1 NO. 90-CI-6033            JEFFERSON CIRCUIT COURT
                                    DIVISION ONE (1)
 2 
   
 3 
   JOYCE FENTRESS, ET AL.                 PLAINTIFFS
 4 
   
 5 VS.
                DEPOSITION FOR PLAINTIFFS
 6 
   
 7 SHEA COMMUNICATIONS, ET AL.            DEFENDANTS
   
 8                 * * * * * * * * * *
   
 9 
   
10 DEPONENT:    DR. H. N. SCHULZE-SOLCE
   
11 
   DATE:        SEPTEMBER 16, 1994
12 
   
13 
                   * * * * * * * * * *
14 
   
15 
   
16 REPORTER:     KATHY NOLD
   
17 
   
18                KENTUCKIANA REPORTERS
                        SUITE 260
19                730 WEST MAIN STREET
               LOUISVILLE, KENTUCKY  40202
20                   (502) 589-2273

                                                 Page 1

 1 
                   * * * * * * * * * *
 2 
   
 3            UNITED STATES DISTRICT COURT
              SOUTHERN DISTRICT OF INDIANA
 4                INDIANAPOLIS DIVISION
   
 5 IN RE ELI LILLY AND COMPANY  )
     Prozac Products Liability  )  MDL Docket No. 907
 6   Litigation                 )
   
 7                 * * * * * * * * * *
   
 8                   NO. 91-02496-A
   
 9 JACKIE LYNN BIFFLE, ET AL  )  IN THE DISTRICT
                              )  COURT OF
10 V.                         )  DALLAS COUNTY, TEXAS
                              )
11 ELI LILLY & COMPANY AND    )  14TH JUDICIAL
   DISTA PRODUCTS COMPANY     )  DISTRICT
12 
                   * * * * * * * * * *
13 
                     NO. 92-14775-E
14 
   RICHARD HAROLD CROSSETT, JR.,       ) IN THE
15 CHAD H. CROSSETT, AMY MICHELLE      ) DISTRICT
   CROSSETT AND KRISTEN ANN CROSSETT,  ) COURT OF
16 INDIVIDUALLY AND AS SURVIVORS OF    )
   AND ON BEHALF OF THE ESTATE OF      )
17 JOCQUETTA ANN CROSSETT, DECEASED    )
                                       )
18 V.                                  ) DALLAS COUNTY,
                                       ) TEXAS
19 ELI LILLY & COMPANY, DISTA          )
   PRODUCTS COMPANY, TEXAS             )
20 PSYCHIATRIC COMPANY, INC.           )
   D/B/A/ HCA WILLOW PARK              ) 101ST JUDICIAL
21 HOSPITAL, JAMES K. WITSCHY, M.D.,   ) DISTRICT
   AND DOUG BELLAMY, ED.D.             )

                                                 Page 2

 1 
                   * * * * * * * * * *
 2 
                     NO. A-921,405-C
 3 
   MARIA GUADALUPE REVES               ) IN THE
 4 INDIVIDUALLY AND AS NEXT            ) DISTRICT COURT
   FRIEND OF GRANT JULIAN REVES        ) OF
 5 A MINOR CHILD, AND ON BEHALF        )
   OF THE ESTATE OF CHRISTIAN          )
 6 MARIE REVES, DECEASED               )
                                       ) ORANGE COUNTY,
 7 V.                                  ) TEXAS
                                       )
 8 ELI LILLY & COMPANY, DISTA          )
   PRODUCTS COMPANY, RAVIKUMAR         )
 9 KANNEGANTI, M.D., HOSPITAL          )
   CORPORATION OF AMERICA, A           )
10 TENNESSEE CORPORATION, HEALTH       )
   SERVICES ACQUISITION CORP.,         )
11 A DELAWARE CORPORATION,             )
   HCA PSYCHIATRIC COMPANY, A          )
12 DELAWARE CORPORATION, TEXAS         )
   PSYCHIATRIC CO., INC.. A/K/A        )
13 AND/OR D/B/A HCA BEAUMONT           )
   NEUROLOGICAL HOSPITAL, AND HCA      )
14 HEALTH SERVICES OF TEXAS, INC.      ) 128TH JUDICIAL
   A/K/A AND/OR BEAUMONT               ) DISTRICT
15 NEUROLOGICAL HOSPITAL               )
   
16                 * * * * * * * * * *

                                                 Page 3

 1    IN THE CIRCUIT COURT OF COOK COUNTY, ILLINOIS
            COUNTY DEPARTMENT - LAW DIVISION
 2 
   RENATO DI SILVESTRO, Individually  )
 3 and as Special Administrator of    )
   the Estate of JOHN DI SILVESTRO,   )
 4 Deceased,                          )
                                      )
 5                  Plaintiff,        )
                                      )
 6      v.                            ) No. 91 L 7881
                                      )
 7 ROBERT L. NELSON, et al.,          )
                                      )
 8                  Defendants,       )
                                      )
 9 GEORGE MELNICK, M.D. and PETER     )
   FINK, M.D.                         )
10                                    )
             Respondents in Discovery.)
11 
                   * * * * * * * * * *

                                                 Page 4

 1 IN THE CIRCUIT COURT OF THE SIXTH JUDICIAL CIRCUIT
               CHAMPAIGN COUNTY, ILLINOIS
 2 
   LINDA GARDNER, Individually and    )
 3 as Special Administrator of        )
   the Estate of SHANE GARDNER,       )
 4 deceased,                          )
                                      )
 5                     Plaintiff,     )
                                      )
 6      v.                            ) No. 91 L 1066
                                      )
 7 ELI LILLY AND COMPANY, a foreign   )
   corporation,                       )
 8                                    )
                       Defendant.     )
 9 
   
10                 * * * * * * * * * *

                                                 Page 5

 1 
        SUPERIOR COURT OF THE STATE OF CALIFORNIA
 2 
              FOR THE COUNTY OF LOS ANGELES
 3 
   DR. MARIUS SAINES, etc., et al.,    ) Case No:
 4                                     ) SC 008331
                       Plaintiffs,     )
 5                                     )
        vs.                            )
 6                                     )
   ELI LILLY & COMPANY, a corporation; )
 7 DISTA PRODUCTS COMPANY, a division  )
   of Eli Lilly & Company; and DOBS 1- )
 8 100, inclusive,                     )
                                       )
 9                     Defendants.     )
   ____________________________________)
10 
   
11                 * * * * * * * * * *
   
12                   NO. 93-8792-D
   
13 DAVID KUNG, DALE KUNG COHEN     ) IN THE DISTRICT
   ROBERT KUNG, AND TIMOTHY KUNG,  ) COURT OF
14 INDIVIDUALLY AND AS SURVIVORS   )
   AND STATUTORY BENEFICIARIES     )
15 OF MAY YUN KUNG, DECEASED       )
                                   )
16 VS.                             ) DALLAS COUNTY
                                   ) T E X A S
17 ELI LILLY AND COMPANY, DISTA    )
   PRODUCTS COMPANY, AND MONIQUE   )
18 KUNKLE, PH.D.                   )

                                                 Page 6

 1                * * * * * * * * * *
   
 2 
    IN THE DISTRICT COURT OF JOHNSON COUNTY, KANSAS
 3              CIVIL COURT DEPARTMENT
   
 4 
   EUGENE HUSLIG, AS ADMINISTRATOR     )
 5 AND EXECUTOR AND ON BEHALF OF       )
   THE ESTATE OF DEBORAH G. WEATHERS   )
 6 HUSLIG, DESCEASED, AND AS SURVIVING )
   HUSBAND AND HEIR AT LAW OF DEBORAH  )
 7 G. WEATHERS HUSLIG, DECEASED,       )
   AND IN HIS INDIVIDUAL CAPACITY AS   )
 8 HUSBAND OF DEBORAH G. WEATHERS      )
   HUSLIG, DECEASED, AND RONALD C.     )
 9 WEATHERS, SON OF DEBORAH G.         )
   WEATHERS HUSLIG, DECEASED,          ) CASE NO.:
10                                     ) 94 C 192
                    PLAINTIFFS,        )
11                                     )
   VS.                                 )
12                                     ) COURT NO. 7
   MARY L. BILLINGSLEY, EXECUTOR OF    ) CHAPTER 60
13 THE ESTATE OF THAD BILLINGSLEY,     )
   M.D., DECEASED D/B/A THE BENESSERE  )
14 CENTER, SUSAN C. JOHNSON, PH.D.,    )
   BILLINGSLEY ENTERPRISES, INC.,      )
15 F/K/A THAD H. BILLINGSLEY, M.D.     )
   CHARTERED, D/B/A THE BENESSERE      )
16 CENTER, ELI LILLY AND COMPANY,      )
   AND DISTA PRODUCTS COMPANY,         )
17                                     )
                    DEFENDANTS.        )

                                                 Page 7

 1 
                   * * * * * * * * * *
 2 
   
 3               CAUSE NO. 93-04911-A
   
 4 
   LINDA JILL WELCH, CARLINDA
 5 WELCH REX, CONNAN ROSS WELCH
   AND CHAD MICHAEL WELCH,
 6 INDIVIDUALLY AND AS SURVIVORS
   AND STATUTORY BENEFICIARIES
 7 OF CARL EUGENE WELCH, DECEASED        PLAINTIFFS
   
 8 V.
   
 9 ELI LILLY AND COMPANY, DISTA
   PRODUCTS COMPANY, NOE NEAVES,
10 M.D., AND MINITH-MEIER
   CLINIC, P.A.                          DEFENDANTS

                                                 Page 8

 1            THE DEPOSITION OF DR.
 2 H. N. SCHULZE-SOLCE, TAKEN AT THE OFFICE OF BAKER
 3 & DANIELS, 300 NORTH MERIDIAN STREET, SUITE 2700,
 4 INDIANAPOLIS, INDIANA 46204, ON SEPTEMBER 16,
 5 1994; SAID DEPOSITION TAKEN PURSUANT TO NOTICE IN
 6 ACCORDANCE WITH THE RULES OF CIVIL PROCEDURE.
 7                 * * * * * * * * * *
 8                A P P E A R A N C E S
 9 
   
10      NANCY ZETTLER
        COUNSEL FOR PLAINTIFFS
11      1405 WEST NORWELL LANE
        SCHAUMBURG, ILLINOIS  60193
12 
        STEVE LORE
13      COUNSEL FOR ELI LILLY AND COMPANY
        FREEMAN & HAWKINS
14      4000 ONE PEACHTREE CENTER
        303 PEACHTREE STREET, N.E.
15      ATLANTA, GEORGIA  30308-3243
   
16      MARGARET M. HUFF
        ELI LILLY AND COMPANY
17      LILLY CORPORATE CENTER
        INDIANAPOLIS, INDIANA  46285
18 
        VIDEOGRAPHER:  STEVE BOUR

                                                 Page 9

 1                      I N D E X
 2 
 3 DEPOSITION OF DR. H. N. SCHULZE-SOLCE
 4 
 5     DIRECT EXAMINATION BY MS. ZETTLER         11
 6 
 7     CERTIFICATE                              285
 8     ERRATA                                   286
 9 
10                     EXHIBITS
   
11     PLAINTIFFS' EXHIBIT NO. 1.................78
       PLAINTIFFS' EXHIBIT NO. 2................100
12     PLAINTIFFS' EXHIBIT NO. 3................112
       PLAINTIFFS' EXHIBIT NO. 4................121
13     PLAINTIFFS' EXHIBIT NO. 5................139
       PLAINTIFFS' EXHIBIT NO. 6................166
14     PLAINTIFFS' EXHIBIT NO. 7................203
       PLAINTIFFS' EXHIBIT NO. 8................221
15     PLAINTIFFS' EXHIBIT NO. 9................234
       PLAINTIFFS' EXHIBIT NO. 10...............240
16     PLAINTIFFS' EXHIBIT NO. 11...............250
       PLAINTIFFS' EXHIBIT NO. 12...............256
17     PLAINTIFFS' EXHIBIT NO. 13...............258

                                                 Page 10

 1 
 2            COMES DR. H. N. SCHULZE-SOLCE, CALLED
 3 BY THE PLAINTIFFS, AND AFTER FIRST BEING DULY
 4 SWORN, WAS DEPOSED AND TESTIFIED AS FOLLOWS:
 5                 DIRECT EXAMINATION
 6 BY MS. ZETTLER:
 7            Q.      Doctor, could you state your
 8 full name for the record, please?
 9            A.      Yes.  Starting with the first
10 name, it's Hans, H-A-N-S, hyphen, Nikolaus,
11 N-I-K-O-L-A-U-S, family name Schulze-Solce,
12 S-C-H-U-L-Z-E, hyphen, S-O-L-C-E.
13            Q.      Where do you currently reside?
14            A.      In Japan, in Kobe, city of
15 Kobe.
16            Q.      Can you spell that?
17            A.      K-O-B-E, Kobe, Japan.
18            Q.      How long have you been there?
19            A.      More than -- well, four and a
20 half years now, since April 1990.
21            Q.      Before moving to Japan, where
22 did you live?
23            A.      In Germany.
24            Q.      Where in Germany?

                                                 Page 11

 1            A.      In Bad Homburg, B-A-D,
 2 H-O-M-B-U-R-G.
 3            Q.      Are you a German citizen?
 4            A.      Yes, I am.
 5            Q.      Where were you born?
 6            A.      In Oldenburg, spelled
 7 O-L-D-E-N-B-U-R-G.
 8            Q.      And when were you born?
 9            A.      On the 20th of May, 1948.
10            Q.      Where did you learn to speak
11 English?
12            A.      Basically at school.
13            Q.      And how long have you been
14 speaking English?
15            A.      Well, you know, we usually
16 start at fifth grade and since we go up to
17 thirteenth grade, it was about nine years at
18 school and that provides basically a level close
19 to what I'm speaking right now and it usually
20 deteriorates because you don't have practice.
21 But when I joined Lilly, an American company,
22 which I did in '83, well, then obviously it
23 improves again and in particular the last four
24 years because in Japan, I basically conduct my

                                                 Page 12

 1 business in English.
 2            Q.      Do you speak Japanese?
 3            A.      Not as good as English.  I
 4 have some knowledge of Japanese, but as you might
 5 know also the writing is different from our
 6 writing so I cannot read, only very, very basic
 7 knowledge, not fluent.
 8            Q.      Do you read and write English?
 9            A.      Yes.  I mean English is easier
10 to write and to read than Japanese.
11            Q.      Absolutely.  Do you consider
12 yourself fluent in reading and writing English?
13            A.      That's always a judgment call,
14 I mean if you have a scale of zero to one
15 hundred, maybe I'm eighty-five, ninety percent.
16            Q.      Have you ever found a problem
17 in reading or writing English in your job with
18 Lilly?
19            A.      Well, of course, there's
20 always missing one specific word you might need
21 to look up or I'm sometimes very critical, but by
22 far and large I think what is needed to operate,
23 it's okay.
24            Q.      How about speaking English, do

                                                 Page 13

 1 you consider yourself fluent in speaking English?
 2            A.      If it comes to business in
 3 certain areas, yes.  From watching a movie,
 4 depending on what the movie is all about, there
 5 may be areas that I have difficulties following.
 6            Q.      Problems with slang maybe?
 7            A.      Definitely so.
 8            Q.      Are you comfortable in giving
 9 your deposition today in English?
10            A.      I hope so.
11            Q.      Because we have an interpreter
12 here and we can keep him here if you're
13 uncomfortable.  If you're comfortable in giving
14 your deposition, then we'll let him go, but if
15 you would like, we'll keep him here.
16            A.      Basically, I'm comfortable.
17 On the other hand, after a couple of minutes
18 only, I'm not so sure what's going to come.
19 Obviously now it works quite well, so if this
20 would continue, then yes, I'm comfortable.  It
21 depends on you and your questions.
22            Q.      I tend to talk very fast, but
23 I'm working on it.
24            A.      Yes, but still you're good to

                                                 Page 14

 1 understand, it's no problem.
 2            Q.      What we'll do then is we'll
 3 ask Mister Detlief to stay for a while and see
 4 how it goes.  Part of it may be because Kathy
 5 might have some trouble with your accent,
 6 allthough you don't seem to have a very thick
 7 accent.
 8            A.      Thank you.
 9            Q.      Compared to other people we
10 talk with.  We'll give it a while and see how it
11 goes and then later on we'll tell Mister Detlief
12 he can leave.  Okay?
13            A.      That's okay, yes.
14            Q.      Have you given a deposition
15 before, Doctor?
16            A.      No, not even in my own
17 country.
18            Q.      Let me give you some of the
19 ground rules.  Obviously we have a court reporter
20 here and we have a videographer here.  The court
21 reporter's job is to take down everything we say.
22 So what we're going to need from you is answers
23 out loud.  You can't shake your head and go
24 uh-huh because while the camera can take that

                                                 Page 15

 1 down and the audio from the camera can take that
 2 down, Kathy can't take that down.  Is that fair?
 3            A.      Understood.
 4            Q.      Like I said -- by the way, my
 5 name is Nancy Zettler, and I represent a number
 6 of plaintiffs in Prozac cases across the country.
 7 If you have any problems understanding any of my
 8 questions or for some reason you don't hear me or
 9 I talk too fast or something like that, please
10 let me know and I'll be happy to restate the
11 question.  Okay?
12            A.      Good.
13            Q.      If you want to take a break at
14 any time, let us know and we'll take a break.
15 This isn't an endurance test, okay?
16            A.      Good, yes.
17            Q.      It's going to take you a
18 little while.
19            A.      Just to adjust to the pattern.
20            Q.      It'll take you a little while
21 and it's perfectly normal so don't be embarrassed
22 about it, okay.
23                    Are you still working with Eli
24 Lilly and Company?

                                                 Page 16

 1            A.      Yes, I do.
 2            Q.      What do you do for them now?
 3            A.      Yes, I'm in Japan for Lilly
 4 and my title there is director of scientific
 5 affairs and that basically means I have the
 6 responsibility for the Japan RND group, what we
 7 call the medical group, and what's called medical
 8 quality assurance.  So all areas related to RND
 9 and medical for Lilly in Japan.
10            Q.      Is Prozac registered to be
11 sold in Japan?
12            A.      No, it is not.
13            Q.      Has the company tried to get
14 Prozac registered there for sale?
15            A.      No, not.
16            Q.      Has never submitted an
17 application?
18            A.      Correct, never submitted an
19 application.
20            Q.      Why is that, do you know?
21            A.      Well, it was, you know, when
22 Prozac was developed, basically during the '80s
23 if we talk about the clinical development, first
24 of all I was not in Japan obviously, but what was

                                                 Page 17

 1 even more important, Lilly at that point in time
 2 only had what we would call a liaison office,
 3 they did not have established their own full
 4 fledged affiliate.  That means it was not Lilly
 5 if at all to carry out any development and at
 6 that time we were incorporating and still do in
 7 other areas with the Japanese company called
 8 Shionogi.  So the usual pattern was to offer
 9 compounds to this Japanese company, Shionogi, and
10 basically ask them if they're interested to
11 develop, which in this case it turned out to be
12 not that much interest obviously.  And again, I
13 was not there but as you may also know the
14 culture is a little bit different in Japan and I
15 would just guess retrospectively they thought it
16 might not be worthwhile, I mean for the Japanese
17 market.  So that's basically what I know about
18 it.  But the fact is that Lilly didn't have a
19 full operation at that time so it was offered to
20 Shionogi and for some reason it was not, there
21 may have been some early investigations, but it
22 never went into patients and it never was an NDA
23 assembled and submitted, so we in Japan do not
24 have Prozac at all.

