite, difficulty
 6   concentrating, suicide.  You may have
 7   improvement in those symptoms, but it is not a
 8   given.  It is not a given that every suicidal
 9   patient will respond to Paxil.
10   Q.    And if you interpreted my question to
11   mean that, then I did a poor job of phrasing
12   it.  I wasn't suggesting that it was.  All I
13   was saying is, it is true that Paxil
14   alleviates the suicidal symptom of some
15   depressed patients; isn't that true?
16   A.    It is true that Paxil, as an effective
17   treatment for depression, will alleviate the
18   symptoms of depression, and in some instances,
19   that may include suicide, yes.
20   Q.    Now, is suicide a simple human
21   phenomenon or a complex human phenomenon?
22   A.    It is a very complex human phenomenon.
23   Q.    Is it almost, by definition, always
24   multifactorial?
25   A.    Well, you have to tell me what you mean
0093
 1   by multifactorial.
 2   Q.    What I mean is that when people kill
 3   themselves, ordinarily, there are several
 4   different things that contribute to cause them
 5   to do it?
 6   A.    Again, you have to be clear what you
 7   mean by things.
 8   Q.    I mean both __ well, I mean several
 9   kinds of things.  I mean personality, I mean
10   an illness, I mean life stressors, I mean
11   biology.
12                      In other words, what I'm
13   suggesting is that there are many different
14   influences both on that person's mind and on
15   that person's body that would cause them to
16   commit suicide?
17   A.    There can be a number of different
18   influences.  Sometimes, it may not be a number
19   of different influences.
20                      For example, in the case of
21   a person with schizophrenia, he may have
22   command hallucinations to kill himself, and he
23   is responding solely to that command
24   hallucination.  So it is not a simple answer
25   is what I'm saying.
0094
 1   Q.    I think we are communicating.
 2                      In most cases, there are
 3   usually several factors that contribute to a
 4   person's suicide?
 5   A.    That would be an assumption, yes.
 6   Q.    And that's what you were taught in your
 7   psychiatry residency, isn't it?
 8   A.    Right.
 9   Q.    Now, were you taught any kind of
10   reliable methodology to sort of sort the wheat
11   from the chaff after a suicide had occurred
12   and determine what factor or factors, plural,
13   contributed to cause that person's suicide?
14   A.    That is not really something one does in
15   routine practice.
16   Q.    Have you ever heard the term
17   psychological autopsy?
18   A.    I have heard it used, yes.
19   Q.    And is that a method of analysis that
20   psychiatrists use sort of after the fact to
21   determine what factor or factors contributed
22   to a person's suicide?
23   A.    I know that there are some people that
24   use that particular paradigm, but it is not
25   necessarily a very widely utilized approach,
0095
 1   no.
 2   Q.    Is it, in essence, the only available
 3   methodology within the field of psychiatry
 4   that can help us answer the question, what
 5   caused Johnny to commit suicide?
 6   A.    No.
 7   Q.    What else is there, other than a
 8   psychological autopsy?
 9   A.    Well, again, and perhaps, we need to
10   agree on what you mean by psychological
11   autopsy.
12   Q.    Well, what do you mean by it?
13   A.    It, quite frankly, is not a term that I
14   use, so I'm not very clear what you are
15   referring to.  I just heard that term used.
16   Q.    Okay, well, then, maybe we will talk
17   about something else.
18                      Is there any method by
19   which you would make the determination, after
20   a person had killed himself, and let's say,
21   you were asked, Doctor Wheadon, you are a
22   psychiatrist, can you tell us what made Johnny
23   kill himself?  How would you go about doing
24   that?
25   A.    Well, certainly, if I was following a
0096
 1   patient, I should be very cognizant of the
 2   issues that was prevalent for that patient.
 3   Q.    If you were his treating physician?
 4   A.    Exactly.
 5   Q.    I agree.  What if you weren't?
 6   A.    Then I would be very hard_pressed to
 7   offer an opinion about what forced an
 8   individual to kill themselves, if I was not
 9   his treating physician.
10   Q.    Well, what if he was depressed?  I mean,
11   would it be fair to say, well, gosh, he was
12   depressed, that must be it, it must be the
13   depression made him do it?
14   A.    Well, as we have discussed, yes,
15   depression __ suicide is a core component of
16   depression, so that would be a very strong
17   factor.  But you would also look at other
18   issues.
19   Q.    Because other things could contribute to
20   exacerbate the depression; isn't that true?
21   A.    It depends on the social situation, yes.
22   Q.    And it depends on the biological
23   situation, too, doesn't it?
24   A.    I'm not sure what you mean by biological
25   situation.
0097
 1   Q.    Let's say the person got drunk.  Let's
 2   say they were drunk when they killed
 3   themselves.  They were depressed, but they
 4   were drunk.
 5                      Wouldn't you say, in those
 6   circumstances, that probably, the two things
 7   that we can say for certain is that depression
 8   and alcohol killed this man?  Maybe something
 9   else contributed as well, but we know almost
10   for certain that depression and alcohol were
11   two of the culprits here?
12   A.    That would be an assumption.
13   Q.    That would be a valid assumption for a
14   psychiatrist to make in those circumstances,
15   wouldn't it?
16   A.    Not necessarily.  Not all drunk,
17   depressed people kill themselves.
18   Q.    Of course not, but I'm talking about if
19   you were dealing with the death of our
20   hypothetical Johnny, and you knew Johnny was
21   depressed, and you knew Johnny was drunk, and
22   you were asked the question, Doctor Wheadon,
23   as a psychiatrist, can you tell us what made
24   Johnny kill himself, wouldn't you say, well, I
25   can't tell you everything, but I guarantee you
0098
 1   that the depression and the alcohol probably
 2   contributed to it?
 3   A.    You could say that with some
 4   assumptions, yes.
 5   Q.    The reason I ask you all of this is I
 6   want to ask you whether or not, if a person is
 7   depressed, and they commit an act of violence
 8   or suicide, can we automatically assume that
 9   depression and only depression made them do
10   it?
11   A.    Well, you have to separate violence and
12   suicide.
13   Q.    Why?
14   A.    Depressed patients are not, as a core
15   symptom of their depression, violent.  So I
16   can't answer for violence and suicide lumped
17   together, no.
18   Q.    So violence towards other people,
19   towards third parties, is not a core symptom
20   of depression?
21   A.    It is not, no.
22   Q.    Violence towards one's self is?
23   A.    In the form of suicide.
24   Q.    All right, so let me rephrase my
25   question then, using just suicide.  I have
0099
 1   forgotten my question completely.
 2                      If a person commits
 3   suicide, and they were depressed, is it fair
 4   for us to say, well, obviously, it was the
 5   depression and only the depression that caused
 6   that person to commit suicide?
 7   A.    It would be fair to say that depression
 8   would be a prime factor in the suicide of that
 9   individual, yes.
10   Q.    That doesn't, with all due respect,
11   answer my question.
12                      Is it fair to say that
13   depression and only depression, in other
14   words, depression is the sole cause of that
15   person's suicide?
16   A.    I can't comment beyond answering the way
17   I have, in that depression would be a prime
18   factor.  Not having a particular example, not
19   having all the scenarios on the table, I can't
20   comment beyond that.
21   Q.    The reason I asked you this is, you know
22   from your days at Eli Lilly, when all of this
23   became a matter of public concern, in the wake
24   of the Teicher and Cole article, that the
25   public relations positions of the company and
0100
 1   the legal position in lawsuits was, the
 2   depression made him do it, it was depression,
 3   not the drug that did it.
 4                      Don't you know that?
 5   A.    Are you asking me if I know that that
 6   was statements made by Lilly?
 7   Q.    Yes, sir.
 8   A.    I don't know that those were the exact
 9   statements made by Lilly.
10   Q.    Wasn't that the gist of the company's
11   position publicly that depression is what
12   makes the people commit these acts of suicide,
13   not our drug?
14   A.    That is not the gist of what Lilly said.
15   Q.    Is that the gist of SmithKline Beecham's
16   position in this case?
17   A.    The position of Lilly and SmithKline has
18   been consistently that suicide is a core
19   component of depression; that because of that,
20   the more likely cause, if you will, of suicide
21   is the fact that these people are suffering
22   from depression.
23   Q.    And when you say more likely cause, do
24   you mean the sole and only cause or do you
25   mean the prime contributing factor?
0101
 1   A.    The prime contributing factor.
 2   Q.    But that does not mean that other things
 3   don't contribute as well, does it?
 4   A.    There could, in some situations, be
 5   other contributory factors, yes.
 6   Q.    We need to change our tape, but I don't
 7   want to break right yet, because I kind of
 8   have a train of thought I want to follow up
 9   with you.
10                      THE VIDEO TAPE OPERATOR:
11   Going off the video record.  The time is
12   11:19.  This concludes Tape Number 1.
13                      THE VIDEO TAPE OPERATOR:
14   Back on the video record.  The time is 11:20,
15   the beginning of Tape Number 2.
16   BY MR. VICKERY:
17   Q.    Before we changed tapes, Doctor Wheadon,
18   we were talking about depression as a prime
19   suspect in the suicide of someone who is both
20   depressed and commits suicide.
21                      Is it accurate to say that
22   SmithKline Beecham's position is that if a
23   person is depressed, and they commit suicide,
24   then the depression would be a prime suspect
25   but not the exclusive suspect?
0102
 1   A.    Well, it is certainly our position that
 2   depression is the prime factor in the suicide
 3   of depressed patients.  But as I mentioned,
 4   you have to factor in other issues, such as
 5   psychosocial issues, life situation, what have
 6   you.  So you can't divorce yourself of those
 7   considerations as well.  You are right on
 8   that.
 9   Q.    And in the example that we used in
10   talking about it before of a person who was
11   both depressed and drunk, the other factor
12   that you clearly would pin as a causative
13   agent in addition to depression is the
14   alcohol, right?
15   A.    Not necessarily.  It is a matter of,
16   one, how much was ingested; two, the state of
17   affairs; three, if there are other medications
18   on board.
19                      For example, was the
20   patient abusing benzodiazepines and drinking
21   heavily?  In which case, yes, the alcohol and
22   benzodiazepine combination would probably be a
23   prime factor in that suicide, yes.
24   Q.    If a person is drunk, and I use the word
25   drunk to indicate had too much alcohol, if a
0103
 1   person is drunk and depressed, and they commit
 2   suicide, in your opinion, are alcohol and
 3   depression two things both of which are
 4   substantial factors in the death of that
 5   person?
 6   A.    Depression would be the prime factor in
 7   the suicide of that individual.  Alcohol could
 8   potentially be a contributing factor, yes.
 9   Q.    What makes depression the prime factor?
10   A.    As I mentioned, suicide is a core
11   component, core symptom of depression.
12   Suicide is not a core symptom of alcoholism.
13   Alcoholics do commit suicide, but it is not a
14   core symptom of alcoholism.
15   Q.    But what if the person had lived with
16   depression for four years and never had any
17   thoughts or attempt of suicide, and it was
18   only when they drank, only when they drank too
19   much that one time that they really did it?
20   Are you still going to say that the depression
21   is the prime suspect here, is the prime
22   causative agent?
23   A.    Absolutely.  In the example you have
24   given, absolutely, a hundred percent.
25   Q.    And alcohol, how much would you put on
0104
 1   alcohol then?
 2   A.    I would not give very much credence to
 3   the alcohol role.
 4   Q.    So even though they lived with
 5   depression for four years and didn't kill
 6   themselves until they took the alcohol, you
 7   would still put most of the blame on
 8   depression?
 9   A.    Absolutely, because alcohol is known to
10   be a depressant.  It can exacerbate your
11   depression, it can make you more despondent,
12   it can actually enhance the symptoms of your
13   depression.  So in the example you have given,
14   depression stands foremost at the front as the
15   prime factor.
16   Q.    Have you ever had an occasion, Doctor
17   Wheadon, when you cautioned someone else who
18   was trying to blame suicides on depression?
19   Does that ring any bell with you?  Can you
20   ever think of a time when you did that?
21   A.    Quite frankly, I'm not sure what you are
22   referring to.
23   Q.    Do you remember, to put it in sort of
24   historical context, that the Teicher and Cole
25   article, which caused the public hullabaloo
0105
 1   over this issue came out in February of 1990?
 2   A.    That's correct.
 3   Q.    And do you remember that for some months
 4   thereafter, you and Doctor Beasley and Doctor
 5   Heiligenstein did a lot of work regarding this
 6   issue of whether Prozac causes or triggers
 7   suicide in some patients?
 8   A.    That is correct.
 9   Q.    Do you recall that one of the men that
10   was higher up in the chain there at Lilly than
11   you is a fellow named Leigh Thompson?
12   A.    Doctor Thompson was head of __ at the
13   time, I think he was executive director for
14   Lilly Research Laboratories.
15   Q.    Was he the top scientist in the company?
16   A.    No, he was not.
17   Q.    Who was?
18   A.    At that time, it was probably Doctor
19   Earl Herr, who was the head of research and
20   development.
21   Q.    Do you recall, in September of 1990,
22   when Doctor Thompson was going to go to the
23   board of directors of Eli Lilly and Company
24   and make a presentation on this issue, does
25   our drug, you know, is it implicated in any
0106
 1   way in the suicide of any of our patients, and
 2   he asked you and your colleagues, Doctor
 3   Heiligenstein and Doctor Beasley to comment on
 4   his presentation?
 5   A.    I don't recall that.  I recall seeing
 6   that in a previous deposition, but I don't
 7   recall that situation.
 8   Q.    Well, let's see if I can jog your memory
 9   a little bit.
10                      Do you recall that you and
11   Doctor Heiligenstein and Doctor Beasley wrote
12   a memo to him, cautioning him, in essence,
13   saying, don't just blame the depression,
14   because we ourselves have suspected that our
15   drug had a role in some of these cases?
16   A.    I do not recall that at all.
17   Q.    Let's see if I can jog your recollection
18   on it.  Well, maybe I can, and maybe I can't.
19   Hold on.  Bear with me just a minute, Doctor.
20                      MR. PREUSS:  Do you want to
21   take a break?
22                      MR. VICKERY:  Sure.  Why
23   don't we take a break?  I have a document to
24   show you, and I will just show it to you after
25   the break.
0107
 1                      THE VIDEO TAPE OPERATOR:
 2   Going off the video record.  The time is
 3   11:27.
 4                            _ _ _
 5                      (Whereupon the court
 6   reporter marked document as Exhibit 6 for
 7   identification.)
 8                            _ _ _
 9                      THE VIDEO TAPE OPERATOR:
10   We're back on the video record.  The time is
11   11:39.
12   BY MR. VICKERY:
13   Q.    Doctor Wheadon, what is Exhibit 6?
14   A.    From what I can tell, it is a bit
15   blurred in sections, but it seems to be a copy
16   of an e_mail from the Lilly e_mail system.
17   Q.    Now, the date on the bottom e_mail is
18   September 13, 1990, and then on the top,
19   reply, September 14, 1990, right?
20   A.    That's correct.
21   Q.    Is this the document that you said you
22   recall having been questioned about in a
23   previous deposition?
24   A.    I don't recall being shown this
25   particular document, no.
0108
 1   Q.    Do you __ you see down there where it
 2   says Charles, David and I __ I'm sorry, right
 3   under September 13, 1990, it says, proposed
 4   presentation to the board.
 5                      That would be the board of
 6   directors, right?
 7   A.    I assume so, yes.
 8   Q.    And then it says Charles, David and I
 9   have reviewed your presentation and offer the
10   following thoughts, comments.
11                      Are you the David to whom
12   it refers?
13   A.    I assume so, since I am cc'd on this
14   particular e_mail.
15   Q.    And since you worked with both Doctor
16   Beasley and Doctor Heiligenstein, right?
17   A.    Right, but I'm not sure who sent this
18   e_mail, because it is not clear on what you
19   have given me.
20   Q.    I think, if you look over on Page 3, you
21   will see it was sent by John Heiligenstein.
22   A.    Okay.  But he is also a cc.  That's why
23   it is not particularly clear.
24   Q.    But you see his initials there at the
25   end, JHH, and then his name, John H.
0109
 1   Heiligenstein?
 2   A.    Right.
 3   Q.    Now, read for me, if you would, and I
 4   apologize for my copy, it is just the best I
 5   have, under Verbatim Number 4, the first two
 6   sentences?
 7   A.    Actually, I would like to read the
 8   entirety of the Verbatim Number 4.
 9   Q.    That's fine.
10   A.   "We feel that caution should be exercised
11   in the statement that suicidality and hostile
12   action in patients taking Prozac reflect the
13   patient's disorders and not a causal
14   relationship to PZ.
15   Q.    Does that stand for Prozac?
16   A.    I assume.  "Post_marketing reports are
17   increasingly fuzzy, and we have assigned, yes,
18   reasonably related on several reports.  Our
19   position letter summarizes experience to say
20   that ongoing analyses to date of the
21   prospective randomized double_blind depression
22   clinical trial data taken as a whole do not
23   support the hypotheses __ and I can't read the
24   rest.
25   Q.    When you say there that we have
0110
 1   assigned, yes, reasonably related on several
 2   reports, what does that mean?
 3   A.    In receiving adverse event report, there
 4   is a causality sort of section where you
 5   assign not related, possibly, probably
 6   related, that sort of thing.
 7   Q.    So if you say reasonably related, are
 8   you saying that it is the judgment of the
 9   physicians filling out that report that the
10   hostile or suicidal act was reasonably related
11   to Prozac?
12   A.    No, not necessarily.
13   Q.    Well, what does reasonably related mean?
14   A.    It could reflect and most often reflects
15   the opinion that may have been expressed by
16   the reporter of the event.
17   Q.    I see.  So that the person who had the
18   actual doctor/patient relationship who made
19   the clinical judgment about the effect, if
20   any, of the drug had said, yes, it is
21   reasonably related to the drug?
22   A.    That the adverse effect they were
23   reporting, in their opinion, had some hostile
24   relationship to the drug, yes.
25   Q.    So when it says we have assigned, yes,
0111
 1   you are telling me that you all just did it
 2   sort of parroting what the clinical
 3   investigator thought?
 4   A.    Absolutely.  We collect the adverse
 5   event report based on what the clinician tells
 6   us.
 7   Q.    And so no reviewing physician, such as
 8   yourself or Doctor Beasley or Doctor
 9   Heiligenstein, would make an independent
10   judgment as to whether it was related or not
11   related?
12   A.    In some instances, there may be a
13   requirement for that.
14   Q.    Look over in the middle of the next page
15   if you would, where it says Page 5, under
16   suicidal thinking and clinical trials, would
17   you just read for me what it says there?
18   A.    It says, "You may want to note that
19   trials were not intended to address issue of
20   suicidality, also in Paragraph 2, patients
21   were excluded who were serious suicidal risk."
22   Q.    Okay, now, is it true that the Lilly
23   clinical trials were not intended to address
24   the issue of suicidality?
25   A.    The trials were designed __ these trials
0112
 1   were designed to address the issue of
 2   depression, of which suicidality may or may
 3   not be a part of.
 4   Q.    Is it true that the Lilly clinical
 5   trials were not intended to address the issue
 6   of suicidality?
 7   A.    In terms of the issue of emergence of
 8   suicidality as in relation to treatment, they
 9   were not designed with that question in mind,
10   no.
11   Q.    And the same can be said of the
12   SmithKline Beecham clinical trials on Paxil;
13   isn't that true?
14   A.    That is correct.
15   Q.    Now, if a trial were to be designed to
16   address the issue of suicidality, can you tell
17   us how that trial might be different, how the
18   study design might be different than the
19   clinical trials that SmithKline Beecham has
20   actually conducted?
21   A.    Well, again, that's a very broad
22   question, but the answer to your question is,
23   the study design may not be different.
24   Q.    Well, let me ask you about some possible
25   differences.  If you were going to try to
0113
 1   measure treatment_emergent suicidality, would
 2   you use the HAM_D Item 3 as the barometer to
 3   measure it or would you use some more refined
 4   kind of a scale or tool to measure it?
 5   A.    You can use either approach, either
 6   HAM_D Item 3 or a different assessment.
 7   Either one would be valid.
 8   Q.    Have you yourself written and published
 9   documents or articles in which you have
10   acknowledged openly the limitations of the
11   HAM_D Item 3?
12   A.    I can't recall that I have written
13   anything where that question has been raised,
14   but I may be wrong.  I can't recall it.
15   Q.    You can't recall an article in which you
16   were an author, in which it was acknowledged
17   that this is just not a very refined measure
18   of treatment_emergent suicidality?
19   A.    There may be an article where the issue
20   of treatment_emergent suicidality of the sort
21   described by Doctor Teicher that HAM_D Item 3
22   may not be the best, if you will, assessment,
23   but it is an adequate assessment.
24   Q.    Are you familiar with the literature in
25   this area?
0114
 1   A.    I am reasonably familiar, but I'm not
 2   totally familiar, no.
 3   Q.    How about the 1991 Mann and Kapur
 4   article?  Are you familiar with that?
 5   A.    I don't recall that offhand, no.
 6   Q.    Do you know who John Mann is?
 7   A.    Yes, I do.
 8   Q.    And what is his reputation in the field
 9   of psychopharmacology and suicidology?
10   A.    John Mann has done a number of studies
11   on psychopharmacology, as well as analyses
12   looking at the issue of suicide.
13   Q.    Isn't he really the premiere
14   suicidologist in the world?
15   A.    I don't know that I would necessarily
16   say that he is the premiere suicidologist in
17   the world, no.
18   Q.    He is right up there, isn't he?
19   A.    He is certainly well respected in the
20   field, yes.
21   Q.    And if I can jog your memory on it, the
22   article he wrote in 1991 recommended the use
23   of something called the Beck Suicidal Ideation
24   Scale?
25   A.    I can't comment without seeing the
0115
 1   article.
 2   Q.    Do you know what the Beck scale is?
 3   A.    There are several Beck scales.
 4   Q.    Do you know the Beck Suicidal Ideation
 5   Scale or Suicide Scale?
 6   A.    There is a Beck scale that looks at
 7   suicide, yes.
 8   Q.    And how many different questions does
 9   the patient or physician have to answer on the
10   Beck scale?
11   A.    I don't recall offhand.
12   Q.    Is it more than five?
13   A.    I quite frankly don't recall.
14   Q.    How many questions does one have to
15   answer regarding suicide on the Hamilton
16   Depression Scale, which I have used the
17   shorthand for HAM_D?
18   A.    There is the Question Number 3, Item 3,
19   which discusses suicide in particular.
20   Q.    And tell us, as best you can recollect
21   it, how many different points of rating are on
22   that scale.
23   A.    It goes from 0 to 4.
24   Q.    All right, now, if a person was a 2, and
25   became a 4, would that person have become more
0116
 1   suicidal?
 2   A.    Well, the way the scale reads, 0 is no
 3   suicidal ideation; 1 is sort of passing
 4   thoughts that life is extraordinarily
 5   difficult, and it might be better if you
 6   weren't around; 2 is life is not worth living;
 7   3 is frank thoughts of not wanting to continue
 8   to live; and 4 would be, I want to kill myself
 9   or suicide attempts.
10   Q.    All right, so a person that was a 2 that
11   said __ that was just thinking, life isn't
12   worth living, but then actually made a suicide
13   attempt and became a 4, that person has gotten
14   a lot worse, haven't they?
15   A.    In terms of that assessment, yes.
16   Q.    Now, tell me whether or not in the
17   retrospective after the fact meta analyses
18   that have been done by Lilly, by SmithKline,
19   and by Pfizer on Zoloft, that person who went
20   from a 2 to a 4 would be picked up?
21   A.    Yes.
22   Q.    I thought that your meta analysis, both
23   at Lilly and at SmithKline, only picked up
24   people who went from a 0 or 1 to a 3 or 4?
25   A.    That is not correct.
0117
 1   Q.    They pick up anybody that goes along?
 2   Is that what you are telling me?
 3   A.    Several analyses were done, including 0,
 4   1, 3 to 4, including any change on the HAM_D
 5   Item 3.  So a 2 to 4 change would be picked up
 6   in the analyses that we have done.
 7   Q.    The analyses that SmithKline has done?
 8   A.    And the analyses that Lilly did.
 9   Q.    In the Lilly analyses, did they exclude
10   76 out of 97 actual suicides?
11   A.    I don't recall.
12   Q.    Do you recall that the majority of the
13   people who actually killed themselves were
14   excluded from this meta analysis?
15   A.    I don't recall that.
16   Q.    If that were true, do you think that's a
17   scientifically valid way to analyze the issue?
18   A.    I would have to have more information
19   before offering an opinion on that.
20   Q.    So you mean if I simply tell you that 97
21   people killed themselves, but that when the
22   company purported to analyze it, it excluded
23   76 out of 97, that you can't tell me from
24   those simple facts that that would cause red
25   flags to go off for you or bells to go off?
0118
 1   A.    Absolutely not.
 2   Q.    So that could be perfectly proper as far
 3   as you are concerned?
 4   A.    Yes.
 5   Q.    Perfectly proper as far as SmithKline
 6   Beecham is concerned?
 7   A.    Yes.
 8   Q.    If one were designing a clinical trial,
 9   and it was intended to address the issue of
10   suicidality, would one do, as Doctor Mann
11   recommended in his 1991 article, and use some
12   kind of a rating instrument or tool to measure
13   akathisia?
14   A.    Not necessarily, no.
15   Q.    Why not?
16   A.    There would be no reason to do that.
17   You are talking about suicide.  You are
18   talking about depression.  You have not
19   mentioned akathisia.
20   Q.    Does akathisia increase the risk of
21   suicide?
22   A.    Not necessarily.
23   Q.    Can it?
24   A.    There has been reports of some patients
25   with akathisia being at increased risk of
0119
 1   suicide, but it is not a well_founded
 2   phenomena, no.
 3   Q.    Do you have in your office the APA
 4   Textbook on Psychiatry?
 5   A.    The APA Textbook on Psychiatry?
 6   Q.    The American Psychiatric Association
 7   Textbook?
 8   A.    I don't have that particular one.  I
 9   have several different ones, but not that
10   particular one, no.
11   Q.    Is that a reliable text in your field?
12   A.    Well, yes, APA is the professional
13   association for psychiatrists, yes.
14   Q.    Have you not seen where they suggest
15   that a biologically plausible explanation for
16   why some people paradoxically become suicidal
17   on SSRI drugs is that these drugs activate
18   these people and cause them to have akathisia?
19   A.    I cannot comment, because I have not
20   seen that particular section you are referring
21   to.
22   Q.    If they do say that, would that be a
23   cause for concern for you?
24   A.    No.
25   Q.    So even if you were designing a test to
0120
 1   measure treatment_emergent suicidality, you
 2   would not look for or measure akathisia?
 3   A.    Not as a stand_alone issue, no.
 4   Q.    How about agitation?
 5   A.    No.
 6   Q.    Nervousness?
 7   A.    No.
 8   Q.    Anxiety?
 9   A.    No.
10   Q.    Jitteriness?
11   A.    No.
12   Q.    Does Paxil cause jitteriness?
13   A.    Jitteriness, per se, I'm not sure what
14   you are asking.  You have to be more specific.
15   Q.    Have you written an article saying that
16   Paxil and SSRI drugs cause jitteriness?
17   A.    I don't recall writing an article that
18   used that term, no.
19   Q.    Let me see if I can help you on that.
20                      Do you recall jointly
21   authoring an article with Doctor Ballenger and
22   others called Double_Blind, Fixed_Dose,
23   Placebo_Controlled Study of Paroxetine in the
24   Treatment of Panic Disorder?
25   A.    I do recall that, yes.
0121
 1   Q.    Let's mark a copy as Exhibit 7.  I
 2   apologize.  I didn't have extra copies of
 3   these articles.  We will just ask someone here
 4   if they will make us a couple of copies at a
 5   break.
 6                            _ _ _
 7                      (Whereupon the court
 8   reporter marked document as Exhibit 7 for
 9   identification.)
10                            _ _ _
11   BY MR. VICKERY:
12   Q.    The court reporter has handed you
13   Exhibit 7.  And would you identify that for
14   the record in the same manner as you did the
15   other article, with the author, the title and
16   the publication?
17   A.    Double_Blind, Fixed_Dose,
18   Placebo_Controlled Study of Paroxetine in the
19   Treatment of Panic Disorder; principal author,
20   James C. Ballenger, M.D.; additional authors,
21   David E. Wheadon, M.D., Martin Steiner, Ph.D.,
22   William Bushnell, M.S., and Ivan P. Gergel,
23   M.D., received August 8, 1996; revisions
24   received May 27th and July 14th, 1997;
25   accepted August 8, 1997, American Journal of
0122
 1   Psychiatry, 155:1, January 1998.
 2   Q.    Is it typical in articles of this nature
 3   to list the person to whom reprint requests
 4   should be made?
 5   A.    Yes.
 6   Q.    And what does that mean?
 7   A.    That this was the person that is the
 8   prime author that's signing off on the
 9   information and the conclusions and the
10   discussion within the paper.
11   Q.    You don't mean to suggest that the other
12   authors don't stand by the conclusions of
13   something that has their name on it, do you?
14   A.    No, I'm not suggesting that, no.
15   Q.    So if a person wants a copy or a reprint
16   of that article, then the article itself tells
17   them who they need to write to get one, right?
18   A.    Yes.
19   Q.    And to whom should reprint requests for
20   this article be sent?
21   A.    Doctor Ballenger.
22   Q.    Is Doctor Ballenger an employee of
23   SmithKline Beecham?
24   A.    No, he is not.
25   Q.    Where was he employed at this time?
0123
 1   A.    He is presently and was at this time
 2   Chairman of Psychiatry at the Medical
 3   University of South Carolina in Charleston,
 4   South Carolina.
 5   Q.    How many of the authors on that paper
 6   were employees of SmithKline Beecham?