                                                 Page 18

 1            Q.      You say it was offered to
 2 Shionogi, is that a company in Japan?
 3            A.      Yes, Shianogi is a Japanese
 4 company.  It's the company we have done and do a
 5 lot of business through because again I mentioned
 6 that we did not have those days our own
 7 affiliate, it was simply also due to the fact
 8 that in Japan only for a certain point of time
 9 you're allowed to have full operations by law and
10 so most foreign companies were doing business via
11 a Japanese company for licensed deals or
12 sometimes later through joint ventures.  And this
13 is very important to understand, in fact Lilly
14 has started to develope its own operations in
15 terms also of RND and own distribution back in
16 the States, and starting from basically '86 and
17 that was after that, so --
18            Q.      Are there any current plans to
19 try to register Prozac for sale in Japan?
20            A.      No, we don't have that.
21            Q.      Are you a psychiatrist?
22            A.      I'm not.
23            Q.      To your knowledge, does the
24 Japanese psychiatric community prescribe

                                                 Page 19

 1 antidepressants?
 2            A.      To my knowledge, yes, they do.
 3            Q.      So it's not a problem with the
 4 Japanese psychiatric community being against
 5 prescribing antidepressant medication?
 6            A.      This is a correct statement,
 7 it's not -- I mean there is depression also in
 8 Japan, maybe not that frequently diagnosed, and
 9 the psychiatrists who diagnose depression also
10 prescribe antidepressants, yes.
11            Q.      Could you give us your
12 educational background starting with high school?
13            A.      Okay.  Now, in -- the
14 education system is not totally the same, we
15 don't have college, so basically after the
16 thirteen years of also including high school, you
17 graduate, and then you qualify for going to the
18 university.  So in '67, 1967, I graduated from
19 high school and then started to study pharmacy,
20 which at that time was to start with a two years
21 kind of apprenticeship, so you were to go to a
22 public pharmacy, and there was a very special
23 curriculum resulting in a kind of pharmaceautical
24 preexaminations after two year which I took in

                                                 Page 20

 1 '69.  And only after that, you would then enter
 2 the pharmacy school at the university, which I
 3 did in the -- well, spring, 1970, simply because
 4 the start of the semester didn't allow me right
 5 after my other examination to do that.  So then
 6 from 1970 until 1973, I visited pharmacy school
 7 of the Philipps, I spell P-H-I-L-I-P-P-S,
 8 Philipps University in Marburg, M-A-R-B-U-R-G, in
 9 Germany.  And there I graduated with a master
10 degree in pharmacy and I'm also a licensed
11 pharmacist in Germany.  But after having done
12 that, decided that medicine might be more
13 exciting, anyway I mean I continued and studying
14 and actually visited medical school at the same
15 university, also Marburg, and graduated there in
16 1978 and then wrote my thesis and in '79 obtained
17 the M.D. medical degree, which is also a little
18 different from the U.S.  So I'm basically M.D.
19 and M.S. pharmacy and I'm a licensed physician
20 and a licensed pharmacist.  And then according to
21 the German law, I was still under thirty, and
22 that means subject for potential draft into the
23 army, which in fact happened, so I from early '79
24 until March '80, yes, fifteen months, I had to

                                                 Page 21

 1 serve the Army, but I did this as a physician, so
 2 I wasn't charged to take care of a battalion in
 3 the German army.  And only after that could
 4 continue my career at the university, which I did
 5 again at university hospital in Marburg, internal
 6 medicine department, and there I stayed on until,
 7 well, September '83, meaning that over those a
 8 little bit more than three years, I trained in
 9 internal medicine and according to German system,
10 that does not mean I'm a board certified
11 internist simply because I mean it takes a little
12 longer.  By U.S. standards you might say I'm an
13 internist because it's only three years it takes
14 to be trained as an internist.  Anyway, I'm
15 internal medicine, however no subspecialty in
16 terms of cardiology or something like that,
17 because at that time, then I decided to join
18 Lilly in Germany.  So from October 1st, 1983, I
19 worked for Lilly, and again I started in Germany
20 and I started as what was called then medical
21 monitor but which compares to clinical research
22 physician in the corporate terminology, and in
23 fact also today we use this in the international
24 clinical research physician, and initially I was

                                                 Page 22

 1 responsible for a product which might be --
 2            Q.      Okay, let me stop you there
 3 and let's go back.  I'm really interested in
 4 concentrating on your education at this point,
 5 okay.
 6            A.      Good.
 7            Q.      Okay.  So you graduated from
 8 the equivalent here in the United States of high
 9 school in 1967, correct?
10            A.      That's correct.
11            Q.      And from there, you wanted to
12 become a pharmacist so you had to perform this
13 two year public pharmacy apprenticeship, correct?
14            A.      Correct.
15            Q.      And then from there you went
16 to the Philipps University and obtained your
17 Masters in Pharmacy?
18            A.      That's correct.
19            Q.      And then became a licensed
20 pharmacist after that, correct?
21            A.      Uh-huh.
22            Q.      You have to say yes or no.
23            A.      I'm sorry, yes.
24            Q.      Now, did you ever work as a

                                                 Page 23

 1 pharmacist?
 2            A.      Yes, I did.  Of course,
 3 actually very useful qualification to have as a
 4 medical student because during holidays, at least
 5 the town which was free, and I didn't spend for
 6 travel or other things, and I in fact worked as a
 7 fully licensed pharmacist in pharmacies, mainly
 8 there where the boss was taking some vacation and
 9 just as a holiday substitute.  So yes, I worked
10 in public pharmacies until then finally I
11 completed medical studies and since then never
12 worked in pharmacies again.
13            Q.      So while you were in medical
14 school, you occasionally worked as a pharmacist?
15            A.      Correct.
16            Q.      Did you work exclusively in
17 public pharmacies or did you just work in
18 institutional pharmacies as well?
19            A.      No, public pharmacies.
20            Q.      Like the Walgreens here.
21            A.      Which is also a little
22 different than the United States but definitely
23 not hospital pharmacy or institutional, so yes,
24 what you would call a retail public pharmacy.

                                                 Page 24

 1            Q.      When you worked as a
 2 pharmacist, did the German government require
 3 package inserts with drugs?
 4            A.      Yes.
 5            Q.      And package inserts in Germany
 6 are a little different than what we call package
 7 inserts here in that the package insert is
 8 actually information that goes with the patient
 9 with the medication, correct?
10            A.      That's correct.
11            Q.      And you also have something
12 that's called prescribing information I believe
13 that goes to the doctor and not to the patients?
14            A.      That's correct, although at
15 that time when I was pharmacist, that was not
16 really separated.
17            Q.      It was the same thing?
18            A.      It was basically the same
19 thing.
20            Q.      Okay, and so the same thing
21 would go to the patient, as well as the doctor?
22            A.      Right.  But of course today
23 that is two different.
24            Q.      When did that change?

                                                 Page 25

 1            A.      Oh, I don't know exactly when
 2 it changed.
 3            Q.      Was it while you were a
 4 pharmacist?
 5            A.      No, I think it was a little
 6 bit later.
 7            Q.      Was it while you were working
 8 with Lilly?
 9            A.      I really don't know when it
10 changed, I definitely know that when I was a
11 pharmacist that it was the same and then sometime
12 it was not anymore.
13            Q.      Okay, do you recall -- I'm
14 just trying to refresh your recollection, okay?
15            A.      Uh-huh.
16            Q.      Do you recall whether or not
17 the change was made before Fluctin, which is
18 Prozac in Germany, was approved for sale in
19 Germany?
20            A.      Yes, before.
21            Q.      Do you recall how long?
22            A.      Because simply as far as I
23 remember because we have both fluoxetine -- I had
24 to prepare it and that would prove that it's --

                                                 Page 26

 1 but when before it has been established, I don't
 2 know.
 3            Q.      And you started as a
 4 pharmacist in 1973, I believe, is that correct?
 5            A.      Yes, obviously after getting
 6 the license.
 7            Q.      Then you worked on and off as
 8 a pharmacist during this period of time you were
 9 telling us about earlier where you had free time
10 during medical school through 1983?
11            A.      Well, let me see, no, no, not
12 '83.  Basically you can say '78.
13            Q.      Okay, so about five years?
14            A.      Uh-huh.
15            Q.      You have to say yes or no.
16            A.      Yes.
17            Q.      Could you give us an idea of
18 what a pharmacist in Germany does?
19            A.      Well --
20            Q.      In the position that you
21 worked at in the public sector?
22            A.      Well, one is dispensing
23 prescribed medicine and the system works, the
24 doctor obviously like here writes a prescription

                                                 Page 27

 1 so the patient comes with a prescription and
 2 then, I mean, you just deliver the medicine
 3 accordingly.  And as you know and as I confirmed,
 4 there always has been this package insert, so
 5 that means patient always receive some
 6 information, and only if there are specific
 7 further directions for use required by the doctor
 8 and that may be written on the prescription, then
 9 of course as pharmacist you are also supposed to
10 take a sticker and put this on the pack, package.
11 So that's basically it.  And then you have the
12 OTC part where obviously patients come in and
13 whether have a cold and either say specifically
14 what they want and you give them or they might
15 ask for your advice.  So that's basically -- it's
16 dispensing both OTC drugs and prescription drugs
17 and I think that's also the difference in the
18 United States.  Here you can go into any
19 supermarket and just take, I mean, painkillers or
20 whatever off the shelf.  This all goes through
21 the pharmacy in Germany, so it's basically a
22 pharmacist to hand it to you.
23            Q.      So when you say OTC, you mean
24 over-the-counter, correct?

                                                 Page 28

 1            A.      Right, over-the-counter, which
 2 basically means no prescription required.  But
 3 again the things which you can -- you just have
 4 it next to the baby food and you just grab it,
 5 that's not in Germany, that all runs through the
 6 pharmacy and actually through the pharmacist.
 7            Q.      Okay.  Before you joined Lilly
 8 in October of 1983, had you been involved in any
 9 clinical trials on drugs?
10            A.      Yes.  There was one really
11 minor in terms of scientific significance, it was --
12 I was contributing a few hypertension patients to
13 be treated with a beta blocker to a minor trial
14 conducted by Hoechst Germany.
15            Q.      I'm sorry, could you repeat
16 that last for me?
17            A.      Hoechst is a company which is
18 pretty large spelled H-O-E-C-H-S-T.
19            Q.      And you said a beta blocker?
20            A.      That was the drug.
21            Q.      Okay.
22            Q.      So some of the patients you
23 were treating, was it while you were in medical
24 school were included in this clinical trial?

                                                 Page 29

 1            A.      Well, that was I mean when I
 2 was working in the university hospital as a
 3 licensed physician, so it was after graduation.
 4            Q.      Do they have an internship and
 5 residency program over there like we have here?
 6            A.      Well, to be honest, I'm not a
 7 hundred percent familiar with the system here.
 8 Of course working for the company and knowing a
 9 lot of American physicians, you talk here and
10 there so I have some idea, and what I understand,
11 yes and no.  Because I better describe the system
12 and then it's up to you to say if it's the same,
13 yes or no.  So what we do is, yes, five years is
14 basically the minimum you do, which means ten
15 semesters.  You do it just for kind of
16 therapeautic training, seminars, courses.  During
17 the time, you also have to accumulate, what is
18 it, two or four months, which you're supposed to
19 do during your holidays in terms of nursing-like
20 of activity, activities like nurses would do, so
21 that's part of the idea that, you know, also
22 doctors should know the other part of the health
23 business, so you have to do that.  And you also
24 during that time should join the GP and just

                                                 Page 30

 1 seeing a little bit, you know, as kind of
 2 apprentice, the outside outpatient business.  And
 3 this is just I mean a kind of thing you run
 4 through this, you do not need to go through
 5 special examinations, it's just being testified
 6 that you did it, but it's part of all the papers
 7 you have to submit before applying for the final
 8 examination.  And then once you've done that,
 9 yes, there is what we call proctorship year which
10 would translate to practical year which may be
11 something like the residency, although you're not
12 really a resident, you go home at night as
13 everyone else.  But yes, you usually -- during
14 that time, you need to rotate through internal
15 medicine for four months, surgery four months and
16 four months is just up to you.  In my case, I
17 took pediatric medicine.  So yes, and there --
18 but during that time, because you don't have the
19 license, I mean you are not fully entitled to --
20 I mean just under instruction of a real doctor,
21 you're entitled to do or execute medical
22 procedures and you would, depending on your
23 performance and your immediate supervisor, be
24 very much involved in making diagnoses and

                                                 Page 31

 1 delivering treatment but you cannot on your own
 2 responsibility apply it.  So that's then after
 3 this.  So after this one year, you take another
 4 final examination and then after that
 5 automatically comes the license.  And then what
 6 you usually -- well, theoretically then, you can
 7 say bye-bye, I form my own practice as a GP, but
 8 this is not very advisable because in our health
 9 system, you know, the social insurances play a
10 bigger role than in the U.S. and the social
11 insurance will not do any reimbursements to a
12 doctor who just has graduated, so you need at
13 least two years until you can claim any
14 reimbursement, which is a healthy kind of hurdle
15 to force on a clinical practice.  So basically
16 what the people do, I mean they stay at any
17 hospital to accumulate further clinical
18 experience and then obviously, it becomes very
19 much the same as in any other country, depending
20 on what and where you do that, this may result
21 in, well, just experience or a board certified
22 specialist, and that's of course defined.  I mean
23 you can -- you need six years at least for an
24 internist in Germany and the same for surgery and

                                                 Page 32

 1 there are some, I think, pediatricians it's only
 2 four years, ENT it's four years, so I mean that's
 3 the same as in the U.S., it's defined how long
 4 you need and what you have to do during that
 5 time.  Now again, you can also do two years
 6 surgery and two years internal medicine and then
 7 settle down as a GP and that's also possible.
 8 But the usual thing to do is after graduation,
 9 you stay at the hospital in order to just learn
10 more about real medicine.  And in my case, I also
11 did this as I mentioned and that was the internal
12 medicine department of the University of Marburg.
13            Q.      Okay.  So before you can take
14 your test and become Board certified, you have to
15 spend a certain amount of time practicing in the
16 area that you're interested in becoming certified
17 in?
18            A.      Correct.
19            Q.      Let me make sure I understand
20 this.  After medical school, you're required to
21 do a short apprenticeship, so to speak, with the
22 GP, correct?
23            A.      Yes, well, that's actually in
24 between.  I mean again from -- it's up to you

                                                 Page 33

 1 when you do it but before you apply for the
 2 examination, after the last theoretical semester,
 3 you need to do that, yes.
 4            Q.      So you can do that while
 5 you're actually in medical school if you want to
 6 also?
 7            A.      Correct.
 8            Q.      And then also during that
 9 period of time before you take the exam to go on
10 to your residency, so to speak, you would also
11 get that nursing experience that you talked
12 about?
13            A.      Yes.  Again, just to make it
14 clear, if we say year, one to five is, so to
15 speak, the theoretical education because I mean
16 that's the medical school kind of thing.
17            Q.      The classroom work?
18            A.      During that time you would
19 have these, and again I don't recall if it's two
20 or four months, you have to do a little bit of
21 the GP and nursing experience, and then again I
22 mean after that time, that's the first big exam,
23 there are others in between, but the first big
24 one and then you do this residency type of thing

                                                 Page 34

 1 and then you do another one and then you're done.
 2 So that's the sequence.
 3            Q.      So the five years is basically
 4 classroom work?
 5            A.      Correct.
 6            Q.      But also during that period of
 7 time you can work as an apprentice with a general
 8 practitioner and do this nursing stuff?
 9            A.      Right.  I should mention that
10 what I said is -- I mean, whatever, the two or
11 four month, it's a minimum and everybody has to
12 do it.  Of course there are people doing more.
13            Q.      But I'm just trying to get a
14 basic idea of what is required of the physicians
15 over in Germany, okay?
16            A.      Okay.
17            Q.      So the five years is
18 essentially classroom work with the two
19 requirements of the nursing-type work --
20            A.      Uh-huh, yes.
21            Q.      -- and the apprenticeship with
22 the general practitioner, correct?
23            A.      Yes.
24            Q.      And those are minimum

                                                 Page 35

 1 requirements, but you are not limited into how
 2 long you can do those?
 3            A.      That's correct.
 4            Q.      And then after that, you take
 5 an exam to qualify for the one year residency
 6 type program?
 7            A.      Well, basically it's so far
 8 more complicated because as I mentioned there is
 9 one in between, what they call the state exam
10 based down to three parts.  One is just, you
11 know, between the classroom, summer in between,
12 and then there is the second after the classroom
13 and before going to the residency, and the last
14 part three is after the residency.  And of course
15 you can proceed only to the next part once you
16 have passed the --
17            Q.      Okay, but to get from the
18 classroom part to the residency, you take one
19 exam?
20            A.      Correct.
21            Q.      And that exam comes after the
22 five years --
23            A.      Correct.
24            Q.      -- of medical school and

                                                 Page 36

 1 classroom work?
 2            A.      Yes.
 3            Q.      And then the residency is a
 4 one year residency?
 5            A.      Yes.
 6            Q.      And that is broken down like
 7 you said earlier into three quarters essentially,
 8 a surgery quarter, right?
 9            A.      Yes.
10            Q.      Let me ask you.  I just want
11 to make sure I get it correct, okay.  There's the
12 surgery quarter, the general practice quarter, I
13 believe?
14            A.      Internal medicine.
15            Q.      Internal medicine.  And then
16 the last quarter you can choose an area you want
17 to specialize in, correct?
18            A.      Correct.
19            Q.      And then after that, you are
20 still required before you can become Board
21 certified in a specialty to practice, depending
22 on the specialty, four to six years in that area,
23 correct?
24            A.      Correct.

                                                 Page 37

 1            Q.      But like I said, you could opt
 2 to just become a GP or general practitioner or
 3 internist by leaving the system at that point but
 4 that's not advisable from a state point of view?
 5            A.      The earliest possible point to
 6 leave it is after this last examination after the
 7 residency.
 8            Q.      Okay.
 9            A.      But as you say most people do
10 not do that.
11            Q.      Even if you wanted to become
12 eventually an internist, you still would stay at
13 the university for a while and get a little more
14 education?
15            A.      Well, not necessarily the
16 university.  I mean, there are other hospitals
17 authorized to provide the education.  But the
18 point is you need to stay at the hospital, it's
19 not that you get this experience in a private
20 practice.
21            Q.      So it doesn't have to be at a
22 university hospital, it can be a private
23 hospital?
24            A.      Yes.

                                                 Page 38

 1            Q.      Now, during the period of time --
 2 and you went through all of that, correct, you
 3 went through the five years obviously and you got
 4 your M.D.?
 5            A.      No, I did not go through the
 6 full five years.  That's why I was mentioning,
 7 according to German system, I did not make the
 8 six years and I'm also not a Board certified
 9 internist.
10            Q.      Okay.
11            A.      The three, you know, from '80
12 to '83 until I joined Lilly, I exclusively spent
13 in internal medicine at the university hospital
14 so that's where my experience is.  But according
15 to the German system, I'm not a board certified
16 internist.
17            Q.      Okay.  Now the last rule I
18 forgot to mention is you have to let me finish my
19 question before you start your answer because I
20 think we got confused there.  When I said the
21 five years, I meant the classroom work.
22            A.      Okay.  I have finished that,
23 of course.
24            Q.      So you took that, you got that

                                                 Page 39

 1 part done, correct?
 2            A.      Yes.
 3            Q.      And then you did your one year
 4 internship, correct?
 5            A.      Yes.
 6            Q.      And then what you're saying is
 7 that you were three years into your hospital work
 8 after the internship in internal medicine?
 9            A.      Yes.
10            Q.      And during that time is when
11 you left to go work for Lilly.
12            A.      Yes.
13            Q.      While you were in the one year
14 internship period, did you treat any psychiatric
15 patients?
16            A.      No.
17            Q.      How about in the three year
18 period that you worked prior to going to Lilly
19 when you worked in the hospital in internal
20 medicine, did you treat psychiatric patients?
21            A.      I did not treat them.
22            Q.      Did you work with any
23 psychiatric patients?
24            A.      It happens that you see

                                                 Page 40

 1 psychiatry or potentially -- or patients with
 2 potentially psychiatry diseases.  The practice
 3 then is in particular in a university hospital,
 4 we have all specialists next door that we just
 5 consult with the psychiatry, that's what in fact
 6 we did.  So that's why I emphasized I did not
 7 treat or even diagnose, but of course I
 8 occasionally ran into potentially psychiatry
 9 patients, but then you consult.  And if it's
10 confirmed that this is rather a psychiatry case,
11 then it's transferred away from the internist
12 ward.  So I did not diagnose or treat psychiatry
13 patients.
14            Q.      During your medical school,
15 the five year period where you did your classroom
16 work, did you take any special -- other than --
17            A.      Just what is -- yes.
18            Q.      Just what is required?
19            A.      Right.
20            Q.      So some basic psychiatry or
21 psychology courses?
22            A.      That's correct.
23            Q.      Did you do any part of your
24 open quarter, so to speak, of your internship in

                                                 Page 41

 1 psychiatry, or did you just strictly do that in
 2 pediatrics?
 3            A.      Just strictly in pediatrics.
 4            Q.      How about the internal
 5 medicine quarter of your internship, did that
 6 involve any specialized training in psychiatry or
 7 psychology?
 8            A.      No, it did not.
 9            Q.      When you did your
10 apprenticeship with the general practitioner, did
11 that involve any specialized training in
12 psychiatry or psychology?
13            A.      No, also it did not.
14            Q.      So is it fair to say you don't
15 consider yourself a psychiatrist?
16            A.      That's a correct statement.
17            Q.      Would you feel comfortable in
18 treating a psychiatric patient as far as
19 rendering psychotherapy or prescribing
20 psychotropic medications?
21            A.      I rather say no, in
22 particular, considering that I'm ten years out of
23 the practical clinical business.  So I'd rather
24 say no, I would not feel comfortable.

                                                 Page 42

 1            Q.      Did you feel comfortable
 2 during your three years at the hospital after
 3 your internship prescribing psychotropic
 4 medications to psychiatric patients or to any
 5 patients without a psychiatric consult?
 6            A.      I would like you to repeat and
 7 specify because -- yes, just to be sure.
 8            Q.      Okay.  My understanding is
 9 that in the system that you were in, the hospital
10 that you were in, you had available to you
11 psychiatrists to consult with if you found a case
12 where you thought there was a psychiatric element
13 to an illness, correct?
14            A.      Yes.
15            Q.      During that period of time,
16 did you feel comfortable in treating the
17 psychiatric aspect of a particular patient's
18 illness that you came across in your practice by
19 yourself without a consult, or did you generally
20 get a psychiatric consult for those patients?
21            A.      That's why exactly I asked you
22 to repeat.  Let me rephrase it to some extent
23 because there are always distinctions, at least
24 as we in medical terms perceive it, between

                                                 Page 43

 1 psychiatric patients or psychiatric symptoms as
 2 opposed to whatever psychological aspects which
 3 may be a part of almost any disease.  So that's
 4 why I would like to distinguish between the two.
 5 And in terms of other psychiatric patients or
 6 where I did not consult, the question is no,
 7 because I mean I did not do this, simply because
 8 of lack of experience and familiarity.  Now, the
 9 question, did you prescribe, whatever --
10            Q.      Psychiatric drugs.
11            A.      Yes, well, here again,
12 psychiatric drugs, may go with a connotation that
13 it's always something to do with depression and
14 schizophrenia, that is at least for me not the
15 exception, but if for example you're talking
16 about benzodiazepines or more popular Valium kind
17 of drugs, then the answer is yes, I have
18 prescribed such drugs to patients, however, who
19 were suffering primarily from internal diseases.
20            Q.      They were having problems
21 sleeping, for instance?
22            A.      Yes.
23            Q.      They were anxious because they
24 were ill in other ways?

                                                 Page 44

 1            A.      That's exactly the point.
 2            Q.      As far as treating somebody
 3 who was say suffering from depression?
 4            A.      I did not do that.
 5            Q.      Okay, not even if it was
 6 somebody who was suffering from depression
 7 related to another underlying illness, say for
 8 instance they were seriously ill and they were
 9 depressed because they were seriously ill, would
10 you feel comfortable in treating that depression
11 or would you at that point bring in a psychiatric
12 consult?
13            A.      I would have brought a
14 psychiatric consult in.
15            Q.      Did you have a private
16 practice during the period of time you were at
17 the hospital?
18            A.      No.
19            Q.      It was strictly the hospital?
20            A.      Right.
21            Q.      During that period of time,
22 did you work under the supervision of other
23 physicians?
24            A.      Yes.

                                                 Page 45

 1            Q.      Other than this clinical trial
 2 hypertension patients you told us about with the
 3 beta blocker drug, did you participate in any
 4 other clinical trials, either while you worked at
 5 the hospital or at any other time during your
 6 medical training?
 7            A.      No, that was the only trial
 8 activity I had during my time before Lilly.
 9            Q.      Prior to joining Lilly, did
10 you have any familiarity with the requirements of
11 the BGA as far as getting drugs registered in
12 Germany?
13            A.      Prior to joining Lilly, the
14 answer is no.
15            Q.      So everything you learned
16 about the BGA, you learned through Lilly?
17            A.      In terms of registering drugs,
18 yes, because of course every health care
19 professional knows about that there is the BGA
20 and having some missions in terms of the health
21 of the German people.  But if you talk about
22 specific procedures in particular with regard to
23 drug, drug monitoring, and more specifically even
24 drug registration, then the answer is clearly no

                                                 Page 46

 1 prior to Lilly and it's only through Lilly that I
 2 have become more exposed and familiar with that.
 3            Q.      Is it fair to say that the BGA
 4 is the counterpart to our FDA here with regard to
 5 drugs?
 6            A.      Well, I think, although they
 7 operate differently and there are different
 8 regulations, it's the counterpart, yes.
 9            Q.      Their purpose is essentially
10 the same.
11            A.      The purpose is essentially the
12 same, I would say, yes.
13            Q.      When you joined Lilly, did
14 they give you any specialized training or
15 courses, things of that nature, on the workings
16 of the BGA as far as the registration process,
17 the drug monitoring process, things of that
18 nature?
19            A.      Well, there are courses
20 available usually run by independent agencies who
21 give insight in the practices and regulations of
22 drug development in general and sometimes also
23 more specific.  I was encouraged and also --
24 well, I took such a course and there are also,

                                                 Page 47

 1 well, very similar here in the United States that
 2 on a regular basis also you can update yourself
 3 on regulations or how they are interpreted and
 4 should be implemented and that's rather the
 5 vehicle to learn about this.  Because also
 6 important to mention, Lilly Germany is not as big
 7 as Lilly here in this town, that means we did not
 8 have when I was joining such a big group to have
 9 somebody specially setting up training program or
10 training so that was basically through outside
11 sources which were available in the country.
12            Q.      What position did you hold
13 when you first started with Lilly in Germany?
14            A.      Again, the title was medical
15 monitor but it corresponds to and is even called
16 today clinical research physician.
17            Q.      What were the responsibilities
18 of clinical research physician, medical monitor,
19 back in '83?
20            A.      Back in '83, it was to be
21 responsible for clinical trials in the terms of
22 planning, designing, monitoring, evaluating,
23 analyzing them, finally reporting them.  I should
24 mention though that at that time in the

                                                 Page 48

 1 affiliates of Lilly, we did only very, very late
 2 phase work, basically only with drugs which were
 3 already on the market.  At that time we were not
 4 really involved in early stage work, early
 5 development.  But basically clinical trials is
 6 one responsibility.  The other that is very
 7 important, I think, every drug as we know while
 8 it's on the market, I mean there are additional
 9 observations being made and they're usually
10 reported by physicians or through other ways and
11 it's also in every country that there are certain
12 requirements, not only from ethical but from
13 legal point of view, to collect them, to assess
14 them and to report them, and I think in
15 particularly, the assessment is a truly medical
16 task, so for a certain range of products, usually
17 the physician in the office has the
18 responsibility to do that.  So if you wish, all
19 the regulatory aspects around a certain area in
20 terms of usually therapeautic area responsible
21 for certain products, and after all what is also
22 a significant piece, that doctors might simply
23 have questions and because this is a very
24 sophisticated area and field, and in particular

                                                 Page 49

 1 doctors also sometimes prefer to talk doctor-to-
 2 doctor, it's very often that what we call medical
 3 information, that you need to respond to
 4 questions.  And just to give you an idea, usually
 5 these questions are obviously not what is in the
 6 package insert because that's what the doctor can
 7 read, but the reality is always different, and
 8 that means that a doctor may see a child which
 9 has ingested much more accidently, so it's just
10 he wants to know are there any experiences, so
11 what can I do, or he reports that patient's not
12 responding and can he get in with a higher dose
13 or is that really not recommendable, all kind of
14 stuff, and also some are more scientifically
15 oriented and would like to know more
16 pharmacokinetics or about the field.  So this is
17 a mixture of from the drug company's point of
18 view service to the doctor but also serving an
19 important need in terms of answering proper use
20 of the drug.  So medical information, clinical
21 trials and the regulatory aspects which center
22 very much on the safety and assessment of risks
23 with the drug and that usually related to one or
24 a group of products, that's what typically a

                                                 Page 50

 1 clinical research physician does.
 2            Q.      Okay.  Those were your
 3 responsibilities?
 4            A.      Right.
 5            Q.      At least as of 1983 when you
 6 first started working at Lilly?
 7            A.      Correct.
 8            Q.      And when you say collecting
 9 and assessing and recording experiences that
10 doctors have with the drug --
11            A.      Uh-huh.
12            Q.      -- you're referring to
13 postmarketing adverse events or adverse events
14 that also happened on the clinical trials?
15            A.      Well, happened also in
16 clinical trials, but as I mentioned at that time
17 in Germany, we did only clinical trials of
18 marketed drugs.  So it were basically
19 observations occurring with more or less pretty
20 well known drugs.
21            Q.      Now, obviously when you first
22 started at Lilly, Fluctin or Prozac had not been
23 approved in Germany at that point, correct?
24            A.      Right, that was a little bit

                                                 Page 51

 1 later.
 2            Q.      When was it eventually
 3 approved, do you recall?
 4            A.      That was just shortly before I
 5 was transferred to Japan and so far it must have
 6 been early '90, I think, early '90.
 7            Q.      Did you have -- when you first
 8 started at Lilly in October of '83, did you have
 9 any responsibilities with regards to Prozac
10 specifically?
11            A.      No, I did not.
12            Q.      When did you first start
13 becoming involved with Prozac in any area?
14            A.      Yes, well, I do not recall the
15 years specifically but there was another
16 colleague actually directing the development in
17 the first phase in Germany, and this colleague
18 then left the company simply because -- well,
19 actually became medical director at a competitive
20 company which obviously was the main driver to
21 leave Lilly, so she could get one step up.
22 Anyway so she left the company and after that I
23 was assigned Prozac to continue the works which
24 had been initiated.  And again '84, '85, I'm not

                                                 Page 52

 1 pretty sure when that was after this lady -- it
 2 was a lady left --
 3            Q.      You're talking about Johanna
 4 Schenk, correct?
 5            A.      Correct.
 6            Q.      And where did she go to?
 7            A.      Yes.  She was leaving for
 8 Bristol Myers and again she became medical
 9 director at Bristol Myers and I think that was
10 the main reason for her to go.
11            Q.      Was there any cross-over time
12 that you worked on Prozac while Doctor Schenk was
13 still in Germany, still with Lilly?
14            A.      I remember only one
15 investigator meeting which she basically had, you
16 know, prepared for and I was going to take over
17 and that was rather to tell the -- this is the
18 new guy, so I mean it was very short and rather
19 related to the outside contacts and introducing
20 me to the physicians which were designated to
21 participate in, I think it was basically the
22 in-patient trial which you also may be having on
23 your records.
24            Q.      What was Hans Weber doing

                                                 Page 53

 1 during this period of time?
 2            A.      He was my boss.
 3            Q.      So both you and Doctor Schenk
 4 worked under Doctor Weber?
 5            A.      That's correct.  I mean he was
 6 medical director in Germany when I joined so
 7 actually he recruited me, and Doctor Schenk and
 8 myself were in the same kind of positions just
 9 for different product areas reporting to Weber.
10            Q.      Did -- when you first took
11 over responsibility for Prozac -- do you mind if
12 I call it Prozac, is that okay?  I could call it
13 Fluctin but --
14            A.      I know what --
15            Q.      When I say Prozac, I mean
16 Fluctin.
17            A.      Well, you could say
18 fluoxetine.  But that's fine, I know what Prozac
19 is.
20            Q.      When you took over
21 responsibility for Prozac, was Doctor Weber still
22 in Bad Homburg or had he gone to Indianapolis at
23 that point?
24            A.      No, at that time he was still

                                                 Page 54

 1 in Bad Homburg.
 2            Q.      Do you recall whether or not
 3 you took over responsibility for Prozac before or
 4 after the intent to reject letter was issued by
 5 the BGA in February of 1985?
 6            A.      Excuse me, say that again.
 7            Q.      Okay.  We know that the intent
 8 to reject letter was issued by the BGA in
 9 February, 1985, okay?
10            A.      Uh-huh.
11            Q.      Do you recall whether or not
12 you started with your responsibilities on Prozac
13 before or after that?
14            A.      After.
15            Q.      Do you recall how long after?
16            A.      No, I don't, because actually
17 I didn't know that this was February, '85, and I
18 think it was rather late in '85 -- I mean the
19 latter half of the year that I was taking over
20 and I don't know precisely the period, but it was
21 after.
22            Q.      Okay.  Before taking over from
23 Doctor Schenk, did you have any responsibilities
24 whatsoever with regards to Prozac?

                                                 Page 55

 1            A.      No, I did not have any
 2 responsibility.
 3            Q.      Before you took over for
 4 Doctor Schenk, did you have -- strike that.
 5                    Before you took over for
 6 Doctor Schenk, had you worked on registering
 7 other Lilly drugs in Germany?
 8            A.      No, because as I said, it was
 9 basically evolving with Prozac that Lilly Germany
10 and also other affiliates became more involved in
11 what you would call development work.  And up to
12 then, we were only working I mean on one other
13 kind of trials.  And that -- well, that's the
14 answer to the question, that means by then, there
15 was actually nothing to register for me.  I was
16 responsible for all we're marketed products with
17 one exception, where I do not actually know
18 anymore when we submitted this, if this was
19 shortly before or after, because the problem was
20 when I was taking over, it didn't immediately
21 mean, we had a new physician so there was a
22 period when I was responsible for quite a lot.
23 So there might have been some overlap with
24 another drug, in a totally different field,

                                                 Page 56

 1 submitted also but I thought that was later, and
 2 probably not the sequence.
 3            Q.      Do you know prior to Prozac
 4 being registered in Germany, had Lilly registered
 5 any other antidepressant drugs in Germany?
 6            A.      I'm just hesitating here
 7 because I mean Lilly has another antidepressant
 8 which is a very old product and I'm even not sure
 9 if it's on the German market, if so, it had been
10 registered long before I joined Lilly.  But that
11 would have been the very old type of thing, you
12 know, you take the U.S. data and within three
13 months, the BGA says yes.  So again I'm not sure
14 if this ever happened.  For us and while I was
15 there, Prozac was definitely the first one.
16            Q.      Is this drug nortriptyline?
17            A.      Yes, if at all we talk about
18 nortriptyline, but again I'm not sure if or when
19 it has registered and, again, when that was
20 totally different.
21            Q.      When you say it was totally
22 different, you mean the registration or the
23 regulatory requirements were different?
24            A.      Exactly.