 7   A.    Four of the five.
 8   Q.    So he is the only one that's not a
 9   SmithKline Beecham employee?
10   A.    That is correct.
11   Q.    And was the actual text of that article
12   drafted at SmithKline Beecham?
13   A.    If I recall correctly, this was actually
14   drafted as a joint effort between Doctor
15   Ballenger and ourselves.
16   Q.    Didn't you all really put the laboring
17   in in terms of writing the article?
18   A.    I don't think that is true, no.
19   Q.    So it is your testimony that he had as
20   much to do with writing the article as you
21   did?
22   A.    Absolutely.  No, Doctor Ballenger is an
23   expert in panic disorder, and he had a very
24   strong hand in writing this article, yes.
25   Q.    Now, insofar as you and the other
0124
 1   SmithKline authors were concerned, was this
 2   done on company time?
 3   A.    It was done during the course of
 4   business, yes.
 5   Q.    I mean done as part of your jobs as
 6   SmithKline Beecham employees?
 7   A.    It was done in the course of a regular
 8   business day, and as such, it was done as a
 9   SmithKline Beecham employees, yes.
10   Q.    How much of your job, since you have
11   been at SmithKline Beecham, has been involved
12   in the preparation of publication of papers
13   like this?
14   A.    What do you mean by how much?
15   Q.    Just give me an idea of a percentage or
16   number of articles.  I mean, is this something
17   you do regularly or infrequently?
18   A.    It would not be a regular occurrence,
19   no.
20   Q.    Now, is there some kind of a
21   publications committee that sort of on behalf
22   of the company reviews and approves articles
23   like this before they are submitted for
24   publication?
25   A.    Only articles that are published solely
0125
 1   by SmithKline Beecham employees.
 2   Q.    So you mean because there is an outside
 3   author on this, that the publications
 4   committee had nothing to do with this article?
 5   A.    With this particular article, I don't
 6   recall, quite frankly.
 7   Q.    But is it your testimony, then, so I'm
 8   clear on it, that if there is any outside
 9   author, then the publications committee at
10   SmithKline Beecham has nothing to do with it?
11   A.    In general, that is true.  The
12   publications committee is intended to review
13   manuscripts and articles that are coming out
14   of SmithKline Beecham by SmithKline Beecham
15   authors.
16   Q.    Is it fair to say, Doctor Wheadon, that
17   when company employees spend company time
18   writing articles, that by and large, what you
19   are writing about is things that will enhance
20   the __ either the image or reputation or
21   marketability of the product?
22   A.    I wouldn't necessarily describe it that
23   way, no.
24   Q.    How would you describe it?
25   A.    SmithKline Beecham is an ethical
0126
 1   pharmaceutical company with scientists that
 2   are very devoted to their craft, that being
 3   scientific investigation, feel very strongly
 4   that information should be disseminated in
 5   articles that are of interest to the
 6   prescribing community.
 7                      Yes, of course, we are
 8   interested in articles that help further
 9   elucidate the benefits of our product, but
10   that's not the sole method or reason for doing
11   articles, no.
12   Q.    You used a term, and so that we are
13   clear on it, it is a term that is historical,
14   rather than descriptive, is it not, the term
15   ethical pharmaceutical company?
16   A.    That is a historical descriptor for
17   companies such as Lilly, SmithKline Beecham,
18   what have you, yes.
19   Q.    To differentiate them between what?
20   A.    Quite frankly, I don't know the
21   historical perspective behind it.
22   Q.    There were patent pharmaceutical
23   companies and ethical pharmaceutical
24   companies, and that's the distinction?
25   A.    I'm not sure about that.
0127
 1   Q.    Would you turn over to the last page
 2   there?  And since I have given you my only
 3   highlighted copy, I would ask you __ I think
 4   it is the last or next to the last page.
 5   Obviously, not the last.  There is no
 6   highlighting there.  The one that has the
 7   highlighted sentence about jitteriness and
 8   anxiety?
 9   A.    The last page, actually, in terms of
10   what you have highlighted is a citation.  It
11   is not anything that the authors have
12   written.  It is Number 26.  The authors are
13   Amsterdam JD, Hornig_Rohan, Maislin:  Efficacy
14   of alprazolam in reducing Fluoxetine_induced
15   jitteriness in patients with major
16   depression.  That's what you have highlighted.
17   Q.    I know.  Flip back a page or two for me,
18   if you would.  This table is just so big, I
19   can't lean over it.  And there is a couple of
20   sentences that I have highlighted that have to
21   do with jitteriness and anxiety.
22                      Would you find those and
23   read them?
24   A.    On the Page 41, the last page of text,
25   there is a highlighted section that says,
0128
 1    "This study was not designed to measure the
 2   early treatment_related jitteriness or
 3   anxiety_like symptoms that have been reported
 4   with other SSRI's and tricyclic
 5   antidepressants.
 6   Q.    Would you have allowed this article to
 7   be published with your name on it if you did
 8   not believe that jitteriness was treatment
 9   related?
10   A.    That's not what this says.
11   Q.    I thought you just said the early
12   treatment_related jitteriness?
13   A.    I will read it again.  "This study was
14   not designed to measure the early
15   treatment_related jitteriness or anxiety_like
16   symptoms that have been reported with other
17   SSRI's and tricyclic antidepressants."
18   Q.    Fine.  Now, read it again for me and
19   omit the word treatment related.
20   A.    I'm sorry?
21   Q.    Just read it again without the words
22   treatment related.
23   A.    I don't understand what you are asking.
24   Q.    I'm asking you to read it and omit the
25   words treatment related when you read it.
0129
 1   A.   "This study was not designed to measure
 2   the early __ treatment related omitted __
 3   jitteriness or anxiety_like symptoms that have
 4   been reported with other SSRI's and tricyclic
 5   antidepressants."
 6   Q.    You see, if what you were trying to say
 7   is that jitteriness and anxiety have been
 8   reported, you wouldn't have included the term
 9   treatment related?  You wouldn't have said
10   that, unless you, the authors, thought that
11   the jitteriness and anxiety was related to the
12   treatment, would you?
13   A.    That is not correct.
14   Q.    Well, it is noon now.  Why don't we go
15   ahead and take a break?
16                      THE VIDEO TAPE OPERATOR:
17   Going off the video record.  The time is
18   12:03.
19                      THE VIDEO TAPE OPERATOR:
20   Back on the video record.  The time is 1:04.
21   BY MR. VICKERY:
22   Q.    Doctor Wheadon, you know what chiral
23   chemistry is, don't you?
24   A.    I know what you __ I think I know what
25   you mean by chiral chemistry, but you might be
0130
 1   more specific.
 2   Q.    Is Paxil a racemic mixture, a
 3   stereoisomer?
 4   A.    No.
 5   Q.    It is a single isomer drug?
 6   A.    Yes.
 7   Q.    Is there anything about it being a
 8   single isomer drug that you believe would tend
 9   to reduce or minimize any side_effects
10   associated with it?
11   A.    In terms of it being a racemic mixture
12   or not, off the top of my head, again, I'm not
13   a specific chemist from that standpoint, I'm
14   not aware of any, no.
15   Q.    Are you aware of the fact it has sort of
16   become public knowledge in the last three or
17   four months that Doctor Teicher, the same guy
18   we have been talking about and others have
19   invented a method whereby they can get a
20   single isomer version of Prozac or Fluoxetine
21   hydrochloride?
22   A.    I have seen some mention of that, but I
23   have not delved very deeply into it.
24   Q.    Did the mention that you saw include the
25   fact that in order to get that patent, they
0131
 1   said that it would help reduce certain
 2   side_effects?  In other words, it was useful,
 3   it is a new formulation of the Fluoxetine
 4   hydrochloride molecule, but what's useful
 5   about it is, it would reduce certain
 6   side_effects, including suicidal ideation and
 7   self_mutilation?
 8   A.    I'm not familiar with that claim.
 9   Q.    Is there anything to your knowledge, and
10   I realize this may be sort of advanced
11   microchemistry chemistry or something, but to
12   your knowledge, is there anything about a
13   molecule being a single isomer, as opposed to
14   a stereoisomer, that would either increase or
15   reduce the propensity of that molecule to
16   cause adverse effects?
17   A.    Not that I am aware of, no.
18   Q.    Now, is Paxil a psychoactive drug?
19   A.    You have to define what you mean by
20   psychoactive.
21   Q.    Is that a term that you have some
22   definition for in your field?  It is really
23   not my field.  It is, I guess, a
24   psychiatrist's field if a drug is
25   psychoactive, isn't it?
0132
 1   A.    Right, but you may be asking from a
 2   certain standpoint.  I need to be very clear
 3   about what you mean by the term psychoactive.
 4   Q.    Since I'm just a Podunk lawyer from
 5   Houston, Texas, why don't you tell me what
 6   psychiatrists mean when they say psychoactive?
 7   A.    Psychoactive is sometimes used as a
 8   descriptor for drugs that have activity within
 9   the CNS, or more particularly, with the brain.
10   Q.    So they are drugs which affect brain
11   chemistry, and thereby alter human behavior,
12   right?
13   A.    No.
14   Q.    They don't?
15   A.    No.
16   Q.    Where am I wrong?  Straighten me out.
17   A.    Your statement was that these are drugs
18   that have an effect on brain chemistry and
19   thereby alter human behavior.  And that is not
20   true.
21   Q.    What's the truth?  What do these drugs
22   do, psychoactive drugs?
23   A.    Well, again, you are using a very
24   general term that encompasses a wide variety
25   of drugs, so you need to be specific.
0133
 1   Q.    Well, I don't want to be specific right
 2   now.  I want to be very broad.  I want to talk
 3   generally about psychoactive drugs.
 4   A.    And as I said, that term is used to
 5   describe drugs that have activity in the
 6   central nervous system in the brain.
 7   Q.    And do you expect that the result of
 8   those biological activities on the central
 9   nervous system is, in many cases, that it will
10   affect the way the person behaves?
11   A.    Not necessarily, no.
12   Q.    I know I didn't ask necessarily.  I
13   said, in many cases, will it affect the way
14   people behave?
15   A.    The answer is no.
16   Q.    But Paxil is a psychoactive drug, as you
17   have defined the term, isn't it?
18   A.    As I have defined psychoactive, meaning
19   having activity within the central nervous
20   system, specifically, the brain, then, yes, it
21   is a psychoactive drug.
22   Q.    I mean, it is designed to alter the
23   brain chemistry with respect to the
24   neurotransmitter serotonin; correct?
25   A.    No, it does not alter the brain
0134
 1   chemistry from the standpoint of serotonin,
 2   no.  As I described before, Paxil, as a
 3   serotonin reuptake inhibitor, will block the
 4   reuptake of some serotonin molecules, allowing
 5   them to stay in the synaptic cleft longer, and
 6   thereby bind to the appropriate receptors for
 7   a longer period of time.
 8                      It is not altering the
 9   brain chemistry.  It is simply, if you will,
10   prolonging the time that serotonin is in the
11   synaptic cleft in those patients that have a
12   diminished level of serotonin.
13   Q.    We need to add the term synaptic cleft
14   to our glossary.  Would you tell us what that
15   means?
16   A.    Synapsis is where two nerves basically
17   come together, and there is a space in between
18   the two nerves that's called the synaptic
19   cleft.  One is an incoming nerve or afferent
20   neuron, and one is the outgoing nerve or
21   efferent neuron.
22                      And the way the signal,
23   let's call it an electric signal, is
24   transmitted across that space, the cleft, is
25   by neurotransmitters, serotonin being one of
0135
 1   those neurotransmitters.
 2   Q.    How selective are the selective
 3   serotonin reuptake inhibitors?
 4   A.    It varies across the various SSRI's.
 5   Q.    Are you conversant both with the
 6   pharmacodynamic and pharmacokinetic properties
 7   on Paxil, and not only Paxil in itself, but
 8   how it differs as between other drugs in that
 9   class?
10   A.    I know some of the salient issues in
11   terms of pharmacokinetics of Paxil versus the
12   other SSRI's.
13   Q.    How about pharmacodynamics?
14   A.    Well, again, pharmacodynamic is sort of
15   a global term.
16   Q.    All right.  How selective is Paxil?
17   A.    Relative to what?
18   Q.    Relative __ when you use the word
19   selective in the general description of
20   selective serotonin reuptake inhibitors,
21   SSRI's, the notion of selectivity is meant to
22   suggest that this drug sort of, to use a
23   metaphor, rifle_shoots it, in other words, it
24   focuses right in on serotonin, and that's the
25   system that it affects, the serotonergic
0136
 1   system, as opposed to, say, the noradrenergic
 2   system or the dopaminergic system; isn't that
 3   true?
 4   A.    Well, to be specific, Paxil binds
 5   selectively, meaning preferentially, to the
 6   reuptake mechanism, the reuptake receptor, if
 7   you will.  So it is selective for that
 8   particular receptor site.
 9   Q.    Does Paxil affect the dopamine system in
10   the body?
11   A.    Paxil itself has not been shown to have
12   an effect on the dopamine system of the body.
13   Q.    Well, does its metabolite affect the
14   dopamine system?
15   A.    Paxil has an inactive metabolite.
16   Q.    Is there anything about a person getting
17   Paxil that would likely affect their dopamine
18   system?
19   A.    In terms of Paxil, there is no likely
20   effect upon the dopamine system.
21   Q.    You are putting the emphasis on a
22   syllable here that causes me to think that
23   there is something about a person getting
24   Paxil that would cause you to believe that
25   their dopamine system might be affected.
0137
 1   Maybe it is a secondary effect, maybe it is a
 2   tertiary effect, I don't know.
 3   A.    And that is not correct.  I am answering
 4   the question that you are asking, though.
 5   Q.    So you would not expect, then, a person
 6   to have a change in the functioning of their
 7   dopamine system because they were on Paxil?
 8   A.    That is correct.
 9   Q.    The same question with regard to
10   norepinephrine?
11   A.    That is correct.
12   Q.    No effect there?
13   A.    In terms of a selective norepinephrine
14   reuptake inhibitor?
15   Q.    In terms of the drug Paxil affecting the
16   norepinephrine system?
17   A.    That is correct, yes.
18   Q.    Does it affect any other
19   neurotransmitter system, as far as you know?
20   A.    In terms of what?
21   Q.    In terms of blocking receptor sites,
22   affecting the reuptake mechanism or otherwise
23   disturbing the normal, natural balance of a
24   system, a neurotransmitter system within the
25   human body?
0138
 1   A.    In terms of Paxil being given in the
 2   therapeutic dose, our best understanding is
 3   that it acts preferentially at binding to the
 4   select __ to the serotonin reuptake inhibitor.
 5   Q.    Can we substitute the word solely for
 6   the word preferentially?  Does it operate
 7   solely on the serotonin reuptake system?
 8   A.    It operates preferentially on the
 9   serotonin reuptake system.
10   Q.    And what distinction do you make between
11   preferentially and solely?
12   A.    Well, there is studies that have been
13   done that shows that if you give enough
14   Paroxetine as a molecule into an assay, you
15   may have some spill_over effect on to __ in
16   terms of binding to other receptor sites.
17   Q.    Other than serotonin receptor sites?
18   A.    No, not necessarily, no, just other
19   receptor sites.  So if you give enough of any
20   one compound, you may have some inadvertent
21   non_preferential binding to other receptors.
22   Q.    Now, does the Paxil affect serotonin
23   receptor sites, other than the reuptake site?
24   A.    The primary binding capacity is to the
25   reuptake site.
0139
 1   Q.    And that wasn't my question.  My
 2   question was, does it affect the other
 3   serotonin receptor sites?
 4   A.    I'm not familiar with data that Paxil
 5   binds to other serotonin receptor sites.
 6   Q.    Does it affect serotinergic functioning
 7   at all, other than the intended effect of
 8   blocking the reuptake?
 9   A.    Well, in terms of blocking the reuptake,
10   as I mentioned earlier, you prolong the time
11   that serotonin is available to bind to the
12   appropriate receptor sites.  So, yes, the
13   sequence is, you block the reuptake of
14   serotonin, it is available in the cleft for a
15   longer period of time, thereby, the serotonin
16   binds to the sites for which it is intended to
17   bind.
18   Q.    Does it have any effect on the
19   metabolism of serotonin?
20   A.    Paxil?
21   Q.    Yes, sir.
22   A.    No.
23   Q.    Does it have any effect on the P450
24   cytochrome enzymes?
25   A.    It is metabolized by some of the
0140
 1   isozymes of the P450 system, yes.
 2   Q.    A few minutes ago, you said that Paxil
 3   has an inactive metabolite.  And I think I
 4   know what you mean, but what you kind of put
 5   that in plain English?
 6   A.    It means that the metabolite of Paxil
 7   has no known biologic activity.
 8   Q.    Metabolite is something that the drug
 9   turns into.  When the body sort of processes
10   it, it turns into that before the body gets
11   rid of it, right?
12   A.    It is the breakdown product, yes.
13   Q.    Now, that's a difference between Paxil
14   and Prozac, isn't it?
15   A.    That is correct.
16   Q.    The metabolite of Prozac is
17   psychoactive?
18   A.    That is correct.
19   Q.    And Prozac also has a much longer
20   half_life than Paxil, doesn't it?
21   A.    That is correct.
22   Q.    What is the significance, if any, of
23   that?
24   A.    Well, there are a lot of different
25   domains where they may or may not be a
0141
 1   significance.  Like, for example, with a
 2   half_life of 24 hours, which is the rough
 3   half_life of Paroxetine, your dosing is once a
 4   day.  With a half_life of roughly seven to ten
 5   days, which is the case for Prozac, you
 6   conceivably could dose at a more sort of
 7   prolonged period regimen of dosing.  So those
 8   sorts of situations are driven mostly by the
 9   half_life.
10   Q.    How extensive is our knowledge about the
11   way that the metabolism of Paxil differs from
12   one human to the next?
13   A.    When you say how extensive, what do you
14   mean?
15   Q.    Have there been studies specifically
16   focused on determining variations among the
17   population of people who get this drug as to
18   how they metabolize it?
19   A.    Well, again, you have to be more
20   specific.  Do you mean in terms of the
21   breakdown product?  Do you mean in terms of
22   the half_life?  What exactly are you asking?
23   Q.    I mean both.  Is it not true that we do
24   know that the ability of a body to metabolize
25   it, the speed at which a body metabolizes it
0142
 1   vary from one human to the next?
 2   A.    Well, there is variance from one
 3   individual to the next in terms of how fast or
 4   how slow one might break down the product to
 5   its components, but in general, there is a
 6   range, and that range falls within roughly a
 7   24_hour time frame in terms of the half_life
 8   of Paxil.
 9   Q.    I want to ask you about possible
10   therapeutic uses of Paxil, and I understand
11   that some of these, your company may be
12   authorized to promote the product for these
13   uses, and some of them, you may not.
14                      And so I'm not asking you
15   whether the FDA has approved your marketing
16   for a particular indication, but I'm asking,
17   merely, does the company believe that this
18   drug might be useful in treating each of the
19   following items, okay?
20                      Alcoholism?
21   A.    We have no information that Paxil would
22   be useful in treating alcoholism.
23   Q.    Anxiety?
24   A.    We have information to indicate Paxil
25   may be used for treating generalized anxiety
0143
 1   disorder.
 2   Q.    Depression?  Obviously, yes?
 3   A.    Yes.
 4   Q.    OCD, yes?
 5   A.    That's correct.
 6   Q.    Panic disorder?
 7   A.    We have an indication for panic
 8   disorder.
 9   Q.    Chronic pain?
10   A.    There are studies that have suggested
11   usefulness of SSRI's for chronic pain.
12   Q.    Obesity?
13   A.    We have no information that Paxil would
14   be useful in the treatment of obesity.
15   Q.    Senile dementia?
16   A.    We have no information that Paxil would
17   be useful in the treatment of senile dementia.
18   Q.    Migraine?
19   A.    There have been some studies with SSRI's
20   concerning their use in migraine, yes.
21   Q.    Bulimia?
22   A.    There have been studies with Fluoxetine
23   in particular and bulimia.
24   Q.    Well, if Fluoxetine, Prozac, was useful
25   in treating bulimia, would that lead you to
0144
 1   suspect that probably Paxil was, too?
 2   A.    Not necessarily, no.
 3   Q.    Anorexia?
 4   A.    We have no information that Paxil would
 5   be effective in anorexia.
 6   Q.    Social phobia?
 7   A.    We have, as you know, a labeled
 8   indication for social anxiety disorder or
 9   social phobia.
10   Q.    And Paxil is the only one of the SSRI's
11   that currently has an approved indication for
12   social phobia; isn't that true?
13   A.    That's correct.
14   Q.    Or some folks call it shyness?
15   A.    That's incorrect.
16   Q.    What's the difference between social
17   phobia and shyness?
18   A.    Social phobia is a significant
19   psychiatric illness with significant morbidity
20   associated with it, effect on lifestyle,
21   ability to function.
22                      Patients with social phobia
23   are unable to interact in social and in
24   professional environments in a way that they
25   need to to carry on the daily aspects of
0145
 1   life.  They have difficulty achieving their
 2   goals in terms of school, in terms of
 3   progressing their career, interacting with
 4   neighbors and family.  They are quite
 5   debilitated and feel quite isolated.  That's
 6   very different from shyness.
 7   Q.    So you are saying this is a very serious
 8   mental illness?
 9   A.    Exactly.
10   Q.    And do you believe that your company
11   television ads, which we all see on TV,
12   advertising Paxil for social phobia, make that
13   distinction very clear and apparent?
14   A.    Yes, I do.
15   Q.    Incidentally, and tell me if this is
16   beyond your bailiwick, but are ads like that
17   what are called reminder ads?  Television ads
18   like your social phobia ad?
19   A.    We don't have just what you are tagging
20   as a reminder ad for social phobia.  If I
21   recall correctly, we have two types of ads,
22   one of which is highlighting the illness of
23   social phobia with all the descriptors, all
24   the limitations, what have you, all the
25   language that one is accustomed in seeing in
0146
 1   direct to consumer advertising.
 2                      The reminder ad, as you
 3   point out, is simply an ad that has the same
 4   Paxil with no indication of proposed use.
 5   Q.    So a reminder ad would be something
 6   like, oh, I don't know, a mug or a
 7   prescription pad that your sales reps might
 8   leave with the doctor, those sorts of things?
 9   A.    That could be called a reminder ad, yes.
10   Q.    Just to remind them of the name Paxil?
11   A.    That's correct.
12   Q.    And can you give me any idea how much
13   money your company spends every year on
14   reminder ads?
15   A.    You have now exceeded my bailiwick.
16   Q.    Back to our list of things that Paxil
17   might treat or prevent, how about PMS?
18   A.    There are studies with SSRI's in
19   treating what's now called PMDD, which is
20   premenstrual dysphoric disorder.
21   Q.    Does Paxil have an approved indication
22   for that?
23   A.    No, it does not.
24   Q.    How about adolescent depression?
25   A.    There are studies with SSRI's looking at
0147
 1   their use in adolescent depression, yes.
 2   Q.    Does Paxil have an approved indication
 3   for adolescent depression?
 4   A.    No, it does not.
 5   Q.    Is it approved for pediatric OCD?
 6   A.    No, it is not.
 7   Q.    Is it approved for any use in a
 8   pediatric population?
 9   A.    Not at this time.
10   Q.    How about a malady called
11   trichotillomania?  Do you know what that is?
12   A.    Yes.
13   Q.    What is it?
14   A.    Trichotillomania is a disorder that's
15   characterized mainly by pulling of the hair.
16   It is compulsive disorder, where people
17   compulsively pull at their hair to the point
18   of pulling large amounts of hair out.  I do
19   not have trichotillomania, by the way.
20   Q.    I wouldn't ask you that, even if I
21   thought it, and I have less hair than you,
22   Doctor Wheadon.
23                      Do you think Paxil might be
24   useful to treat or prevent trichotillomania?
25   A.    I have no idea.  We have not studied
0148
 1   it.  Obviously, there have been studies with
 2   SSRI's, Fluoxetine, for example, and its use
 3   in trichotillomania, but we have not studied
 4   that.
 5   Q.    Is that a first cousin of Tourette's
 6   syndrome?
 7   A.    Tourette's is different.
 8   Q.    Does Paxil have potential usefulness for
 9   treating Tourette's syndrome?
10   A.    Again, based on the literature with
11   SSRI's, there is a possibility, but we have
12   not studied that.
13   Q.    Here is a ten_penny word for you.  How
14   about dysthymia?
15   A.    Dysthymia.
16   Q.    Dysthymia, thank you for correcting me.
17   A.    Again, there has been studies both with
18   Paroxetine, not done by ourselves, but other
19   investigators and with other SSRI's for use in
20   treating dysthymia.
21   Q.    How about substance abuse?  Is it useful
22   for treating that?
23   A.    There have been studies that looked at
24   the use of SSRI's in treating, for example,
25   cocaine abuse.  We have not studied with that
0149
 1   with Paroxetine, however.
 2   Q.    Do you think that SSRI's in general or
 3   Paroxetine, in particular, might be useful for
 4   treating substance abuse?
 5   A.    There is mixed literature on that, so
 6   there is no definitive answer to that yet.
 7   Q.    Well, here is one for you, and I
 8   apologize to both the ladies in the room, but
 9   how about premature ejaculation?
10   A.    Again, there have been studies carried
11   out, certainly not by SmithKline, that have
12   looked at the use of SSRI's in treating
13   premature ejaculation.
14   Q.    Do you know whether or not SmithKline
15   has patent rights, patent rights, giving it
16   the exclusive right to treat premature
17   ejaculation by giving people Paxil pills?
18   A.    I quite honestly have no idea if we do
19   or don't.
20   Q.    You have what?
21   A.    I have no idea if we do or don't have
22   patent rights.
23   Q.    Would it surprise you if your company
24   got a patent, a 17_year legal monopoly for
25   that treatment; i.e., of premature
0150
 1   ejaculation, based on case reports?
 2                      MR. PREUSS:  I object to
 3   the form.
 4                      THE WITNESS:  Would you
 5   like to rephrase the question?
 6   BY MR. VICKERY:
 7   Q.    No, sir.  I don't think it was a good
 8   objection.
 9   A.    Can you reask the question?
10   Q.    I can.
11                      Would it surprise you if
12   your company got a patent, giving it the
13   exclusive right to treat premature ejaculation
14   by administration of Paxil pills on the basis
15   of case reports?
16   A.    Yes, that would surprise me.
17   Q.    Why is that?
18   A.    Again, companies typically use case
19   reports to raise a question, and they go back
20   and investigate their extensive data bases to
21   see if there is any support for that.
22   Q.    So your view, at least in terms of
23   products liability litigation, is that case
24   reports really don't have any scientific
25   value; isn't that true?
0151
 1   A.    I have not said that.
 2   Q.    Well, tell me, do they?  Do they have
 3   scientific validity and value in the context
 4   of a products liability lawsuit?
 5   A.    Case reports are an appropriate __ and I
 6   will speak not from product liability
 7   lawsuits, but from a scientific perspective,
 8   which is what I am here to testify on.  Case
 9   reports are useful in raising questions,
10   either in terms of novel uses of drugs, in
11   terms of side_effects of drugs, in terms of
12   drug interactions.  They raise questions.
13   They do not a priori define an association.
14   Q.    Are case reports ever reasonable
15   evidence of an association?
16   A.    I can't think of an example offhand
17   where a case report is a reasonable evidence
18   of an association.
19   Q.    Well, how about the contraindication
20   between SSRI's and MAOI's?
21   A.    That was not based on a case report.
22   Q.    It was based on eight, wasn't it?
23   A.    That was not based on eight case
24   reports.
25   Q.    It was based on eight case reports and
0152
 1   some preclinical studies primarily of rats;
 2   isn't that true?
 3   A.    That is not correct, no.
 4   Q.    But in any event, if your company tried
 5   to get a legal monopoly based on case reports
 6   that it has been reported to us that it helps
 7   some guys with premature ejaculation problem,
 8   your view as a scientist is that they are on
 9   shaky scientific ground, right?
10   A.    I would agree with that.
11   Q.    Well, let's see.  What should we talk
12   about next?  Help me understand something.
13   There is a term I don't know, and I'm sure
14   that you do.  Propan_2_ol, P_R_O_P_A_N_2_O_L,
15   what is that?
16   A.    Quite frankly, I cannot help you with
17   that.
18   Q.    Let me start checking things off here.
19   It is always a good sign when a lawyer does
20   that.
21                      Let's add to our glossary.
22   What does the word iatrogenic mean?
23   A.    Iatrogenic implies an adverse effect as
24   caused by a medical intervention.
25   Q.    Are you familiar with the German
0153
 1   labeling for Paxil?
 2   A.    I am aware of the German label for
 3   Paxil, yes.
 4   Q.    Tell me in what ways that differs from
 5   the US labeling.
 6   A.    Well, it is written in German, number
 7   one.
 8   Q.    Thank you.
 9   A.    Would you like to be more specific?
10   Q.    Sure, if I can.
11                      Are there any significant
12   differences, as far as you know, between the
13   German labeling and the American labeling?
14   A.    There are no significant differences.
15   We have within our company a system or process
16   called core safety information, which is
17   required to be in all labels worldwide.
18                      So from that standpoint,
19   any significant data concerning a product,
20   Paxil, in this particular case, is listed in
21   labels worldwide, regardless of what country.
22   Q.    Let me see if I can focus our attention
23   more sharply on the question of suicide.
24                      Is there a difference, in
25   your judgment, other than the fact that one is
0154
 1   written in English and one in German, between
 2   the German warning regarding suicide and the
 3   American labeling regarding suicide?
 4   A.    Well, you used some terms that I need to
 5   clarify.  You say a German warning concerning
 6   suicide.
 7   Q.    Yes, sir.
 8   A.    There is in the US label for Paxil a
 9   precaution concerning the use of Paxil as an
10   antidepressant in depressed patients; that
11   depressed patients are inherently at risk for
12   suicide, and as such, they need to be
13   monitored appropriately with the initiation
14   and maintenance of drug treatment.
15   Q.    Let me stop you right there.  And the
16   focus of that precaution is to tell the
17   physician that depression might cause someone
18   to commit suicide, right?  It is to alert them
19   to that danger?
20   A.    No, the purpose of that precaution is
21   that suicide is an inherent risk, an inherent
22   component of depression, and as such, one
23   should not assume, simply because treatment
24   has been initiated, that that risk has gone
25   away.
0155
 1   Q.    I agree with you totally.
 2                      So the purpose and intent
 3   and effect of the statement in the precaution
 4   on the US labeling for Paxil is to say, hey,
 5   depression might make your patient kill
 6   themselves, right?
 7   A.    If you want to put it in those terms,
 8   yes.
 9   Q.    Now, tell me, if you would, sir, what's
10   the difference in the focus and impact and
11   intent and effect of the German labeling with
12   respect to suicide?
13                      MR. PREUSS:  I object to
14   the form, compound, multiple compound.
15                      MR. VICKERY:  That one is a
16   really good objection, because that was a
17   horrible question.
18                      MR. PREUSS:  Thank you.  I
19   am working at it.
20   BY MR. VICKERY:
21   Q.    In what way is the focus or likely
22   effect of the German label different with
23   respect to this issue of suicide?
24   A.    In terms of this issue of suicide, if I
25   recall correctly, the German label has similar
0156
 1   information; that suicide is a core component,
 2   inherent risk of depression, and patients
 3   should be treated accordingly and monitored
 4   accordingly.
 5   Q.    Doesn't the German label say that they
 6   should be very closely monitored during
 7   initial drug therapy?
 8   A.    If I recall correctly, that's also true
 9   in the US label.
10   Q.    Doesn't the German label say that the
11   physicians should consider giving a
12   concomitant sedative?
13   A.    I think that might be in the German
14   label, but I can't say that that is the exact
15   language, because I don't have the label in
16   front of me.
17   Q.    And don't you know, from your time at
18   Lilly, that that was put in there at the
19   insistence of the BGA in Germany for the very
20   reason that they were concerned not that
21   depression was causing people to kill
22   themselves, but that this drug was triggering
23   it?
24   A.    That is not true.
25                      THE VIDEO TAPE OPERATOR:
0157
 1   Going off the video record.  The time is
 2   1:36.
 3                            _ _ _
 4                      (Whereupon a short break
 5   was taken at this time.)
 6                            _ _ _
 7                      THE VIDEO TAPE OPERATOR:
 8   Back on the video record.  The time is 1:46.
 9   BY MR. VICKERY:
10   Q.    Doctor Wheadon, in preparing for the
11   deposition today, you have told me that you
12   reread your one prior deposition from the
13   Fentress case.
14                      Is there anything, when you
15   reread it, anything in that deposition, that
16   struck you as being inaccurate or untrue,
17   anything you said?
18   A.    Not that I recall, no.
19   Q.    Now, did you also, in preparation for
20   the deposition today, do any rehearsal?  And
21   by rehearsal, I mean go through an exercise
22   where a lawyer asked you questions as I'm
23   asking you questions, and you answered them as
24   you are answering here today?
25   A.    My counsel walked me through questions,
0158
 1   and I answered them, yes.
 2   Q.    About how long did that take?
 3   A.    How long did __
 4   Q.    Did the rehearsal session take?
 5   A.    At most, we would do it a day at a time.
 6   Q.    So you have been through several days of
 7   it?
 8   A.    Not in terms of rehearsing, no.
 9   Q.    Was any of the preparation that you did
10   video taped?
11   A.    No.
12   Q.    Did you ever have an occasion to go to
13   the Federal Republic of Germany or other
14   European location specifically for the purpose
15   of visiting with experts in those countries
16   about the question of whether Prozac or any
17   other SSRI drug triggers suicidal behavior?
18   A.    Yes, I did go to Germany and other
19   European countries to discuss data concerning
20   that question.
21   Q.    Let me hand you what we will mark as our
22   next exhibit.  I'm not sure what we are up
23   to.  8.
24                            _ _ _
25                      (Whereupon the court
0159
 1   reporter marked document as Exhibit 8 for
 2   identification.)
 3                            _ _ _
 4   BY MR. VICKERY:
 5   Q.    Do you recognize Exhibit 8?
 6   A.    If I can review it?
 7   Q.    Oh, sure.
 8                      MR. PREUSS:  Again, Andy,
 9   this is out in the public domain?
10                      MR. VICKERY:  Yes, this is
11   in the public.
12                      THE WITNESS:  Okay.
13   BY MR. VICKERY:
14   Q.    Do you recognize this document?
15   A.    Yes.
16   Q.    What is it?
17   A.    It is a trip report concerning my visits
18   with several European consultants during my
19   employment with Lilly.
20   Q.    Who wrote it?
21   A.    It is over my name.
22   Q.    Does that mean you wrote it?
23   A.    Yes.
24   Q.    When?
25   A.    The date __ to be honest, I don't see a
0160
 1   date of when it was written.
 2   Q.    Would it have been written shortly after
 3   the trip, which seems to have been on August 8
 4   through 15, 1990?
 5   A.    It may have been within a month or two
 6   of that trip.  I can't say exactly when I
 7   wrote it.
 8   Q.    What was your purpose in writing it?
 9   A.    In writing this document?
10   Q.    Yes, sir.
11   A.    To brief others in the company
12   concerning my visit.
13   Q.    Now, would you read for me the sentence
14   on the next to the last paragraph on the
15   second page that starts, each of the
16   consultants?
17   A.   "Each of the consultants felt that the
18   most definitive assessment of a potential
19   relationship between Fluoxetine treatment and
20   suicidal ideation or behavior would be some
21   sort of prospective study."
22   Q.    Okay, now, we have already established
23   that neither Eli Lilly, nor SmithKline Beecham
24   has ever done a prospective study to
25   specifically measure the potential
0161
 1   relationship between their drug and suicidal
 2   ideation as a primary outcome of measure,
 3   right?
 4   A.    That is correct.
 5   Q.    Have either of them, to your knowledge,
 6   ever done a large scale epidemiological study
 7   focusing on that?
 8   A.    I can only speak for SmithKline in terms
 9   of recent situation.
10   Q.    Has SmithKline ever, to your knowledge,
11   done a large scale epidemiological study to
12   look at that issue?
13   A.    Not that I am aware of, no.
14   Q.    It says, if a __ the last sentence of
15   that paragraph, if a prospective study of
16   suicidal ideation is done, they recommend
17   utilizing a suicide scale, and then Professor
18   Blank mentioned one by __ and of course it is
19   blanked out.
20                      The one he mentioned was
21   one by Beck, wasn't it?
22   A.    I cannot give an opinion one way or the
23   other, because I don't recall what was there,
24   and that's been blanked out.
25   Q.    You know that there are several
0162
 1   different scales that are available that are
 2   more refined instruments for measuring
 3   suicidality than the HAM_D, don't you?
 4   A.    I wouldn't say they are more refined,
 5   no.
 6   Q.    What would you say?
 7   A.    There are different scales that also
 8   assess the issue of suicide.  There are scales
 9   that may have more questions concerning
10   suicide.  I wouldn't describe them as more
11   refined, though.
12   Q.    To your knowledge, has SmithKline
13   Beecham ever employed any scale to measure
14   suicidality of people on Paxil, except the
15   HAM_D Item 3?
16   A.    Yes.
17   Q.    What?
18   A.    The MADRS, the Montgomery Asberg
19   Depression Rating Scale.
20   Q.    How many questions are involved in that?
21   A.    There is also a single question.
22   Q.    And it has, I believe, seven different
23   rating points?
24   A.    I think it is 0 to 7 or 0 to 6,
25   something along those lines.
0163
 1   Q.    Was that developed by Doctor Stuart
 2   Montgomery?
 3   A.    He is one of the two developers, yes.
 4   Q.    He has done a lot of work for SmithKline
 5   and other pharmaceutical companies, hasn't he?
 6   A.    That is correct.
 7   Q.    Incidentally, did you go in and
 8   calculate the relative risk of suicide of
 9   people on Paxil versus those on placebo in the
10   Montgomery and Baldwin protocol?
11   A.    I'm not sure what you are referring to.
12   Q.    I sent an Interrogatory earlier about
13   this.  Did you help your company's attorneys
14   prepare the answers to those Interrogatories?
15   A.    I reviewed some answers to those
16   Interrogatories, yes.
17   Q.    Did you either make a relative risk
18   calculation yourself or have one done for you?
19   A.    Again, I am not absolutely sure what you
20   are referring to as the Montgomery Baldwin
21   protocol, so if you would like to show it to
22   me or give it to me, I can give you a more
23   definitive answer.
24   Q.    I didn't bring it with me.  The question
25   just popped into my head.  I know I have asked
0164
 1   an Interrogatory about it already.
 2                      I asked you a minute ago
 3   about using other scales for suicidality.
 4                      Has SmithKline Beecham to
 5   your knowledge ever used any scale, be it the
 6   Barnes scale or any other scale, to measure
 7   treatment_emergent akathisia?
 8   A.    I can't recall use of any scale geared
 9   towards measuring akathisia.
10   Q.    Is akathisia, by definition,
11   drug_induced?
12   A.    Not necessarily, no.
13   Q.    What kind of akathisia can there occur
14   that is not drug_induced?
15   A.    You can have akathisia within the
16   context of a psychiatric illness that may not
17   be drug_induced.
18                      Like, for example, there
19   are situations where schizophrenic patients
20   that are not on any active treatment can have
21   what looks very much like akathisia, meaning
22   motoric activity, pacing, feeling like they
23   can't sit still, those sorts of things.  So it
24   has been seen outside the context of drug
25   treatment.
0165
 1   Q.    Is akathisia an inner restlessness?  Is
 2   it an outward motor movement, fidgetiness or
 3   is it both?
 4   A.    Akathisia is a combination of both a
 5   sense of being unable to sit still and an
 6   external expression of that sense of being
 7   unable to sit still by walking, pacing,
 8   getting up and down, what have you.
 9   Q.    You used a Latin phrase earlier, sine
10   qua non.
11                      Is the outward motor
12   movement a sine qua non to diagnose akathisia?
13   A.    It is not necessarily a sine qua non,
14   no, but typically, you see one with the other.
15   Q.    I mean, doesn't medical literature
16   indicate that a lot of akathisia has gone
17   undetected by medical professionals?
18   A.    That is not necessarily true.  It is not
19   true from the standpoint of medical
20   professionals not recognizing it.  It is from
21   the standpoint of patients sometimes not
22   knowing how to describe it to their
23   practitioners.
24   Q.    We talked earlier very briefly about
25   some of the literature in the field.
0166
 1                      The literature you are
 2   familiar with includes the Rothschild
 3   rechallenge article, doesn't it?
 4   A.    I am familiar with that.
 5   Q.    It includes the King, Riddle, et al
 6   article, right?
 7   A.    I am aware of that article, yes.  I have
 8   not reviewed it recently.
 9   Q.    But you were quizzed about that in your
10   prior deposition, weren't you?
11   A.    Yes.
12   Q.    It includes the Wershing and Van Putton
13   article, doesn't it?
14   A.    I'm not recalling that article.
15   Q.    How about any of Doctor Healey's
16   writings?  Do you know Doctor David Healey
17   personally or by reputation?
18   A.    I have heard of Doctor Healey.
19   Q.    And what have you heard?
20   A.    I have seen articles written by him.  I
21   know that he has been consulted by several
22   attorneys concerning this issue.
23   Q.    Well, let's set aside the attorney
24   business.
25                      What do you know, if
0167
 1   anything, about his reputation within the
 2   field of psychopharmacology?
 3   A.    I really don't know very much at all
 4   about Doctor Healey in terms of his
 5   reputation.
 6   Q.    Are you aware that your alma mater, the
 7   Harvard Press, a publication of your alma
 8   mater, I guess, published a book by him, sort
 9   of chronicling the history of the
10   antidepressant era?
11   A.    Well, the Harvard Press is independent
12   of Harvard University, so you have to be clear
13   about that.  Simply the fact that it was
14   published by the Harvard Press does not carry
15   the imprimatur of the Harvard University.
16   Q.    Is the Harvard Press a reputable
17   publishing house?
18   A.    Harvard press is reputable, as is a
19   number of other publishing houses.
20   Q.    Now, are you or are you not aware of the
21   fact that Harvard Press has published a book
22   by Doctor Healey on the antidepressant era?
23   A.    I'm not familiar with that book, no.
24   Q.    I commend it to you.  And given what you
25   do, I think you would enjoy it.
0168
 1                      One our both of us may have
 2   to look back on my notice to see if you are
 3   designated hitter on this subject, but is your
 4   area of knowledge inclusive of the approval
 5   process for Paxil for various indications?
 6   A.    I think there is a split in terms of
 7   that.  If it is concerning the approval of
 8   Paxil or the work leading up to the approval
 9   for the first indication, I think that has
10   been designated to someone else, if I recall
11   correctly.
12   Q.    Yes, because that happened before you
13   were there, right?
14   A.    Right.
15                      MR. PREUSS:  There is some
16   overlap, but __
17                      THE WITNESS:  And then
18   post_depression, I have been designated as the
19   person knowledgeable about that, yes.
20   BY MR. VICKERY:
21   Q.    So for example, when Paxil obtained the
22   approval for social phobia, that was done
23   while you were there, right?
24   A.    It was done while I was at SmithKline.
25   I was in my present position at that time,
0169
 1   however.
 2   Q.    And in your present position, did you
 3   have any responsibilities for that process?
 4   A.    Well, people reporting to me were
 5   responsible from a regulatory perspective for
 6   that approval.
 7   Q.    I think my questions are probably
 8   general enough that they fall within the ambit
 9   of your knowledge, but if I step afield from
10   where you are designated, just tell me.
11                      Can you just explain for us
12   how that process works, the process of getting
13   approval from the FDA to market a drug for
14   some malady in this country?
15   A.    How far back do you want to go?  As you
16   know, it is a fairly long process.
17   Q.    Let's just start when we get to the
18   NDA.  Forget the IND.  Let's start with the
19   NDA, which stands for New Drug Application,
20   right?
21   A.    Well, starting with the NDA, the NDA is
22   intended to be a compilation of the
23   accumulated data on the efficacy and safety of
24   a drug in terms of the various studies that
25   have been carried out under the IND.
0170
 1                      That data is collected in
 2   an organized fashion in a way dictated by the
 3   FDA, so the NDA is structured in a manner that
 4   the FDA requests.
 5                      You present efficacy data,
 6   safety data, an integrated review of efficacy,
 7   as well as safety, toxicological data, what
 8   have you.  All of that is reviewed extensively
 9   by the FDA, and ultimately, a decision is made
10   on approval of the drug for that particular
11   indication.
12   Q.    Does the FDA conduct their own tests or
13   do they rely on pharmaceutical companies to do
14   the testing?
15   A.    When you say their own tests, what do
16   you mean?
17   Q.    On human subjects.
18   A.    The FDA does not do their own
19   investigations on human subjects.  They do,
20   however, take the raw data and do their own
21   analyses from the trials that were carried out
22   by the sponsor.
23   Q.    Does the pharmaceutical company submit a
24   summary of the data to them?
25   A.    Pharmaceutical companies submit both a
0171
 1   summary of the data, as I said, the integrated
 2   summary of efficacy and the integrated summary
 3   of safety, but additionally, we submit the raw
 4   status data files, and the FDA then goes in
 5   and does their own analyses with that data.
 6   Q.    Do they have the manpower or resources
 7   to really investigate all of the primary data,
 8   or, conversely, do they by and large have to
 9   rely on the summaries that you guys prepare?
10   A.    The FDA does religiously do their own
11   analyses and come to their own conclusions.
12   Q.    Are you sure about that?
13   A.    I am sure about that.
14   Q.    What is the FDA view about whether they
15    __ kind of the official view, if you will, on
16   whether they know everything they need to know
17   about a drug, once it is approved for
18   marketing?
19   A.    I don't feel I am able to comment on
20   that.
21   Q.    Well, in order to get regulatory
22   approval, you have mentioned both efficacy and
23   safety, and I want to take them separately.
24                      Safety, first of all, is
25   that principally focused on the inherent
0172
 1   toxicity of the drug?
 2   A.    I'm not sure what you mean by inherent
 3   toxicity of the drug.
 4   Q.    Whether it is a poison, whether it will
 5   kill you?
 6   A.    The safety assessment in the NDA and the
 7   safety assessment that's carried out by the
 8   Food and Drug Administration looks at all of
 9   the safety data, every bit that's collected in
10   every clinical trial that's carried out and
11   submitted to the agency.
12   Q.    Well, I'm sure they do, but the question
13   was whether the primary focus is on the
14   inherent toxicity of the drug.
15   A.    And as I answered, the focus is on all
16   of the safety data.  It is not a microscopic
17   focus on, as you described, the inherent
18   toxicity of the drug.
19   Q.    How many studies __ there is a term of
20   art called well controlled studies, right?
21   A.    There is a term used that's well
22   controlled, yes.
23   Q.    What does that mean?
24   A.    Well controlled implies that there is
25   some sort of a control built into the design
0173
 1   of the study, be it placebo, active comparator
 2   or both, but that's the primary use of that
 3   term.
 4   Q.    Is an active comparator an adequate
 5   control for a randomized clinical trial?
 6   A.    It depends on the question you are
 7   asking.
 8   Q.    But for some questions, it is?
 9   A.    For some questions, it is, yes.
10   Q.    Now, how many well controlled studies
11   does a drug company like SmithKline Beecham
12   have to submit in order to proof efficacy?
13   A.    The standing requirement is that there
14   need to be at least two well controlled
15   studies that are pivotal proofs of efficacy.
16   Q.    By the word efficacy, we just mean it
17   works, right?
18   A.    That it works in the intended
19   population, yes.
20   Q.    And works relative to what?  Better than
21   something else?
22   A.    Well, again, it depends on the question
23   you are asking.  So, for example, in cancer
24   studies, it may be, does it work as good as
25   known cancer treatments?
0174
 1   Q.    Now, what if it is __ what if the
 2   control in the well controlled study is a
 3   placebo control?  How much better does your
 4   drug have to work than the placebo in order to
 5   get approval to market that drug?
 6   A.    There is no hard and fast rule on that.
 7   It depends on the disease under study.
 8   Q.    So what if it works just a wee bit
 9   better than placebo?  What if you have two
10   studies that show it works a wee bit better
11   than a sugar pill?  Is that sufficient to get
12   the FDA to approve it?
13   A.    Again, that's dependent on the disease
14   under study.  So, for example, this is not
15   done, but if, in the case of cancer
16   treatments, or let's take, for example,
17   treatments for aids, where you show that your
18   drug shows an incumbent benefit over no
19   treatment at all, and the risk/benefit
20   equation is one such that the benefit of the
21   drug far outweighs any incumbent risk, that
22   might be a situation where the agency would
23   decide to give approval to a drug.  It depends
24   on the disease under study.
25   Q.    Well, what if the disease under study is
0175
 1   depression?  How much better than placebo does
 2   Paxil have to be in these two well controlled
 3   studies in order to get approval from the FDA
 4   to sell that drug for depression?
 5   A.    In the case of depression, there is no
 6   numerical requirement in terms of how much
 7   better, as you put it, Paxil has to be over
 8   placebo.  It is based upon statistical data,
 9   statistical analyses, showing a significant
10   difference between drug versus placebo.
11   Q.    So it doesn't have to be at least twice
12   as good as placebo?
13   A.    That is not a requirement, no.
14   Q.    And as a vice_president of SmithKline,
15   do you think that that system is one that is
16   fair both to the pharmaceutical company and to
17   the American public?
18   A.    When you say that system, what do you
19   mean?
20   Q.    That system of allowing you to get
21   approval to market that drug based on two
22   studies that show that it is somewhat better
23   than a placebo at treating depression?
24   A.    Well, as I mentioned, the system
25   requires two pivotal proofs of efficacy, and
0176
 1   depending on the disease under study, that
 2   requirement may be something of the order of a
 3   statistically significant difference, which
 4   does not equate with somewhat better, but a
 5   statistically significant difference from
 6   placebo, shown in two independent studies.
 7   Q.    And my question is, do you think that's
 8   fair, both to the pharmaceutical company and
 9   to the American public?
10   A.    I think it is appropriate, yes.
11   Q.    I ask you this, because, quite frankly,
12   I wouldn't be surprised if, somewhere down the
13   road here, we had a legal pleading from your
14   company, saying that my clients had to show a
15   relative risk of 2.0 or greater in order to
16   even have a day in court.
17                      Do you think that would be
18   fair?
19   A.    I quite frankly don't know what you are
20   referring to in that question.
21   Q.    Do you think it would be fair to hold
22   some individual who has had some tragedy that
23   they believe was caused by a drug, to hold
24   that person to a standard of proof that was
25   more demanding and more rigorous than the
0177
 1   scientific standard of proof that your company
 2   has to meet in order to get the drug approved?
 3                      MR. PREUSS:  I object to
 4   the form.
 5                      THE WITNESS:  I quite
 6   frankly still don't understand the question
 7   you are asking, so I cannot comment.
 8   BY MR. VICKERY:
 9   Q.    Let me try it again.
10                      Do you think it is fair to
11   require people who have a complaint against
12   your company, to hold them to a more exacting
13   or scrutinizing standard than you, yourself,
14   are held to when you go to the FDA?
15                      MR. PREUSS:  I object to
16   the form.
17                      THE WITNESS:  I am at a
18   loss in terms of answering that question,
19   because your __ it doesn't make any sense.
20   The standard we were just talking about is
21   what the FDA requires for proof of efficacy.
22   I don't see how you then can ask me to compare
23   that to some issue around a client having a
24   suit against my company.  So I can't answer
25   that question.
0178
 1   BY MR. VICKERY:
 2   Q.    It is only a question of parody, Doctor
 3   Wheadon.  I just want to know from you, as a
 4   vice_president of SmithKline Beecham, whether
 5   you think it would be fair to require someone
 6   who had a claim against your company to run
 7   some scientific gauntlet that was more
 8   demanding or more exacting than that
 9   scientific gauntlet that you have to run to
10   get a drug approved by the FDA.
11                      MR. PREUSS:  I object to
12   the form again.
13                      THE WITNESS:  Again, I
14   cannot answer that question, because the
15   scientific gauntlet is not clear to me in
16   terms of what you are describing.
17   BY MR. VICKERY:
18   Q.    Okay, if you can't answer it, you can't
19   answer it.
20                      Does the company __ when
21   you say they have to show two well controlled
22   studies with statistically significant
23   results, what if there were ten studies, and
24   eight of them were abysmal failures, but two
25   of them showed good results?  Could they get a
0179
 1   drug licensed based on those two studies?
 2   A.    It depends on the disease under study.
 3   Q.    Well, that's exactly what Eli Lilly did
 4   when they got Prozac licensed, isn't it?  They
 5   had two studies to show that it worked, and
 6   they had other studies that showed it didn't
 7   work, but yet, they got regulatory approval
 8   based on the two that worked?
 9   A.    I quite frankly don't recall exactly
10   what the basis of approval was for Prozac.
11   That was some time ago.  But again, it depends
12   on the disease under study.
13   Q.    So is it possible for a company to have
14   two studies that work and other studies that
15   don't work, and yet, still get approval by the
16   FDA based on the two that work?
17   A.    Depending on the disease under study, it
18   is possible, yes.
19   Q.    Has your company been required to modify
20   the labeling with respect to suicide for Paxil
21   in the United Kingdom within the last, say, 60
22   to 90 days?
23   A.    I'm not familiar of anything within the
24   last 60 to 90 days.
25   Q.    Are you familiar with any change in the
0180
 1   labeling of Paxil in the United Kingdom within
 2   the last year?
 3   A.    There have been several changes to the
 4   label.
 5   Q.    Are you aware of any changes to the
 6   label that have to do with the issue of
 7   suicide?
 8   A.    Again, within what time frame?
 9   Q.    Within the last year.
10   A.    I think there may have been some
11   addition of some language around suicidal
12   ideation added, but I don't know exactly what
13   that language is.  If you would like to give
14   it to me, I can refresh my memory.
15   Q.    Doctor Wheadon, under what name is the
16   chemical Paroxetine marketed in the United
17   Kingdom, and then in other countries around
18   the world?
19   A.    Well, there are several different
20   names.  In the United Kingdom, it is Seroxat.
21   Q.    It is what?
22   A.    Seroxat.
23   Q.    Would you spell that for me?
24   A.    S_E_R_O_X_A_T.
25   Q.    And how about in Europe?
0181
 1   A.    I think it is either Seroxat or Paxil,
 2   but there may be some additional names in
 3   other countries.  I'm not very sure.
 4   Q.    Why is it marketed under different trade
 5   names in different places?
 6   A.    It is a matter of cultural differences
 7   and approval of the trade name in different
 8   regulatory arenas.
 9   Q.    What is a meta analysis?
10   A.    A meta analysis generally refers to
11   looking at data that comes from a number of
12   different studies in a coordinated, systematic
13   fashion in terms of analyzing them for
14   findings or statistical significance, what
15   have you.
16   Q.    Is it, by definition, retrospective?
17   A.    Meta analyses are usually retrospective,
18   yes.
19   Q.    Is it a species of an epidemiological
20   study?
21   A.    Not necessarily, no.
22   Q.    So to kind of boil that down to plain
23   English, a meta analysis involves taking a set
24   of data or information that you have, and
25   going back after the fact and analyzing it,
0182
 1   looking for something other than what was
 2   being looked for in the first place, right?
 3   A.    Not always.  A meta analyses may be
 4   retrospective, sometimes may be prospective.
 5   A met analyses is combining data from a number
 6   of different studies, looking for, in some
 7   instances, a finding or a suggestion that was
 8   not the original intent of the study, but in
 9   other instances, it may be looking for the
10   intent of those studies.
11   Q.    The analysis that you referenced earlier
12   that has been done by SmithKline Beecham,
13   Pfizer and Eli Lilly on the question of
14   whether the SSRI drugs trigger suicidal
15   behavior in some people has all been after the
16   fact, retrospective meta analysis of clinical
17   trials that were not designed to measure the
18   issue of suicidality in the first place; isn't
19   that true, sir?
20   A.    That is not correct.
21   Q.    Straighten me out.
22   A.    The analyses that were done __
23   Q.    Let me ask the question.  All right,
24   make a speech, go ahead.
25   A.    Were done on studies that were carried
0183
 1   out by independent companies, Lilly,
 2   SmithKline, Pfizer, others, looking at the
 3   issue of suicidal ideation or behavior
 4   associated with drug treatment.
 5   Q.    But those studies weren't designed to
 6   focus on suicidality in the first place, were
 7   they?
 8   A.    The studies were designed as studies of
 9   depression.  As a component of that, the
10   studies were also designed to assess suicide
11   as a component of depression.  So your answer
12   was __ your question was not correct.  They
13   were designed to assess suicide as a component
14   of depression.
15   Q.    Were they designed to assess
16   treatment_emergent, drug_induced suicide?
17   A.    They were not designed specifically for
18   treatment_emergent, drug_induced suicidal
19   ideation or behavior, that is correct.
20   Q.    Do you know what the Cope's postulates
21   are?
22   A.    I am familiar with them, yes.
23   Q.    What are they?
24   A.    They are primarily around how one
25   assigns causative associations between a
0184
 1   bacterial agent and an illness.
 2   Q.    That's where they were begun, because
 3   Cope was an internal medicine guy, right?
 4   A.    That's correct.
 5   Q.    About a hundred years ago?
 6   A.    I think he was a bacteriologist,
 7   actually.
 8   Q.    And have they been sort of refined and
 9   supplemented by a world_famous epidemiologist?
10   A.    I'm not sure who you are referring to.
11   Q.    I am referring to Sir Alston Bradford
12   Hill.  Do you know the name?
13   A.    I have heard the name.  I am not very
14   familiar with his work on the Cope's
15   postulates, though.
16   Q.    Do the Cope's postulates provide a
17   scientifically reliable framework for
18   analyzing the question of whether or not a
19   drug causes a particular side_effect, either
20   generally or in the specific case of an
21   individual?
22   A.    It depends on the disease you are
23   focusing on.
24   Q.    I am focusing on drug_induced suicide
25   and violence.
0185
 1   A.    In the context of?
 2   Q.    Paroxetine.
 3   A.    And?
 4   Q.    And what?  In human beings.
 5   A.    The disease being depression?  If your
 6   question is that, then the answer is no, it
 7   does not have a direct bearing.
 8   Q.    Well, just generally, I mean, do they
 9   provide a scientifically reliable framework
10   for analyzing the question of whether a drug
11   like Paxil causes or contributes to suicidal
12   behavior in some people?
13   A.    The answer is, again, it depends on the
14   disease you are studying or the context in
15   which you are studying the question.
16   Q.    Why is that?
17   A.    For example, in Cope's postulates, you
18   are talking about the introduction of a
19   foreign body or a foreign entity, that being a
20   bacteria that's causing the illness.
21   Bacterium is introduced, the illness appears.
22   Bacterium is eradicated, the illness goes
23   away.  Bacterium is put back, the illness
24   comes back.
25   Q.    Challenge, dechallenge, rechallenge,
0186
 1   right?
 2   A.    Now, the problem with it is, if that was
 3   a native bacteria that could cause the illness
 4   anyway, Cope's postulates would not stand.
 5   That would be difficult to control that
 6   situation.  So that's the same issue that we
 7   have been addressing here in terms of suicide
 8   within the context of depression.
 9   Q.    So is it your testimony, sir, that if
10   whenever someone is depressed, and they commit
11   suicide, then, all of science and medicine is
12   simply incapable of determining whether and to
13   what extent other factors in addition to the
14   depression contributed to that suicide?