                                                 Page 57

 1            Q.      Were they less strict than
 2 they are now?
 3            A.      Well, first of all, that they
 4 would have been less strict, and also as in many
 5 other countries in the '60s, and maybe even to
 6 some extent the '70s, many drugs were simply
 7 approved on a U.S. package and that's not
 8 possible anymore in Europe.
 9            Q.      So in other words the drug
10 would be approved in Germany based on the U.S.
11 package insert?
12            A.      That's absolutely correct.
13            Q.      Do you know why that changed?
14            A.      Well, I mean I can offer a lot
15 of speculations but actually I don't know because
16 that's in a kind of a political or regulatory
17 aspect.
18            Q.      Do you know when that changed?
19            A.      Well, it definitely started to
20 change in the '80s, and Fluctin is an excellent
21 example because initially it was submitted only
22 with U.S. data and obviously it turned out that
23 for those study populations, there might be
24 different perceptions in different medical

                                                 Page 58

 1 cultures.  Actually there are different
 2 classification schemes, I mean that's a fact, and
 3 so far it became obvious that it's also important
 4 to generate data in the respective country.  So I
 5 see this as an evolving process and fluoxetine
 6 just was in the middle of that.
 7            Q.      When you started with Lilly in
 8 October of '83, was it still pretty much --
 9 strike that.
10                    When you started with Lilly in
11 October of '83, was the registration process
12 still pretty much you could submit the U.S.
13 package and get approval on, based on the U.S.
14 package?
15            A.      Let me put it that way,
16 because I think '83 at least we didn't submit
17 anything at least when I joined there and so it's
18 difficult to judge.  What I can tell you is
19 another very famous drug, Ceclor, which is a
20 Lilly drug and a very widely distributed one, was
21 registered in '78 or '79 exclusively with the
22 U.S. data.  So that might serve as an example of
23 the old style.  But after Ceclor, I actually
24 don't know what we submitted until we then came

                                                 Page 59

 1 in with Prozac.  So there is a period in the
 2 early '80s, I do not really know what happened.
 3            Q.      Is this phenomena of going
 4 from accepting the U.S. package insert in support
 5 of -- or the U.S. package in support of
 6 registration in Europe, was that something that
 7 was exclusive to Germany or was that something
 8 that was pretty much done all over Europe?
 9            A.      As far as I'm aware, it was
10 done in many other countries.  I'm not so sure
11 about the U.K., I would guess they always have
12 been a little bit more demanding than that.  But
13 again to get this straight, the package insert
14 was local and of course always the BGA as the FDA
15 takes, I mean, the liberty and the right to say,
16 I mean that's how we want to have it labeled, so
17 that was not necessarily the same.  But it was
18 granted based on data which had been, I mean,
19 identical to those in the United States.
20            Q.      So when you say the U.S.
21 package, you mean the NDA, not the package
22 insert?
23            A.      Correct.
24            Q.      You can't submit the package

                                                 Page 60

 1 insert --
 2            A.      It's the NDA package or
 3 dossier or whatever and that's based on data
 4 which had been at that time exclusively generated
 5 also in the United States.
 6            Q.      Okay.  Are you familiar with
 7 Lilly's drug, Aventyl?
 8            A.      Excuse me?
 9            Q.      Are you familiar with a drug
10 named Aventyl, Aventyl, A-V?
11            A.      Okay, well that's the
12 nortriptyline.
13            Q.      That's the trade name for
14 nortriptyline, or the brand name?
15            A.      That's the brand name, yes,
16 familiar is exaggerated because I mean we -- I
17 don't know, maybe we have sold ten packages per
18 year in Germany or whatever.  I mean it was not,
19 it really was not on our list for attention.
20            Q.      You sold ten packages a year?
21            A.      It was insignificant, that's
22 why I'm not familiar with that, we didn't do
23 anything for that.
24            Q.      Do you know why it is that it

                                                 Page 61

 1 sold so poorly over there?
 2            A.      You know, there are always --
 3 that has certainly nothing to do with the quality
 4 of the drug, I would rather say it has to do with
 5 Lilly always having been an antibiotic focused
 6 company and not making very much efforts to get
 7 into --
 8            Q.      Do you still consider Lilly an
 9 antibiotic focused company?
10            A.      Well, obviously that has
11 changed.
12            Q.      With the event of Prozac,
13 correct?
14            A.      I think that's correct to say.
15            Q.      What is your -- strike that.
16                    Explain for the jury, Doctor,
17 what the regulatory structure, as you understand
18 it, in Germany is.  When I say that, I mean like
19 the BGA as related to the Commission A, things
20 like that.
21            A.      Well, basically we talk about
22 the new drug approval and so the data, the data
23 package, the dossier, the NDA, is being submitted
24 to the BGA, there are certain procedures within

                                                 Page 62

 1 the agency how and when to review, and at some
 2 point in time of the process this is being
 3 presented to a committee, which in fact we call
 4 Commision Aso or Commission A, and this committee
 5 is composed of non-BGA people, usually experts
 6 from academia, physicians or maybe also Ph.D kind
 7 of professors, if it would make sense, and there
 8 are also different ones according to therapeautic
 9 categories, and this commission -- so those
10 experts get this presented and they obviously
11 give their expert opinion, they deliberated and
12 come up with finally recommendation.  Now the
13 process usually is there might be more than one
14 deliberations, but right at the end there would
15 be a recommendation to approve or not approve the
16 drug, and they may also even specify more under
17 which conditions, and this again is the
18 recommendation.  This goes back then to the BGA
19 and the BGA will then have its final
20 deliberations resulting in a conclusion to
21 approve, yes or no.  That's basically the
22 process.  So the point is that in contrast to the
23 FDA, there is an external body which is served by
24 let's say experts, who takes an important -- or

                                                 Page 63

 1 plays an important role in the approval because
 2 what also should be mentioned, BGA officers, some
 3 may be experts in the area, some not necessarily,
 4 in any case there is as far as I understand it, a
 5 little bit of difference to the typical FDA
 6 reviewer.
 7            Q.      Okay.
 8            A.      So that's basically, maybe you
 9 have more questions to elucidate that.
10            Q.      Let me make sure I understand.
11 The BGA -- you submit your application or your
12 dossier for a particular drug to the BGA itself,
13 correct?
14            A.      Correct.
15            Q.      And the BGA reviews your
16 application, correct?
17            A.      Right.
18            Q.      Now is there a period of time
19 before they submit it to the commission where
20 they may ask for more information?
21            A.      Yes, that's right.
22            Q.      So there's some interchange
23 between the BGA and the drug company before the
24 package goes to the Commission, correct?

                                                 Page 64

 1            A.      That's correct.
 2            Q.      And then the Commission
 3 reviews the information -- when the BGA feels
 4 it's ready, it sends the package to the
 5 Commission, correct?
 6            A.      That's I think a proper
 7 statement.
 8            Q.      Then the Commission's job is
 9 to review the package as it's presented to it by
10 the BGA?
11            A.      Correct.
12            Q.      And deliberate, render
13 opinions and make recommendations on either
14 whether or not to register the drug or additional
15 information it needs, or both, correct?
16            A.      Uh-huh.
17            Q.      In fact, what happened with
18 Prozac is the Commission and the BGA came back
19 with an intent to reject letter saying this is
20 why we're intending to reject this, if you can
21 rectify these problems then we will reconsider or
22 we will recommend registration, correct?
23            A.      Yes.
24            Q.      After the Commission is done

                                                 Page 65

 1 it sends back their opinions and deliberations
 2 and recommendations to the BGA which then makes
 3 the final decision, correct?
 4            A.      The final decision is made by
 5 the BGA, yes.
 6            Q.      It's very rare for the BGA to
 7 make a finding contrary to what the Commission
 8 recommends though, is it not?
 9            A.      I'm not aware of any case they
10 would have done that, although they could, yes.
11            Q.      And to a certain extent, the
12 BGA and the Commission A are set up to be not so
13 much adversarial but to kind of counter-balance
14 one another, aren't they, so that there's no one
15 regulatory body that's making this whole decision
16 on a product?
17            A.      Well, I actually don't know
18 what the intention of, you know, the whole set up
19 was, whoever designed it.  But of course there
20 are occasionally different opinions within the
21 Commission between the officer and the Commission
22 but I would see this as a kind of natural and
23 healthy debate as you would have it also in a
24 scientific setting where not necessarily

                                                 Page 66

 1 everybody interprets results the same way.  And
 2 so far you may be right that it has been set up
 3 in order to get this healthy, maybe sometimes
 4 even tension, to come up with results that for
 5 the community are just beneficial.
 6            Q.      What I'm trying to get at is
 7 the Commission is not beholden to the BGA in any
 8 way, is it?  They're not a part of the BGA, they
 9 aren't responsible to the BGA?
10            A.      That's absolutely so.
11            Q.      And vice-versa, correct?
12            A.      They can do what they want,
13 yes.
14            Q.      And the BGA has the option of
15 either taking their recommendation or not taking
16 their recommendation?
17            A.      Correct.
18            Q.      But it's not like the
19 Commission is a branch that is set up by the BGA,
20 that is responsible to the BGA over who, for
21 instance, somebody at the BGA is the boss of
22 everybody on the Commission, it's set up so that
23 they are two separate entities that work together
24 in some respects and work in a scientific debate

                                                 Page 67

 1 type of level in some respects, correct?
 2            A.      That's correct, I mean all the
 3 members of the Commission A will have any other
 4 job but a BGA job, and the BGA itself is
 5 reporting up to the Ministry, so they're
 6 completely different lines.
 7            Q.      So in fact members of the
 8 Commission are not allowed to work for the BGA,
 9 correct?
10            A.      I don't know if there's an
11 explicit rule but I would perceive that this is
12 basically the intent.
13            Q.      Okay.  Members of the
14 Commission are like you said experts in their
15 field, correct, considered generally?
16            A.      Considered generally, yes.
17            Q.      And some of these were at some
18 time or another all of these members, not just in
19 the psychiatric field but in all the other
20 fields, tend to work either within the industry
21 in private practice or for drug companies,
22 correct?
23            A.      Say that again.  You say the
24 Commission members --

                                                 Page 68

 1            Q.      The Commission members can --
 2            A.      They can be everything, that's
 3 right.  Most of them would come from academia but
 4 they could also work for drug companies, I mean
 5 if they're qualified to speak on the subject, I'm
 6 not aware that this should not be possible.
 7            Q.      Clinical investigators for
 8 drug companies in Germany as they do here in the
 9 United States, a lot of times work for academia,
10 do they not?
11            A.      Clinical investigators who do
12 clinical trials for drug companies, yes, very
13 often work for academia, yes.
14            Q.      And there's no prohibition
15 about having a member of the Commission do
16 clinical trials for drug companies, is there?
17            A.      No, not at all.  So because
18 also the membership rotates and for example I
19 mean if you sit today on the the Commission but
20 not tomorrow, I mean that wouldn't -- we can do a
21 trial but the same time you can do a trial today
22 and then all of a sudden you're appointed
23 tomorrow, so what do we do then.  I think the
24 agreement simply is if such situations occur, and

                                                 Page 69

 1 I know they have occurred, that it's expected,
 2 the one having been involved in whatever program
 3 would either not vote or actually definitely not
 4 vote or even leave the room when things are
 5 deliberated on this subject.
 6            Q.      Okay.
 7            A.      So that's basically I think
 8 the approach.
 9            Q.      Do you know for a fact that
10 for instance if you had somebody on the
11 Commission who was on the Commission when it was
12 considering Prozac, and that person had -- either
13 was or had done a clinical trial for Lilly on
14 Prozac, do you know for a fact that they are
15 required to leave the room or are they just not
16 allowed to vote?
17            A.      Actually, I don't know how
18 they -- how they finally deal with that, but I
19 know that anything to participate in the decision
20 which may be impacted by their, whatever, bias,
21 should be avoided.  So how they actually deal
22 with it in the room, I mean I've never been in
23 this room, I don't know, but I understand can be
24 both basically, I mean, to definitely not to

                                                 Page 70

 1 vote.  Now if it's even to leave the room, I
 2 don't know, maybe they sit in the room but don't
 3 really participate in the discussion, there may
 4 be all variations.  But of course, yes, just
 5 happens because the community is not so large to
 6 choose from and usually those experts, I mean,
 7 are also very active in investigating new drugs,
 8 so, I mean, this coincidence cannot be avoided
 9 and happens.  And again my understanding is that
10 they deal it -- with it that way, that they
11 definitely don't vote and maybe also stay away
12 from the discussion.
13            Q.      Okay.  Are the drug companies
14 allowed to contact the BGA informally other than
15 writing responses to say intent to reject
16 letters, et cetera?
17            A.      Uh-huh.
18            Q.      Say would somebody from the
19 Lilly office in Bad Homburg be permitted to call
20 somebody at the BGA?
21            A.      Yes, well, definitely so.  I
22 mean it's -- there is no prohibition to contact
23 anybody, I mean in terms of BGA or Commission A
24 members.  It's depending on the reviewer, if he

                                                 Page 71

 1 invites that or even dislikes that, and there are
 2 differences in particular because the FDA is a
 3 kind of regular thing.
 4            Q.      Okay.  Doctor Weber was here
 5 last weekend and he was of the opinion that it
 6 was inappropriate to contact people on the
 7 Commission.
 8            A.      Well, Commission, I made a
 9 difference now.  First of all, your question was?
10            Q.      It was on the BGA?
11            A.      It was on the BGA and it's
12 clearly, the answer is yes, you can contact.  But
13 in fact the experience is that many don't like
14 this very much and for the Commission -- I mean
15 it very much depends.  You know, let's take the
16 time today, we have worked over the years now
17 with virtually everybody in the circles which
18 presumably would qualify you to become a
19 Commission member and, you know, and you meet
20 those people at Congresses or whatever, you
21 cannot even have to do that and I think or at
22 least it's my perception, you are not required to
23 go out of the room or to make a by-pass just not
24 to run into those persons.  Sometimes you may not

                                                 Page 72

 1 even know, you know, that they're sitting on the
 2 Commission, this is -- but because there are many
 3 people and who will be the repporteur is not
 4 always known in advance.  Anyway, the point is
 5 that sometimes you cannot avoid, the point is
 6 that you definitely, I think it's a gentleman's
 7 agreement, you would not or should not exert
 8 influence on those people.
 9            Q.      Okay.
10            A.      That's definitely, and I think
11 that's very much depending also on the individual
12 who is sitting on the Commission where he feels I
13 mean now this is something should not be done or
14 not, but again it sometimes is not avoidable that
15 you run into these people.
16            Q.      Okay.  Well, there's a
17 difference between running into somebody who's on
18 the Commission at a meeting and calling them up
19 when your drug is under consideration and asking
20 them questions or telling them your opinion,
21 correct?
22            A.      Yes, that's certainly true.
23            Q.      So there's no prohibition for
24 you to say hello to them at a conference or even

                                                 Page 73

 1 hire them before or after they're on the
 2 Commission to be experts for your clinical
 3 investigators, correct?
 4            A.      Yes.
 5            Q.      Okay.  The problem comes when
 6 you try to contact these people or use your
 7 connections with these people while these people
 8 are on the Commission and considering your drug,
 9 correct?
10            A.      Well, here even I would make a
11 difference what the exact timing is.
12            Q.      So you're saying it's
13 appropriate for somebody to call a drug
14 manufacturer, to use your own words, exert
15 influence over somebody on the Commission through
16 using their contacts while they're considering
17 their drug?
18            MR. LORE:  That's not what he said, so
19 I object to the form.
20            Q.      Clarify it for me, Doctor,
21 because I'm confused.
22            A.      I think it makes a big
23 difference if you try to -- you say while being
24 considered, I mean if I try to brief somebody

                                                 Page 74

 1 before the meeting, then it's definitely
 2 inappropriate.
 3            Q.      Okay.
 4            A.      And I frankly speaking would
 5 never do it because I think the risk is much too
 6 high that this individual is so mad about that
 7 that it would rather unfavorably influence him,
 8 so that's something.  Now, I think when the
 9 discussion has been done, so basically there is
10 no way to influence what happened, but I mean it
11 may be just interesting to know what concerns in
12 the discussion have been raised, then I think
13 it's not totally inappropriate to -- I mean if
14 it's possible to learn something, to do into.
15 Again I would see there a major difference
16 because when the discussion has been done, you
17 cannot really -- I mean you cannot influence it
18 anymore, so I really would make this difference
19 and that means it's always inappropriate and if
20 you try to make a contact with the intention to
21 influence, that's what I would say, but not to
22 get information after the fact.
23            Q.      Okay.  Is it fair to say that
24 it's improper to try to make a contact directly

                                                 Page 75

 1 or indirectly before the decision is made?
 2            A.      Well, again, I mean these are
 3 all gentleman agreements and the community is
 4 small, so again everything to try to influence
 5 inadequately a Commission member before he is
 6 supposed to go into a deliberation on your drug
 7 presumably is inappropriate.  But these things
 8 always are underlying judgment calls because
 9 again, we can, I mean, have a very close
10 relationship through whatever, scientific work or
11 in some cases even because we were classmates in
12 medical school, I mean the situations are very
13 real, and now you happen to sit on the Commission
14 and I happen to be with Lilly, and we can have
15 dinner tonight and I think it's really a matter
16 of the properness of the character or the
17 personality in how far I would exploit that or
18 not, and presumably I would not exploit it to
19 bring a friend not in a bad position, or conflict
20 of interest.  So that's why I'm saying it's a
21 judgment call because you cannot avoid cases
22 where you might come in contact but still -- and
23 you're not supposed, I mean again, to go into the
24 other room, but I still think, yes, you should

                                                 Page 76

 1 not exploit it and it's inappropriate if you take
 2 whatever measure to influence this individual
 3 over-favorably in terms of your company's
 4 interest.  So it's very fine-tuned kind of thing.
 5            Q.      When I say indirectly, I don't
 6 necessarily mean establishing friendships in the
 7 hopes that someday they will benefit you, okay.
 8 What I'm saying is making a contact with somebody
 9 on the Commission, not directly from a Lilly
10 employee to that member of the Commission, but
11 somehow through somebody else who may know the
12 Commission member.  Do you see what I'm saying?
13            A.      Yes, well, but I mean --
14            Q.      Is that appropriate, if
15 they're deliberating on your drug?
16            A.      I think there's -- and I say
17 it again, there's nothing appropriate to
18 influence this process overly in the interest of
19 the company.  But now again, I mean if I talked
20 to Professor X about fluoxetine, and, you know,
21 Professor X knows Professor B, and B sits on the
22 Commission, I mean all those guys talk to each
23 other.
24            Q.      But if you called Professor X

                                                 Page 77

 1 and say I want you to call Professor B, that's
 2 inappropriate, is it not?
 3            A.      Well, that's presumably
 4 inappropriate, but I mean, again, I mean you
 5 would presumably not do it that way.
 6            Q.      Okay.
 7            MS. ZETTLER:  Let's take a break.
 8            (A SHORT BREAK WAS TAKEN.)
 9            Q.      (BY MS. ZETTLER)  Okay.
10 Doctor, when you first started working on Prozac
11 at the German affiliate in Bad Homburg, were
12 there any psychiatrists working on the drug at
13 that affiliate?
14            A.      No.
15            Q.      Have there ever been
16 psychiatrists working on Prozac to your knowledge
17 at the affiliate in Bad Homburg, working on
18 Prozac?
19            A.      Well, not as long as I was
20 there.
21            Q.      So the entire time you were
22 there, there were no psychiatrists working on the
23 drug?
24            A.      Yes.

                                                 Page 78

 1             (PLAINTIFFS' EXHIBIT NO. 1 WAS
 2              MARKED FOR IDENTIFICATION AND
 3              RECEIVED IN EVIDENCE.)
 4            Q.      Doctor, you've been handed
 5 Exhibit Number 1.  Please take a couple of
 6 minutes to look through that.
 7            (WITNESS REVIEWS DOCUMENT.)
 8            Q.      Okay, have you had a chance to
 9 review Exhibit 1?
10            A.      Yes.
11            Q.      Do you recognize that exhibit,
12 Doctor?
13            A.      Well, it was obviously written
14 before I was responsible for the product so I
15 definitely --
16            Q.      Well, the first page of the
17 exhibit appears --
18            A.      Yes, it's even copying me, but
19 anyway I looked into these things retrospectively
20 because when I was responsible for the product,
21 it was also under my time that I made the partial
22 resubmission, and in order to put this together,
23 I looked into some of these documents.
24            Q.      The first page of the exhibit

                                                 Page 79

 1 is a telecopy written by a B. von Keitz in Bad
 2 Homburg, correct?
 3            A.      Uh-huh.
 4            Q.      You have to say yes or no.
 5            A.      Yes.
 6            Q.      And you are listed -- who is
 7 B. Gennery, do you know?
 8            A.      Yes.  Doctor Gennery was -- I
 9 don't recall what his exact title was but he was
10 a physician at our research center in Erl Wood,
11 U.K.
12            Q.      That's in England, right?
13            A.      In England, it's close to
14 London, and he was the head of the Erl Wood
15 medical group.  He, himself, was reporting back
16 to Indianapolis so he was a kind of European
17 medical coordination.
18            Q.      Okay.  And you were listed as
19 a recipient under the carbon copy portion of the
20 telecopy, correct?
21            A.      That's correct.
22            Q.      Would this indicate to you
23 that at the time that this telecopy was written,
24 that you had responsibility for Prozac?