15   A.    I am saying is a very complicated
16   picture.
17   Q.    Can it be done?
18   A.    In terms of what?
19   Q.    In terms of figuring out what else
20   besides his depression made Johnny commit
21   suicide?  Can that be done?
22   A.    There are ways of trying to answer that
23   question, and those have certainly been done.
24   Q.    How?  How would you go about trying to
25   answer that question?
0187
 1   A.    Well, I will describe to you how it has
 2   been done.  I'm sure you are very familiar
 3   with it.  Analyses have been undertaken by
 4   ourselves, as well as other companies, with
 5   very large data bases, asking the question, is
 6   there a difference in the rate of suicides,
 7   attempted suicides or change in suicidal
 8   ideation, drug versus placebo, in depressed
 9   patients?  And the answer has been
10   consistently, there is no difference.  So the
11   answer has been pretty definitively provided.
12   Q.    Well, let me tell you why I have
13   problems with that.  Let's say everyone in
14   this room was suicidal, and let's say everyone
15   but you.  Everyone in this room was suicidal
16   but you.  And we took a HAM_D test, and we
17   measured it, and we were all 3's or 4's.  I
18   mean, we are just bouncing off the walls,
19   ready to hang ourselves.  And we gave us all
20   Paxil.  And we gave you Paxil, too, but you
21   are not suicidal.  And let's say that we then
22   all took the HAM_D again, and Mr. Preuss and I
23   were better.  We were down to a 0 or 1.
24                      Chances are, the Paxil
25   probably helped us, right?
0188
 1   A.    One could argue that.
 2   Q.    But let's say you became absolutely
 3   suicidal and killed yourself.  You were a 0
 4   before, but now, you have killed yourself.
 5                      Now, if we are looking for
 6   statistically significant changes in the
 7   population of people, two got better, one got
 8   decidedly worse, what are the statistics going
 9   to show?
10   A.    Quite frankly, I can't give you an
11   answer in terms of what the statistics will
12   show.
13   Q.    They won't show any statistically
14   significant worsening in this whole population
15   of people, will they?
16   A.    Perhaps not, but your question is?
17   Q.    My question is, that doesn't mean that
18   the Paxil didn't cause you to become suicidal,
19   does it?
20   A.    But you are forgetting an analyses that
21   was carried out to address just the issue that
22   you are raising.
23   Q.    Tell me about it.
24   A.    The 0 to 1 to 3 to 4 analyses of the
25   Hamilton Item 3, 0, 1 meaning there is no
0189
 1   baseline suicidal ideation, 3 or 4 meaning
 2   significant ideation or frank suicide attempt,
 3   all right?  So you have culled out those
 4   people who ostensibly were already thinking it
 5   and acting it and got better.  So that sort of
 6   balancing act, as you describe, has been put
 7   away, put aside.  You are taking people who,
 8   at baseline, have absolutely no hint of
 9   suicidal ideation or behavior.  You then
10   assess if there is a difference in the numbers
11   of people during treatment who progress to 3
12   or 4, meaning significant ideation or
13   behavior.  And you compare the rate of people
14   that evidence that on Paxil versus the rate of
15   that evidence that on placebo.  And the
16   analyses has shown no difference.
17   Q.    And my question to you, sir, is __ it is
18   real simple.  When we focus on statistical
19   differences across a whole population of
20   people, by definition, we may miss individual
21   cases; isn't that true?
22   A.    Not in terms of controlled trials with
23   regular assessments.
24   Q.    I guess I just don't follow you.  If a
25   drug makes five people better, but it kills
0190
 1   one, isn't that one going to get lost in the
 2   shuffle with the statistics?
 3   A.    Absolutely not.  What I have just said
 4   to you, the five people that get better, the
 5   five people that get better are excluded from
 6   that analysis.  So you are only looking at
 7   whether or not there is a differential rate of
 8   people getting worse, drug versus placebo.
 9   And the analyses has not shown that there is a
10   differential rate of people getting worse,
11   drug versus placebo.
12                      So the argument you put
13   forth is a reasonable one.  The analyses
14   addresses that and puts aside the people that
15   get better.
16   Q.    When you say the analyses addresses
17   that, you are talking about the meta analyses
18   done by SmithKline Beecham, both on your
19   clinical data base for depression and your
20   clinical data base for OCD?
21   A.    As well as other indications as well,
22   yes.
23   Q.    And you are telling me that that's
24   abundantly clear in those written reports?
25   A.    Absolutely.
0191
 1   Q.    I will reread them with great interest.
 2                      Have the other clinical
 3   data bases been meta analyzed in a similar
 4   fashion?
 5   A.    When you say the other clinical data
 6   bases __
 7   Q.    I'm talking about the clinical trials
 8   that were done for obesity or social phobia or
 9   any others that you may have done that we
10   don't want to talk about in public because
11   they are secret?
12   A.    Any study that we have done that allowed
13   us to do similar analyses in terms of the
14   Hamilton, those studies have been included in
15   those analyses.  Any study that we do, let's
16   say, social phobia, for example, although we
17   did the Hamilton social phobia, but if there a
18   study, I don't think there is, where we did
19   not do the Hamilton, then we would still be
20   assessing for adverse event reports around
21   suicidal ideation or behavior.
22   Q.    Why would you use the Hamilton
23   depression scale when you are testing the
24   hypothesis that Paxil helps people with social
25   phobia?
0192
 1   A.    Well, again, as you probably know, there
 2   is a significant co_morbidity of depression in
 3   a number of different psychiatric disorders,
 4   not the least of which is social phobia.  So
 5   patients with social phobia also can have
 6   co_morbid depression.
 7                      So one of the questions you
 8   want to ask is, well, is the improvement that
 9   we see in terms of social phobia a result of
10   the underlying or co_morbid depression
11   improving or is it frank improvement in terms
12   of the primary illness, that being social
13   phobia?
14   Q.    We need to add to our glossary.  You
15   have used this term co_morbid several times,
16   and I know it is nearly Halloween, but I don't
17   think you are using it in a seasonal context.
18                      What does co_morbid mean?
19   A.    Co_morbid implies a coexistence, if you
20   will, of two different illnesses or disorders.
21   Q.    So when you say there is co_morbid
22   depression, then what you mean is that people
23   who have social phobia also frequently have
24   depression with it?
25   A.    That's true, yes.
0193
 1   Q.    Is the same true of PMS?
 2   A.    That can be true as well.
 3   Q.    Is the same true of bulimia?
 4   A.    That can be true as well.
 5   Q.    Is the same true of premature
 6   ejaculation?  People get depressed over that?
 7   A.    I think that's definitely true, yes.
 8   Q.    And is that why this drug can work for
 9   so many different things?  Each and every one
10   of them have depression as part of them?
11   A.    Not necessarily, no.
12   Q.    Well, why can't it?  Explain for me why
13   a drug that selectively inhibits the reuptake
14   of serotonin can treat or address all of those
15   maladies that I asked you about for which you
16   agreed?  And by the way, I hate to tell you,
17   but your company has claimed the others as
18   well.  Why is it?
19   A.    Why is it that __
20   Q.    Why is it that __ how can one drug, how
21   can one little pill that selectively inhibits
22   the reuptake of serotonin treat so many
23   different maladies?
24   A.    I think the answer to your question is
25   serotonin is implicated in so many different
0194
 1   maladies, panic disorder, obsessive compulsive
 2   disorder, social phobia.  It is a very
 3   prevalent neurotransmitter, and as such, it is
 4   also implicated in a number of different
 5   psychiatric illnesses.
 6   Q.    Does the Paxil inhibit the reuptake only
 7   in the brain or are there reuptake sites
 8   throughout the body that are inhibited by the
 9   Paxil?
10   A.    The primary site of activity is within
11   the brain.
12   Q.    I want to go back to Exhibit 1 and kind
13   of go down our list.  Do you want to take a
14   break before we do that or how are you doing?
15   A.    I'm fine.
16                      MR. PREUSS:  Do you want to
17   take a short break then?
18                      MR. VICKERY:  Yes, why
19   don't we?  And then I will see if I can kind
20   of wrap it up with my next segment.
21                      THE VIDEO TAPE OPERATOR:
22   Going off the video record.  The time is
23   2:31.
24                            _ _ _
25                      (Whereupon a short break
0195
 1   was taken at this time.)
 2                            _ _ _
 3                      THE VIDEO TAPE OPERATOR:
 4   We're back on the video record.  The time is
 5   2:41.
 6   BY MR. VICKERY:
 7   Q.    Doctor Wheadon, I just have a few
 8   questions, and then I think I will be done.
 9   I'm staying away from those things that
10   happened at SKB prior to February of 1992,
11   because I understand you weren't there, and
12   that there is another witness coming who was,
13   so __
14                      MR. PREUSS:  But I don't
15   want to preclude you from that to the extent
16   he has, as we discussed earlier __
17                      MR. VICKERY:  Institutional
18   knowledge of them?
19                      MR. PREUSS:  Yes, some, so
20   we kind of co_designated them.
21   BY MR. VICKERY:
22   Q.    Do you know whether or not, either
23   before or after February of 1992, SmithKline
24   Beecham has ever undertaken to investigate,
25   whether by psychological autopsy or otherwise,
0196
 1   the circumstances of those patients who have
 2   become suicidal while on Paxil and either
 3   attempted suicide or actually committed
 4   suicide?
 5   A.    Well, all I can say in answer to that
 6   question is that we routinely with any report
 7   of a serious nature, such as suicide or
 8   suicidal behavior, follow up and get as much
 9   information as we can from the reporter,
10   usually, the prescribing physician or whomever
11   is reporting that event to us.
12                      I can't comment beyond that
13   in terms of your descriptor of a psychological
14   autopsy, per se, but we just get as much
15   information as we can concerning the events
16   and the surrounding circumstances.
17   Q.    At the time that the adverse drug event
18   is reported, right?
19   A.    That's correct.
20   Q.    My question really dealt with whether
21   the company has ever gone back in a systematic
22   way after the fact to say, you know, we really
23   need to get the best possible handle on this.
24   Let's do some real sleuthing.  Let's talk to
25   the doctors that were the clinical
0197
 1   investigators.  Let's get the medical records
 2   of the people.  Let's talk to the family
 3   members.  In other words, go back and very
 4   thoroughly analyze the issue.
 5                      Have they ever done that to
 6   your knowledge?
 7   A.    Again, we do that real time, when the
 8   event happens, when memories are fresh, but in
 9   terms of going back historically after some
10   passage of time and doing that sort of, as you
11   call it, sleuthing, I'm not aware of that
12   activity, no.
13   Q.    Well, when you do it real time, do you
14   actually go out and get the medical records
15   and talk to the family members and that or do
16   you merely get as much information as you can
17   from the physician that's reporting it?
18   A.    It is varying, but in some instances, we
19   do try to get medical records, if we are able
20   to get, obviously, those records released.
21   That's often not something that family members
22   are willing to do.  We talk to prescribing
23   physicians.  We talk to psychiatrists that may
24   or may not have been involved in the case.
25                      We usually, for
0198
 1   confidentiality and proprietary purposes, in
 2   terms of the personal family proprietary
 3   issues, unless the family members choose to
 4   speak to us, we don't necessarily go very
 5   strongly to get family member interviews, per
 6   se.
 7   Q.    How important is it __ is the judgment,
 8   the clinical judgment of the physician who is
 9   caring for the patient and makes the report to
10   the company of an adverse drug event?
11   A.    When you say the clinical judgment,
12   concerning what?
13   Q.    Concerning whether the event was or was
14   not precipitated, caused, related to the
15   drug.
16   A.    In terms that individual patient, that's
17   an important part of what we collect, that
18   physician's assessment, based on his
19   experience with the patient of whether or not
20   there may be a possible relationship or not.
21   Q.    I know that another witness is coming to
22   talk about ADE's, adverse drug experiences,
23   generally, and I think Mr. Farber may have
24   some questions for you about it, but just let
25   me ask you kind of one general overview
0199
 1   question.
 2                      It is true, is it not, sir,
 3   that there have been a number of instances in
 4   which the reporting physicians have told
 5   SmithKline Beecham that in their clinical
 6   judgment, treatment_emergent suicide or a
 7   suicide attempt or a completed suicide were
 8   caused by the drug Paxil?
 9   A.    There have been some instances in which
10   the physician has made that statement, yes.
11   Q.    How many?
12   A.    I have no idea.
13   Q.    Isn't that important information for you
14   to know, how many there are?
15   A.    That is not a part of my day_to_day
16   responsibility, as you pointed out.
17   Q.    Is there someone within the company that
18   would know, that could answer that question
19   for us, how many times has the reporting
20   physician stated, in his or her clinical
21   judgment, that the drug caused this behavior?
22   A.    I would assume, but I can't give you a
23   definite answer to that, but I assume that
24   someone who is working in clinical safety, as
25   their day_to_day responsibility, may be able
0200
 1   to answer that question for you.
 2   Q.    If you, as a vice_president of the
 3   company, wanted an answer to that question, to
 4   whom would you turn to get it?
 5   A.    I would ask the question of clinical
 6   safety.
 7                      MR. VICKERY:  Is that who
 8   we got tomorrow?  Bonnie Rosello?
 9                      MR. PREUSS:  No.
10                      MR. VICKERY:  Is that who
11   we have got Friday?
12                      MR. PREUSS:  That's Ian
13   Hudson.  That's Roman Numeral V.
14                      MR. VICKERY:  Got you.
15   BY MR. VICKERY:
16   Q.    Now, are you familiar with the ACNP
17   consensus statement that came out as
18   effective, I think, March 2nd, 1992?
19   A.    I have seen it, yes.
20   Q.    And can you tell me what, if anything,
21   SmithKline Beecham did sort of in the wake of
22   that paper coming out to either, (a),
23   investigate the question of whether Paxil is
24   causing or contributing to suicidal acts by
25   people, or (b), warning about it?
0201
 1   A.    I'm not sure what you mean by that.
 2   Q.    What did SmithKline Beecham do as a
 3   result of the ACNP consensus statement?
 4   Anything?
 5   A.    There was nothing that SmithKline
 6   Beecham did as a direct result of the ACNP
 7   consensus statement.
 8   Q.    I can tell you, for example, your
 9   friends over at Pfizer hired several outside
10   consultants, and they had a big pow_wow, and
11   all would talk about what should be done,
12   whether further research was necessary and
13   that kind of stuff.
14                      Did you all do anything
15   like that?
16   A.    I don't recall doing anything of that
17   sort, no.
18   Q.    Do you know whether or not SmithKline
19   Beecham, either before or after you arrived,
20   ever retained any outside experts to advise
21   the company about whether there was reasonable
22   evidence of an association between Paxil and
23   treatment_emergent suicide or violence?
24   A.    I am aware that SmithKline did consult
25   with outside experts concerning the data
0202
 1   analyses, the findings and their perspective
 2   on that.
 3   Q.    What experts and when?
 4   A.    I cannot give you details, but I am
 5   aware that, for example, as you well know,
 6   Doctor Stuart Montgomery was consulted.
 7   Q.    Who else?
 8   A.    That is really the expert that I am most
 9   familiar with in terms of SmithKline
10   consulting.
11   Q.    And to your knowledge, did Doctor
12   Montgomery ever prepare any written work
13   product, sort of his recommendations to the
14   company on this issue?
15   A.    Not that I have seen.
16   Q.    If there were such a written work
17   product, would you likely have seen it?
18   A.    If it were something that happened post
19   my joining the company, I would have seen it,
20   but prior to February 1992, I would not
21   necessarily have seen it.
22   Q.    Was he hired before or after February of
23   '92?
24   A.    I don't know exactly the date of his
25   entering into a consulting agreement.
0203
 1   Q.    What was the consensus of the September
 2   1991 Psychopharmacologic Drug Advisory
 3   Committee Meeting?
 4   A.    I don't have that transcript in front of
 5   me, so I really can't give you a definitive
 6   answer on that.
 7   Q.    There was some news accounts after that
 8   hearing that said __ that quoted Chairman
 9   Casey, who was the chairman, saying that
10   consensus of the group was that further
11   research needed to be done.
12                      Did you see those?
13   A.    I don't recall necessarily seeing that
14   quote attributed to Doctor Casey, no.
15   Q.    Well, you were at that hearing, right?
16   A.    I was at the hearing, yes.
17   Q.    And did you, either in the formal
18   hearing meeting itself or in discussions with
19   members of the hearing afterward, ask them
20   whether or not further testing needed to be
21   done?
22   A.    I don't recall having that particular
23   discussion, no.
24   Q.    Are you aware of the fact that at least
25   one member of that committee had received
0204
 1   death threats prior to the meeting?
 2   A.    I was not aware of that, no.
 3   Q.    If it is true, and I will tell you it
 4   is, that one of them had received death
 5   threats, and indeed, was wearing a bulletproof
 6   vest during that public meeting, would that
 7   tend to undermine your confidence and the
 8   impartiality of that committee?
 9                      MR. PREUSS:  I object to
10   the form of the question.  Assumes facts not
11   in evidence.
12                      THE WITNESS:  It would
13   not.
14   BY MR. VICKERY:
15   Q.    So you think that an arbitor, be it
16   judge or committee member, who was supposed to
17   impartially decide something, could __ and I
18   ask you this as a psychiatrist, really __
19   could sit there, wearing a vest to keep a
20   bullet from entering their body, and yet, be
21   completely impartial, even if they thought the
22   bullet was coming from these folks over here
23   on the right, they could treat those people
24   just as fair as fair could be?
25   A.    I don't know if you have been to the
0205
 1   Food and Drug Administration, but there are
 2   security measures that are in place at the FDA
 3   that would preclude that event occurring.
 4   Q.    I'm talking about a man who was afraid
 5   enough of his personal safety, that he was
 6   wearing a bulletproof vest, even though in
 7   that building, and I ask you, as a
 8   psychiatrist, whether or not you think that
 9   would tend to make him be somewhat biased
10   against the people that he thought were going
11   to be firing that bullet.
12                      MR. PREUSS:  I object to
13   the form.  Incomplete hypothetical.  Assuming
14   facts not in evidence.
15                      THE WITNESS:  I can only
16   answer from my personal experience.  As a
17   psychiatrist, as someone who has been in an
18   emergency room, faced with people who have
19   threatened my life and threatened to shoot me
20   and to kill me, that did not, in fact, affect
21   my partial __ impartiality or my ability to
22   make objective assessments about that
23   individual and make the right decision in my
24   mind.
25                      MR. VICKERY:  Let's change
0206
 1   our tape now.
 2                      THE VIDEO TAPE OPERATOR:
 3   Going off the video record.  The time is
 4   2:53.  This concludes Tape Number 2.
 5                      THE VIDEO TAPE OPERATOR:
 6   Back on the video record.  The time is 2:54,
 7   the beginning of Tape Number 3.
 8   BY MR. VICKERY:
 9   Q.    At the end of the last tape, Doctor
10   Wheadon, we were talking about impartiality of
11   people whose lives were threatened, and you
12   gave a good example, but I want to ask you, in
13   all fairness, whether or not that's really an
14   apropos example.
15                      If you are in an emergency
16   room, and someone is threatening your life,
17   you have control over that situation.  You
18   know who it is that's threatening your life,
19   and you are in familiar surroundings, and you
20   are able to control the activities of that
21   person; true?
22   A.    That's not necessarily true, no.
23   Q.    At least you know who it is?
24   A.    I know who is sitting in front of me,
25   yes.
0207
 1   Q.    You know who it is that's threatened
 2   you?
 3   A.    I know who it is that's threatened me,
 4   yes.
 5   Q.    And that's different than the situation
 6   of someone who is presiding over a roomful of
 7   people, who believes that the bullet is coming
 8   from this group over to the right, but doesn't
 9   have any idea who it is, but who is so
10   concerned about it, that they are wearing
11   protective body armor?  That's a different
12   situation, isn't it?
13   A.    I would not necessarily agree with that,
14   no.
15   Q.    Have you ever seen any draft warnings
16   about suicide and Paxil, intercompany
17   documents, that somebody at SmithKline Beecham
18   recommended, but that the company elected not
19   to use?
20   A.    No, I have not.
21   Q.    What would be the repercussions for
22   someone's career at SmithKline Beecham if they
23   made such a recommendation?
24   A.    I'm not sure what you are asking.
25   Q.    I'm asking you, would it harm their
0208
 1   chances of success within the company if
 2   someone came along and said, all of a sudden,
 3   hey, I think that there is a small percentage
 4   of people out there that might actually be
 5   caused to commit an act of violence or suicide
 6   by our drug, and I think we ought to warn.
 7   A.    What would be the repercussion?
 8   Q.    Yes, on that person's career at
 9   SmithKline Beecham.
10   A.    I don't think there would be a negative
11   repercussion on that person's career.
12   Q.    So all right, I will take that.
13                      Now I think you are
14   designated on Subject 4_C, which is standard
15   form dear doctor letters or other procedures
16   in place for answering inquiries from doctors
17   or others which come to the attention of the
18   SKB home office; am I right?  Is that in your
19   bailiwick here today?
20   A.    I think that is correct.
21   Q.    Now, tell me just in your own words, if
22   I'm a doctor, and I'm concerned that Paxil
23   that either I have already given to a patient
24   or about to give to a patient might
25   precipitate an act of suicide on their part.
0209
 1   And I call SmithKline Beecham, and you answer
 2   the phone, and I say, Doctor Wheadon, this is
 3   Doctor Vickery, and I'm concerned about this.
 4   What can you tell me?  What would the response
 5   be from your company?
 6   A.    Well, we have a product information
 7   group that fields those calls that are manned
 8   by clinical professionals, and they will
 9   answer the questions appropriately.  So the
10   question would be answered concerning the
11   existing literature and concerning the
12   analyses that have been carried out
13   investigating that question.
14   Q.    Just tell me what the answer is.  Would
15   you say, don't worry about it, we have
16   conducted this extensive meta analysis, and
17   there is no statistically significant
18   difference?
19   A.    No, the answer would be that there have
20   been case reports of the emergence of suicidal
21   ideation during the course of treatment with
22   SSRI's and other antidepressants.  A number of
23   analyses have been carried out through a
24   number of different data bases to investigate
25   this question.  No credible evidence has been
0210
 1   generated to corroborate this suggestion of
 2   the case reports.  As always, you should use
 3   the drug in accordance with the labeling.
 4   Q.    And what if they ask a follow_up
 5   question and says, well, now, wait a minute,
 6   are you saying that you have directly studied
 7   this phenomenon?
 8   A.    The answer would be that we have gone
 9   back to look in our clinical trial data base
10   of depression and other disorders, but
11   focusing on depression and investigated the
12   question at hand whether or not suicide is an
13   emergent phenomenon on drug versus placebo,
14   and the answer is that we have not seen any
15   evidence to support that.
16   Q.    Is the bottom line that you would
17   reassure the prescribing physician that there
18   really is no increased risk of suicide with
19   Paxil?
20   A.    The bottom line is, we would give the
21   physician the information he is requesting.
22   Q.    I take what you have said as being
23   reassurance if I'm a prescribing physician.
24                      Do you interpret it that
25   way?
0211
 1   A.    That is how you are taking it.  We are
 2   providing the data as it is.  We provide data
 3   in an objective fashion.  The physician comes
 4   to his own conclusion.  We are not there to
 5   drive the physician to his own conclusion.  He
 6   comes to his own conclusion.
 7   Q.    But what you tell him is that there is
 8   no evidence indicating that Paxil increases
 9   the risk of suicide?
10   A.    And that is correct.
11   Q.    Were people at serious suicidal risk
12   excluded from the Paxil clinical trials?
13   A.    An exclusion criteria was that if
14   someone at time of assessment was a serious
15   suicidal risk, they were to be excluded, yes.
16   Q.    Were the clinical investigators
17   permitted to give concomitant medications?
18   A.    In most of their protocols, they were
19   allowed to give a short_acting sedative at
20   bedtime to assist with sleep.
21   Q.    I think that I am done for today.  I
22   presume that if your employer asks you to do
23   so, that you will make yourself available for
24   the trial of any of these cases.
25                      Mr. Anderson asked me to
0212
 1   put on the record that we were taking this
 2   deposition not only in conjunction with the
 3   Tobin case, but with the other pending cases
 4   that I have, and I presume, if your employer
 5   says, Doctor Wheadon, we need you in wherever,
 6   be it Texas, Wyoming, Utah or elsewhere, to
 7   testify in this lawsuit, that you would come;
 8   am I correct?
 9   A.    That's my understanding, yes.
10                      MR. PREUSS:  He may draw
11   the line at Utah, though.
12                      MR. VICKERY:  Given that
13   understanding, even though I have enjoyed this
14   very much and have one or two other things I
15   might like to ask you, I will pass the
16   witness.
17                      THE VIDEO TAPE OPERATOR:
18   Going off the video.  The time is 3:02.
19                      THE VIDEO TAPE OPERATOR:
20   Back on the video.  The time is 3:03.
21                      MR. PREUSS:  Before we
22   start, Mr. Farber, I just wanted to put on the
23   record what we discussed off the record, and
24   that is, it is our position with respect to
25   Doctor Wheadon and the other witnesses here
0213
 1   that they are available to respond to
 2   questions as we have designated with respect
 3   to Mr. Vickery's 30(b)(6) notices, and that
 4   you are free to examine him for purposes of
 5   Lacuzong on all those subject matters in that
 6   notice and not to duplicate what Mr. Vickery
 7   has already covered.
 8                      And that's embodied in a
 9   series of letters, which I will be happy to
10   mark as the exhibit next in order, starting on
11   August 25th, and the last one being October
12   12th, that you are free to examine, if you
13   would like to do it, the letters that went on
14   between you and Mr. Pulliam.
15                      MR. FARBER:  I'm sure I
16   have them in my computer or at home, so it is
17   not a point.  I don't need the letters.
18                            _ _ _
19                         EXAMINATION
20                            _ _ _
21   BY MR. FARBER:
22   Q.    And to repeat or state for the first
23   time, I'm Donald J. Farber, an associate
24   counsel for the Plaintiff in the action of
25   Lacuzong versus Davidson, SmithKline Beecham
0214
 1   and Long Drugs in a wrongful death suit.
 2                      And for the record also, I
 3   would like to just put as __ I guess we will
 4   continue the same exhibit numbering system.  I
 5   will put Plaintiff Lacuzong's Notice of
 6   Deposition, Request for Production of
 7   Documents into the record as the next
 8   exhibit.
 9                      Before you protest counsel,
10   I will add to this exhibit, so if we could do
11   that, and add __ is it Exhibit 9?  And I will
12   hastily add that Exhibit 9 has been __ was
13   withdrawn prior to my appearance today, so
14   there is no legal expectation that you are
15   prepared to answer any of those items in the
16   Deposition Notice, Doctor Wheadon, or produce
17   any of the documents, but that it is my
18   expectation and statement that Plaintiff was
19   never served a copy of the notice of Mr.
20   Vickery, and to the extent I will certainly
21   live up to any commitments in the letters that
22   counsel referred to earlier, but I will not be
23   held to anything in the notice to that
24   effect.
25                      MR. PREUSS:  Let me just
0215
 1   state that I am a bit flabbergasted that you
 2   don't have one.  Certainly, it was discussed
 3   specifically in the letters, and if you didn't
 4   have one and wanted one, I'm sure either Mr.
 5   Vickery myself or Mr. Pulliam would have
 6   provided you with a copy.  And indeed, Exhibit
 7   1 to this deposition is, in fact, that
 8   30(b)(6) Notice.
 9                      MR. FARBER:  I note your
10   comments.  And I would just ask you to look at
11   Exhibit 9, Doctor Wheadon, simply to ask you
12   whether you have seen that document before.
13                            _ _ _
14                      (Whereupon the court
15   reporter marked document as Exhibit 9 for
16   identification.)
17                            _ _ _
18                      THE WITNESS:  No, I have
19   not.
20                      BY MR. FARBER:  And
21   actually, you are not a witness, counsel, but
22   I would, for the record, ask you a question,
23   too, whether you are aware that I was given
24   notice or served that document, whether
25   SmithKline Beecham caused that Mr. Vickery's
0216
 1   notice to be served on me or Plaintiff.
 2                      MR. PREUSS:  No, we didn't
 3    __ as far as I know, we did not provide you
 4   with one.  Though, I think it was implicit
 5   that you were going to be talking to Mr.
 6   Vickery about the whole process, and Mr.
 7   Pulliam stepped out for a minute, but I asked
 8   him, and he indicated that if you didn't have
 9   it, he certainly was going to give it to you.
10                      MR. FARBER:  He advised
11   that I get it from Mr. Vickery, but just as a
12   point of legal order, I don't know of any
13   concept of notice in which the noticee is
14   required to go out and get the notice.  That's
15   an alien concept to me.  But in any event, we
16   can get into the crux of the questioning at
17   this time.
18   BY MR. FARBER:
19   Q.    I'm going to approach my deposition
20   quite a bit differently, simply because our
21   cases are different, Doctor Wheadon.
22                      Are you aware of the causes
23   of action that Plaintiff Lacuzong has brought
24   against SmithKline Beecham?
25   A.    No, I'm not.
0217
 1   Q.    Are you aware that there is a fraud
 2   count alleged in the Complaint against
 3   SmithKline Beecham?
 4   A.    No, I'm not.
 5   Q.    There is, so that will affect the way I
 6   question on some of these other issues.  They
 7   may be __ and it is not my intention to do so,
 8   but it may be slightly more contentious in
 9   some applications, but I'm not a contentious
10   person, but I do have to ask some difficult
11   questions on a case like this, wrongful death
12   and fraud allegations against SmithKline
13   Beecham.
14                      Did you ever learn of
15   Reynaldo Lacuzong's death?  Obviously, you
16   know of the suit, but did you, at some point
17   before today, become aware of Reynaldo
18   Lacuzong's adverse experience with death?
19   A.    Not outside the context of this suit.
20   Q.    When did you first become aware of his
21   death?
22   A.    I'm not sure of the exact date.  I just
23   heard the name associated with a suit that had
24   been filed against the company.
25   Q.    Was it like a month ago or a year ago or
0218
 1   a long time ago?  Just state in your words the
 2   general time frame.
 3   A.    I really can't give you a definitive
 4   time period.  It may be somewhere in the order
 5   of six to eight months ago.
 6   Q.    Okay, that's good enough for me.
 7                      What other circumstances do
 8   you understand about the death of Reynaldo
 9   Lacuzong in terms of Paxil dosage?
10   A.    I quite frankly am not familiar with Mr.
11   Lacuzong's case in terms of Paxil dosage or
12   any specifics around his particular case.
13   Q.    Does that include your unawareness as to
14   how many days after he initially took Paxil
15   his death occurred?
16   A.    I'm not familiar with that at all, no.
17   Q.    On the Lacuzong case, when did you first
18   consult counsel, either in_house, out of house
19   or whatever, at what point did you discuss
20   with a lawyer this case?
21   A.    The first discussion with a lawyer was
22   in the context of this deposition and that you
23   may be asking questions associated with that
24   case, but that was the extent of it.
25   Q.    When the deposition was __ either Mr.
0219
 1   Vickery's or mine, when the deposition fact to
 2   be became known by you, when was that?
 3   A.    It must have been, I guess, about mid
 4   summer.
 5   Q.    Do you know anything about Reynaldo
 6   Lacuzong, other than the basic fact that he
 7   has died and that he has used Paxil, and we
 8   are alleging certain illegal behavior?  Do you
 9   know anything else about him at all?
10   A.    No, I do not.
11   Q.    Did you ever hear that he was a heavy
12   drinker?
13   A.    No, I did not.
14   Q.    Did you ever hear that he was a
15   diabetic?
16   A.    No, I did not.
17   Q.    Are you familiar with the name Simms,
18   S_I_M_M_S, in the context of Simms allegedly
19   being a Paxil victim?  Does that name ring a
20   bell to you?
21   A.    That name does not ring a bell, no.
22   Q.    Does an incident in Ontario, Canada in
23   which a Paxil victim burned a vehicle a while
24   after he had taken Paxil, does that ring a
25   bell with you?
0220
 1   A.    No, it does not.
 2   Q.    Just to keep the chemistry going, this
 3   is not really on my outline, but I want to
 4   follow up on some of Mr. Vickery's questions
 5   while it is still fresh in our mind.
 6                      And to that extent, you
 7   recall, about an hour ago, you were talking
 8   about alcohol, and do you recall the context
 9   of which you made a point, I thought, to Mr.
10   Vickery, that contrary to alcohol being a
11   second factor, that an alcohol intoxication
12   can, in fact, enhance and aggravate
13   depression?
14   A.    That is correct.
15   Q.    Do you remember that?
16   A.    Yes.
17   Q.    And in the context, you basically
18   stated, well, of course, that was the case,
19   and I'm going to ask you a question on your
20   abstract reasoning on that set of facts.
21                      On that set of facts, would
22   you agree, in the abstract, that had alcohol
23   not been used at all during that entire
24   period, that the suicide would not have
25   occurred simply by definitional application?
0221
 1   A.    First of all, there were no set of
 2   facts.  If I recall correctly, Mr. Vickery was
 3   doing a supposition.  He was not discussing a
 4   specific case.
 5   Q.    Maybe here, we have having a lawyer and
 6   another specialty thing, but in law school, I
 7   was taught that these are the facts.  If there
 8   is two things, those are the facts.  There may
 9   be a million facts not listed, but in the
10   abstract, you have to deal with the
11   abstraction, and that was what I wanted to
12   pose to you as your abstraction on the fact
13   that alcohol, in fact, worsened the depression
14   and made that hypothetical case commit
15   suicide.
16   A.    What I said was, alcohol, in and of
17   itself, can be a depressant.  As a result, it
18   could exacerbate the depression.  That is the
19   statement that I made.
20   Q.    And I think you brought into __
21   actually, Mr. Vickery's hypo presupposed that,
22   and my question in the abstract again, is,
23   without that precipitating event, by
24   definition, by our abstraction, the death
25   would not have occurred?
0222
 1   A.    That is not correct.
 2   Q.    Well, that was the supposition.
 3   A.    No, that is not correct.
 4   Q.    Now, while you were at Eli Lilly, and
 5   even today __ first of all, let me just change
 6   it.  I appreciate the fact you are here today
 7   as a fact witness, not an expert witness;
 8   although, I'm sure, in many contexts, you
 9   would be a very capable expert witness, but
10   you are here today, as far as I am concerned,
11   as a fact witness, to testify to facts, your
12   state of mind of the corporation and so forth,
13   but I will therefore never ask you any
14   question about a standard of care as to
15   Reynaldo Lacuzong or anything, so all of my
16   technical questions, as I think Mr. Vickery's
17   were, were in the context of your corporate
18   position and what your contentions are both
19   technically, bureaucratically, legally and
20   everything insofar as that position is
21   concerned, as a fact witness.
22                      So I just want to counsel
23   questions that I know he is not an expert
24   witness, and I'm not going to probe him in
25   that way, but there will be many technical
0223
 1   questions.
 2                      Has SmithKline Beecham ever
 3   conducted a study, and I use the term
 4   generically, ever conducted a study to
 5   determine the long range effect on the human
 6   body or any bodily system from the use of
 7   SSRI's?
 8   A.    That's a very broad question.
 9   Q.    It is.
10   A.    And I need a bit more specifics in order
11   to answer it.
12   Q.    Well, I will make it as broad as you
13   want.  Let's just use the term long term.
14                      Has there been any
15   discussion or present intentions to study the
16   effects of SSRI's in the long term on the
17   body?
18   A.    Well, I will answer the question as
19   specifically as I can, since you are not
20   asking it specifically.
21   Q.    That's all I can ask.
22   A.    SmithKline has done long term studies of
23   Paxil in the treatment of such disorders as
24   depression, obsessive compulsive disorder,
25   panic disorder, so, yes, we have done long
0224
 1   term studies, and as a part of those studies,
 2   we have assessed the safe use of the product
 3   over the long term.
 4   Q.    Give me an idea of a depressed patient
 5   starting in __ what time frame are we talking
 6   about?  1985, 1988 or what?
 7   A.    I'm not sure __ quite sure what you are
 8   referring to.
 9   Q.    What did you mean by long term?  You
10   mentioned patients that had long term studies
11   done.
12   A.    What I mean is that we have done
13   clinical trials that look at the use of the
14   drug over the course of one year or longer in
15   a clinical trial setting, and we have done
16   that in depression, OCD, panic disorder.
17   Q.    I'm glad we got into that, because your
18   definition __ my definition of long term would
19   be like ten years.
20                      Do we have or do you have
21   any studies on the board now or contemplated
22   that would evaluate the effects of SSRI's on a
23   body that took that drug for ten years?
24   A.    No, there are no studies that have been
25   done or that are planned to look at the use of
0225
 1   Paxil over the course of ten years, no.
 2   Q.    None planned?
 3   A.    No.
 4   Q.    Do you think that would be a good idea?
 5   As a corporate official, would you recommend
 6   that to your board of director or your chain
 7   of command?
 8                      MR. PREUSS:  Which question
 9   do you want him to answer?
10                      MR. FARBER:  Whether it was
11   a good idea __ well, I will make it less than
12   a compound.
13   BY MR. FARBER:
14   Q.    Would you recommend, based on your
15   current knowledge, that this, such a study of
16   a long term effect be undertaken?
17   A.    No, I would not.
18   Q.    Why?
19   A.    Well, for a number of reasons.  Number
20   one, clinical trials are extraordinarily
21   difficult to carry out over such long spans of
22   time, such as ten years.
23                      Number two, if you look at
24   the average length of time that any one
25   patient may be on an antidepressant, it is not
0226
 1   of the order of ten years.  The reality is,
 2   unfortunately, that most depressed patients
 3   that are on antidepressants rarely stay on for
 4   as long as one year, let alone, as long as ten
 5   years.
 6   Q.    I didn't know that.  I'm glad I came
 7   today.  I really didn't know that.  And that's
 8   good to know.
 9                      Now, you have had people
10   that were taking __ in these clinical trials,
11   Phase II, back in the '80s __ I'm not talking
12   about Lilly now.  I am talking about
13   SmithKline __ that took Paxil in 1985;
14   correct?
15   A.    If you are saying that there were
16   clinical trials that were carried out in 1985
17   with Paxil, that is true.
18   Q.    That's what I am saying.
19   A.    But that does not imply that those
20   trials are still going.
21   Q.    No, it doesn't imply it.  In fact, we
22   don't know without doing the study.
23                      So my question to you is,
24   have you attempted to identify patients who
25   have been taking the drug since 1985 that
0227
 1   started with the clinical trials and
 2   discontinued with the drug until now, 15 years
 3   later?
 4   A.    Well, any patient that would be in a
 5   clinical trial, we know about.  So as I
 6   answered earlier, there are no clinical trials
 7   that have been of the order of time in terms
 8   of length of time of ten years or more, as you
 9   asked about.
10   Q.    No, I know that.  I will accept the
11   premise that your clinical trials are four
12   weeks, six weeks, one year.  They are
13   relatively short.  But you wouldn't deny,
14   would you, that there are probably many
15   patients, maybe over 100, maybe over 200,
16   patients who started the drug in 1980 __ in
17   the '80s and are still taking Paxil?
18   A.    Not in the US, seeing as though the drug
19   was not available in the US until 1992.
20   Q.    Well, let's just change it to SSRI's.
21   Well, if I could object, I'm not talking
22   approval now in '92.  I'm talking about people
23   who took the drug in the late '80s.
24                      You wouldn't deny that
25   there is some body of patient population that
0228
 1   has been taking SSRI's for ten years, would
 2   you?
 3   A.    There may be a very small subset of
 4   patients that may have been on one or another
 5   form of SSRI over the course of ten years, but
 6   continuously, I simply cannot comment on
 7   that.  I have no ability to answer yes or no
 8   to that question.
 9   Q.    Professionally, you must consider
10   theoretical questions like this, don't you?
11   A.    Of course, we all consider theoretical
12   questions.
13   Q.    So I'm asking you, as your corporate
14   position as an official, a very high official,
15   wouldn't you conceptualize in questions like
16   this?
17   A.    I don't think I'm here to
18   conceptualize.  I'm here to answer questions
19   in fact, as you indicated.
20   Q.    Well, I know, but you are not an expert,
21   and I'm not asking you for standard of care.
22   I'm asking you for the state of mind of
23   SmithKline Beecham is what I'm asking.  And as
24   their agent, the vice_president, I'm asking
25   you for your state of mind on that subject.
0229
 1                      MR. PREUSS:  What is your
 2   question?
 3                      MR. FARBER:  Whether he
 4   would think that would be a good idea to
 5   conceptualize and recommend to SmithKline
 6   Beecham that such a long term study might be
 7   advisable for SSRI __ patients who have been
 8   on SSRI's for ten years.
 9                      MR. PREUSS:  All SSRI's or
10   Paxil?
11                      MR. FARBER:  SSRI's.
12                      THE WITNESS:  I think I
13   have answered that question.
14                      MR. FARBER:  I don't think
15   you have.
16                      THE WITNESS:  I think I
17   answered the question that, no, I would not
18   recommend that.
19   BY MR. FARBER:
20   Q.    You have now.  Why wouldn't you
21   recommend that?
22   A.    Well, again, there is an extant safety
23   data base about SSRI's, both in terms of
24   Paxil, Prozac, Zoloft, Selexa, others, and
25   that safety data base is illustrative of what
0230
 1   one would expect in the use of the drug over
 2   the long term.
 3                      As I also indicated, we
 4   have looked at the use of the drug over the
 5   course of a year and longer, and we have not
 6   seen anything in those studies that says that
 7   the drug has an effect from a safety
 8   standpoint any different from what has been
 9   described in the shorter term trials.
10   Q.    I got the one year.  I got that one.  I
11   was discussing in my own mind, as I mentioned,
12   ten years.  And let me ask you this question.
13                      Have you read in the press
14   or other articles by pharmaceutical industry
15   critics at any time that said one of the
16   weaknesses of this program or one of the
17   deficiencies is that they have done no long
18   term studies on the effect of SSRI's?  You
19   have seen these critical commentaries, haven't
20   you?
21   A.    I have seen some comments along those
22   lines, yes.
23   Q.    And when you read them, what was your
24   impression?  What was your state of mind as to
25    __ if any?
0231
 1   A.    My impression was that the people making
 2   those comments were not aware of the fact that
 3   long term studies have been done, as I have
 4   described to you.
 5   Q.    Well, let's get off the one year for a
 6   minute.  I will agree with you that one year
 7   is not long term, but I'm talking longer
 8   term.
 9   A.    I did not say one year is not long
10   term.  I said studies have been done for at
11   least a year or longer, and that is long term.
12   Q.    By your definition, but not mine.  But
13   okay, I understand where you are coming from.
14   I will get on to the next subject.
15                      Now, also, you have seen
16   critics or heard critics criticize SmithKline
17   and other pharmaceutical companies for not
18   doing studies on other bodily systems, have
19   you not?
20   A.    I'm not familiar with that.
21   Q.    Now, I know, in looking over your data,
22   that you do a lot of tests on blood chemistry,
23   biology and all systems of the body,
24   endocrine, I know that, but has any __ other
25   than adverse experience reports, has there
0232
 1   been any studies undertaken to study the
 2   effect on other bodily systems through use of
 3   SSRI usage over one year?
 4   A.    I'm still not quite sure what you are
 5   asking.  If what you are asking, and I'm going
 6   out on a limb here, because you are not being
 7   very clear __
 8   Q.    I'm disappointed.
 9   A.    __ whether or not we have assessed the
10   effect of Paxil, that's what I'm here to
11   address, on functioning such as cardiac
12   functioning, renal functioning, liver
13   functioning and that sort of thing, and the
14   answer is, yes, we have, indeed, assessed the
15   effect of Paxil on those body systems.
16   Q.    Okay, I think renal systems is probably
17   a good example here.
18                      Have you studied the
19   effects of Paxil on renal systems __ on the
20   renal system over a five plus year period?
21   A.    We have looked at the effect of Paxil on
22   renal systems in terms of its acute effects
23   over the course of six, eight weeks, and in
24   the case of the long term studies, we have
25   also assessed if there have been any changes
0233
 1   over the course of a year or longer.
 2   Q.    What is the maximum, this year or longer
 3   phrase?  What are we talking about?  How much
 4   is longer?
 5   A.    I think our longest studies may have
 6   gone out through three years.
 7                      THE VIDEO TAPE OPERATOR:
 8   Going off the video record.  The time is
 9   3:26.
10                      THE VIDEO TAPE OPERATOR:
11   Back on the video record.  The time is 3:28.
12   BY MR. FARBER:
13   Q.    And back again, again, picking up loose
14   ends from Mr. Vickery's questioning, Doctor,
15   you remember discussing akathisia and DSM_4?
16   A.    I remember discussing akathisia, but not
17   in the context of DSM_4.
18   Q.    Let me add to it.
19                      In regard to akathisia in
20   DSM_4, you are aware that that term is in
21   there, are you not?
22   A.    Yes.
23   Q.    Are you aware that that term is in DSM_4
24   only in regard to a substance_induced
25   disorder?
0234
 1   A.    I'm not aware of that, no.
 2   Q.    Isn't there such a disorder as a
 3   neuroleptic __ acute neuroleptic induced
 4   akathisia?
 5   A.    Akathisia is most commonly associated in
 6   terms of drug association with neuroleptics,
 7   yes.
 8   Q.    And do you know that DSM_4 also
 9   addresses specifically SSRI_induced akathisia?
10   A.    I am not aware that DSM_4 addresses
11   specifically SSRI_induced __
12   Q.    It does.  Well, I won't ask you the
13   question.  I don't want to be __ I won't pull
14   a George Bush on you and ask you to name all
15   the capitals, because I understand this, but
16   yes, it does mention that the symptoms are
17   exactly the same, and that it is only
18   substance_induced, but getting on __
19                      MR. PREUSS:  Let me just
20   object.  Whatever the DSM_4 says, it says.
21                      MR. FARBER:  That's right.
22   It is just my background, offering to
23   clarify.
24   BY MR. FARBER:
25   Q.    Now, many, many times, maybe 10 or 12,
0235
 1   maybe 15, you had mentioned going back and
 2   doing studies based on existing data banks.
 3                      Do you recall that?
 4   A.    I recall discussing doing analyses on
 5   existing data bases, yes.
 6   Q.    And in regard to the suicide issue and
 7   these retrospective studies, particularly, we
 8   had lengthy or you had lengthy responses on
 9   the subject.
10                      Now, would you agree that
11   if that data bank is invalid, the definition
12   of it invalid, that that analyses is really
13   not __ is not scientifically accurate, is it?
14   A.    I don't know what you mean by invalid
15   definition.
16   Q.    Well, that's my hypo.  It is garbage in,
17   garbage out, and I'm telling you, it is
18   garbage in.  That's the hypo.
19                      You wouldn't rest on your
20   analysis being a successful result if that
21   were the case, would you?
22   A.    If there was a data base, where, as you
23   term it, garbage went in, then, yes, there
24   would be some issue with the data that comes
25   out of that data base.
0236
 1   Q.    Yes, that's just logic, isn't it?
 2   Okay.
 3                      Now, when you appeared
 4   before the 36th committee, advisory committee
 5   at FDA on October 5, 1992, you had just been
 6   on the job with your present employer then
 7   since the preceding February; correct?
 8   A.    That is correct.
 9   Q.    And at that time, you had essentially
10   made a presentation before that committee,
11   both actively to brief them, and also to
12   respond to questions, did you not?
13   A.    If I recall correctly, I presented the
14   sponsor's safety presentation.  Someone else
15   presented the efficacy data.
16   Q.    Now, before you attended that October
17   meeting, you had done quite a bit of homework,
18   hadn't you?  You studied the data __ I will
19   leave it at that.
20                      You had studied the data
21   leading up to that recommendation that had
22   been compiled by SmithKline all the way back
23   into the mid '80s, had you not?
24   A.    I was familiar with the data that was in
25   the new drug application, the NDA, upon which
0237
 1   the approval was based.
 2   Q.    And were you satisfied that your
 3   recommendations that you were then giving were
 4   sound ones?
 5   A.    I was very satisfied with the data that
 6   I was providing to the committee, yes.
 7   Q.    And you analyzed that data at least
 8   mentally or unofficially or however you want
 9   to phrase it, you had reviewed it, had you
10   not?
11   A.    I reviewed the data, yes.
12   Q.    But did you go back and look at the
13   grounding of the data, such as an individual
14   principal investigator's study __ let's just
15   pull one out of the air, Par 0203.
16                      You didn't go back or did
17   you go back and review Par 0203 principal
18   investigator's data collection efforts?
19   A.    That is a part of the standard process
20   of carrying out clinical trials, so SmithKline
21   Beecham, as the sponsor, insured that the data
22   collected by each individual investigator was
23   done per protocol, according to good clinical
24   practice, according to all the requirements of
25   effective and safe carry_out of clinical
0238
 1   trials.
 2   Q.    Okay, are these __ it is a legal term,
 3   but I think you will understand.
 4                      Are these, for the most
 5   part, independent contractor physicians or are
 6   they employees in some cases of SmithKline?
 7   A.    Investigators that carry out clinical
 8   trials are independent of SmithKline.  They
 9   carry out the work as consultants to
10   SmithKline, but they are not employees of
11   SmithKline.
12   Q.    So they are all independent
13   contractors.  So at the start of the IND, and
14   then NDA, you had given them __ let's take Par
15   0203 again.  You had a delineated protocol for
16   the PI's __ I will call them PI's for short __
17   to follow, did you not?
18   A.    For any clinical study, there is a
19   protocol which the investigators follow, yes.
20   Q.    And I have seen, I think, one, but
21   generally speaking, if you put all of the
22   protocols of one Par study together, how thick
23   is it, paper wise?
24   A.    I have no idea.
25   Q.    I mean, is it like __ I will make an
0239
 1   extreme example here.  Is it like three pages
 2   or is it more like 15 pages or a book or two
 3   books?  Give me a feel.
 4   A.    I really am not able to answer that
 5   question with any definition.  I'm sorry.
 6   Q.    I guess it would depend on the study,
 7   too, would it not?
 8   A.    Yes.
 9   Q.    Now, leading up to that 1992 committee
10   vote on October 5th, there were certain
11   preferred terms that were in documents, were
12   there not, for statistical analysis, such as
13   adverse experiences, anxiety, agitation, CNS,
14   various statistical analysis of various
15   preferred terms, were there not?
16   A.    I am not understanding what you are
17   asking.  In the NDA, there is a listing of the
18   adverse events that occurred during the course
19   of the clinical trials, and those adverse
20   events could be a panoply of terms.  So your
21   question is not very clear.
22   Q.    You are right.  I don't think it was.
23                      There was a certain FDA
24   category, was there not and is, on frequent
25   occurrences?
0240
 1   A.    There are categorizations in terms of
 2   the rate of occurrence of adverse events in
 3   terms of how you classify them as frequent,
 4   infrequent and rare.
 5   Q.    And doesn't the frequent categorization
 6   kick in at one percent?
 7   A.    If it is one in a hundred or more
 8   frequent than that, yes, that's frequent.
 9   Q.    And less than one is down to __ what's
10   the one lower than frequent?
11   A.    Between one and a hundred and one in a
12   thousand would be infrequent, and greater than
13   one in a thousand would be rare.
14   Q.    Were you aware of certain adverse
15   experiences __ that's not a proper term __ of
16   certain __ whether it is a malady, I don't
17   think is the correct term, but many of these
18   adverse experience preferred terms were
19   categorized as frequent initially by
20   SmithKline, but later taken off the frequent
21   list; isn't that correct?
22   A.    I'm not aware of that, no.
23   Q.    You are not?  Are you aware of Doctor
24   Tom Laughren, starting in July of '92,
25   corresponding to SmithKline officials on those
0241
 1   categorizations?
 2   A.    I am aware Doctor Laughren corresponded
 3   with the company concerning the broad listing,
 4   not just frequent, but the broad listing of
 5   adverse events that were in the proposed
 6   label, which is traditional for the FDA to
 7   do.
 8   Q.    Right, and was one of those categories
 9   back and forth between Doctor Laughren and
10   SKB, SmithKline Beecham, in regard to mania?
11   A.    I quite frankly don't recall mania as
12   being an issue that was communicated about.
13   So if you have a document you can show me, I
14   could give you a more definitive answer on
15   that.
16   Q.    I will.  I will show it later.  Again,
17   my purpose here is not to give you a gotcha,
18   because after all, I do want everything to get
19   out quickly, and I will provide you that
20   information or your counsel.
21                      Are you aware that the
22   initial list, meaning the frequent
23   categorization in '91, by the time it got to
24   the committee meeting in October of '92, was
25   reduced by more than one category?
0242
 1   A.    Which initial list?
 2   Q.    Well, there were several, were there
 3   not?  There were more than one list, but there
 4   was only one list that was finally put before
 5   the committee on October 5 for frequent
 6   occurrences of adverse experiences; isn't that
 7   correct?
 8   A.    There is one list of adverse effects.
 9   Now, if what you are asking me is, is it
10   possible for an event to be listed as
11   frequent, and then moved to infrequent during
12   the course of time?  It is very possible.
13   Why?  Because in the course of review of
14   clinical trial data bases by the FDA, clinical
15   trials that were not completed at the time the
16   NDA was filed complete, and by FDA
17   regulations, we have to do what's called a
18   120_day safety update, and then, oftentimes,
19   another safety update prior to the drug
20   finally being approved.
21                      As a result of those
22   updates, incorporating clinical trials that
23   completed after the NDA was filed, the data
24   base is updated.  So an adverse event that may
25   be characterized as frequent, because of the
0243
 1   update of the data base, the greater number of
 2   patients in the denominator, that adverse
 3   event may then go into the infrequent
 4   category.
 5   Q.    I understand what you are saying, and I
 6   totally agree.  You are adding to the data
 7   bank, maybe you are getting better data or
 8   more accurate data, and maybe you got dips
 9   below into the infrequent.  I understand
10   that.
11   A.    No, it is not better data, not more
12   accurate data.  It is simply more data.  And
13   as a result, an event that may be one in a
14   hundred, may, because of a larger denominator,
15   trip over into being one out of 300.
16   Q.    I'm with you.  I understand what you are
17   saying.  I do understand, but I'm not sure you
18   understand what I'm getting at.  And that is,
19   if you had more data, 300 more patients, after
20   a particular listing of adverse experiences,
21   and let's say it is 1.1, but with 300 more
22   patients, for some reason, the data is much
23   more positive in terms of fewer adverse
24   experiences, that 1.1 could dip below 1
25   percent based on additional data; correct?
0244
 1   A.    Based on additional data, meaning a
 2   changing denominator.
 3   Q.    Safety updates, more patients?
 4   A.    With your denominator changing, it
 5   stands to reason that your frequency rate will
 6   also change.
 7   Q.    I'm with you.  I understand.  And I
 8   agree.  Logically, that's __ now, my question
 9   is whether there is ever any justification to
10   recategorize __ let's take a manic response or
11   mania to something else based on the original
12   data because of a new analysis of what really
13   went on out on the site.
14   A.    Well, there may be situations where
15   additional information has been obtained from
16   the site, and what was originally described as
17   a manic episode may turn out not to have been
18   a manic episode.
19   Q.    Now, we are getting somewhere.
20                      Now, you came on the scene
21   in February of '92.  You have done some of
22   that work at Lilly before, but you picked up,
23   and then from February '92 onward, you have
24   done this regularly in your assigned duties,
25   haven't you, in looking at preferred terms,
0245
 1   investigator terms and categorizing them
 2   accurately in an NDA; correct?
 3   A.    That was not necessarily part of my
 4   assigned duties.
 5   Q.    By your assigned duties, I'm referring
 6   to responsibilities, not necessarily a
 7   hands_on __ I mean, you do have people working
 8   for you, right?
 9   A.    Well, again, part of my responsibilities
10   as a clinician when I first joined SmithKline
11   was looking at the totality of the data, the
12   efficacy, the safety, what have you.  Then in
13   terms of the analyses that would be done to
14   generate the tables, delineating those that
15   were frequent, infrequent and rare, that was
16   done both by clinical safety along with
17   statisticians.
18   Q.    Now, when you got a manic or mania
19   category, SmithKline, did you look at that
20   more closely than another category that was
21   more innocuous?  And I will give you an
22   example, something like rash.  Did you look at
23   mania more closely than an investigative term
24   rash?
25   A.    Absolutely not.  You look at rash with
0246
 1   equal scrutiny as mania.  Why?  Rash could be
 2   indicative of an allergic reaction, which
 3   could progress to very significant medical
 4   sequelae.  So rash would be investigated very
 5   seriously, manic reaction would be
 6   investigated very seriously.
 7   Q.    Okay, former military guy, I will use
 8   the term command interest.  That's my term for
 9   it.  Do you know what I am referring to, this
10   is a command interest item?
11   A.    No.
12   Q.    Let's talk corporate interest, boss's
13   interest, something that gets the boss's
14   attention, because it is very important to the
15   company, but maybe doesn't carry much weight
16   down in the low ranks.
17                      Are you telling me that a
18   hundred categories of manic categorizations on
19   adverse experiences gets the same attention at
20   SmithKline as a hundred cases of rash?
21   A.    Yes.
22   Q.    Has that always been the case?
23   A.    Yes.
24   Q.    Since you arrived at SmithKline?
25   A.    Yes.
0247
 1   Q.    Now, you talked earlier about data, and
 2   I think the issue was on the HAM_D or MADRS or
 3   one of them, where it lowered from like 1 to
 4   3, and you told Mr. Vickery it was wrong, but
 5   that did show up on the data as being a
 6   reduction of two points, and that your data
 7   system was capable of uncovering that and
 8   reporting that; is that correct?
 9                      MR. PREUSS:  I object to
10   the form of that question.  His testimony is
11   as recorded.  If you have a question, please
12   ask it.
13                      MR. FARBER:  I think I am
14   just restating his testimony that he said __
15                      MR. PREUSS:  That's what
16   I'm objecting to.  I think you are
17   characterizing testimony that is reflected in
18   the record.  I object to that.
19                      MR. FARBER:  There is no
20   valid objection on depositions for asked and
21   answered.  There is case law on that in
22   California.
23                      MR. PREUSS:  That's not my
24   objection.
25                      MR. FARBER:  What is your
0248
 1   objection?
 2                      MR. PREUSS:  My objection
 3   is that you are characterizing what he said
 4   before, and my statement is that the record is
 5   the most accurate recording of what he stated,
 6   so my request to you is, please ask a
 7   question, and then he will respond to it.
 8                      MR. FARBER:  If we want to
 9   take the time to always go back to the record,
10   that's fine with me.  I will tell you, I'm not
11   going to finish in three days, but I was
12   trying to be fair and to categorize his
13   testimony accurately.  And I believe I did,
14   and I believe he disagreed with Mr. Vickery
15   and said that a reduction of two points on the
16   HAM_D Item 3 would show up in the data base.
17   BY MR. FARBER:
18   Q.    Is that __ first of all, forget whether
19   you said it or not.  Is that accurate as to
20   what the data base's capability is?
21   A.    If your question is, is the data base
22   capable of capturing a patient that had a
23   change on the Hamilton depression scale Item 3
24   of two points?
25   Q.    Yes.
0249
 1   A.    The answer is yes.
 2   Q.    Has that always been the case in the __
 3   we have made a lot of progress in software and
 4   data and so forth.  Was that the case back in
 5   1990 or '91 as well?
 6   A.    You are asking questions concerning a
 7   time that I was not at the company.  My
 8   understanding is that that was, indeed, the
 9   case.