                                                 Page 80

 1            A.      Yes, I would think so,
 2 although this is not dated here.
 3            Q.      The second page has a date at
 4 the top of February 26, 1985.
 5            A.      Yes.
 6            Q.      Does that refresh your
 7 recollection as to when you became responsible
 8 for Prozac?
 9            A.      As far as I recall, that would
10 have been before I was responsible, yes, it was,
11 must have been before.
12            Q.      Do you know why you would have
13 been included as a carbon copy on B. von Keitz's
14 telecopy then?
15            A.      Well, actually this fax here
16 is not dated, I'm really not sure when it was
17 sent.  It might have been sent later.  I'm just
18 referring to this document.  But anyway, I mean
19 the attachment here obviously is from the BGA.
20            Q.      It's their intent to reject
21 letter, is it not?
22            A.      And the point is that when
23 they sent this as you say intent to reject letter
24 to Lilly Germany, I mean that was really to the

                                                 Page 81

 1 best of my knowledge before I became responsible.
 2 But because it's such a major document, it was
 3 referred to later and of course I was involved in
 4 some of the points which are mentioned here.
 5            Q.      Okay.  Do you recall having
 6 seen -- strike that.
 7                    The letter attached to Barbara
 8 von Keitz's telecopy is in fact a translation of
 9 the BGA's intent to reject letter on fluoxetine,
10 correct?
11            A.      Yes, I think so.
12            Q.      Okay.  Do you recall seeing
13 this letter, either the German version or the
14 English translation before today?
15            A.      Well, I mean, having worked on
16 fluoxetine basically from -- well, anyway, I
17 specified the period before, the end of '85 and
18 then basically before I left to Japan, and
19 because it's such an important document, I would
20 be rather sure to have seen or read it at some
21 point.
22            Q.      Are you familiar with the
23 issues that they raised though, are you not?
24            A.      I'm familiar with most of

                                                 Page 82

 1 them, not all, because in the later course of the
 2 registration, there were basically -- not all of
 3 them were raised again or were an issue of
 4 discussion.
 5            Q.      Did you not in fact work on
 6 the response to this letter?
 7            A.      Yes, that's what I said, I was
 8 doing the resubmission and yet it is -- there
 9 were points of more importance requiring more
10 deliberation than others, and that's what I mean
11 with I'm more familiar with some of them.
12            Q.      Which points are you more
13 familiar with?
14            A.      Well, one I can in particular
15 remember is on the second page, the 2.3 which
16 refers to this so-called lipidosis thing which in
17 fact was a preclinical finding and which was also
18 of course part of the first submission and
19 induced this concern and there were many
20 investigations and including an expert opinion
21 also from a German internist which, well, which
22 we just all needed to generate and to discuss
23 before we could sufficiently respond to that.  So
24 that's clearly something which had quite a lot of

                                                 Page 83

 1 attention.
 2            Q.      What about 2.1, are you
 3 familiar with that issue?
 4            A.      Yes, well, of course, there
 5 always has been discussion.
 6            Q.      2.1 says --
 7            A.      Yes, well, I mean first of
 8 all, I think -- do you have the German original?
 9            Q.      No.  But let me say, the
10 translation reads, the use of the preparations
11 seems objectionable as the increase in agitating
12 effect occurs earlier than the mood elevating
13 effect and therefore an increased risk of suicide
14 exists, correct?
15            A.      Yes, that's correct what you
16 read, but that's why I'm asking for the original
17 because I'm not sure how that was really phrased
18 in German.
19            Q.      Did you bring up the
20 difference, at least your perceived differences
21 in the German way it was written and the way it
22 was translated before today?
23            A.      The point is that --
24            Q.      No, Doctor, answer my

                                                 Page 84

 1 question.  Did you raise a difference --
 2            A.      Did you --
 3            Q.      When you read the question,
 4 when you read this translation, did you raise the
 5 difference when you first read it or is today the
 6 first time that you noticed a difference between
 7 the German version and the English translation?
 8            MR. LORE:  I object to the form
 9 because he's asked for the German translation.  I
10 don't know that he has said there is a
11 difference, he just requested it so that he could
12 see if there was a difference.
13            Q.      Let me -- you seem to have a
14 question on whether or not this translation is
15 accurate, correct?
16            A.      Yes.
17            Q.      At least to this one
18 paragraph, What is it that raises the question of
19 whether or not this is accurate in your mind?
20            A.      Well, because of the
21 agitating.  But the point is that in fact there's
22 always -- translation is a difficult business in
23 terms of really conveying what is intended and
24 that's why I was -- because we're talking here

                                                 Page 85

 1 about very technical and difficult to assess
 2 terms.  That's why I was asking for that.
 3            Q.      What word do you think should
 4 have been used instead of agitated?
 5            A.      Well, basically, there is more
 6 the talk about sedating on the one side and
 7 activating on the other.
 8            Q.      Did the German government to
 9 your recollection use the word activating as
10 opposed to agitating?  Because this is not a
11 Lilly created document, this is a Lilly
12 translation of the BGA document, correct?
13            A.      Yes.
14            Q.      Do you have a specific
15 recollection of the German government using the
16 word or the equivalent of the word activating as
17 opposed to the equivalent of the word agitating?
18            A.      This is -- I mean without
19 seeing the document and years ago and being under
20 both, it's difficult for me to say yes or no.  I
21 would assume it's rather activating.
22            Q.      I'm not asking you about what
23 your assumption of the drug is, I'm asking you
24 what your recollection of what the word the

                                                 Page 86

 1 German government used is?
 2            A.      So then I must say that right
 3 now many years after, I cannot say yes or no, so
 4 I don't have precise enough recollection to say
 5 what the German government used in the German
 6 original.
 7            Q.      Okay.  Did you review any
 8 documents in preparation for your deposition?
 9            A.      No.
10            Q.      Did you ask to see any
11 documents in preparation for your deposition?
12            A.      No.
13            Q.      Regardless of your
14 recollection or your possible recollection of
15 what wording was used by the German government as
16 opposed to what language is used here --
17            A.      Uh-huh.
18            Q.      -- do you recall there being
19 an issue raised by the BGA in their intent to
20 reject letter or at any other time, as to whether
21 or not fluoxetine causes an increased risk of
22 suicide in patients taking it?
23            A.      Well, that's all of the same.
24 I mean, first of all, activating --

                                                 Page 87

 1            Q.      I'm not asking about
 2 activating, listen to my question.
 3            A.      Well then you asked about
 4 suicide and this is something different.
 5            Q.      I'm just asking if you recall
 6 if you have, your recollection of the German
 7 government raising the issue, regardless of how
 8 it happened, raising the issue of whether or not
 9 fluoxetine caused an increased risk of suicide?
10            A.      This is correct.  They raised
11 this issue but this is not 2.1, that's why I was
12 confused, sorry.
13            Q.      Let me ask you this, point 2
14 says:  For the drugs' concerned there is
15 according to their specific profile of adverse
16 effects, the justified suspicion that they have
17 unacceptable damaging effects.  Do you see that?
18            A.      Uh-huh.
19            Q.      You have to say yes or no.
20            A.      Yes.
21            Q.      And after that, it seems to
22 quote a regulation, does that look like a
23 regulation quote to you?
24            A.      Yes, that's the drug rule.

                                                 Page 88

 1            Q.      Okay.  What is that specific
 2 regulation, does it have to do with unacceptable
 3 damaging effects of the drug?
 4            A.      I'm not sure what is
 5 specifically in paragraph twenty-five but I would
 6 think it relates simply to the provision of the
 7 drug law that in order to approve drugs or
 8 actually make them available to use of the
 9 public, they must have an appropriate
10 benefit/risk ratio.  That's a kind of term like
11 this and that's presumably what this refers to.
12            Q.      They cannot have unacceptable
13 damaging effects obviously.
14            A.      Well, that's very obvious.  I
15 mean, so -- but the law is obviously very
16 unspecific of that, so it's basically saying that
17 benefit/risk must be okay and it says here
18 unacceptable.
19            Q.      Section 2.1 and 2.2 and 2.3 go
20 on to explain what they mean by unacceptable
21 damaging effects, do they not?
22            A.      Well, obviously the answer to
23 your question is it appears that what is listed
24 here the agency sees as effects, which they think

                                                 Page 89

 1 that are unacceptable, and I should add as
 2 presented in the dossier, they could review
 3 first.
 4            Q.      Okay.  My simply -- strike
 5 that.
 6                    My question is simply whether
 7 or not the unacceptable damaging effects referred
 8 to in paragraph two are then elaborated on in
 9 paragraphs 2.1 through 2.3, at least in the
10 opinion of the BGA?
11            A.      Uh-huh.
12            Q.      Does that appear to be
13 correct?
14            A.      Yes.  So the -- let's say it --
15 so the negative -- there are positive effects and
16 negative effects and the negative effects which
17 they think to be unacceptable, it says here are
18 obviously addressed in 2.1 point 2.3.
19            Q.      So your understanding is that
20 the unacceptable damaging effects that the BGA
21 was referring to was their perception of an
22 increased risk of suicide, correct?
23            A.      Yes.
24            Q.      And that in 2.2, what appeared

                                                 Page 90

 1 to be an increase in symptoms of the underlying
 2 disease, such as anxiety, insomnia and agitation,
 3 correct?
 4            A.      Correct.
 5            Q.      And then the one you talked
 6 about earlier, the possibility of lipidosis of
 7 the lung as a result of using the drug, correct?
 8            A.      Correct, those are what they
 9 list as their concerns.
10            Q.      They list them as unacceptable
11 damaging effects in their opinion.
12            A.      Here also I would like to see
13 the original wording, but anyway that's what they
14 say.
15            Q.      Okay.  Now, the first
16 paragraph of the second page of Exhibit 1 which
17 we've established is the translation of the
18 intent to reject letter from the BGA says, after
19 the Commission according to paragraph 25 --
20 section 25, paragraph 6, of the AMG was heard,
21 correct?
22            A.      Yes.
23            Q.      Does that indicate to you that
24 this was after Commission A reviewed the dossier?

                                                 Page 91

 1            A.      Yes.
 2            Q.      So is it your understanding
 3 that the Commission agreed with the BGA at this
 4 point that there was at least still some more
 5 information they wanted to see on the drug?
 6            A.      It appears so.  I mean it says
 7 it heard the Commission and we can assume that
 8 they were all -- maybe we don't know, because the
 9 BGA issue as we worked through earlier,
10 basically, I mean, is not depending on what is
11 being said here.
12            Q.      So at least at this point, the
13 Commission agreed with the BGA's decision to send
14 an intent to reject letter on the drug?
15            A.      Well, I mean, I don't know,
16 but we do not have any evidence that the
17 Commission obviously was in favor of an approval.
18            Q.      Do you recall ever having any
19 evidence that at this point the Commission was in
20 favor of the approval?
21            A.      No, I don't.
22            Q.      The first paragraph of the
23 intent to reject letter, section 1, says that in
24 effect the drug wasn't sufficiently tested

                                                 Page 92

 1 according to the state of scientific knowledge,
 2 correct?
 3            A.      It says here so.
 4            Q.      It goes on to say in 1.1 that
 5 a definite judgment on the efficacy is not
 6 possible because of the methodological problems
 7 at the carrying out of the studies, and then it
 8 lists some examples, correct?
 9            A.      Correct.
10            Q.      Those examples are a short
11 wash-out period, meaning the placebo wash-out
12 period, correct?
13            A.      Correct.
14            Q.      Concomitant treatment with
15 other psychotropic drugs.
16            A.      Correct.
17            Q.      And the choice of control
18 drug, correct?
19            A.      Correct.
20            Q.      These are all issues that were
21 raised by the BGA earlier in their medical
22 opinion, were they not?
23            A.      As far as I recall, yes.
24            Q.      And between the time that the

                                                 Page 93

 1 medical opinion came out and the time that this
 2 intent to reject letter came out, the company had
 3 submitted more information in support of the
 4 application of the drug, correct?
 5            A.      I don't know what they really
 6 had submitted because I mean that was before my
 7 time.
 8            Q.      They responded to the original
 9 letter of concern.
10            A.      Obviously, they need to
11 respond to that but it's a difference if you
12 generate new data or if you just, you know,
13 reevaluate and re-present existing data.
14            Q.      Do you know --
15            A.      I don't know what they really
16 did.  I mean definitely they presented a
17 reevaluation.  I'm not sure if they presented
18 actually new data because for the shorter period
19 of time, presumably not.
20            Q.      But they made an attempt to
21 explain some of the concerns that the BGA saw
22 with the drug, correct?
23            A.      That's presumably fair to
24 assume.

                                                 Page 94

 1            Q.      Still in February of 1985,
 2 after reviewing what the company did in response
 3 to the original letter of concerns --
 4            A.      Uh-huh.
 5            Q.      -- the BGA and the Commission
 6 it appears still thought that the drug wasn't
 7 appropriate for registration, correct?
 8            A.      That's correct.
 9            Q.      What did Lilly do after they
10 got this intent to reject letter?
11            A.      Well, we simply followed the
12 advice of the BGA and started to work on the
13 demonstration of efficacy, and as it's pointed
14 out here in-patient data were missing, so we
15 planned, initiated and finally executed an
16 in-patient trial and we followed their advice in
17 selecting amitryptiline as a comparator, which
18 had not been selected in the United States, and
19 as I mentioned before, we also took very
20 seriously to work on this phospholipidosis issue
21 in several preclinical and clinical experiments,
22 and in terms of methods and other things, we also
23 consulted with experts in order to hear what they
24 would do in order to respond to these concerns.

                                                 Page 95

 1            Q.      So you conducted an in-patient
 2 trial in Germany, correct?
 3            A.      Yes.
 4            Q.      You started using
 5 amitryptiline as a comparator drug?
 6            A.      Yes.
 7            Q.      In the German trials?
 8            A.      Yes.
 9            Q.      And you conducted experiments
10 on the issue of phospholipidosis?
11            A.      They weren't conducted in
12 Germany, but that was done in other place.
13            Q.      But actual experiments were
14 conducted in the trials?
15            A.      Yes.
16            Q.      It wasn't a reanalysis of old
17 data, it was new data?
18            A.      That's right, there were
19 totally new data generated.
20            Q.      What was done in response to
21 the BGA's concerns about the increase in
22 agitating effects and increased risk of suicide?
23            A.      Just all the new data which
24 were accumulated, not only through the in-patient

                                                 Page 96

 1 trial, but also other studies which had been
 2 performed after '95 and were basically -- I don't
 3 know exactly when we resubmitted, but before
 4 that, I mean in that time span, all these data
 5 where reevaluated and looked into in particular
 6 with regard to these concerns.  So that's what we
 7 did.
 8            Q.      This new data that you talked
 9 about, though, was not data that was specifically
10 designed to look at the issue of suicidal
11 ideation or suicidality, was it?
12            A.      That's correct.  I mean these
13 were trials in depressed patients which also and
14 always carry the risk of suicide, the trial were
15 not specifically designed or labeled to be a
16 suicide trial, that's correct.
17            MS. ZETTLER:  I object to the
18 response, everything after that's correct.
19            A.      I'm sorry?
20            Q.      I'm making an objection for
21 the record, Doctor.
22            MR. LORE:  That was an objection she's
23 making for the record, you don't need to pay any
24 attention to that.

                                                 Page 97

 1            Q.      Were any trials conducted on
 2 the issue of activation and the use of
 3 fluoxetine, specifically, not a general
 4 depression trial conducted on the use of
 5 fluoxetine but a specific trial conducted to look
 6 at the issue of whether or not fluoxetine was
 7 agitating or activating?
 8            A.      No, we did not conduct a
 9 specific trial, but in order to get answers to
10 these questions, you do not need to perform a
11 specific trial.
12            MS. ZETTLER:  Object to everything
13 after no, we did not conduct a specific trial, as
14 nonresponsive.
15            Q.      So, in response to the BGA's
16 concerns, the company reevaluated data that it
17 had collected in its other clinical trials on
18 other issues like the efficacy of fluoxetine in
19 certain types of depression or with certain types
20 of patients, correct?
21            A.      That's correct, but I mean
22 that does not mean that through the analysis you
23 do and the way you design the protocols, you
24 wouldn't address these points.  I think there is

                                                 Page 98

 1 nothing like the suicide trial or the agitated
 2 trial, what you said.  You always must consider
 3 what are the appropriate scientific methods to
 4 get the answers to these questions.  And the
 5 trials we designed in fact gave a lot of
 6 information about these problems and these
 7 results were finally also summarized in part of
 8 the resubmission and I think they had been
 9 carefully evaluated by the BGA and all others
10 being involved, and as you might know finally the
11 drug has been approved in Germany.  So it's very
12 natural that on a piece of data which was
13 submitted initially, I mean these concerns were
14 raised, additional investigations were undertaken
15 and these concerns were obviously not that valid
16 anymore.
17            Q.      The BGA, at least as late as
18 1988, wanted to contraindicate this drug for use
19 in patients that were suicidal or agitated, did
20 it not?
21            A.      We had a lot of discussions
22 what would be the appropriate instruction for use
23 and these type of things may have been discussed.
24 I only know that finally conclusions were

                                                 Page 99

 1 reached.
 2            Q.      And one of those conclusions
 3 is that the package insert is to contain a
 4 recommendation that if you have somebody who is a
 5 suicidal risk or agitated that you give a
 6 concomitant sedative on top of fluoxetine, is
 7 that not correct?
 8            A.      Well, I think it's a little
 9 bit more differentiating.  The point is first
10 that any depressive patients has a substantial
11 risk of suicide.
12            Q.      Doctor, my question is what is
13 in the package insert.
14            A.      Well, then please can you let
15 me see before I respond to that?
16            Q.      Sure, sure.
17             (PLAINTIFFS' EXHIBIT NO. 2 WAS
18              MARKED FOR IDENTIFICATION AND
19              RECEIVED IN EVIDENCE.)
20            A.      Now, it says here --
21            Q.      And you're referring to the
22 English translation?
23            A.      It's the English translation
24 and it's under page number two.