10   Q.    Is the data base also capable __ in the
11   adverse experience profile, are you aware of a
12   category that indicates the onset day of the
13   adverse experience, like Day 36 or Day 2 or
14   Day 29 or something?  Are you aware of that
15   category?
16   A.    Data base does capture the event date in
17   terms of the visit date where the event was
18   noted.
19   Q.    Well, let's speak now, and forget eight
20   years ago, but now, can your company pick up
21   adverse experiences that commenced between __
22   let's take an example __ Day 3 and Day 7 as to
23   all adverse experiences occurring between Day
24   3 and Day 7, can your data base pick that up
25   now?
0250
 1   A.    The data base is able to indicate the
 2   time frame at which an adverse event occurs
 3   based on the patient visit.  So if the patient
 4   visit occurred at Day 7, the data base would
 5   indicate that the adverse event happened
 6   between Day 0, Day 1 and Day 7.
 7   Q.    I'm confused by patient visit.  You mean
 8   the date the patient first went to the
 9   physician or the date that the patient first
10   took Paxil or was prescribed Paxil?
11   A.    The way clinical trials are done __
12   Q.    But my question __ let me clarify my
13   question.
14   A.    I'm trying to help you understand.
15   Q.    I wasn't necessarily talking about
16   clinical trials.  I'm also talking about all
17   Medwatch reporting and AER's, where it could
18   be a physician reporting this.
19   A.    Well, I'm sorry.  You are not being
20   clear.  I can only comment about __ you were
21   talking about NDA, you were talking about the
22   data base that was presented at the advisory
23   committee.  You need to be very clear about
24   what you are asking.
25                      And I'm referring to the
0251
 1   clinical trial data bases.  We are now talking
 2   about the post_marketing experience data base,
 3   and that's a separate question.
 4   Q.    Okay, well, let's deal with them
 5   separately.  Okay, the clinical trial base,
 6   back to '88 or even earlier, is that data
 7   available by data review at this time as to
 8   what date the onset of the adverse experience
 9   occurred?
10   A.    As I mentioned, the data can be analyzed
11   looking at the patient visit date where the
12   adverse event was noted, yes.
13   Q.    Define for me the patient visit date.
14   A.    That would be the date at which time the
15   patient came into the investigator's office
16   and was evaluated and was asked questions
17   concerning the occurrence of adverse events
18   between the last time they were seen and that
19   date when they were being evaluated.
20   Q.    I'm confused.  It is not you.  I'm sure
21   it is me.  But as to __ let's take a case
22   where he comes in, a male patient, he, comes
23   in and is prescribed Paxil, and he takes it
24   Monday, takes it Monday, and on Wednesday,
25   there is an adverse experience, but he doesn't
0252
 1   come back in to report this to the doctor
 2   until Sunday.
 3                      So on this category you are
 4   talking about, would it be two days or would
 5   it be five that's listed on that data column?
 6   A.    The date that the adverse event was
 7   noted would be Sunday, okay?
 8   Q.    The date the physician learned about it?
 9   A.    The date the physician learned about it,
10   exactly.
11   Q.    Now, on your data now in the __ well,
12   this is NDA data, where it says date of onset,
13   that standard was used to establish that date
14   of onset column?  Is that what you are saying?
15   A.    What I'm saying is, in terms of
16   identifying the patient, the patient visit
17   would be how you identify when that event was
18   reported.  You then would pull up the record.
19   And in most situations, you can also pull out
20   adverse event date onset and the date that the
21   adverse event was no longer present.
22                      So the way you identify the
23   patient is at the visit.  You then pull out
24   that record, and you can then scroll down, if
25   you will, further into the data, and you have
0253
 1   an onset date, because once the patient notes
 2   to the physician that they had headache, the
 3   physician then asks, when did this adverse
 4   event start?  Patient gives a date.  When did
 5   it end?  Patient gives a date.  So you do have
 6   an onset and an end date within the data base,
 7   but you identify the patient based on the
 8   visit date.
 9   Q.    I thought you contradicted what you
10   earlier said, but maybe you didn't.  Forget
11   clinical trials.  Let's talk now about
12   Medwatch and AER reporting from the world
13   now.
14                      If we get an adverse event
15   today that happened in San Francisco on
16   Wednesday, the same day, a doctor prescribes
17   Paxil to the patient on Wednesday, on
18   Thursday, he goes out, and he commits suicide,
19   and on Friday, the doctor reports it, calls
20   SmithKline headquarters and reports that the
21   doctor thinks that Paxil caused the suicide,
22   but the doctor hasn't made a written report to
23   you, okay?
24                      When you get around to
25   making your report to FDA, what is the time
0254
 1   frame for these events you are just talking
 2   about as to this Wednesday, Thursday and
 3   Friday chronology?
 4   A.    If I'm hearing your question correctly,
 5   if it is an adverse event that is serious,
 6   meaning it involves death, hospitalization
 7   what have you, that's what's called a 15_day
 8   report, and it has to be reported to the FDA
 9   within 15 days.
10   Q.    I understand that, but that is not the
11   question.  The question was, in my hypo, that
12   the suicide occurred one day after he took
13   Paxil, but the doctor didn't find out about it
14   until the second day, but he then phoned the
15   report in to your company.  And I'm asking you
16   whether the one day that he had been on Paxil
17   would be reported in the data column.
18   A.    In terms of post_marketing events, the
19   information is collected based on what the
20   physician tells us.  So there is no data
21   column, per se, for onset.  We just collect
22   the information verbatim in terms of what the
23   physician tells us.  That's collected in the
24   form, also entered electronically.
25   Q.    I also want you to know that I have done
0255
 1   some reading in this, and I do understand what
 2   you said earlier, that through the narrative
 3   and pulling certain things, you can get
 4   information that may not be available in some
 5   read_out initially, but the narrative is
 6   available, is it not, that was originally
 7   submitted for further review?
 8                      So my question is, when the
 9   physician makes a report to you, let's say, by
10   paper, let's say, by letter or submits the
11   paperwork himself, does that physician,
12   treating physician's narrative, get in your
13   data base in toto?
14   A.    Yes.
15   Q.    You are Board_eligible in psychiatry,
16   you have been a physician for many years, and
17   you run with physicians, you have friends that
18   are physicians, you have dealt with physicians
19   for most of your adult life, haven't you?
20   A.    That's correct.
21   Q.    Now, tell me what physicians, general
22   practitioner in Chicago, average 50 percentile
23   physician, what does that physician know or
24   believe about akathisia?
25   A.    I'm struggling with your statement of 50
0256
 1   percentile physician.
 2   Q.    Let's just say he is a run_of_the_mill
 3   internal medicine specialist, practicing in
 4   primary care in an HMO setting.  What does
 5   that physician know about akathisia?
 6   A.    It depends on the patients that he has
 7   in his practice.  If he has schizophrenics in
 8   his practice, he knows about akathisia.  If he
 9   has depressed patients in his practice, he may
10   or may not know about akathisia.  It depends
11   on what his experience base is.  I can't
12   really give you an answer beyond that.
13   Q.    Well, of course, it depends on the
14   individuals, but we are talking __ don't we
15   have any information on a large setting?  I
16   mean, we got a population, now, talking of
17   statistical sampling, we have an HMO setting
18   in a big city, that's the hypo, and we have
19   2,000 patients that's under this physician's
20   care, and can't you get some sort of a model
21   of what the experience, whether it is
22   depression or schizophrenia or high blood
23   pressure, don't you have a feel for the range
24   of patient diseases and treatment programs
25   that he is involved with?
0257
 1   A.    No, I do not.
 2   Q.    You don't?
 3   A.    No.
 4   Q.    Okay, fair enough.
 5                      Now, I want to talk to you
 6   about pre_marketing and post_marketing
 7   methodology.
 8                      Now, when you went before
 9   that October '92 committee meeting, and the
10   board voted 6 to zip to approve Paxil, and the
11   FDA bought that recommendation, that did not
12   include the labeling information and
13   prescribing information that was subsequently
14   dealt with, did it?
15   A.    Advisory committees to the FDA do not
16   review proposed labeling.
17   Q.    Yes, I read that, and that's logical.
18                      So after the review was
19   granted, approved, what process occurs between
20   SmithKline and FDA to get a labeling scheme
21   approved?  Tell us generally what happens on
22   who recommends, where it goes through and some
23   of the __ if you could keep it to two or three
24   minutes, nothing real elaborate, but I'm
25   interested in the scenario of how this
0258
 1   labeling scheme gets approved.
 2   A.    With an NDA, one of the sections that
 3   you include in an NDA is proposed labeling.
 4   So that goes in at the time you submit the
 5   NDA.
 6                      After review by the FDA,
 7   there is an advisory committee after review of
 8   the data by an advisory committee and their
 9   recommendations, the FDA may then come back to
10   the sponsor with their proposal for labeling
11   using as a template what you filed with your
12   original NDA.
13   Q.    Can I stop you just a minute?  You used
14   the word proposal.  Is that a polite way of
15   saying __ I mean, they are not __ do they have
16   the authority to make it an edict?
17   A.    Well, in the situation I am describing,
18   which you have asked me to do, I'm telling you
19   what the back and forth is.  It is an
20   iterative procedure.
21   Q.    Maybe I am being finicky on the word
22   proposal, but I guess it is my military
23   background.  Seniors don't propose, unless
24   they are being very polite.  So okay, they
25   say, we don't like your input, here is what we
0259
 1   think is a better input and back to you, SKB?
 2   A.    The FDA comes back with their proposal
 3   for the labeling.  The sponsor, in our case,
 4   SmithKline Beecham, may then come back with a
 5   counter_proposal for labeling, different
 6   wording, different positioning of statements,
 7   what have you, and finally, an agreement is
 8   reached between the sponsor and the FDA on the
 9   final labeling.  And obviously, FDA has the
10   ultimate authority to agree to that final
11   labeling.
12   Q.    A side question, I didn't ask this
13   before, but does FDA have the authority
14   internally or by statute or regulation to
15   impose a labeling requirement that was not
16   even included in SKB's initial submission?
17   A.    Yes.
18   Q.    Okay, now, pre and post, let's __ I have
19   to give you a hypo that you may not like, but
20   I'm going to give it to you, anyway.
21                      Let us assume that you, at
22   SKB, as a vice_president, have discovered,
23   let's say you discovered this in 1995, you
24   have been there three years, you discovered
25   back in '87, by looking at records, that there
0260
 1   was a massive series of errors made based on
 2   one misconcept interpretation, and you say,
 3   oh, my God, this is a major error in concept.
 4                      Would you, at that point,
 5   go back and report that, first of all, to the
 6   FDA voluntarily?
 7   A.    Yes.
 8   Q.    Now, at that point, would you recommend
 9   that the pre_marketing or clinical trial data,
10   in other words, other than post_marketing,
11   would you go back and __ let's say there was a
12   massive clinical trial error.  Would you go
13   back and recommend that that entire data bank
14   that was presented in that little labeling be
15   amended?
16   A.    It depends on what the error was, and it
17   depends on implications of that error.
18   Q.    Is it fair to say, a real major error,
19   you would do that, but if it was a little
20   minor error, maybe it would require
21   appropriate adjustments, but not necessarily
22    __
23   A.    I really can't comment, because, again,
24   it depends on the specifics of even what the
25   major error might be.
0261
 1   Q.    Do you agree with the concept that
 2   American physicians place more credence in
 3   clinical trials and pre_marketing entries than
 4   they do post_marketing commentary that's
 5   printed in those prescribing information
 6   PDR's?
 7   A.    I don't know that I have an opinion one
 8   way or the other on that.
 9   Q.    So okay, you have no opinion whether
10   pre_marketing carries greater weight or less
11   weight or the same or whatever, okay.
12                      Now, talk to me about
13   recommended labeling insofar as data, I will
14   call it statistical summaries, and you know
15   what I am talking about with the data, 2
16   percent, 1 percent and all that, and
17   narrative.
18                      Is there some sort of a
19   requirement that you list statistical tables
20   or is it simply appropriate depending on the
21   situation whether you add tables or narrative
22   or __ I'm trying to get your view on the
23   interplay between narratives and strict raw
24   data that should be placed in the PDR's.
25   A.    You have to be specific about the
0262
 1   particular section of the prescribing
 2   information that you are referring to.
 3   Q.    Okay, let's talk about dose, dose
 4   dependent on adverse experiences.  Let's say
 5   we have a 10, 20, 30 and 40 milligram dose,
 6   and then we have various preferred terms, like
 7   nervousness, anxiety, agitation, tremor and so
 8   forth, and let's say, at ten milligrams, we
 9   have 5.9 percent; at 20 milligrams, we have
10   6.1 percent and so forth.
11                      Is data like that important
12   to be placed in a statistical table?
13   A.    First of all, there is no such thing in
14   the label as a statistical table.  Data may be
15   presented in prescribing information depending
16   on a number of factors.  Sometimes, it may be
17   in tabular form.  Other times, it may be in
18   short, descriptive form.  It really is not a
19   determinant of statistical or not.  It is just
20   something that's varying across several
21   different types of prescribing information.
22   Q.    I agree with you.  You are not telling
23   me anything, but __ that's probably a good
24   answer, but do you agree that even PDR's for
25   doctors should be user_friendly?  Do you write
0263
 1   them to be user_friendly?
 2   A.    Well, PDR is the Physician Desk
 3   Reference.  That's a collection of prescribing
 4   information.
 5   Q.    Prescribing information.
 6                      When you propose labeling
 7   to the FDA, do you have user friendliness as
 8   one of your goals?
 9   A.    Certainly, one of our goals, because we
10   want physicians to understand how to
11   effectively and safely use the product.
12   Q.    You wouldn't try to slip anything in
13   there just to cover yourself, would you?
14   A.    I don't understand what you mean.
15   Q.    Just slip in a little statistic, just to
16   say, well, it is in there, if you read it?
17   A.    I'm still not understanding what you are
18   asking.
19   Q.    Don't you know what slipping in
20   something __ I don't want to be vulgar here,
21   but you know what covering your behind means,
22   right?
23                      MR. PREUSS:  I object to
24   the form.
25   BY MR. FARBER:
0264
 1   Q.    I know you do.  Do you know what I'm
 2   talking?
 3   A.    We include in our prescribing
 4   information sound, credible data, and that's
 5   what it is based upon, and that's what the FDA
 6   insists that we put in our prescribing
 7   information.
 8   Q.    That wasn't my question.  My question
 9   is, do you know what I'm talking about when I
10   am telling you that one method by some people
11   is to include printed items simply to protect
12   themselves and not necessarily to educate the
13   recipient or the reader?
14                      MR. PREUSS:  I object to
15   the form.
16   BY MR. FARBER:
17   Q.    Do you understand what I'm talking
18   about?
19   A.    I understand what you are talking about,
20   yes.
21   Q.    And my question is __ I will make it a
22   friendly, leading question.  You have never
23   done that at SKB for that purpose, have you?
24   A.    We have never done what?
25   Q.    Slip in something in a prescribing
0265
 1   information label simply to cover yourself?
 2   A.    We include in our prescribing
 3   information data, one is contraindications,
 4   adverse event profile that we feel pertinent
 5   for physicians to know in terms of safely and
 6   effectively using the drug.
 7   Q.    Now, would you answer the question?
 8   A.    I just answered the question.
 9   Q.    No, you didn't.  You said what's in
10   there, which I can read.  I have read your
11   prescribing information many times.  I don't
12   understand it like you understand it, but I
13   have read it.  And that's not my question.
14                      My question is, do you put
15   stuff in the prescribing information just to
16   protect SmithKline and not to look out for the
17   welfare primarily of the physicians and
18   patients?
19   A.    Absolutely not.  We always look out for
20   the welfare of patients.
21                      MR. PREUSS:  Can we have a
22   break here?
23                      MR. FARBER:  Okay, that's
24   fine.
25                      THE VIDEO TAPE OPERATOR:
0266
 1   Going off the video record.  The time is
 2   4:05.
 3                      THE VIDEO TAPE OPERATOR:
 4   Back on the video record.  The time is 4:17.
 5   BY MR. FARBER:
 6   Q.    Doctor Wheadon, do you remember the
 7   testimony about an hour ago, when Mr. Vickery
 8   was asking you about the commentary on the
 9   prescribing information on suicide, and that
10   suicide __ I am paraphrasing now __ is a risk
11   of depression, and physicians should monitor
12   depressed patients carefully and so on?  Do
13   you recall that discussion?
14   A.    I recall discussing suicide as a core
15   component of depression, and as such, patients
16   should be monitored carefully under treatment,
17   yes.
18   Q.    And that that was in the prescribing
19   information under that category; correct?
20   A.    Under precautions, yes.
21   Q.    Just from a position of an agency
22   recommending these to the FDA, why would a
23   warning like that be needed __ correction.
24                      Don't all physicians know
25   that suicide is a risk from depression?
0267
 1   A.    Yes.
 2   Q.    Then why is that warning needed?
 3   A.    That precaution is in all labels of
 4   antidepressants by FDA requirement, it is a
 5   class labeling, and the issue there is that
 6   the agency wants physicians to be cognizant of
 7   the fact that, despite starting treatment, the
 8   risk of suicide has not gone away; that
 9   patients need to continue to be carefully
10   monitored, despite the fact that treatment has
11   been initiated.
12   Q.    Thank you.  That's just about exactly
13   what you said an hour ago.  That's
14   consistent.
15                      Why does FDA think that
16   way?  Why does that need to be stated as such,
17   in your opinion?
18   A.    Because it is important in the safe and
19   effective use of an antidepressant.
20   Q.    Do you think doctors could be misled, a
21   certain maybe minority percentage of
22   physicians, would be misled to think, Paxil,
23   I'm giving the patient Paxil, his depression
24   is going to go away and no more __ what
25   doctors would think that?
0268
 1   A.    Well, certainly, in a situation where
 2   physicians may, based on patients coming back
 3   and saying, within a week or two, I feel much
 4   better, to think, well, perhaps, they are out
 5   of the woods, and that is there to alert
 6   physicians to the fact that, indeed,
 7   depression takes a bit longer than one or two
 8   weeks to fully respond to treatment, and as
 9   such, you are not out of the woods, and as
10   such, you need to be cognizant of the
11   significant risk that suicide may pose in
12   depressed patients.
13   Q.    That's a little different than saying to
14   the doctor that the patient is still being
15   depressed.  In other words, I agree with you,
16   maybe there is a doctor who would __ after the
17   patient comes in two weeks later and says, I
18   feel great, that the doctor would conclude,
19   oh, he doesn't have any depression anymore, I
20   think, then, your logic holds up.
21                      But if the logic is that
22   the doctor still thinks that he is being
23   depressed and suffering from depression; yet,
24   the suicide issue is not present, I don't
25   understand your logic for that.
0269
 1                      Could you explain?
 2   A.    My logic is the same as what I have just
 3   described, that depression is an illness that
 4   takes several weeks to respond completely;
 5   that patients that are being treated for
 6   depression are at risk for suicide, and as
 7   such, should be monitored for that.
 8   Q.    But in the example you cited just a
 9   minute ago about the two weeks later, coming
10   in and telling the physician that he feels
11   much better, in your example, did you mean to
12   imply that the physician thought that
13   depression was now abated?
14   A.    The physician may not think that
15   depression has abated, but the physician may
16   sit back a bit in terms of his intensity of
17   monitoring.  That is what I was implying.
18   Q.    Now, I want to get __ again, you
19   presented this recommendation on October of
20   '92, after you reviewed the data, and I
21   understand you weren't on the job very long,
22   six months or so, but you had to take this
23   forward to the FDA committee and recommend
24   your new company's product.
25                      Back to adverse experiences
0270
 1   and the worldwide __ I will call it the non_US
 2   and the US data banks on adverse experiences,
 3   and here, I want to get into some detail, we
 4   may go on on this concept for a while.
 5                      Investigator term, define
 6   an investigator term, quote, unquote.
 7   A.    Investigator term is the term that the
 8   investigator uses to describe an adverse
 9   effect.
10   Q.    Can I stop you just a second, before you
11   take off on that issue?
12                      Terminology in medicine is
13   extremely important.  Would you agree with
14   that?
15   A.    Terminology is important in several
16   fields of study, medicine included, yes.
17   Q.    But particularly important in medicine,
18   isn't it?
19   A.    Well, yes.
20   Q.    I mean, critical, isn't it?
21   A.    I'm not sure what you mean by critical.
22   Q.    Well, if you labeled me as a
23   schizophrenic, that's a critical label, isn't
24   it?
25   A.    That's a diagnosis.  That's not a label.
0271
 1   Q.    Well, it is also a label.  It may be a
 2   diagnosis, but it is also a label.
 3                      And an investigator term __
 4   I want to develop this with you maybe in
 5   conjunction.  It is the investigator's
 6   analysis, it could be a diagnosis, but there
 7   is many systems, is there not, are there not,
 8   for medical terminology on __ like we have CPT
 9   codes, do we not?  We have Medra and the
10   United Nations World Health __ there is so
11   many lexicons of terminology.  DSM has
12   terminology.
13                      When you do a protocol __
14   let's go back to if you were starting one
15   today.  What guidance would you give to
16   investigators to formulate their investigator
17   term methodology?
18   A.    We instruct investigators to provide us
19   with their feedback concerning adverse effects
20   that are reported to them by their patients.
21   We do not put words in their mouths about the
22   sorts of terms to use.  We allow the physician
23   to decide how he chooses to describe the event
24   that the patient has described to him.
25   Q.    I understand that, and that's logical,
0272
 1   because no two physicians are exactly
 2   identical, and there is different disciplines
 3   and so on, and there is a little bit of
 4   flexibility, notwithstanding the
 5   professionalism and scientific approach.
 6                      But on a diagnosis such as
 7   major depressive disorder, multiple episodes
 8   or something like that, would that be an
 9   investigator term that might be used out in
10   the field to describe emotional ability?
11   A.    You are, I think, confusing terms.
12   Q.    That's why I am raising the issue of
13   investigator terms.
14   A.    Major depressive disorder is a
15   diagnostic category, like schizophrenic, like
16   panic disorder, like obsessive compulsive
17   disorder.  So that's not an investigative
18   term, per se.
19   Q.    Could it be?
20   A.    Not necessarily, no.
21   Q.    That's not the question.  Could it be an
22   investigator term, under your protocol?
23   A.    Depending on what's being studied.  For
24   example, if a patient is being studied for
25   social phobia and had no indication of
0273
 1   depression at the time the patient started
 2   treatment, came in describing depressive
 3   symptoms, the physician may use the term major
 4   depressive disorder as an adverse event term,
 5   yes.
 6   Q.    So it could be?
 7   A.    It could be, yes.
 8   Q.    Now, in that case __ we will go one
 9   hierarchy up.  In that case, would the
10   investigator term be the same as the preferred
11   term that's been adopted in your reporting
12   system?
13   A.    The preferred term refers to something
14   different.
15   Q.    So let's stick with investigator terms
16   for just a few more questions.
17                      Manic episode, is that an
18   investigator term or a preferred term or both?
19   A.    It could be both.
20   Q.    So there are certain diagnoses and codes
21   that could be and are both investigator terms
22   and preferred terms?
23   A.    There are certain adverse events that
24   could be both investigator terms and preferred
25   terms, yes.
0274
 1   Q.    Would you agree that __ and all these
 2   people, physicians that __ let's take the Par
 3   2 and Par 3 series.  Let's take all the seven
 4   supportive and positive studies that showed
 5   the efficacy of Paxil.  Let's take those as an
 6   example.
 7                      Are all those principal
 8   investigators, were they psychiatrists?
 9   A.    I'm not familiar with the background of
10   all the investigators involved in the
11   preapproval studies.
12   Q.    If you were starting a study today at
13   SmithKline, and you had to repeat this, would
14   you make sure that all of the principal
15   investigators were psychiatrists?
16   A.    Not necessarily.
17   Q.    At least Board_eligible __ okay.
18                      So their play on
19   psychiatric terms wouldn't necessarily be
20   technically accurate, would they?
21   A.    That is not necessarily true.
22   Q.    But I posed the question in the
23   opposite.  It wouldn't necessarily be the
24   case, and then the answer, I would think,
25   would be yes, that's correct?
0275
 1   A.    No, that is not true.
 2   Q.    What would your level of detailed
 3   instruction on the protocol be for a
 4   non_psychiatrist principal investigator who
 5   would do a Paxil efficacy study?
 6   A.    I don't understand what you are asking.
 7   Q.    Are your instructions or your protocol,
 8   your guidance, call it whatever you want, to
 9   the principal investigators on a study in the
10   case of a Paxil application, would the
11   instruction to the principal investigator be
12   the same, were he or she a psychiatrist, as
13   opposed to an internal medicine physician?
14   A.    Yes.
15   Q.    Now, let's talk about the investigator
16   term comes in from the field, and now, what
17   happens to that term to get it to a preferred
18   term status?
19                      Let's take one report.  Let
20   us say that the investigator term is restless
21   legs.  How do we get from restless legs into
22   the preferred term that ultimately results?
23   A.    I can't give you an exact mapping for
24   the example of restless legs.  That's not
25   something I have reviewed recently, so I can't
0276
 1   give you an answer for that.
 2   Q.    That wasn't my question, whether you
 3   could, but the question of how this would be
 4   resolved at the SmithKline Beecham level.
 5   A.    As I have indicated, I cannot give you a
 6   specific answer to your question on restless
 7   legs.
 8   Q.    Let's take another example.  Let's take
 9   fidgety.  And now, it comes in.  How would
10   that be handled?
11   A.    If you are asking me the general
12   process, I can answer that question.
13   Q.    Okay, let's start with the general
14   process.
15   A.    An investigator term comes in, an
16   investigator uses whatever term he wants to
17   use, say dry mouth or what have you.  As you
18   know, there is a dictionary to which those
19   terms map that's based on the World Health
20   Organization collection of terms.  So the
21   investigator term is then mapped to a
22   preferred term.  The investigator term may be
23   a preferred term.  The investigator term may
24   then be mapped to a different preferred term
25   that captures the same essence as that
0277
 1   investigator term.
 2   Q.    In this whole process, hundred percent
 3   process, in taking into consideration all the
 4   maladies, all the __ what percentage of that
 5   process is subjective based on judgment, and
 6   what percentage is based on objectivity and
 7   precise criteria for code __ that's a little
 8   gobbly_gook.
 9                      What percentage is based on
10   subjective judgment, and what percentage is
11   based on specific code criteria?
12   A.    It is a hundred percent based on
13   specific code criteria.  If there is any
14   question around what the investigator meant, a
15   query is sent back to the investigator to get
16   more specifics around exactly what he meant by
17   the term.  So it is a one hundred percent
18   objective process.
19   Q.    One hundred percent objective?
20   A.    Yes.
21   Q.    Now, do you agree that some __ just for
22   the record, I know you know, but I'm going to
23   ask you, anyway.  What does ICD stand for?
24   A.    International Classification of
25   Diseases.
0278
 1   Q.    And current edition is 9 that's now
 2   effective worldwide, isn't it?  It may be a 9
 3   CD?
 4   A.    I think there may be a more recent
 5   version, but I'm not sure what the
 6   classification is.
 7   Q.    I think there is a 10, but I don't think
 8   it is approved by most of the countries yet.
 9   I think they are still using 9.
10                      But my question is, the
11   interface between, let's take ICD codes and
12   the DSM disorder digits.  Is there a code
13   transfer or recommended code in any
14   publication to tell you how to get from one to
15   the other?
16   A.    There is an attempt to tie in DSM_4
17   classifications into ICD 9 or 10 codes, yes,
18   there is an attempt to do that.
19   Q.    And that's consistent with my recent
20   homework.  And again, I'm not telling you I'm
21   an expert.  I'm not trying to compete with you
22   here, because I had to study a lot, so I'm
23   just asking you to reinforce, but on the issue
24   of whether there isn't a direct translation
25   from one code to the other idea, what process
0279
 1   would be engaged to select preferred term?
 2   A.    Well, you are mixing two different
 3   issues.  DSM_4, ICD 9 and 10 are diagnostic
 4   category classifications.  We were talking
 5   about before adverse event terms and a mapping
 6   to a preferred term, so they are two different
 7   situations.
 8   Q.    I know what you are saying, and that's
 9   consistent with my understanding, but on the
10   case of restless legs syndrome, that's all you
11   got, are you __ you are not saying, are you,
12   or testifying that it is an objective process
13   to get from restless leg syndrome into anxiety
14   as a preferred term?
15   A.    As I commented earlier, I am not
16   prepared to discuss specifics around restless
17   legs and how it maps to a preferred term or
18   not.  I am not prepared or able to comment on
19   that.
20   Q.    The issue is not restless legs.  I
21   intend the question to be on any sort __ take
22   fidgety or any one of them that doesn't have a
23   specific preferred term, how we get from this
24   investigator term to the preferred term, and
25   the methodology __ in other words, let's
0280
 1   assume we have a PI out in Tennessee, who
 2   sends in a hundred reports with, let's just
 3   take restless legs, and they are dumped at
 4   SmithKline Beecham as restless legs,
 5   investigator term for a hundred patients.
 6                      What do you do to get those
 7   a hundred codes transferred into a hundred
 8   preferred terms?
 9   A.    Well, as I tried to explain, and I will
10   try one more time, there is a mapping process,
11   where the world of investigator terms as best
12   can be fathomed is then translated into a
13   smaller subset, but still large, of preferred
14   terms.
15                      So there is a mapping
16   objective process that takes a litany of
17   possible investigator terms and maps them to a
18   set of preferred terms.
19                      If there is any question
20   around what the investigator meant by that
21   investigator term, there is also a process
22   where you go back to the investigator and ask
23   specifically, can you give us some more
24   information to help us understand exactly what
25   you meant by this term?