                                                 Page 100

 1            Q.      That is the current package
 2 insert or at least the one that was dated March
 3 16th?
 4            A.      Well, obviously --
 5            Q.      Look at the last page, Doctor.
 6            A.      Pardon?
 7            Q.      Look at the last page of the
 8 exhibit.
 9            A.      This is '92, it says here.
10            Q.      International Full Disclosure,
11 IFD, March 16, 1992, correct?
12            A.      Uh-huh.
13            Q.      Okay.  I wanted to make sure
14 we know what we're looking at here.  Okay, under
15 risk patients, it says risk of suicide, does it
16 not?
17            A.      Yes.  I'm just looking through
18 that because '92 obviously was much later.
19 Anyway, yes, so it says under Risk Patients, Risk
20 Of Suicide, Fluctin does not have a general
21 sedative effect on the central nervous system.
22 Therefore, for his/her own safety, the patient
23 must be sufficiently observed until the
24 antidepressive effect of Fluctin sets in.  Taking

                                                 Page 101

 1 an additional sedative may be necessary.  This
 2 also applies in cases of extreme sleep
 3 disturbances or excitability.  That's what it
 4 says.  So I was a little bit, you know -- may be
 5 necessary.
 6            Q.      Well, my question was whether
 7 or not they recommended the use of a concomitant
 8 sedative, not that they required the use.  But
 9 regardless, with regards to suicidal patients or
10 patients with sleep disturbance or who are
11 excitable, it recommends that the doctor may want
12 to use an additional sedative with fluoxetine,
13 correct?
14            A.      May want to use is correct.
15            Q.      Okay.  But at one point in
16 time, the BGA wanted to contradict the use of
17 fluoxetine -- or contraindicate the use of
18 fluoxetine in patients who were suicidal,
19 agitated or had sleep disturbances, correct?
20            A.      I do not recall this because
21 all patients who have depression are suicidal,
22 that would have meant --
23            Q.      All patients who have
24 depression are suicidal?

                                                 Page 102

 1            A.      Have the risk for suicide,
 2 that's a textbook item.
 3            Q.      Please listen very closely to
 4 my question, okay.  The question is, the BGA
 5 wanted to contraindicate the use of Prozac in
 6 patients who were suicidal or a risk of suicide,
 7 not simply depressed patients who were not
 8 suicidal, patients who are suicidal or a risk of
 9 suicide, as well as patients who were agitated or
10 suffering from sleep disturbances, correct?
11            A.      Well, I'm not a psychiatrist
12 but what I know from the textbook is that all
13 patients suffering from depression have a risk of
14 suicide.
15            Q.      Well, I'm not debating
16 psychiatry, Doctor.
17            A.      That's why I cannot respond --
18            Q.      I'm trying to get what your
19 recollection is on what the BGA wanted to do with
20 your drug.
21            A.      Well, then, I must say I don't
22 have the recollection precise enough to answer
23 your question.
24            Q.      Who is a Professor Moeller,

                                                 Page 103

 1 Moeller, are you familiar with a Professor
 2 Moeller, M-O-E-L-L-E-R?
 3            A.      Yes, that's a professor of
 4 psychiatry in Germany.
 5            Q.      How are you familiar with
 6 Professor -- how do you say it, Moeller?
 7            A.      Moeller.
 8            Q.      How are you familiar with
 9 Professor Moeller?
10            A.      Not very much compared to
11 other professors of psychiatry.  I got into touch
12 with him only at the very end of my time in
13 Germany.
14            Q.      Why did you get in touch with
15 Doctor Moeller?
16            A.      I do not recall this but I
17 think there was an -- after the approval, we had
18 a postmarketing surveillance program planned and
19 he also was interested in doing studies.  Anyway,
20 there were some contacts on that.
21            Q.      How about with regards to his
22 position as a member of the Commission, did you
23 ever contact him during that period of time?
24            A.      I have not contacted him with

                                                 Page 104

 1 regard to Commission A.
 2            Q.      When did you first meet
 3 Professor Moeller?
 4            A.      I cannot recall.
 5            Q.      Was it before or after the
 6 drug was approved?
 7            A.      I would rather say after but I
 8 cannot really recall, because as I said, if you
 9 are at academic meetings, you meet one or the
10 other, but because he was not a physician
11 participating in our trials, I did as I said not
12 have very much contact with him.
13            Q.      Do you know of anybody else at
14 Lilly during the period of time before the BGA
15 approved flouxetine in Germany who knew Doctor
16 Moeller?
17            A.      No, I'm not aware of that.
18            Q.      Doctor Weber testified in his
19 deposition that at some point Doctor Moeller
20 acted as an expert on fluoxetine, an efficacy
21 expert.
22            A.      Maybe you're confusing
23 Mueller-Olighausen and Moeller.
24            Q.      No, we talked about both of

                                                 Page 105

 1 them.
 2            A.      Well, but I mean before or
 3 after the approval, when?
 4            Q.      I don't recall if he said
 5 before or after, but I know it wasn't while he
 6 was a member of the Commission.  I'm trying to
 7 get an idea of what your recollection is of when
 8 Doctor Moeller first started working for Lilly as
 9 an expert on fluoxetine?
10            A.      That was definitely after.
11            Q.      How do you know that?
12            A.      Well, I know it for sure that
13 in terms of being involved in trials, there was
14 nothing before.
15            Q.      How about Doctor or Professor
16 Kleinsorge, K-L-E-I-N-S-O-R-G-E?
17            A.      Well, he is a very prominent
18 figure in the German drug industry, clinical
19 research area, so he speaks on a lot of
20 conferences, symposia, on general problems of
21 drugs and drugs' regulation, so I knew his name
22 from there.
23            Q.      Have you ever met Professor
24 Kleinsorge?

                                                 Page 106

 1            A.      I have also met him but I
 2 don't recall when this was.
 3            Q.      Has he ever done any work for
 4 Lilly as far as you know?
 5            A.      I am not aware, I think he was
 6 once invited as a speaker but that's about all, I
 7 don't know more about this.
 8            Q.      How about a Professor Bass?
 9            A.      Professor Bass is the head of
10 the toxicology division of the BGA and I know
11 him, I think he knows me.
12            Q.      How do you know him?
13            A.      Well, same thing, I mean it
14 happens that you know people who work basically
15 in the same area.  The last time I met him was
16 last year at the Conference Of International
17 Immunization in Orlando.
18            Q.      How about Professor
19 Gundert-Remy?
20            A.      Well, she's the boss or was
21 the boss I think of the drug division.  I did not
22 meet with her, I did not know her very well.
23            Q.      Do you know of anybody at
24 Lilly who knew Doctor -- or Professor

                                                 Page 107

 1 Gundert-Remy?
 2            A.      Well, I'm sure Doctor Weber
 3 knows or knew from earlier times.  But no, not
 4 specifically more than that.
 5            Q.      Are you familiar with a
 6 gentleman named Straeter or Straeter?
 7            A.      Yes.
 8            Q.      Who is that?
 9            A.      He is a lawyer who used to be
10 a lawyer at the BGA and served Lilly as a
11 consultant.
12            Q.      What is his first name?
13            A.      Burkhard, spelled B-U-R -- I
14 don't know, there's several ways -- K-H-A-R-D or
15 R-D-T.
16            Q.      Is he a doctor?
17            A.      Well, he definitely is not a
18 medical doctor, he's a lawyer.  I don't know if
19 he is a, what you say, a Ph.D.
20            Q.      He goes by Mister Straeter?
21            A.      Again, I actually don't know
22 because being a doctor myself I usually drop the
23 title for other people.
24            Q.      In fact, Mister Straeter used

                                                 Page 108

 1 to be the head lawyer at the BGA, the head of the
 2 legal department at the BGA, correct?
 3            A.      That's right, uh-huh.
 4            Q.      And Lilly hired him as a
 5 consultant on regulatory issues?
 6            A.      Yes, well, it should be
 7 mentioned, I mean Mister Straeter decided to
 8 leave the BGA and establish his own private
 9 practice and consult with many firms, yes.
10            Q.      He still had a lot of contacts
11 at the BGA when he left, did he not?
12            A.      Well, I think so.
13            MS. ZETTLER:  Let's change the tape.
14            MR. BOUR:  This is the beginning of
15 Tape Number 2 and the time is 11:45.
16            Q.      (BY MS. ZETTLER)   Doctor, are
17 you familiar with a Mister or Doctor Lode,
18 L-O-D-E?
19            A.      L-O-D-E.
20            Q.      Lode, Lode.
21            A.      Yes, I know a Lode who is
22 however an infectious disease specialist.
23            Q.      Okay.
24            A.      But, he's spelled L-O-H-D-E.

                                                 Page 109

 1            Q.      All right.
 2            A.      And you said L-O-D-E?
 3            Q.      Right, are you familiar with
 4 him?
 5            A.      Any more, I think I don't know
 6 him, or I have not.
 7            Q.      How about Claude Bouchy?
 8            A.      Well, that was my boss.
 9            Q.      Okay, Claude was your boss.
10            A.      Uh-huh.
11            Q.      Who is Claude Bouchy, besides
12 your boss?
13            A.      Well, he's French.
14            Q.      Okay.
15            A.      He's a Harvard MBA.
16            Q.      Okay.
17            A.      What else do I know?
18            Q.      He worked for Lilly?
19            A.      He worked for Lilly, yes.
20            Q.      What position did he have when
21 he was your boss?
22            A.      He was general manager of
23 Lilly Germany.
24            Q.      Was he a doctor?

                                                 Page 110

 1            A.      No, he's not.
 2            Q.      Is he an MBA?
 3            A.      He's an MBA, yes.
 4            Q.      He's a businessman, basically.
 5            A.      He is a businessman.
 6            Q.      And where is Mister Bouchy
 7 now?
 8            A.      He is in France working for
 9 another company.
10            Q.      Do you know what company?
11            A.      I think it is Servier or
12 something like this.
13            Q.      When is the last time you
14 talked to Mister Bouchy?
15            A.      Talked, would include
16 telephone?
17            Q.      Yes.
18            A.      That might have been about a
19 year ago.
20            Q.      And did you call Mister Bouchy
21 or did he call you?
22            A.      No, he called me.
23            Q.      Why did he call you?
24            A.      Because of a private business.

                                                 Page 111

 1            Q.      Did he call you with regards
 2 to the depositions that are being taken in these
 3 cases?
 4            A.      No.
 5            Q.      Did the subject matter of the
 6 litigation with Prozac come up during the
 7 conversation?
 8            A.      No, not at all.
 9            Q.      Did he make a business offer
10 to you?
11            A.      Not a business offer in terms
12 of my profession as a physician.  The business
13 was a private business I was relating to was more
14 the offer or invitation to join an investment
15 which has to do with French wine.
16            Q.      Okay.
17             (PLAINTIFFS' EXHIBIT NO. 3 WAS
18              MARKED FOR IDENTIFICATION AND
19              RECEIVED IN EVIDENCE.)
20            A.      This is the same.
21            Q.      I gave you two copies of the
22 same thing, Doctor, because the second copy has
23 names blacked out and the first one is three hole
24 punched on the side which makes it difficult to

                                                 Page 112

 1 read.  Between the two, we have one full copy.
 2            A.      Okay.
 3            Q.      So if you can make it through
 4 the first two pages, I don't think you need to
 5 read the second because it's the same.
 6            A.      Okay.
 7            Q.      Do you recognize Exhibit 2,
 8 Doctor?
 9            MR. LORE:  Isn't that 3?
10            MS. ZETTLER:  I'm sorry, 3.
11            Q.      Do you recognize Exhibit 3?
12            A.      Well, obviously I have
13 received it.  I would not have remembered
14 spontaneously all the details on this.
15            Q.      Do you recall the issues
16 raised within this exhibit?
17            A.      Yes.
18            Q.      Okay.  The exhibit purports to
19 be an August 23, 1989 electronic mail message
20 from Claude Bouchy to yourself as well as others
21 in Germany and in Indianapolis, correct?
22            A.      Yes.
23            Q.      Lilly employees, correct?
24            A.      Uh-huh, yes.

                                                 Page 113

 1            Q.      At the top of the exhibit, it
 2 says under the addressees, it says strictly
 3 sonfidential in capital letturs, does it not?
 4            A.      It does.
 5            Q.      It says regarding the Review
 6 Of Fluoxetine By Commission A, correct?
 7            A.      Yes.
 8            Q.      Does this refresh your
 9 recollection as to whether or not the BGA and in
10 particular Doctor Karkos of the BGA who was the
11 reviewer on fluoxetine, wanted to contraindicate
12 the use of Prozac in people who were suicidal or
13 agitated?
14            A.      The BGA reviewers and also
15 Doctor Karkos had opinions that were not
16 necessarily all shared by us.
17            Q.      Okay.  That's not my question
18 though.  Does this refresh your recollection that
19 Doctor Karkos wanted the drug contraindicated for
20 use in people who were -- who needed sedation?
21            A.      Frankly, I don't recollect it
22 but it's stated here.
23            Q.      In fact it says, on the issue
24 of the indication, the proposal of Doctor Karkos,

                                                 Page 114

 1 the BGA reviewer, to have fluoxetine reserved
 2 when the treatment with other antidepressants was
 3 successful and when no sedation is required,
 4 correct?
 5            A.      That's what it says here.
 6            Q.      Okay.  So it was Doctor
 7 Karkos' position that the drug should only be
 8 used as a second line antidepressant, correct?
 9            A.      That is what it suggests.
10            Q.      And in cases where a person
11 was not suffering a condition where they needed
12 sedation before they even got on Prozac, correct?
13            A.      Yes.
14            Q.      The paragraph goes on to say
15 that Doctor Karkos' position was strongly and
16 apparently successfully challenged by the
17 rapporteur, Professor Moeller and by Professor
18 Kleinsorge, correct?
19            A.      Yes.
20            Q.      And that means that Doctor
21 Moeller and Doctor Kleinsorge at this time were
22 members of the Commission A, correct?
23            A.      Correct.
24            Q.      It goes on to say, both had

                                                 Page 115

 1 been contacted directly and indirectly by us and
 2 based on what I heard through Straeter and Lode,
 3 the Commission A voted in the end that fluoxetine
 4 be indicated for the treatment of depression,
 5 correct?
 6            A.      That's what it says here.
 7            Q.      Do you know who contacted
 8 Professors Moeller and Kleinsorge directly and/or
 9 indirectly from Lilly?
10            A.      I really don't know because I
11 have not contacted Professor Moeller or Professor
12 Kleinsorge directly.
13            Q.      In your opinion is it
14 appropriate for people from Lilly to directly or
15 indirectly contact members of the Commission when
16 they're getting ready to debate a drug that is
17 under consideration?
18            A.      I talked about this before,
19 you can contact them, it's a matter of what you
20 talk to them.
21            Q.      Well, it sure appears from
22 Mister Bouchy's memo that they contacted them
23 directly and indirectly on the issue of the
24 indications for the use of Prozac, does it not?

                                                 Page 116

 1            A.      That's what Mister Bouchy
 2 says.
 3            Q.      If that in fact is the case,
 4 is that appropriate, in your opinion?
 5            A.      To exert inappropriate
 6 influence on the Commission members is definitely
 7 inappropriate.
 8            Q.      And you feel at least as it's
 9 set out in this memorandum that it appears that
10 there was some inappropriate influence exerted on
11 Professors Moeller and Kleinsorge?
12            MR. LORE:  I object to the form of the
13 question, that's not what he said and that's not
14 what this memo says.
15            MS. ZETTLER:  Well, it certainly is.
16            MR. LORE:  It does not say anything
17 about exerting inappropriate influence, Nancy,
18 but the memo says what it says and the doctor has
19 responded to your question earlier.
20            Q.      Doctor, you can answer the
21 question.
22            MR. LORE:  You can still answer it if
23 you understand what her question, what she's
24 talking about.

                                                 Page 117

 1            A.      Yes, well, again, I mean, that --
 2 inappropriately exert influence is to push
 3 somebody in doing something which he might
 4 otherwise have not done and that's exactly what
 5 is inappropriate.
 6            Q.      Well, we've got a situation
 7 here, Doctor, where Commission A initially is in
 8 line with the BGA on what they're requiring that
 9 Lilly show with regards to the drug back in 1985,
10 correct?
11            A.      That's correct, but there have
12 been totally different members.
13            Q.      Okay, but now we have a
14 situation where we have direct and indirect
15 contact by Lilly to two members of the BGA who
16 then strongly and successfully challenge the
17 BGA's opinion on how the drug should -- what
18 indications the drug should be used for, correct?
19            A.      That's what it says here in
20 the message.
21            Q.      Is that appropriate in your
22 opinion?
23            A.      I mean we can turn in circles.
24            Q.      You have no opinion either

                                                 Page 118

 1 way?
 2            A.      I have no opinion in the
 3 context of your question.
 4            Q.      Do you have an opinion in the
 5 context of the memorandum?
 6            A.      I'm repeating that
 7 inappropriately exerting influence is
 8 inappropriate.
 9            Q.      It goes on to say on the issue
10 of contraindications and warnings, all I have
11 been able to gather at this point in time is that
12 they should be reworded, correct?
13            A.      Excuse me, which one was that
14 again?
15            Q.      The third paragraph down, it
16 says on the issue of contraindications and
17 warnings, all I have been able to gather at this
18 point in time is that they should be reworded,
19 correct?
20            A.      Yes.
21            Q.      Doctor Karkos went on vacation
22 yesterday, he had to delay his holidays because
23 of the Commission A and is not expected to
24 rewrite his proposal until mid- September,

                                                 Page 119

 1 correct?
 2            A.      Yes.
 3            Q.      The last paragraph says, we
 4 are of course very pleased that it went so well,
 5 but it is clear that the battle is not yet over
 6 because the advice of the Commission A is not
 7 binding on the BGA, correct?
 8            A.      Yes.
 9            Q.      In the past, there have been
10 very few cases where the BGA has made decisions
11 against the recommendation of Commission A and we
12 clearly have here a case where the BGA reviewer
13 has been voted down by the Commission A, correct?
14            A.      Yes.
15            Q.      We know however that Professor
16 Gundert-Remy, the chief of pharmacology and the
17 boss of Doctor Karkos, in principle is not ready
18 to support him against the advice of the
19 Commission A, do you see that?
20            A.      Yes.
21            Q.      How would Lilly know
22 something, how would Mister Bouchy know that?
23            A.      Well, I mean obviously he as
24 he said had sources of information.

                                                 Page 120

 1            Q.      Those sources are Mister
 2 Straeter and this Lode person up here that's
 3 written after Mister Straeter's name, correct?
 4            A.      Maybe, I don't know.
 5            Q.      He could have other sources?
 6            A.      Yes, he could have, all
 7 members of academia who are close to those
 8 professors, it's a small community.
 9            Q.      Small enough to discuss the
10 inner politics or inner workings of the BGA on a
11 particular drug?
12            A.      Yes, I think so, and again
13 this is Commission A and BGA and we should not
14 mix this up.
15             (PLAINTIFFS' EXHIBIT NO. 4 WAS
16              MARKED FOR IDENTIFICATION AND
17              RECEIVED IN EVIDENCE.)
18            A.      I've read it.
19            Q.      Exhibit 4 appears to be
20 another E-mail by Claude Bouchy to yourself, as
21 well as Brian Gennery, Walter Lange, Gerhard
22 Mayr, Sidney Taurell and Allan Weinstein,
23 correct?
24            A.      Correct.

                                                 Page 121

 1            Q.      These are again all employees
 2 of Lilly either here in Indianapolis or outside
 3 the United States, correct?
 4            A.      Yes.
 5            Q.      It's dated August 30, 1989,
 6 and again it's listed as confidential, correct?
 7            A.      Correct.
 8            Q.      It says Regarding, Additional
 9 Feedback Regarding The Fluoxetine Review By The
10 Commission A, correct?
11            A.      Yes.
12            Q.      It says:  Through additional
13 contact, I have been able to find out the
14 following information, and he lists five points
15 of information, right?
16            A.      Yes.
17            Q.      The second point is that the
18 proposal of the Commission A for the indication
19 would be for the treatment of depressive illness
20 when no sedation is necessary, do you see that?
21            A.      Yes.
22            Q.      Do you recall that
23 recommendation by Commission A?
24            A.      I do not recall specific

                                                 Page 122

 1 wordings as they have been but there was of
 2 course as always is before approval a long
 3 discussion how to most appropriately word the
 4 package insert.
 5            Q.      Okay.  And it says this is
 6 very, very close to the English package insert,
 7 correct?
 8            A.      It says so.
 9            Q.      What does the English package
10 insert have to do with the German package insert?
11 I assume you mean when you say English, you mean
12 the U.K. and not English.
13            A.      Well, I'm not sure what he
14 really means here but I would incline to believe
15 the same as you, it might refer to the U.K.
16 package insert.  Well, see, during drug
17 development, you collect a vast amount of data
18 and you analyze them, interpret them and draw
19 conclusions, then submit them to various
20 regulatory authorities in the world.  They have
21 different approaches, different people, different
22 philosophies, so they come to different
23 conclusions.  So it's always for, in particular
24 also the scientist in the drug company of

                                                 Page 123

 1 importance in either supportive or rather not,
 2 what these different agencies says, and in this
 3 particular case, it was that in particular U.K.
 4 agency also being a very prestigious one or one
 5 well accepted and recognized, that if they had
 6 come obviously to a similar conclusion then this
 7 is just a confirmation of something we have
 8 elaborated and it's just, I mean that it is.  So
 9 it's a confirmation of sometimes things which
10 might be seen differently.  And again, as an
11 international company, we usually try to label
12 our drugs with some conformity if possible, so if
13 this is within Europe, close to the English
14 label, that obviously is just a thing to be
15 mentioned as a good thing.  So that's why I guess
16 he has put it in here.  But I mean --
17            Q.      Do you recall the English, do
18 you recall --
19            A.      No, I don't.
20            Q.      You don't recall that being an
21 issue, the English package insert being an issue
22 or what the English government did with the drug?
23            A.      I do not really recall what
24 the exact wording in England was.  What I

                                                 Page 124

 1 definitely recall that all of -- well, not all, I
 2 shouldn't say that, but particularly the issues
 3 we are discussing today world wide would only be
 4 an issue with the BGA.
 5            Q.      You don't recall the suicide
 6 issue ever being raised by any other government
 7 other than --
 8            A.      Well, maybe some smaller --
 9 I'm not familiar with each European country, but
10 at least the major ones didn't raise it.
11            Q.      How about Sweden?
12            A.      Sweden, well, that's what I'm
13 saying, the small countries, I don't know what
14 they talked about suicide, at that point in time.
15            Q.      Do you know if the drug has
16 been approved in Sweden at this time?
17            A.      Frankly, I don't know.  I
18 think it was not before I left for Japan and I
19 don't know now.
20            Q.      How about Norway?
21            A.      Same, I don't know.
22            Q.      You don't know whether or not --
23 you don't know whether or not the English
24 government's package insert requires an

                                                 Page 125

 1 indication such as what's set out by Mister
 2 Bouchy in number two here, for the treatment of
 3 depressive illness when no sedation is necessary,
 4 do you?
 5            A.      Again, I do not know how they
 6 exactly word that.
 7            Q.      Number 3 says:  The
 8 contraindication because of acute suicidality
 9 should become a warning whereby the physician
10 should be advised that in the absence of sedation
11 the risk of higher suicidality should be taken
12 into account.  Do you see that?
13            A.      Yes.
14            Q.      This indicates to me at least,
15 Doctor, that the BGA wanted to contraindicate the
16 drug initially in suicidal patients acutely?
17            A.      Well, even if it's indicating
18 that, I mean so what?
19            Q.      Do you recall that happening?
20            A.      Well, as I mentioned to you
21 before, and that's why I mean -- also what
22 reviewers' agency say is not always, I mean the
23 combined wisdom of the world, and because all
24 depressive patients are suicidal and to

                                                 Page 126

 1 contraindicate this is a little bit of a problem.
 2            Q.      Do you really believe that all
 3 patients suffering from depression are suicidal?
 4            A.      Have the risk, this is part of
 5 the disease, have the risk of suicide.
 6            Q.      In every single patient who is
 7 depressed?
 8            A.      The risk, I'm talking about
 9 the risk.  Each smoker has the risk to develop
10 lung cancer, is the same.
11            Q.      What you said earlier --
12 Steve's shaking his head.  What you said earlier
13 is all patients who were depressed are suicidal.
14 I want to make sure you don't mean --
15            A.      I must correct this but I very
16 well remember that you phrased your earlier
17 question with the risk of suicide, and this is in
18 fact for everyone.  I agree and would like to
19 correct me, it's not necessarily each depressive
20 patient's definitely suicidal, meaning making
21 suicide attempt.
22            Q.      The BGA doesn't require
23 sedation with every antidepressant that's on the
24 market in Germany, does it?

                                                 Page 127

 1            A.      I don't know what the
 2 situation is today.  At the time Prozac was
 3 approved, that is correct.  But at that time
 4 Prozac was competing with a totally different set
 5 of compounds.
 6            Q.      Tricyclic-type antidepressants
 7 with sedative properties, correct?
 8            A.      What?
 9            Q.      It was competing with
10 tricyclic or other types of antidepressants that
11 have sedative properties built into the drug, or
12 as a part of the drug?
13            A.      This is contentious in the
14 scientific community, but to some extent, yes,
15 there may be slightly different profiles.
16            Q.      What Mister Bouchy is talking
17 about here when he says the contraindication
18 because of acute suicidality, he's not talking
19 about it in the general depressed population, is
20 he?  He's talking about the BGA wanting to
21 contraindicate the use of Prozac in suicidal
22 patients.  Specifically because of Prozac, not
23 because of the depressive illness, correct?
24            A.      Well, obviously so.

                                                 Page 128

 1            Q.      Number 4 says the
 2 contraindication for agitated patients and for
 3 patients with pronounced sleep disturbances
 4 should not be an absolute contraindication but
 5 rather a relative contraindication, in Germany
 6 this is very similar to a precaution, do you see
 7 that?
 8            A.      I see that.
 9            Q.      That indicates to me again
10 that the BGA, and especially Doctor Karkos,
11 wanted to contraindicate the drug for use in
12 agitated patients and in patients with pronounced
13 sleep disturbances, does it not?
14            A.      Well, obviously he wanted to
15 do that.
16            Q.      And here Mister Bouchy -- this
17 is not a translation of a German document, is it?
18 This is a document actually written in English,
19 correct?
20            A.      By a Frenchman, yes.
21            Q.      And here he says
22 contraindication for agitated patients?
23            A.      Yes, and that's exactly the
24 difference.  The classification of this group is

                                                 Page 129

 1 agitated versus retarded.  This is a very
 2 specific terminology.  But the drug activating
 3 both agitating means something different, so you
 4 shouldn't confuse the two.
 5            Q.      Do you think they think Prozac
 6 is --
 7            A.      So the proper use of the term
 8 here in classifying this group as agitated
 9 patients, which is a literal translation from the
10 German agitiert, but in terms of describing the
11 effect of the drug, it has at least for me as a
12 physician a different connotation.
13            Q.      Okay.  Do you believe that
14 Prozac is activating, as a physician?
15            A.      Well, the problem was that all
16 the data we have generated, it neither showed
17 really one or the other.
18            Q.      That's not my question,
19 Doctor.  My question is, as a physician -- let me
20 finish my question.  As a physician, not as a
21 Lilly employee, as a physician, do you believe
22 that Prozac is activating, yes or no?
23            A.      No.
24            MR. LORE:  And he doesn't have to say

                                                 Page 130

 1 yes or no, he can explain his answer.  I'm sorry,
 2 you said no.
 3            A.      I said no to make it easier,
 4 but it's unfortunately not so simple as you think
 5 and maybe I can finish --
 6            Q.      I know what the data
 7 generated.
 8            A.      Well, and that's why we
 9 decided to say it's neither nor, and I think
10 that's a very important think to say.
11            Q.      It's neither sedating or
12 activating?
13            A.      It's basically not sedating,
14 that's what we said.
15            Q.      In the package insert it says
16 it's not generally sedating, does it not?
17            A.      Well, it does, that's correct.
18            Q.      And in fact you and your
19 colleagues in Germany wanted to put in the
20 package insert initially that Prozac does not
21 have a sedating effect, period, did you not?
22            A.      Does not have a sedating
23 effect is correct.  That is not the same as
24 activating.

                                                 Page 131

 1            Q.      Okay.  Do you believe that it
 2 causes agitation?
 3            A.      Well, in some patients, as it
 4 causes in some patients sleepiness or nausea or
 5 whatever, so of course that can be observed, but
 6 as a drug does it cause agitation, I must say no.
 7            Q.      Well, no drug acts the same in
 8 every single person that takes it, does it,
 9 Doctor?  I mean you have some people who are for
10 instance allergic to penicillin and they can die
11 from taking penicillin, correct?
12            A.      Yes.
13            Q.      And you have other patients
14 that do just fine on the drug and you have other
15 patients that it doesn't do anything for them at
16 all?
17            A.      That's what I said, there are
18 patients that you can observe this, it's a
19 benefit/risk assessment.
20            Q.      So the answer to my question
21 is yes, it can cause agitation?
22            A.      Yes, that was not your
23 question.  Can cause, yes.  You asked cause.
24            Q.      Can it cause activation?

                                                 Page 132

 1            A.      It can cause, yes.
 2            Q.      Can it cause sleep
 3 disturbance?
 4            A.      Yes, it can.
 5            Q.      The last paragraph, it says at
 6 the moment we do not have information on the
 7 other contraindications for epilepsy, renal
 8 impairment, hepatic insufficiency, acute
 9 intoxication, correct?
10            A.      Yes.
11            Q.      But Nick will try to speak to
12 Professor Blank, the rapporteur, to find out
13 more.  Professor Blank the rapporteur is
14 Professor Moeller, is it not?
15            A.      That's correct.
16            Q.      Are you the Nick he's talking
17 about?
18            A.      Nick, that's exactly me
19 sitting here.
20            Q.      Okay.
21            A.      But I didn't talk to him.
22            Q.      Did you talk to Doctor
23 Moeller?
24            A.      I didn't talk to him.

                                                 Page 133

 1            Q.      Did you refuse to talk to him?
 2            A.      Well, I did not openly refuse
 3 but as I have tried to explain before, I did not
 4 know Professor Moeller very well.  Actually at
 5 that time, I think I did not know him at all.
 6 And to approach, as I say I think it's not
 7 forbidden to contact or to talk to Commission A
 8 members, but to come from Lilly and see him the
 9 first time and with this thing going on it would
10 have been very difficult to not do that, what I
11 was referring to before, exerting whatever
12 influence or it might have been perceived very
13 badly.  So that's why I didn't do that.  Actually
14 it didn't develop the opportunity to see him or
15 talk to him on that.
16            Q.      Did Mister Bouchy ask you to
17 call him or contact him?
18            A.      I cannot remember if he said
19 Nick, go and do that, I think that was not his
20 style, he never would have done it.  Maybe he
21 said it would be nice to have it or some kind of
22 thing but I really don't know about that.
23            Q.      Earlier you said when I asked
24 you if you refused, you said not directly or

                                                 Page 134

 1 something to that effect, which indicates to me
 2 that he had some sort of conversation with you
 3 about going to talk with or contacting Doctor
 4 Moeller somehow.  Do you recall him asking you in
 5 any way, whether it be a direct order or a
 6 mentioning it in the hallway, do you recall that
 7 conversation taking place?
 8            A.      I wouldn't exclude that.
 9            Q.      Do you recall how you felt
10 about him requesting that you do that, did you
11 feel uncomfortable?
12            A.      Well, you always feel
13 uncomfortable to do things which are
14 inappropriate or might be perceived as
15 inappropriate, yet it sometimes -- it's not
16 always so easy because it's depending on what
17 opinions you talk about, so -- and actually I
18 don't want to comment how I felt because I also
19 didn't know anymore how I specifically felt at
20 that time.
21            MS. ZETTLER:  Okay.  Let's take a
22 lunch break.
23             (A LUNCH BREAK WAS TAKEN.)
24            Q.      (BY MS. ZETTLER)  Doctor,

                                                 Page 135

 1 before lunch, we were talking a little bit about
 2 the intent to reject letter that was sent by the
 3 BGA to Lilly in February of '85, do you remember
 4 that?
 5            A.      Yes.
 6            Q.      And did you participate in the
 7 response that was sent to the BGA to that letter?
 8            A.      Well, the initial response,
 9 no.  In the final response which was sent
10 together with the new data, yes.
11            Q.      Okay, when you say the initial
12 response, what do you mean?
13            A.      Yes, because I think at least
14 that when the letter was received that there was
15 a company response.
16            Q.      Okay.  Of what sort, was it
17 like a letter or was it more data or --
18            A.      That's what I actually don't
19 really recall.  But let's put it in the
20 following, I mean I was involved in the partial
21 resubmission we did eventually as a response to
22 these things, and that was I guess around '86 or
23 '87 even.
24            Q.      Why did it take so long to

                                                 Page 136

 1 make that partial resubmission?
 2            A.      Excuse me, say again.
 3            Q.      Why did it take so long after
 4 the intent to reject letter to make that partial
 5 submission?
 6            A.      The major reason is that we
 7 decided to conduct the in-patient study and to
 8 prepare for such a study, to enroll the patients
 9 and actually to perform such a study, that takes
10 some time, so that was the major reason.  And we
11 waited or had to wait for the completion of this
12 trial, and that was the time-limiting factor.
13            Q.      The intent to reject letter
14 gives you three months I believe to respond
15 before they'll -- it says I guess to amend,
16 before they'll actually reject the drug.  What
17 happened in that three month period of time after
18 you received the drug -- or the letter, I'm
19 sorry?
20            A.      Well, again, that was before,
21 I really don't know.  The fact is that we
22 resubmitted the data much later, that -- I mean
23 beyond the three months period, but that
24 obviously was for whatever reason accepted by the

                                                 Page 137

 1 BGA.
 2            Q.      Did the company withdraw their
 3 application of fluoxetine after the intent to
 4 reject letter?
 5            A.      No, we did not.
 6            Q.      Do you know what happened in
 7 between that three month period of time or what
 8 happened to extend the period of time?  That
 9 sounds a lot longer than the three months that
10 you were initially given.
11            A.      Again, I really do not know
12 precisely but it may have been that we have
13 requested an extension and may have been granted
14 it.
15            Q.      You don't know either way?
16            A.      I don't know.  The only thing
17 I know is that when we made the resubmission it
18 was only a partial submission, meaning not
19 sending in the whole package again but referring
20 to what has been already sent and then adding the
21 new data that I was mentioning.
22            Q.      So you didn't have to resubmit
23 all the data that you had submitted, I believe it
24 was in March of '84, the original data?

                                                 Page 138

 1            A.      That's correct.
 2            Q.      So as far as what the
 3 company's initial response was, you did not
 4 participate in that, you participated in the
 5 submission of additional data?
 6            A.      If you wish, the final
 7 response for the latest stage of the registration
 8 process, yes.
 9             (PLAINTIFFS' EXHIBIT NO. 5 WAS
10              MARKED FOR IDENTIFICATION AND
11              RECEIVED IN EVIDENCE.)
12            Q.      If you could take a look at
13 Exhibit 5, Doctor.  I apologize for the quality
14 of the first couple of pages of the copy, but
15 that's the best that we could do with what we
16 received from Lilly.
17            (WITNESS REVIEWS DOCUMENT.)
18            Q.      Doctor, you're free to read
19 the entire exhibit.  I'm not going an ask you
20 about every single page, but if you want to read
21 through the whole thing, that's fine.  But if you
22 feel comfortable in reviewing it and then refer
23 back to it when I ask you a question, that's fine
24 also.

                                                 Page 139

 1            A.      Well, it's -- let's start.
 2            Q.      Okay.  Do you recognize this
 3 exhibit?
 4            A.      Uh-huh.
 5            Q.      Can you tell us what it is,
 6 please?
 7            A.      Well, this is this response I
 8 was referring to, guessing '86, '87, so obviously
 9 it was '86, which we sent in as a resubmission
10 and final response to the concerns raised by the
11 BGA briefly addressing basically all points but
12 emphasizing the major points, which have been the
13 phospholipidosis, the question about suicide and
14 also simply the testing in in-patients which is
15 not really much elaborated here but which was
16 also attached.
17            Q.      Let's turn to the translation
18 of the letter that you were writing to the BGA, I
19 believe it's about ten pages or so into the
20 exhibit.  If you look in the lower right-hand
21 corner, they have the Pz numbers, it'll be 218.
22            A.      218.
23            Q.      Yes.
24            A.      218.

                                                 Page 140

 1            Q.      I think it's hard to read but
 2 I think it's enclosure three at the top.
 3            A.      Which 218 do you mean?
 4            Q.      If you look in the lower
 5 left-hand corner of the page, 218 is the last
 6 three digits of the number.
 7            A.      Okay.
 8            Q.      Did you find it?
 9            A.      Yes.
10            Q.      It says at the top,
11 Translation Of Our Answer Letter To The BGA,
12 correct?
13            A.      Yes.
14            Q.      Is that your handwriting?
15            A.      No, it's not.
16            Q.      Do you recognize that
17 handwriting?
18            A.      Could be Mrs. Heymanns or
19 Barbara von Keitz's.
20            Q.      Is it now your recollection
21 that this letter was submitted to the BGA in late
22 1986?
23            A.      Yes, well, that presumably was --
24 it's signed by Doctor Bamberg who was the

                                                 Page 141

 1 regulatory guy or in charge of regulatory and
 2 myself being in in charge of the medical
 3 department at that time, yes.
 4            Q.      And this -- before you
 5 submitted this to the BGA, you submitted this
 6 translation to the Indianapolis office for their
 7 comments and approval, right?
 8            A.      Correct.
 9            Q.      And in this letter, starting
10 at page Pz 2467 218, you addressed the specific
11 points that were raised by the BGA in the
12 approvable letter -- or I'm sorry, the intent to
13 reject letter that we already discussed earlier
14 this morning, correct, Exhibit 1?
15            A.      Yes.
16            Q.      In fact, you quote essentially
17 or reiterate essentially in your responses the
18 wording that they used in their questions,
19 correct, like in number one, you say it's not
20 true that the therapeautic efficacy of fluoxetine
21 has not been sufficiently proven?
22            A.      Yes.
23            Q.      Okay.  If you go to the next
24 page, I'm sorry, two pages.

                                                 Page 142

 1            A.      So 220?
 2            Q.      Yes.  Response number two, we
 3 see no suspicion of unjustifiable adverse effects
 4 in fluoxetine.  Do you see that?
 5            A.      Yes.
 6            Q.      So at this point in time, you
 7 clearly knew what the BGA meant when they said
 8 that the side effects were unacceptable and they
 9 had damaging -- unacceptably damaging side
10 effects?
11            A.      Well, we can conclude what
12 they might have meant.
13            Q.      They were pretty specific in
14 their letter, were they not?
15            A.      Yes, and with regard to those
16 being raised as what we have submitted, we came
17 to different conclusions.
18            Q.      Okay.  But it was your
19 understanding as of December of 1986 that what
20 they meant by unacceptable damaging effects was
21 the issues raised regarding suicidality and
22 worsening of depressive-type symptoms as well as
23 phospholipidosis, correct?
24            A.      Correct.