0281
 1   Q.    I understand that.  I understood it
 2   then, too.  But let us say that when you go
 3   back, and in any case, that you assign this to
 4   a section or division or certain officials at
 5   SKB to perform this function, do you not, to
 6   transfer the investigative term into the
 7   preferred term?
 8   A.    People involved in clinical safety who
 9   are responsible for doing that, yes.
10   Q.    So the hundred reports come in in my
11   scenario.  Then that division is responsible
12   for translating those one hundred restless
13   legs syndromes into one hundred preferred
14   terms, and you are saying __ I understood you
15   to say it is a completely objective process,
16   but number two, you can and should also check
17   back if you have any questions with the
18   principal investigator?
19   A.    That is correct.
20   Q.    How does this checking with the
21   principal investigators occur?  By telephone,
22   letter or what?
23   A.    Multiple ways of communicating.  It
24   could be by telephone, by fax.  If there is an
25   issue around the investigator wanting to see a
0282
 1   copy of the report to be sent in, you may send
 2   a letter with a copy of the report.  There are
 3   a number of ways of communicating.
 4   Q.    And some of those, true or not, would
 5   not be in writing, telephone only, for
 6   example?
 7   A.    Some may be by phone, that is correct.
 8   Q.    So the change from the term used by the
 9   investigator to the preferred term could be
10   strictly on the basis of oral information by
11   the SmithKline official, based on a telephone
12   call to the principal investigator?
13   A.    There is a notation made that
14   investigator provide clarity, and there is a
15   written clarification of what the investigator
16   provided.
17   Q.    Originally or with the new phone update?
18   A.    Well, both.
19   Q.    So there is a phone record on every
20   telephone conversation in which an
21   investigator was queried on the reason for a
22   particular investigator term?  Is that what
23   you are saying?
24   A.    There are queries that are sent out, and
25   there is a record of those queries being sent
0283
 1   out.
 2   Q.    Now, you said it was objective.  I have
 3   some problems with that, but I will let you
 4   explain it.  You said it is a hundred percent
 5   objective.  Didn't you say that?
 6   A.    Yes, I did.
 7   Q.    What if I showed you in the record where
 8   we had, let's say, a hundred restless or
 9   restlessness investigator terms with anxiety,
10   we had a hundred or so restless terms with CNS
11   maladies, and we had another restless or
12   restlessness in agitation as an example.
13                      Under your hundred percent
14   objective analysis, that couldn't happen,
15   could it?
16   A.    It absolutely could happen.  I don't
17   have specifics, so I can't give you any more
18   clarity than that.
19   Q.    And that could happen based on your
20   statement that the investigator was queried on
21   telephone and so forth?
22   A.    Exactly.
23   Q.    So if I ask in discovery or if I ask you
24   on the street whether each of these categories
25   in the different adverse experience events
0284
 1   were different, you would have a record at
 2   SmithKline on all of these phone
 3   conversations?
 4   A.    I'm not saying there would be always a
 5   retrievable record, but there is a process
 6   where that is recorded.
 7                      Now, again, you have
 8   exceeded the extent of my responsibility, and
 9   there is someone who can give you more clarity
10   on that, but I have given you the answer that
11   I know.
12   Q.    Well, that's fair.  That's all you can
13   give me, and that's fine.  But you may not
14   know the details, but you are, I'm sure __ I
15   would assume that you are responsible for
16   accuracy of the records, ultimately?
17   A.    Right, and I have given you the answer
18   concerning that.
19   Q.    Did you base your hundred percent
20   objective conclusion on the fact that the
21   phone call could be made and verified to
22   everyone 99.99 __ well, you included the
23   telephone input or oral input as part of that
24   process?
25   A.    I base it upon the mapping process
0285
 1   that's clearly ear_marked.  I also base it
 2   upon the process of going back when there is
 3   any need for clarity and querying the
 4   investigator to provide further information to
 5   help clarify what was intended by the
 6   investigator term.
 7   Q.    What if the principal investigator
 8   disagreed with your final choice of preferred
 9   term?  Let's say there is a difference of
10   opinion.  In this phone conversation, the guy
11   calls up and says, hey, that wasn't mania,
12   that was anxiety or whatever, and he goes, I
13   don't agree with you, I'm the doctor.
14                      How would that discussion
15   or dispute be resolved, assuming they couldn't
16   work it out between themselves?
17   A.    There would not be a dispute.  The
18   investigator would provide clarity around the
19   term that he is providing, and then the
20   mapping would occur.  There would not be a
21   dispute.
22   Q.    There would never be any dispute on a
23   preferred term between an SKB official that
24   you mentioned and a principal investigator?
25   There is never any dispute?
0286
 1   A.    A preferred term is generated based on
 2   the mapping.  The investigator is consulted
 3   for clarity around the term that he is using.
 4   Q.    So the principal investigator, other
 5   than providing input of data for designation
 6   of the preferred term, really has no authority
 7   to change that then?  That's your company's
 8   call totally; correct?
 9   A.    In terms of the mapping, it is the
10   mapping process that's an adopted procedure
11   across companies.  So the mapping process is
12   one that occurs objectively.
13   Q.    Now, on your prescribing information and
14   your labeling, you, SmithKline, indicates that
15   you use co_start terms; correct?
16   A.    That is correct.
17   Q.    In your opinion as a SmithKline
18   official, and not as an expert witness, do you
19   think the co_start system is accurate enough
20   for your purposes?
21   A.    Co_start is a system that the FDA
22   requires us to use.
23   Q.    What about Medra, M_E_D_R_A?  Are you
24   familiar with that system?
25   A.    Medra is a coding system for
0287
 1   post_marketing surveillance reports.
 2   Q.    Is it your understanding that the
 3   experts in the field, others, believe co_start
 4   is a weak or deficient system for reporting
 5   adverse events?
 6   A.    That is not my understanding, no.
 7   Q.    It is your understanding that it is a
 8   fairly reliable system?
 9   A.    Yes.
10   Q.    Have you looked at the data base, not
11   today, but after you took over your job in
12   February of '92, did you look at the adverse
13   experience data base available at SmithKline,
14   let's say, in 1992?  Did you review that?
15   A.    I don't understand what you mean by look
16   at the data base.
17   Q.    Well, the same thing I did.  I took one
18   of those books, and I got a lot of paper, and
19   basically, there was non_US data adverse
20   experiences, and there was US data, and I
21   looked at it, and they were characterized by
22   anxiety, agitation, CNS, and so on and so
23   forth.  Did you __
24   A.    As I pointed out, I became familiar with
25   the data that was in the NDA prior to the
0288
 1   approval of Paxil for depression, yes.
 2   Q.    So in this case, that would be the NDA
 3   data base and others.  So you have done that
 4   then?
 5   A.    That is correct.
 6   Q.    Did you specifically look at the types
 7   and categories of adverse events by bodily
 8   system?
 9   A.    They are usually categorized that way,
10   so in the NDA, adverse events are
11   characterized by body system, yes.
12   Q.    Would you or did you give as much
13   attention to the cardiovascular system as the
14   central nervous system?
15   A.    Everything was reviewed across all body
16   systems.
17   Q.    I have a question.  Central nervous
18   system is a pretty broad term, isn't it?
19   A.    Not necessarily.
20   Q.    What is your definition of the central
21   nervous system?
22   A.    The central nervous system is your __
23   Q.    Let me be more specific.  Central
24   nervous system in terms of adverse experience
25   reporting.
0289
 1                      Are you aware that __ I'm
 2   going to guess.  I could be off on my figures
 3   okay?  Are you aware that in non_US reporting,
 4   central nervous system adverse events as to
 5   specific malady far outnumbered the US CNS
 6   category?
 7   A.    I was not aware of that, no.
 8   Q.    Let's get back to Mr. Vickery's topic of
 9   akathisia.  Oh, excuse me.  Let me get back.
10                      Back to investigator terms
11   in the data base, NDA or __ it doesn't make
12   any difference.
13                      On the printouts available
14   for the data, is there only a certain number
15   of spaces for a phrase or word?
16                      And I will give you my
17   background.  A lot of those words were chopped
18   off at the third word, indicating to me there
19   is a space limitation of 20 spaces or 10
20   spaces or something.  There is a lot of
21   half_words at the end.
22   A.    I really can't comment without seeing
23   what you are referring to.
24   Q.    Do you have knowledge that there is a
25   limited space for reporting investigator
0290
 1   terms, a limited space in the number of spaces
 2   of a word processor or __
 3   A.    I am not aware that that is a
 4   limitation, no.
 5   Q.    When the SKB personnel changed
 6   investigative term to a preferred term, do
 7   they have all narrative records before them as
 8   to that particular patient?
 9   A.    Again, the process is not changing
10   investigator terms to preferred terms.  It is
11   a mapping process.  So the investigator term
12   is mapped to a preferred term.  If there is
13   any question, they may go back and consult the
14   narrative or go back and consult the
15   physician.
16   Q.    Okay, you use map, I use change.  There
17   are different words, I call it a change, but I
18   won't quibble over that.
19                      But whatever the process,
20   mapping or changing, are narrative reports on
21   the patient's event or even his general
22   medical history included with the report that
23   provides the source of the mapping
24   categorization into the preferred term?
25   A.    There are two different processes.  The
0291
 1   mapping is, as I described, a mapping that's
 2   dictated by definition and paradigm from
 3   investigator term to preferred term.  If there
 4   is any question concerning the investigator
 5   term, the person doing the mapping may go back
 6   and refer to the narrative and/or go directly
 7   to the investigator to get further
 8   information.
 9   Q.    I used narrative.  I notice you did,
10   too.  Is that a technically accurate term,
11   narrative, as opposed to some other term?
12                      For example, I have seen
13   notes.  I mean, different doctors have used
14   different things to describe maybe the same
15   thing, maybe different things, but if a doctor
16   writes up a report on a patient's adverse
17   experience?
18   A.    We describe it as a narrative.
19   Q.    Okay, yes, I do, too.
20                      And is that narrative
21   available as that preferred term is mapped
22   into fruition?
23   A.    The narrative is available, yes.
24   Q.    Is it available when he does it
25   instantly or only available for further
0292
 1   checking?
 2   A.    If there is a question, the narrative
 3   can be retrieved for further checking.  It is
 4   available.
 5   Q.    Is it available manually?  I'm speaking
 6   now in 19 __ well, I will start with 1992,
 7   before approval.  Was it available then only
 8   manually or was it available by instant
 9   computer recall?
10   A.    I quite frankly don't recall what the
11   situation was in '92.
12   Q.    It may be available now, but not then.
13   We made a lot of progress since then.
14                      Now, have you studied the
15   data base __ let's start with the NDA __ data
16   base on akathisia?
17   A.    I have not recently, no.
18   Q.    What if I __ let's pose this as a hypo.
19   Let us assume I told you that all the non_US
20   adverse event reports, which you know are
21   true, are distinguished from the US reports.
22   What if I told you that in the non_US, the
23   term akathisia occurred numerous times, 30, 40
24   times, but in the US data, the word akathisia
25   is not mentioned at all.
0293
 1                      As a clinical supervisor,
 2   would that strike you as unusual?
 3   A.    First of all, I'm not sure that that is
 4   the case.
 5   Q.    No, it is my hypo.  If that were the
 6   case, would that strike you as unusual?
 7   A.    If that is the way it was reported, that
 8   is the way it was reported, and that's what we
 9   would deal with.
10   Q.    That's not my question.  My question is,
11   would you find that a bit unusual?
12   A.    Not necessarily, no.
13   Q.    Not necessarily, but what would be your
14   reaction at all if you saw that?  What if one
15   of your subordinates came to you and said, you
16   know, Doctor Wheadon, we have got 30
17   akathisias here from Germany, England and
18   Denmark, but we don't have any from the United
19   States.
20                      Based on your standard
21   operating procedures as a corporate manager,
22   how would you handle that?  Would you have
23   ignored it?
24   A.    It would be an interesting finding, but
25   it wouldn't be anything that I would find
0294
 1   inordinately unusual.  There is cultural
 2   differences in terms of diagnoses and
 3   reporting of adverse events and that sort of
 4   thing.  So it is not at all unusual to have a
 5   difference in terms of findings outside the
 6   United States versus what you see in the
 7   United States.  Different ways of practicing
 8   medicine.
 9   Q.    I understand that, but that's more of a
10   general subject in my opinion than in the
11   specific area I'm asking.
12   A.    I can only give you a general response
13   to a hypothetical situation.  I really can't
14   give you more specifics than that.
15                      MR. FARBER:  How long do
16   you want to go, counsel?  I won't finish
17   today, obviously.
18                      MR. PREUSS:  Well, how long
19   do you need before you finish?
20                      MR. FARBER:  I'm not going
21   to finish, I can tell you, even in the next
22   hour.  I have barely scratched the surface.
23   You can look at my notes.  I won't let you see
24   my notes, but I have got pages and pages of
25   questions.
0295
 1                      Now, if Doctor __ as far as
 2   I'm concerned, I don't know about Mr. Vickery,
 3   if Doctor Wheadon is unavailable after noon
 4   tomorrow, then I think maybe we have to honor
 5   his schedule, and we can work on it, but as
 6   far as I'm concerned, I'm not going to finish
 7   Doctor Wheadon in the next two hours.
 8                      MR. PREUSS:  Well, what
 9   should we do about planning for the next
10   witness?
11                      MR. FARBER:  I mean, if he
12   is available, fine.  I'm just telling you that
13   I'm willing to either go now for a couple of
14   hours __ I am really at your beck and call as
15   to schedule and Doctor Wheadon's as well.  I'm
16   traveling, so I don't have to go home to a
17   family or anything.  I can work until
18   midnight.  It doesn't make any difference to
19   me.  I'm just telling you, and I'm not blaming
20   Doctor Wheadon for being evasive, and I know
21   he has to qualify, but it is taking me longer
22   than I thought, and I have a lot more.  I
23   probably did only 15 percent.
24                      MR. PREUSS:  Well, let me
25   talk with the witness for a second.
0296
 1                      THE VIDEO TAPE OPERATOR:
 2   Going off the video record.  The time is
 3   4:51.
 4                      THE VIDEO TAPE OPERATOR:
 5   We're back on the video record.  The time is
 6   4:59, beginning of Tape Number 4.
 7   BY MR. FARBER:
 8   Q.    Resuming questioning, Doctor Wheadon, we
 9   were talking about mapping the investigative
10   terms into the preferred terms, and you were
11   mentioning that they are down at company
12   headquarters.  And is there a special division
13   that does only this?
14   A.    As I mentioned, the clinical safety
15   group is responsible for doing that.
16   Q.    Clinical safety group, okay.  And they
17   have other duties, other than transferring
18   these codes.  What are their other duties?
19   A.    Their responsibilities include receiving
20   reports on safety on preapproval products, as
21   well as marketed products.  They do both
22   preapproval and post_marketing adverse event
23   reporting surveillance.
24   Q.    And what would be the skill expertise of
25   a person who transferred the investigator
0297
 1   terms into preferred terms?  Bachelor's Degree
 2   or a clerk or Master's?  What type of a person
 3   would do this function?
 4   A.    My understanding, and again, that's not
 5   a function I'm responsible for, but my
 6   understanding, these are people that have
 7   clinical training.  There are a large number
 8   of nurses, actually, who are involved in this
 9   process.
10   Q.    So based on your understanding, if the
11   nurse would be the one to see this
12   investigative term and try to get it into a
13   preferred term that was logical and correct,
14   and she had a question, would the nurse call
15   back or contact the principal investigator or
16   would she go to her boss, who is maybe a
17   physician or something, and have that person
18   do that?
19   A.    Let me correct the statement that you
20   have made.  The nurse doesn't try to take
21   investigator term and assign it to a preferred
22   term that's logical or correct.  There is a
23   mapping process that's dictated objectively
24   about investigator terms mapping to preferred
25   terms.
0298
 1                      So that given, the nurse
 2   may then go back to query the investigator
 3   concerning his investigator term, or in some
 4   instances, she may ask the clinical monitor,
 5   that being a physician, who may call and query
 6   the investigator about the term.
 7   Q.    Now, the clinical monitor works here at
 8   SmithKline?
 9   A.    That is correct.
10   Q.    Would be the supervisor, one of the
11   supervisors of the nurse, in this example?
12   A.    No, not necessarily.  The clinical
13   monitor would be the physician responsible for
14   the study, the protocol.
15   Q.    And that's in the clinical safety
16   division or another division?
17   A.    What's in the clinical safety division?
18   Q.    The clinical monitor.
19   A.    That's the clinical research group,
20   which is separate from clinical safety.
21   Q.    So this nurse, in your example, if this
22   happened, this scenario, she would go to
23   somebody, if she couldn't work it out or
24   didn't know what to do, she would go to a
25   person in another division, if a physician was
0299
 1   needed to do that?
 2   A.    She would go to the clinical research
 3   physician responsible for the protocol.
 4   Q.    Now, earlier, you had testified as to
 5   the symptoms, certain symptoms of akathisia.
 6                      Could you now give me a
 7   little more detail on what bodily systems
 8   could be affected by someone suffering from
 9   akathisia?
10                      For example, we used the
11   example of restless legs.  How about other
12   bodily parts?  How about the arms?
13   A.    As I described, akathisia is typically
14   both an inner and outer expression of
15   restlessness.  So there is an inner sense of
16   restlessness, not being able to sit still.
17   The outer expression includes pacing,
18   fidgeting, getting up and down out of a chair,
19   walking around the room.  Those are the
20   classic symptoms of akathisia.
21   Q.    Okay, excuse my ignorance on the
22   subject, but I don't know whether you are
23   using the term physically, such as inner and
24   outer.
25                      If someone is not __ let's
0300
 1   say there is no bodily movement at all.  There
 2   is no fidgety, there is no shaking, there is
 3   no movement of anything.
 4                      Could that person, under
 5   your definition, the one you just gave, be
 6   suffering clinically from inner akathisia?
 7   A.    Typically, someone that has the inner
 8   sense of restlessness expresses it with outer
 9   movement.  So walking, pacing, getting up and
10   down.  But there are situations where someone
11   could have akathisia and have that sense of
12   restlessness inside, but not express it
13   motorically.
14   Q.    So I guess your answer is, yes, there
15   could be those cases where they are suffering
16   inner akathisia, but there is no outward
17   symptom at all?  That's how I interpret your
18   answer.
19                      Is this inner and outer __
20   and I have seen this referred to in other
21   documents, and even in the newspaper.  Is this
22   inner and outer a clinical diagnosis founded
23   on terminology that's in a book somewhere?
24   A.    No, it is just a phenomenological
25   description that psychiatrists and others have
0301
 1   used.
 2   Q.    Informal?
 3   A.    Yes.
 4   Q.    So under that definition, there could be
 5   literally tens, hundreds, thousands of people
 6   suffering inner akathisia that are not
 7   exhibiting outer akathisia?
 8   A.    No, I wouldn't agree with that.
 9   Q.    How would you correct that statement to
10   make it a more generalized __
11   A.    It is very rare for someone to be
12   experiencing the inner sense of restlessness
13   and not be expressing it externally, such that
14   you could observe it.
15   Q.    One way or another?
16   A.    Exactly.
17   Q.    What if somebody basically really has
18   the shakes __ and I'm not talking about a
19   neuroleptic or a tardive dyskinesia, but
20   basically, something like __ I know I can't
21   get this on the record, but severe hand shakes
22   that are not attributable to another disorder,
23   and that the diagnosis would, in fact, be
24   akathisia?
25                      How much notice or how many
0302
 1   outward movements would need to be made to
 2   categorizing the disorder as outer akathisia?
 3   A.    What you have described, and that is a
 4   shaking of the hands, would not, to my
 5   opinion, meet the criteria of akathisia.
 6   Q.    Such as if somebody was nervous or
 7   extremely frightened or something of that
 8   nature?
 9   A.    Right.
10   Q.    And you get the shakes?
11   A.    Right, that would not meet the criteria
12   of akathisia.
13   Q.    Now, we talked earlier a bit about the
14   Chicago physician and the reaction to
15   akathisia.  Let's now categorize a physician
16   who is familiar with the dangers, the pitfalls
17   and the commonality or characteristics of
18   akathisia.
19                      And this physician read the
20   document pertaining to a patient and
21   determined that akathisia was present.
22                      Would that term akathisia
23   in that situation send up a red flag to that
24   physician that suicide or violence was
25   possible?
0303
 1   A.    First, I'm not sure what document you
 2   are referring to.
 3   Q.    Would akathisia in that situation send
 4   up a red flag to that physician?
 5   A.    Again, I'm not sure what document you
 6   are referring to the physician reading and
 7   seeing the term akathisia.  Could you be more
 8   specific?
 9   Q.    Well, if in any document, any
10   prescribing information __ well, that's not a
11   good example, either.
12                      Let's take a clinical
13   report, a medical report.  In the Navy, we
14   called them service records, medical records.
15   If a physician affixed in writing akathisia,
16   let's say, a nurse, for some reason, she is an
17   expert nurse or a nurse that has confidence in
18   herself, and she says, doctor, this patient is
19   suffering from akathisia.  Would that term by
20   itself send up a red flag to the physician?
21                      So cut to its abstract,
22   does the term akathisia send up a red flag to
23   a medical professional?
24   A.    The term akathisia, in and of itself,
25   does not send up a red flag from the
0304
 1   standpoint of anything other than
 2   understanding what might be causing the
 3   akathisia.
 4   Q.    Are you denying that akathisia could be
 5   a red flag to a mental health professional
 6   that suicide was a risk with this person?
 7   A.    No.
 8   Q.    You are not denying that?
 9   A.    No, I am __ yes, I am denying that.
10   Q.    You are denying that?
11   A.    Yes.
12   Q.    That the term akathisia would never send
13   up a red flag to a mental health professional
14   that this patient might be suffering the risk
15   of suicide?
16   A.    Not in and of itself, no.
17   Q.    Of course, the question was ever.
18   A.    And I have answered the question, not in
19   and of itself, no.
20   Q.    To be practical, you are not going to
21   have akathisia on a piece of paper.  I mean, I
22   guess you could, but you are going to have
23   some sort of a medical report.  That's the
24   premise of the question.  So it is never in
25   and of itself.  There is always something else
0305
 1   there.  No question there, okay.
 2                      Could a person suffering __
 3   let's go back to investigator terms and
 4   preferred terms.
 5                      Could the investigative
 6   term restlessness, could it depict akathisia?
 7   A.    That is such a general term.  I need
 8   more information.
 9   Q.    Well, your worldwide data base has that
10   virtually hundreds of them, and that's all the
11   information there is.
12                      So is it your testimony
13   that that term alone would trigger your extra
14   telephonic contacts with the PI __
15   A.    Not necessarily, no.  Restless could
16   imply similar to sitting here, thinking about
17   other things.  You may move from one side to
18   the other in your chair and be described as
19   restless.  That is not akathisia.
20   Q.    Is the term restless or restlessness
21   described as a condition in DSM_4 for
22   neuroleptic induced akathisia?
23   A.    Restlessness is one of the things that's
24   used in describing the constellation of
25   symptoms that one sees in the context of
0306
 1   akathisia.
 2   Q.    It is one of the symptoms listed in
 3   DSM_4, isn't it?
 4   A.    That's one of the symptoms that one
 5   looks for in terms of the constellation of
 6   symptoms in defining akathisia.
 7   Q.    In DSM_4?
 8   A.    Restlessness, in and of itself, does not
 9   define akathisia.
10   Q.    No, not in and of itself, but that is
11   one of the terms, is it not?
12   A.    It is one of the terms, yes.
13   Q.    How about fidgety?  Is fidgety another
14   term that could describe akathisia or a person
15   suffering from it?
16   A.    Possibly.
17   Q.    That's also one of the terms in DSM_4,
18   isn't it?
19   A.    That, I don't recall.
20   Q.    How about the term swinging legs?  Could
21   that describe akathisia?
22   A.    Possibly.
23   Q.    Swinging arms?  And I'm taking these
24   examples from your own data base, in case you
25   are wondering where I'm getting these terms.
0307
 1   A.    Swinging arms, I would not necessarily
 2   describe as possibly related with akathisia,
 3   no.
 4   Q.    It wouldn't possibly be?
 5   A.    No.
 6   Q.    How can you be so certain, with just
 7   this term?  You talk about in and of itself.
 8   How can you be so certain that the principal
 9   investigator wasn't trying to describe
10   akathisia?
11   A.    That wasn't the question you asked.
12   Q.    Well, no, but I asked you on the other
13   three, and you said it is possibly a term that
14   could imply akathisia, but under swinging
15   arms, you said it couldn't, and I'm wondering
16   why.
17   A.    It is not something that typically one
18   uses to describe akathisia.
19   Q.    How about unable to remain stationary?
20   A.    That is a possibility, yes.
21   Q.    How about rocking?
22   A.    That is a possibility.
23   Q.    Pacing?
24   A.    That is a possibility.
25   Q.    Inability to sit still?
0308
 1   A.    That is a possibility.
 2   Q.    Inability to stand still?
 3   A.    That is a possibility.
 4   Q.    And inner restlessness?
 5   A.    That is a possibility.
 6   Q.    When you went through your data base,
 7   either '92 or later, presumably, you looked at
 8   all the investigator terms, at least
 9   spot_checked them or some sort of monitoring
10   process, did you not?
11   A.    As I mentioned to you, I reviewed the
12   NDA data base, which includes investigator and
13   preferred terms, yes.
14   Q.    If you had seen these terms, as I
15   described them in your review, would that have
16   caught your attention as something that needs
17   to be investigated?
18   A.    Not necessarily.
19   Q.    What is tardive dyskinesia?
20   A.    Tardive dyskinesia refers to
21   involuntarily muscular movements associated
22   primarily with neuroleptic use.
23   Q.    Would that necessarily imply by your
24   definition response that that person had been
25   given drugs of some nature to cause that?
0309
 1   A.    As I mentioned, tardive dyskinesia is
 2   most commonly associated with neuroleptic use.
 3   Q.    I was trying to get the word cause, but
 4   would you buy that?  It, by definition, causes
 5   it?  Just by mere invocation of the term, you
 6   are implying that the drugs caused the
 7   condition?
 8   A.    It is fairly well established that
 9   neuroleptics may cause tardive dyskinesia,
10   yes.
11   Q.    Is that also true of tardive dystonia?
12   A.    That is true also for neuroleptics,
13   yes.
14   Q.    If you had in one of your trials a
15   subordinate PI, who reported that under
16   tardive dyskinesia and under the category of
17   whether it was related to drug __ I think it
18   is just drugs, drug related, and there is five
19   scales, 1, 2, 3, 4, 5, and this physician
20   reported tardive dyskinesia and used the
21   middle code of 3 of possibly, what would be
22   your professional evaluation of that
23   physician, based on your definition now that
24    __
25   A.    I'm not sure what you are asking.
0310
 1   Q.    In other words, this physician __ I'm
 2   setting up a hypo __ this physician reported
 3   that the patient is suffering from tardive
 4   dyskinesia.  Under the column drug related, if
 5   that physician put Code 3, meaning possibly
 6   drug related, what would you think of that
 7   physician's professionalism?
 8   A.    I'm still not sure what you are asking.
 9   Q.    I am playing with words, but I think
10   they are important.  You defined the condition
11   as requiring and being caused by drugs, by
12   definition, neuroleptic drugs.  And I have
13   stated the proposition that the person is
14   suffering that, and asking you, if a physician
15   evaluated that condition as drug related, and
16   he responded possibly, rather than the way you
17    __
18   A.    What is the drug in your question?  In
19   your hypothetical question, you haven't
20   specified what the drug is.  If the drug is
21   aspirin, I may have a different answer.  If
22   the drug is a neuroleptic, I will have a
23   different answer.  You have to be far more
24   specific.
25   Q.    It is your form, not mine, and the FDA,
0311
 1   I guess, but you have adopted the form, drug
 2   related.  What do you mean?  Do you mean
 3   aspirin?
 4   A.    Again, in your hypothetical question,
 5   you have not been specific in terms of what
 6   drug the physician is saying is possibly
 7   related to the tardive dyskinesia.  For me to
 8   answer your question, you have to be more
 9   specific.
10   Q.    I will be specific by telling you that
11   I'm incorporating your definition of drug
12   related.  Whatever that means in your company
13   under the question drug related, question
14   mark, that's the drug I'm talking about.
15                      And even if that were the
16   case, even if it were, by your own definition,
17   it couldn't be aspirin, could it?  Do you
18   think aspirins can induce tardive dyskinesia?
19   A.    Your question was, what would I think of
20   a physician that checked drug related,
21   possibly drug related, to a response of
22   tardive dyskinesia.
23   Q.    Yes, that was my question.
24   A.    And my query back is, you have to be
25   specific about what drug is implicated.  I
0312
 1   can't answer that question in the abstract.
 2   Q.    What do you mean by drug in the
 3   question, in the format that you send out to
 4   investigators?  When you say, was it drug
 5   related, you are asking for the field
 6   physician's opinion, what do you mean by, is
 7   it drug related?  Do you mean aspirin, as well
 8   as __
 9   A.    It could be aspirin.  The form that goes
10   out is general.  It is used for any drug
11   report.  It could be aspirin, it could be
12   Vitamin C, it could be Paxil, it could be
13   Haldol, it could be any of a number of
14   things.  So the specifics relate to what drug
15   is in question.  So you have to give me
16   specifics for me to answer the question.
17   Q.    I don't think so, because I see your
18   point, but on the issue of aspirin, I see your
19   point, but by your own definition of
20   neuroleptic drugs, they are drugs, this is not
21   an aspirin.  This is a drug_induced tardive
22   dyskinesia.
23                      MR. PREUSS:  So are you
24   telling him that the drug in question is a
25   neuroleptic?
0313
 1                      MR. FARBER:  I'm basing his
 2   definition of tardive dyskinesia on the fact
 3   that a __ can I use for a lay term a strong
 4   drug causes tardive dyskinesia?
 5                      THE WITNESS:  I'm sorry.  I
 6   cannot answer that question.  I don't
 7   understand what a strong drug means.
 8   BY MR. FARBER:
 9   Q.    I knew you were going to say that, but
10   the point is, tardive dyskinesia can't be
11   induced by aspirins, can it?  Do you know of
12   any cases where it has?
13   A.    I'm not aware of any cases where aspirin
14   has induced tardive dyskinesia.
15   Q.    To your knowledge, what type of drugs
16   induce tardive dyskinesia in your experience?
17   A.    As I have said earlier, neuroleptics are
18   most commonly associated with tardive
19   dyskinesia.
20   Q.    And under the question, is this drug
21   related, you have a problem with the
22   definitions now, because you don't know what
23   kind of drug it is, but you don't need to
24   know, do you, to answer that question?
25   A.    Yes, I do need to know.
0314
 1   Q.    Okay, if that's your answer, that's your
 2   answer.
 3                      I'm sorry.  You told me
 4   this twice.  The division __ is it the
 5   clinical safety division?
 6   A.    That's correct.
 7   Q.    Who is the head of that division now?
 8   A.    Doctor Ian Hudson.
 9   Q.    Hudson?
10   A.    Yes.
11   Q.    Approximately how many employees are in
12   that division, that headquarters there?
13   A.    I have no idea.
14   Q.    If I gave you a list of 400 people who
15   were listed in your data bank during the FDA
16   as having restless or restlessness or restless
17   legs and all this, do you records __ would
18   your records support the ultimate path at
19   which the preferred term for that investigator
20   term was established?
21   A.    I quite frankly cannot answer that
22   question.  I don't know exactly how the
23   records would indicate the mapping.
24   Q.    If, for example, this phone
25   conversation, phone call to the principal
0315
 1   investigator back in __ actually, it could be
 2   ten years ago, I suppose, at least on the NDA
 3   thing, the record would have to be __ well,
 4   here is the question.  Would you keep a
 5   telephonic __ is there a company policy __ I
 6   guess you can speak for the company __ is
 7   there a company policy of keeping records on
 8   telephone conversations germane to an NDA?
 9   A.    There is not a company policy, per se,
10   on records of telephone conversations, no.
11   Q.    No, but if it were material __ let's
12   take the case of the preferred term.  You
13   would consider that a material issue, wouldn't
14   you, changing or establishing a preferred term
15   from restlessness, and if it were to be an
16   issue where the person at headquarters had to
17   check on it and then change something or at
18   least divert it into a different category,
19   wouldn't you consider that material?
20   A.    I will try one more time.  In terms of
21   preferred term, the mapping doesn't change.
22   There is a distinct mapping from investigator
23   terms to preferred terms.  If there is a
24   question around the investigator term, then
25   there may be a query back to the investigator
0316
 1   to establish exactly what he meant by that
 2   term.
 3                      Sometimes, investigators
 4   use vague terms.  And if that is the case,
 5   then the change in the investigator term would
 6   be documented in the record based on the
 7   feedback from the investigator.
 8   Q.    That wasn't the question.  The question
 9   is whether that would be material, whether
10   that would induce or cause a record to be
11   maintained.  The question was on records, not
12   on the process.
13   A.    And I just answered the question.  If
14   the investigator term was changed based on an
15   interaction with the investigator, it would be
16   notated in the record, the case report form,
17   in which that investigator term was used,
18   investigator gave further clarity, and the
19   term is now X.
20   Q.    The next question is, even if that
21   occurred ten years ago?
22   A.    Again, I can't comment specifically, but
23   that would be my expectation, but I cannot
24   comment specifically about what happened ten
25   years ago.
0317
 1   Q.    I know, but you know what your company
 2   policy is on maintaining records.  I guess the
 3   broader question is, old NDA records, let's
 4   say, from 1990, in fact, I know you have a lot
 5   of them, because I went through a lot of
 6   them.  Do you have a company policy on how
 7   long those records must be maintained?  Maybe
 8   it is an FDA requirement.  Maybe it is a
 9   company requirement.
10   A.    The NDA is maintained in the archives.
11   The NDA is maintained in perpetuity.
12   Q.    Taking off on that, if this conversation
13   occurred, as you just described it, would that
14   record of that conversation be maintained with
15   the NDA in the archives?
16   A.    As I mentioned, I cannot give you an
17   answer concerning the record of a
18   conversation.  I can only say that the policy
19   is that if there is a change in the
20   investigator term based on a conversation,
21   that will be notated in the case record form.
22   Q.    And maintained in the archives?
23   A.    It should be maintained in the archives,
24   yes.
25   Q.    Speaking of akathisia, what does the
0318
 1   term motor akathisia do to our definition?  Is
 2   that just another one of qualifying __
 3   A.    Yes.
 4   Q.    That term was used quite a bit in
 5   Europe, motor akathisia, and I guess it is
 6   part of the same scheme here.
 7                      Let's take a case now, for
 8   hypo, actual akathisia, inner and outer,
 9   induced by Paxil, one week after the patient
10   took Paxil, goes in, and the PI properly
11   records it as an akathisia, inner and outer,
12   and tells you everything, fidgety, jumpy and
13   so forth.
14                      How would that description
15   be channeled into __ what would be the most
16   appropriate preferred term for that event?
17                      MR. PREUSS:  Is this a
18   hypothetical?
19                      MR. FARBER:  Hypothetical.
20                      THE WITNESS:  As I answered
21   before, I have not familiarized myself with
22   the exact mapping, so I cannot answer that
23   question today.
24   BY MR. FARBER:
25   Q.    My __ well, I won't give you my opinion,
0319
 1   unless it is relevant to my questioning, but
 2   it would be my view that, possibly, there can
 3   be several that might fit.
 4                      Central nervous system?
 5   Would you agree with that?
 6   A.    Central nervous system is a body
 7   system.  We are talking about mapping to a
 8   preferred term, not to a body system.  And I'm
 9   not able to give you any further clarity
10   around exactly how akathisia would map,
11   investigator or preferred term, because I have
12   not reviewed that mapping.
13   Q.    Is it fair to say that with all your __
14   you really have a worldwide operation in
15   clinical trials, don't you, in many cases?
16   A.    That's correct.
17   Q.    And you mentioned culture in countries
18   and different __ various data from different
19   sources come in.
20                      Is it fair to say that two
21   symptoms of akathisia, one in the one country
22   and one in the other could come up, and they
23   could wind up in different categories a
24   preferred term?
25   A.    Not necessarily.
0320
 1   Q.    Well, my question wasn't necessarily.
 2   My question is __ I guess the question was, is
 3   that a fair statement?  Could they wind up in
 4   different categories?
 5   A.    If the term akathisia was used, it would
 6   map to the same preferred term.  That's my
 7   expectation.  I can't give you further clarity
 8   than that, because I have not reviewed exactly
 9   how the mapping occurs.
10   Q.    Now, I know you got there in February of
11   '92, but you have looked at records, and
12   obviously, you have been familiar for the last
13   eight years.  Help me on describing guidance
14   on the protocols that go out on a clinical
15   trial, let's say, on investigator terms.
16                      Do you have detailed
17   guidance or just no guidance or general
18   guidance on what investigator terms to use?
19   A.    We do not instruct, I think as I have
20   said earlier, investigators as to what terms
21   to use to describe the events that are
22   presented them to by their patients.
23   Investigators choose the terms, the language
24   they use to describe the events.
25   Q.    And they are professionals, aren't they?
0321
 1   A.    They are professionals, yes.
 2   Q.    So you assume their general professional
 3   training to kick in at some point and __
 4   okay.
 5                      Since you have been there,
 6   has there ever been any communications to or
 7   from SmithKline on investigator terms to use?
 8   A.    Not that I'm aware of, no.
 9   Q.    Have you ever heard that subject
10   discussed among others at SKB on __ and this
11   is just a hypo, but possible guidance that was
12   not put in writing, but this is what the boss
13   expects?
14   A.    Not that I am aware of, no.
15   Q.    What is your company e_mail policy on
16   archives for your server or whatever for
17   retrieving e_mails?
18   A.    I'm quite frankly not familiar with that
19   policy.
20   Q.    Has there been any company guidance on
21   that subject?
22   A.    Not that I'm aware of.
23   Q.    In other words, e_mails will be retained
24   for five years or any information along that
25   line that would tell you or tell somebody __
0322
 1   A.    I am not familiar with or aware of any
 2   policy of that sort.
 3   Q.    Around headquarters, in your job, you,
 4   did you use e_mail a lot in communicating with
 5   other officers of the corporation?
 6   A.    I use e_mail in the conduct of my daily
 7   job, yes.
 8   Q.    Is there things that you don't trust
 9   e_mail to, because you consider it so
10   sensitive?
11   A.    I wouldn't say that, no.
12   Q.    Now, we talked about communications to
13   and from FDA, you, personally.
14                      Since 1992, is it fair to
15   say that you have communicated directly by
16   telephone to FDA officials on numerous
17   occasions?
18   A.    That is correct.
19   Q.    Are there any occasions that you
20   communicate with FDA officials that you have
21   not made a written memo of it?  I don't mean
22   about __ I'm talking about material issues of
23   your profession.
24   A.    Not that I am aware of, no.
25   Q.    Is it your policy that a conversation
0323
 1   with an FDA official will be summarized in a
 2   typewritten memo?
 3   A.    We have a standard FDA correspondence
 4   record that's required to be filled out with
 5   any discussion with the FDA.
 6                      THE VIDEO TAPE OPERATOR:
 7   Going off the video record.  The time is
 8   5:30.
 9                      THE VIDEO TAPE OPERATOR:
10   Back on the video record.  The time is 5:31.
11   BY MR. FARBER:
12   Q.    Your record system or data bank at
13   SmithKline, if I would give you a patient
14   number from an NDA, could you retrieve all the
15   information on that particular patient?
16   A.    It could be retrieved, yes.  I would not
17   personally be able to retrieve it, but it
18   could be retrieved.
19   Q.    So patient numbers, you can tap into the
20   system and get the data?
21   A.    Exactly.
22   Q.    What is generally __ let me ask this
23   specifically.  What is the logic of different
24   patient numbers?  Some start with four
25   digits.  Others have points and letters.  Is
0324
 1   there some logic to assigning patient numbers?
 2   A.    I'm not familiar with the system for
 3   patient number assignment.
 4   Q.    Do you think the term, investigator
 5   term, tense muscles could be a description of
 6   akathisia?
 7   A.    No.
 8   Q.    It couldn't be, okay.
 9                      Now, in your adverse
10   experience data bank, non_US and US, and we
11   will just keep it to the NDA 20031 for the
12   time being, let's assume that one patient had
13   three adverse experiences of the same type
14   over three months, three different incidents
15   that were reported.
16                      In your ultimate data bank,
17   would that be reported as one incident or
18   three?
19   A.    Three.
20   Q.    Now, on __ well, your 15_day report or
21   Medwatch or just out in the population now, an
22   adverse event from, let's say, Paxil is
23   reported.  Let's say it is reported by a
24   physician in Nevada, and he calls your
25   headquarters by telephone and says that he has
0325
 1   prescribed Paxil for __ correction, let me
 2   pick it up.  He tells you that none of his
 3   patients, none of my patients can tolerate
 4   Paxil, unquote.  Well, the hypo sets up you
 5   don't know how many patients.  You don't know
 6   whether he is talking about two or he is
 7   talking about 50 or he is talking about his
 8   whole patient population.
 9                      What is your duty at that
10   time, if any, to determine the number of
11   patients who suffered adverse experiences?
12   A.    In your hypothetical situation, a
13   physician calls in and says none of his
14   patients can tolerate Paxil, the questions
15   would be generated around, one, what does he
16   mean, what does he mean by not being able to
17   tolerate, what were the specific adverse
18   effects that he was describing, but also,
19   there would be an attempt to get an idea of
20   how many patients he was describing in terms
21   of each individual adverse effect.
22   Q.    Okay, so there would be an attempt to
23   amplify his information from his original
24   report?
25   A.    Yes.
0326
 1   Q.    If you determined that 12 patients had
 2   suffered tremor, would that ultimately be in
 3   12 different serial numbers for reporting or
 4   would it simply be in one report?
 5   A.    If the physician noted 12 different
 6   individual patients that noted tremor, they
 7   would be separate adverse event reports.
 8   Q.    So 12 different serial numbers, 12
 9   different reports for the system?
10   A.    Yes, individual patients have individual
11   reports.
12   Q.    Ideally, right?  If you knew that you
13   had tremendous disproportionate inputs on
14   particular terms from Europe and different
15   ones from the United States, would that cause
16   you to investigate why that was the case?
17   A.    As I have answered when you asked that
18   question before __
19   Q.    I didn't ask it quite that way.
20   A.    Well, you did.  But as I answered, it
21   would not necessarily cause me to investigate
22   further.  It would be an interesting finding;
23   however, the US experience would be the US
24   experience, the European experience would be
25   the European experience, and that is what you
0327
 1   have to deal with.
 2   Q.    And that's what I understood your
 3   response to be, but I was asking you in the
 4   hypo whether you would investigate that as to
 5   why.  I understand what could be.  I'm not
 6   interested in what could be the case.  I'm
 7   interested in what you would do about that, if
 8   anything.
 9   A.    We would simply illustrate that the US
10   reporting rate or experience was different
11   from the European experience.  You deal with
12   the data that you collect.  That is the data.
13   That's the experience.  We have to report it
14   that way, and that is exactly how we do it.
15   Q.    Don't you feel you have the power or
16   authority to influence future events on how
17   these things are corrected, if, indeed,
18   correction is needed?
19   A.    That is absolutely not my power or
20   authority to correct these things.  If this is
21   the way the reports have been collected, if
22   this is the way the treating clinicians have
23   reported the adverse effects or the effects,
24   that is reality.  We have to deal with
25   reality, and that's exactly how we do it.
0328
 1   Q.    I can see your point as to professionals
 2   out in the field that are not under your
 3   direct control.
 4                      What about the same
 5   situation, but in_house at SmithKline, as if
 6   you were of the belief that the eventual
 7   preferred term differences was a problem of
 8   SmithKline's process of transferring that
 9   information __ I forgot.  What verb did you
10   use?
11   A.    Mapping.
12   Q.    Mapping, okay, if you were convinced
13   that it was a mapping problem, you would have
14   the authority to recommend correction of that,
15   wouldn't you?
16   A.    That would not happen.  As I mentioned,
17   mapping is a defined process.  It is not
18   subjective.  It is objective.  It is a defined
19   process.
20   Q.    Okay, I think I have beat that one dead
21   enough.
22                      Do you concede that there
23   could be cases where akathisia, actual
24   akathisia, reported in terminology by
25   principal investigators wound up in multi
0329
 1   different categories, even though the hypo is
 2   that they are all exactly the same?  I'm
 3   assuming that you are saying that that
 4   couldn't happen?
 5   A.    If akathisia was reported as akathisia,
 6   it should map to the preferred term as
 7   dictated by the mapping, and unfortunately, as
 8   I have said before, I cannot tell you exactly
 9   what the mapping would be.
10   Q.    So under your testimony, there could be
11   no situation like that, because it is a
12   hundred percent objective?
13   A.    Exactly.
14   Q.    So this is a variety of the same
15   question, but let's just take jerking of
16   limbs.
17                      First of all, let me get
18   the terminology of the computer and the data
19   bank, I may have an example here.  We don't
20   need to put this in the record, but just take
21   any one of this.  Let's talk about, for the
22   record here, drowsiness.  Do you see
23   drowsiness there?
24   A.    Is this something you want to enter in
25   as evidence?
0330
 1                      MR. PREUSS:  If you are
 2   going to ask him, I think we need it as an
 3   exhibit.
 4                      MR. FARBER:  I will make it
 5   part of the record.  I am on Page Bates Number
 6   638, numbered 184 of appendix Roman Numeral
 7   V.1.
 8                      MR. PREUSS:  Why don't you
 9   take that out and then put a sticker, and then
10   you won't lose your place, and we will copy it
11   tomorrow?  But let's mark it as an exhibit,
12   please.
13                      MR. FARBER:  Well, I don't
14   think I want to do that, but I will
15   accommodate your request here.
16   BY MR. FARBER:
17   Q.    Let's take a term drowsiness as the
18   investigator term.  Drowsiness has ten
19   letters.  And if drowsiness were listed under
20   a hundred cases, does that mean that
21   drowsiness was put in the blank for
22   investigative term in the primary line?
23   A.    I really don't know what you are asking,
24   so without seeing what you are looking at, I
25   cannot answer that question.
0331
 1   Q.    Okay, we will do that then.  I don't
 2   want to be unreasonable here.  I want this
 3   back, because it is my only page, but I have
 4   already stated on the record, we will make
 5   this Exhibit 10, Bates Number 638.
 6                            _ _ _
 7                      (Whereupon the court
 8   reporter marked document as Exhibit 10 for
 9   identification.)
10                            _ _ _
11   BY MR. FARBER:
12   Q.    Up in the second or third column, you
13   see drowsy or drowsiness up and down the
14   entire page, right?
15   A.    That's correct.
16   Q.    Now, the form that was filled out by the
17   principal investigator to get this into your
18   data bank, that's my first question.  Was this
19   written by hand or does he have a certain
20   amount of word processing spaces and
21   limitation?
22   A.    Without having the case report form in
23   front of me, I can't comment about the form
24   that the investigator actually filled out that
25   led to populating this table.  I can't comment
0332
 1   on that.
 2   Q.    Wouldn't that raise another issue?
 3   Let's say the space was as big as a fist, and
 4   you could put everything in there.  Let's say
 5   you could put a hundred words in that space,
 6   theoretically.  The printout here, we have
 7   drowsiness only as the investigator term;
 8   correct?
 9   A.    What we have here are investigator terms
10   of drowsiness, yes.
11   Q.    I'm getting to the issue of flexibility
12   and space in this term that is submitted by
13   the principal investigator to convey that
14   drowsiness message from the field to your
15   headquarters.
16   A.    And as I mentioned, I have no ability to
17   comment __
18   Q.    If you don't mind, Doctor, I haven't
19   asked the question yet.
20   A.    Well, I'm saying, I have no ability to
21   comment about the actual form the investigator
22   filled out.  This is not the form.  I don't
23   know what the form looked like.  I don't know
24   the number of spaces that were available.  I
25   cannot comment further on that.
0333
 1   Q.    If you don't know, that's fine.  I can
 2   certainly accept that.  But you do agree,
 3   obviously, the record shows that the exact
 4   word was used up and down the page,
 5   drowsiness?
 6   A.    In terms of what you have shown me, yes,
 7   drowsiness is listed down the page.
 8   Q.    Would you further agree that if it were
 9   a big form, that there would be some degree of
10   editing necessary to get drowsiness in one
11   category, if, indeed, it was other than the
12   first word of that narrative report or the
13   first word of that category?
14   A.    That's not necessarily true.
15   Q.    So it is not necessarily true that
16   drowsiness was the first highlighted word of
17   that submission for the investigator term?  It
18   could have been picked up three sentences
19   down, if the space provided for it?
20   A.    Quite frankly, I'm still wrestling with
21   your question.  If you are asking me, if the
22   physician actually said, patient returned to
23   clinic today.  Patient noted good effect with
24   drug.  Patient also noted drowsiness.
25   Q.    Yes, something like that.
0334
 1   A.    Then, no, all of that narrative would
 2   not be in there.  The only germane point of
 3   that narrative in terms of the adverse event
 4   was the notation of drowsiness.
 5   Q.    So under that scenario, there is __ you
 6   call it a hundred percent certainty, but there
 7   is a degree of subjectivity and judgment for
 8   your in_house person to pull that out of the
 9   investigator's input and slip it in that
10   column?
11   A.    No, also in the case report form, there
12   is a listing of adverse events, in addition to
13   the physician narrative, the physician is then
14   asked to take what he has written and put into
15   blocks specific adverse events that the
16   patient has noted, onset date, termination
17   date, treatment, if any, for the adverse
18   effect, concomitant meds, all of that is
19   captured, and the physician, the actual person
20   evaluating the patient, fills that out.  So it
21   is not a person external to the process
22   subjectively taking what the physician said
23   and putting it into the box.  The physician
24   does it himself.
25   Q.    That's what I asked you earlier, and you
0335
 1   answered it.
 2                      Now, with set blocks, there
 3   is a number of set blocks?
 4   A.    There are spaces, but I can't tell you
 5   how wide or small they are.
 6   Q.    I'm not asking whether there is 20 or 50
 7   or 10.  I'm not asking that.  But I am asking
 8   whether the term investigator __ or excuse me
 9    __ the term drowsiness in that example would
10   necessarily have to have been put in that
11   block by the investigator.
12   A.    The investigator would have had to list
13   drowsiness as the adverse effect in the space
14   called for.
15   Q.    I used this before, but I didn't
16   specifically ask you about it.  The term
17   restless leg syndrome, you consider that an
18   informal categorization?  You have never heard
19   that formally, have you, on a diagnosis called
20   restless leg syndrome?
21   A.    I have heard the term restless leg
22   syndrome used, yes.
23   Q.    As far as you know, is it an informal
24   term, as some of the other terms we talked
25   about today?
0336
 1   A.    Some people use it as a way of
 2   characterizing what they observe, yes.
 3   Q.    Now, CNS being the central nervous
 4   system, is it logical or consistent with your
 5   reporting system to have alcohol intolerance
 6   used as an adverse event under the central
 7   nervous system?
 8   A.    Potentially, yes.
 9   Q.    Now, we agree.  I mean, I don't agree.
10   I listen to you, and you report the testimony,
11   and that's what I take.  And that is what the
12   principal investigator reports.  That's, in
13   fact, what you get, and then you may make
14   certain adjustments or further verification,
15   but if the principal investigator, let's take
16   in the case of a Par trial, reports sweating,
17   you have seen that in the dermatological
18   system, haven't you, the many instances of
19   sweating?
20   A.    I'm not exactly sure how sweating maps,
21   but it may map to dermatological body system.
22   Q.    Now, if a person is really spaced out on
23   a drug and has an emergent symptom, and he is
24   really bad, imagine the worst possible case,
25   and he comes into the clinician the next day
0337
 1   and says, I'm spaced out, and the guy is
 2   sweating profusely, do you consider it
 3   possible that this situation could be
 4   classified as sweating, rather than other
 5   bodily systems that may be adversely affected,
 6   such as the central nervous system or any
 7   other system?
 8   A.    Not in the scenario that you describe,
 9   no.
10   Q.    So it is basically almost iron_tight
11   that a sweating case in the record could not
12   be a central nervous system case?
13   A.    Sweating would not be central nervous
14   system, but you also said the patient stated
15   he is spaced out, which means there would be a
16   different adverse event capturing the
17   phenomenon of being, quote, spaced out.
18   Q.    And there are __ I know diagnosis is
19   supposed to be as an exact science as
20   possible, but there are subjective judgments
21   in diagnosis, are there not?
22   A.    In terms of physicians deciding what the
23   patient is describing to them, yes.
24   Q.    And many of these are multiaxial and
25   could have several symptoms with different
0338
 1   bodily systems due to the same adverse event;
 2   correct?  I mean, a person sweating could also
 3   have a gastrointestinal disorder, diarrhea,
 4   for example; isn't that correct?
 5   A.    Well, yes, there could be a concordance,
 6   meaning happening at the same time, of
 7   sweating and diarrhea, but it is not
 8   necessarily indicating they are linked in any
 9   way.
10   Q.    No, not necessarily, but in this case,
11   where the principal investigator reported
12   sweating on that control block we talked
13   about, that would wind up in the preferred
14   term as in the dermatological disorder,
15   wouldn't it?
16   A.    If that is the body system that sweating
17   would map to, yes.
18   Q.    That he reported.
19                      How about in the
20   cardiovascular system, a palpitation?  Could
21   that __ what I just described apply to that as
22   well?  That if it were a cardiovascular
23   palpitation, it could really be a central
24   nervous system reaction, instead of a
25   cardiovascular event, couldn't it?
0339
 1   A.    No.
 2   Q.    Would you briefly or take as many words
 3   to explain why that couldn't be, why a
 4   principal investigator couldn't make that
 5   mistake?
 6   A.    Well, again, in the scenario you
 7   described, palpitations, meaning arrhythmias
 8   or racing heart or some unusual sort of heart
 9   beat would map to the cardiovascular system,
10   because the heart is involved.  So it would
11   map to the cardiovascular system.
12   Q.    Well, yes, by definition, the way you
13   have described it, that would necessarily be
14   the case, but if the guy has a CNS reaction,
15   let's say, his pulse goes up to 170, couldn't
16   that find its way reasonably into a
17   cardiovascular adverse event, rather than a
18   central nervous system or agitation or anxiety
19   or any one of the other ones?
20   A.    I don't understand what you are saying.
21   If he is having a CNS event, let's say __
22   Q.    All of the above.
23   A.    Let's say the patient had a syncopal
24   episode, meaning he passed out, syncope would
25   map to the CNS body system.  Within the
0340
 1   context of that syncopal episode, he may also
 2   have had arrhythmia or rapid heart beat.
 3   Palpitations, as you described, would go to
 4   the cardiovascular system.  So you take each
 5   individual adverse event, and that maps to a
 6   specific system.
 7   Q.    Don't you see what you are doing?  Or do
 8   you agree, by defining the terms up front, you
 9   are already defining the result?  By defining
10   a cardiovascular event, you are automatically
11   defining a cardiovascular system.  But the
12   scenario I asked you about in lay terms was
13   all of the above.  If a patient comes in, all
14   of the above, and he is sweating, he is
15   palpitating, he is nervous, he is developing
16   __ all of the above, my question is, how sure
17   can you be that this palpitation code that I
18   get on that report is accurate?
19   A.    The code is accurate, because it is the
20   adverse event that is described.  If what you
21   are asking is, is there an additional step in
22   terms of looking at safety data bases in
23   assessing whether or not a set of adverse
24   effects happen at the same time in a single
25   individual across a number of different
0341
 1   patients, those analysis are done as well.
 2                      We go in, and we look at
 3   whether or not there is a constellation of
 4   adverse effects that happen, same time, same
 5   patient, across a number of different
 6   patients, to describe a potential syndrome.
 7   So those analyses are done as well.  It
 8   doesn't just simply stop at the mapping, as we
 9   have been talking about for the past hour or
10   so.
11   Q.    Now, in this mapping scenario that you
12   have properly indoctrinated me on, in the case
13   of the verification back to the PI, are the
14   preferred terms that ultimately used ever get
15   changed from knowing there is a mapping
16   process there, could a central nervous system
17   malady originally diagnosed as such be
18   transferred to dermatological, because it has
19   been determined that sweating applies, rather
20   than palpitation, for example?
21   A.    Each investigator term maps to a
22   preferred term, so if there was sweating,
23   sweating would map to a preferred term.  If
24   there is palpitations, palpitations would map
25   to a preferred term.  In the case of those two
0342
 1   events, they also map to different body
 2   systems.  I can't help you any further on this
 3   one.
 4   Q.    Okay, I understand where you are coming
 5   from.  And I guess you would rest on the
 6   premise that it is the principal investigator
 7   that really determines that, at least the
 8   initial term?
 9   A.    The investigator term is determined by
10   the principal investigator, yes.
11   Q.    Dermatological system, that's kind of
12   what you start with, and that's where you end
13   up with?
14   A.    You start with the investigator term.
15                      MR. PREUSS:  You want to
16   break for today?
17                      MR. FARBER:  Yes, that's
18   fine.  It is a good time to break.
19                      THE VIDEO TAPE OPERATOR:
20   Going off the video record.  The time is
21   5:54.  This concludes today's video tape
22   deposition.
23   
24   
25   
0343
 1                      C E R T I F I C A T E
 2                            _ _ _
 3   STATE OF NEW JERSEY        :
 4                              :   SS
 5   COUNTY OF BURLINGTON       :
 6   
 7                        I, Jeanne Christian,
 8   Court Reporter_Notary Public within and for
 9   Burlington County, Commonwealth of New Jersey,
10   do hereby certify that the foregoing testimony
11   of David Wheadon, M.D. was taken before me at
12   2600 One Commerce Square, Philadelphia,
13   Pennsylvania on Wednesday, October 18, 2000;
14   that the foregoing testimony was taken in
15   shorthand by myself and reduced to typing
16   under my direction and control, that the
17   foregoing pages contain a true and correct
18   transcription of all of the testimony of said
19   witness.
20   
21   
22                            .....................
                              JEANNE CHRISTIAN
23                            Notary Public
24   
                              My Commission expires
25                            May 21, 2003
0344
 1               INSTRUCTIONS TO WITNESSES
 2         Read your deposition over carefully.  It
 3   is your right to read your deposition and make
 4   changes in form or substance.  You should
 5   assign a reason in the appropriate column on
 6   the errata sheet for any change made.
 7         After making any change in form or
 8   substance which has been noted on the
 9   following errata sheet along with the reason
10   for any change, sign your name on the errata
11   sheet and date it.
12         Then sign your deposition at the end of
13   your testimony in the space provided.  You are
14   signing it subject to the changes you have
15   made in the errata sheet, which will be
16   attached to the deposition before filing.  You
17   must sign it in front of a witness.  Have the
18   witness sign in the space provided.  The
19   witness need not be a notary public.  Any
20   competent adult may witness your signature.
21         Return the original errata sheet &
22   transcript to deposing attorney, (attorney
23   asking questions) promptly!  Court rules
24   require filing within 30 days after you
25   receive the deposition.  Thank you.
0345
 1                      I have read the foregoing
 2   deposition and the answers given by me are
 3   true and correct, to the best of my
 4   knowledge and belief.
 5   
 6   
 7   
 8                            ......................
                              DAVID WHEADON, M.D.
 9   
10   .......................
     Witness to signature
11   
     .......................
12   Address
13                           My Commission expires
14                           ......................
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17   
18   
19   
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22   
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24   
25   
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