                                                 Page 143

 1            Q.      In fact, you discuss those
 2 issues pretty thoroughly in your response here,
 3 do you not?
 4            A.      In response 2.1.
 5            A.      I made my efforts to.
 6            Q.      Pardon?
 7            A.      I made my best efforts to
 8 respond to the authority, yes.
 9            Q.      And you talk about the
10 incidence of suicide world wide up to August 31,
11 1986?
12            A.      Yes.
13            Q.      And talk about the differences
14 between the control group and the patients in the
15 fluoxetine group, correct?
16            A.      Yes.  I have not read it in
17 all this detail, but basically yes, that was all
18 discussed here.
19            Q.      At the bottom of page four of
20 your letter, but 221 on the lower right-hand --
21 well, lower right-hand corner of the page.
22            A.      Yes.
23            Q.      At the bottom it says:  Time
24 and again it is brought forward that the

                                                 Page 144

 1 initially strongly sedating effect of the
 2 tricyclic antidepressant drugs amitryptiline and
 3 imipramine possesses an effect protecting from
 4 suicide and that substances lacking initial
 5 sedation or those which even bring about a
 6 stimulation are subject to the risk of activating
 7 patients prior to the onset of antidepressive
 8 effect, and that, therefore, suicidal ideation
 9 may occur more frequently.  Do you see that?
10            A.      I see that, that's written
11 here.
12            Q.      Do you agree with that?
13            A.      So far time and again it's
14 brought forward that, yes, in that context.
15            Q.      Then you go on discussing
16 about whether or not there should be -- strike
17 that.
18                    You talk about in the next
19 page submitting cases of suicidal actions to an
20 expert for causuistic working up.  Do you see
21 that at the bottom of the first full paragraph?
22            A.      Bottom of the first full
23 paragraph, so that's this one.
24            Q.      Starting after --

                                                 Page 145

 1            A.      Oh, okay, yes.
 2            Q.      And coming to the conclusion
 3 based on those conclusions by that expert that
 4 there was no indication that the majority or all
 5 of the suicide attempts happened early on in
 6 treatment, correct?
 7            A.      Let me just read this, Ma'am.
 8            Q.      Sure.
 9            A.      Yes.
10            Q.      But you concede that in
11 response to requests made by the BGA, you were
12 going to put into the package insert the
13 statement that is in the middle of the page
14 there, correct?
15            A.      Yes.
16            Q.      And that statement says
17 fluoxetine does not produce a sedating effect,
18 correct?
19            A.      Yes.
20            Q.      For patients suffering from
21 agitation or from distance sleep disturbances,
22 additional administration -- I'm sorry, distinct
23 sleep disturbances, additional administration of
24 a sedating or sleep promoting medication is

                                                 Page 146

 1 recommended at the beginning of the Fluctin
 2 therapy, correct?
 3            A.      Yes.
 4            Q.      Up to the onset of the
 5 antidepressive effect, especially severely ill
 6 patients and patients with the risk of attempting
 7 suicide ought to be placed under sufficient
 8 observation, correct?
 9            A.      Correct.
10            Q.      And these are patients that
11 are on fluoxetine that should be placed under
12 sufficient observation, correct?
13            A.      Yes.
14            Q.      Then under response 2.2, you
15 state that the review of the Lilly data did not
16 demonstrate that there was an increase in the
17 symptoms of the underlying disease, such as
18 anxiety, sleeplessness and agitation, correct?
19            A.      That's stretching over two
20 pages, where do you start, please?
21            Q.      At the bottom of page five.
22            A.      The reanalyses of August 14th.
23            Q.      Right.
24            A.      Correct.

                                                 Page 147

 1            Q.      But you go on to say that some
 2 patients were clearly showing signs of agitation
 3 possibly induced by the product, correct?
 4            A.      Correct.
 5            Q.      Also attached you have some
 6 examples of the enclosed final versions of the
 7 patient -- physicians' information, which is that
 8 physician prescribing information we talked about
 9 earlier, correct?
10            A.      Yes.
11            Q.      And also various examples of
12 patient information for different milligram
13 dosages of the drug, correct?
14            A.      Yes.
15            Q.      The patient information for
16 the various milligram dosages are essentially the
17 same, are they not?
18            A.      Correct, except for the dose.
19            Q.      Except for the dose and
20 talking about how much of the active medication
21 is in each capsule?
22            A.      Right.
23            Q.      And the -- let's go back to
24 the physician information.  It starts at page 206

                                                 Page 148

 1 at the bottom.
 2            A.      Yes, I have it.
 3            Q.      At the top it says this drug
 4 contains a substance of which the action is not
 5 commonly known to the medical science and for
 6 which the manufacturer has to submit an
 7 experience report to the responsible federal
 8 authority according to section 49 slash 6, I
 9 believe, AMG.  Do you see that?
10            A.      Yes.
11            Q.      What experience report are you
12 talking there?
13            A.      Well, this is a standard for
14 all new chemical entities.
15            Q.      But what is -- when you say an
16 experience report, what do you mean?
17            A.      Well, that's also a legal
18 requirement as you have your annual report in the
19 United States, that periodically you need to
20 update the agency on your findings in your
21 postmarketing observations, and in this case
22 after a defined period of time, you have to turn
23 in this report and this is the experience report,
24 that's how it's being translated here.

                                                 Page 149

 1            Q.      Okay.  Is that like a safety
 2 update?
 3            A.      Yes, this is this kind of
 4 routine equivalent to that, yes.
 5            Q.      Okay.  And then it says with
 6 some of these other portions like
 7 contraindications, it refers to the patient
 8 information but without precaution statements,
 9 things like that, correct?
10            A.      Yes.  Excuse me, I think it's
11 proper to mention that the sections it's
12 following here is just the standard of any form
13 we have for this in Germany.
14            Q.      Okay.  Under the side effects,
15 number six, do you see that?
16          ` A.      Yes.
17            Q.      It says depressed leucocyte
18 counts and elevation of serumtransaminases has
19 been observed rarely, do you see that?
20            A.      Yes.
21            Q.      Is that -- is this what the
22 BGA was referring to in their intent to reject
23 letter when they said severe organ damage?
24            A.      I think so, at least the

                                                 Page 150

 1 serumtransaminases I think were referring to
 2 that.  The other, I really don't recall, that was
 3 the early concern.
 4            Q.      Okay.  Under interactions, it
 5 says the elimination of diazepam was prolonged in
 6 interaction studies in volunteers.  Do you see
 7 that?
 8            A.      Yes.
 9            Q.      Is that true, do you agree
10 with that?
11            A.      Well, I don't know.  Well, the
12 statement is made here, I'm sure it refers to
13 data we had and so far it's true, it's correct.
14 You see also the sentence following that
15 obviously it did not have any major impact or
16 clinical relevance.  But as a measured data
17 derived from plasma samples in volunteers,
18 obviously it's a fact, that's why it's mentioned
19 here.
20            Q.      Are you aware that at least
21 some of the clinical trials on fluoxetine that
22 were submitted as part of the original NDA on
23 fluoxetine allowed for the coadministration of
24 diazepam and other like drugs for treatment of

                                                 Page 151

 1 agitation or sleep disturbances that occurred
 2 during the clinical trials?
 3            A.      Well, I do not know which
 4 protocols exactly but there are protocols which
 5 allowed comedication of basically tranquilizers,
 6 yes.
 7            Q.      For the purpose of treating
 8 adverse events such as agitation or sleep
 9 disturbance?
10            A.      Which part of the disease
11 initially, so --
12            Q.      Okay.  Do you know how long
13 they were allowed to be administered throughout
14 the study?
15            A.      Again, I do not recall the
16 specific phrasings in these protocols, but I
17 wouldn't be surprised if it was allowed
18 throughout the study.
19            Q.      Throughout the study?
20            A.      And these studies usually were
21 four or five week periods.
22            Q.      Does it strike you as unusual
23 that the coadministration of a psychotropic
24 medication would be allowed during a clinical

                                                 Page 152

 1 trial on another psychotropic medication?
 2            A.      No, it doesn't strike me
 3 because the benzodiazepines were not perceived to
 4 have -- the benzodiazepines, that's the drug
 5 group we're talking about, the tranquilizer, are
 6 not supposed to have a direct antidepressant
 7 effect, so they would not impact the target for
 8 measurement and so far, no, I wouldn't be
 9 surprised because let me also add this, from a
10 theoretical point of view, from a scientific
11 point of view, it's of course always easier if
12 only one agent you change, but that's the
13 scientist, that's the theory.  In terms of
14 clinical practice where you have to implement
15 such trials, you would find a lot of resistance
16 among clinicians to be that much bound to a
17 protocol, so we usually allow that, and again,
18 because the expected effect is something
19 different than -- I mean the expected effect of
20 the test drug, it's possible to evaluate it.
21            Q.      But certainly if you have a
22 drug with a side effect profile that includes
23 agitation and sleep disturbance as part of their
24 side effects, the coadministration of such drugs

                                                 Page 153

 1 would in effect in some patients mask that, would
 2 it not?
 3            A.      First of all, that's why we
 4 have controlled trials so that you have a
 5 comparative group, and we have this -- and you
 6 also can break down and stratify by patients who
 7 received it and do not.
 8            Q.      What if it's not recorded that
 9 they received it in terms of an adverse event?
10            A.      First of all, everything is --
11 I mean you cannot even distinguish if it's an
12 adverse event or if it's a matter of the disease,
13 you also cannot distinguish that.
14            Q.      So you assume that it --
15            A.      You can also only by further
16 evaluation and the observation of many data and
17 looking from different angles and different
18 patient groups, you can come to some conclusions.
19 But again, the most powerful is basically that
20 you have control groups.  And in the German study
21 we had amitryptiline and the protocol was
22 basically the same for these treatments and so
23 far I think finally you can make some statements
24 of what you see.

                                                 Page 154

 1            Q.      Did it allow for the
 2 coadministration of benzodiazepines?
 3            A.      I'm not totally sure what
 4 really was in the German in-patients trial, I'm
 5 really not sure, but I wouldn't be surprised if
 6 it was allowed simply because of the ease of
 7 implementation of such a trial, because again,
 8 usually the clinicians are not very happy to have
 9 too stringent protocols because they also have to
10 treat patients, it's not just the study they do.
11            Q.      Is it your testimony, Doctor,
12 that it's your understanding that generally in
13 psychotropic medication type clinical trials, not
14 just with Prozac but other antidepressants, that
15 the coadministration of sedative type drugs is
16 generally allowed throughout the clinical trials?
17            A.      It's difficult for me to
18 testify because I do not know enough of the drug
19 trials, but it wouldn't surprise me if so, yes.
20            Q.      But would it surprise you if
21 that is not the case?
22            A.      If the whole data package is
23 generated with trials only applying the
24 antidepressant and no other at all, I would be

                                                 Page 155

 1 surprised.  I might even add, I do not think it
 2 would be a proper way of evaluation because of
 3 the clinical practice, you definitely also would
 4 coadminister and the clinical trial program
 5 should be designed also to resemble the practice
 6 situation.
 7            Q.      And if you find that a drug
 8 produces side effects that may require the
 9 coadministration of a sedative drug, the
10 physicians who in the clinical practice who are
11 going to be using this drug should be informed,
12 should they not?
13            A.      If it's required, yes.
14            Q.      Okay.  The BGA was concerned
15 about the coadministration of chloral hydrate and
16 benzodiazepines and other drugs throughout the
17 studies, were they not?
18            A.      Could you just repeat the list
19 again?
20            Q.      Sure.  The chloral hydrates,
21 benzodiazepines were the two main ones, but there
22 were hypertensive analgesics, things of that
23 nature.
24            A.      Could you read the whole thing

                                                 Page 156

 1 again?
 2            Q.      Sure.  It says no interactions
 3 had been observed in clinical trials --
 4            A.      Okay.
 5            Q.      But my question is, that the
 6 BGA was concerned and set out I believe in their
 7 medical opinion, that they were concerned about
 8 the use, the coadministration of benzodiazepines,
 9 chloral hydrate, sedative type drugs throughout
10 the clinical trials, correct?
11            A.      Were they concerned about
12 that?
13            Q.      Uh-huh.
14            A.      I'm not sure they were
15 concerned about it.
16            Q.      That's not your recollection?
17            A.      Well, at least that was not a
18 major issue because based on what I said and also
19 what we have discussed with clinical experts in
20 trial testing, that for me is not a real --
21            Q.      Go back to Exhibit 1.
22            A.      Well, but it's not all what
23 agency say, based on one reviewer's collective
24 wisdom of the world.

                                                 Page 157

 1            Q.      Do you recall Lilly having to
 2 do a reanalysis of the initial data that it
 3 submitted to the BGA separating out those people
 4 who used concomitant medications from those who
 5 did not?
 6            A.      Well, first of all, it doesn't
 7 say here what concomitant treatment, because if
 8 you coadminister a second antidepressant, which
 9 in fact is sometimes done, particularly in the
10 United States as far as I know, that makes a
11 whole lot of difference.
12            Q.      Okay, but my question is --
13            A.      So it just says other
14 psychotropic drugs, but it's actually not
15 specifying the tranquilizer drugs which are
16 allowed in many trials.
17            Q.      Do you recall, Doctor, Lilly
18 going through the exercise of reanalyzing the
19 clinical data was first submitted to the BGA,
20 especially protocol 27, the imipramine study, to
21 look at those patients who were not on any
22 concomitant medications, mostly sedatives or
23 benzodiazepines, versus those who were to look
24 for efficacy, the differences in efficacy, do you

                                                 Page 158

 1 recall that exercise being done?
 2            A.      Well, obviously this exercise
 3 was done, but so what?  I mean that was -- maybe
 4 that was satisfactory to the BGA.
 5            Q.      That's not my question.  My
 6 question was -- my initial question was was the
 7 BGA concerned about the concomitant
 8 administration of other psychotropic medications,
 9 and in particular -- let me finish my question --
10 in particular benzodiazepines and other sedative
11 type drugs or drugs with sedative properties?
12            A.      Well, that's exactly what you
13 cannot read out of this and I haven't been in the
14 very initial evaluation.  First of all, it says
15 here as you say concomitant treatment and other
16 psychotropic drugs, so it does not state which
17 type.  Now you say based on the reanalyzed,
18 obviously it had been those, now I don't know
19 what was in the final -- in the very, very first
20 submission package.  What I suspect is that this
21 break down into concomitant therapy and not -- or
22 free of concomitant therapy hasn't been done in
23 the very first analysis and this is in fact very
24 confusing, so that's why another one was

                                                 Page 159

 1 resubmitted breaking this down and that's
 2 basically the answer to the question.
 3            Q.      Do you know of any evidence
 4 that the use of concomitant additional
 5 antidepressants was allowed regularly in the
 6 clinical trials?
 7            A.      Definitely that should not be
 8 in a clinical trial where you're testing
 9 antidepressants.
10            Q.      Okay.  So you agree that the
11 BGA was concerned about the coadministration of
12 concomitant psychotropic drugs, you just don't
13 recall which ones those were?
14            A.      That's maybe a correct
15 statement.
16            Q.      Look at page four of the
17 physician's information.
18            A.      Yes.
19            Q.      Under precautions, section
20 fourteen, about halfway down that paragraph, it
21 says Fluctin does not have sedating properties,
22 period, correct?
23            A.      Yes.
24            Q.      In agitated patients or with

                                                 Page 160

 1 significant sleep disturbances, it is recommended
 2 to coadminister a sedative medication at the
 3 start of treatment with Fluctin, correct?
 4            A.      Yes.
 5            Q.      Do you agree with that
 6 statement?
 7            A.      I find it acceptable.
 8            Q.      Okay.  It goes on to say manic
 9 and psychotic states have been reported in single
10 cases in susceptible patients, do you see that?
11            A.      Yes.
12            Q.      Until the antidepressive
13 effect occurs, particular severe depressive
14 patients and patients with suicidal risk have to
15 be observed sufficiently.
16            A.      Yes.
17            Q.      Do you agree with that
18 statement?
19            A.      Yes.  It should be done with
20 any drug in this area.
21            Q.      In what area?
22            A.      In the area of this disease.
23            Q.      The coadministration of
24 sedatives?

                                                 Page 161

 1            A.      No, to observe them
 2 sufficiently.
 3            Q.      Okay.  But this is tying
 4 together the fact that Fluctin does not have
 5 sedating properties, is it not?
 6            A.      Well, that's -- I mean
 7 notwithstanding, but I'm just adding that in
 8 fact, you know, such patients you should always
 9 observe sufficiently.  So it's a very generous
10 statement, that's what I'm --
11            Q.      Well, sufficient observation
12 may be different if you have a person who is
13 depressed and not on drug therapy and a person
14 who is on drug therapy that may cause them some
15 problems, correct?
16            A.      Well, I don't see that as
17 causing problems.  All drugs have certain risks,
18 that's why doctors need to prescribe them and
19 monitor them carefully.
20            Q.      But in this case, the risk
21 comes from the lack of sedating properties,
22 correct?
23            A.      No, that's not necessarily
24 related.

                                                 Page 162

 1            Q.      So you're saying that these
 2 two statements are not related?  Because the
 3 precaution starts, Fluctin does not have sedating
 4 properties.  And it goes on to say in agitated
 5 patients or patients with significant sleep
 6 disturbances, it is recommended to coadminister
 7 sedative medication at the start of treatment
 8 with Fluctin.  And that's Lilly's language that
 9 they suggested for this package insert, correct?
10            A.      Yes.
11            Q.      That's not language that was
12 directly required by the BGA, correct?
13            A.      Yes, although --
14            Q.      You knew that they wanted
15 something to that effect in there?
16            A.      This is absolutely right, and
17 that's why I said I find it acceptable.
18            Q.      Okay.
19            A.      From both points of view, from
20 my medical point of view, as what they thought.
21            Q.      From your medical point of
22 view and your regulatory compliance point of
23 view?
24            A.      Well, see, all this is a

                                                 Page 163

 1 judgment call, and there are different opinions,
 2 they may be among doctors or between doctors,
 3 they may be within regulatory authorities, they
 4 may be between experts, and all together, so I
 5 think it's absolutely not uncommon or kind of
 6 problematic to come to an agreement where we say
 7 okay, I can live with that, that's acceptable.
 8 And I think it so far it's acceptable, and to
 9 come to the other point, just to clarify what I
10 said, the second one until the antidepressive
11 effect occurs could be in fact in any
12 antidepressant's package insert.
13            Q.      But the BGA's concern was that
14 the activating or agitating effects of the drug
15 set in before the antidepressant effect of the
16 drug set in, correct?
17            A.      That's what they said.
18            Q.      Let's go on to the patient's
19 information.  On the first page, it says
20 precaution at the bottom and again this is the
21 information that goes to the patient, correct?
22            A.      Yes.
23            Q.      And initially it said, Fluctin
24 lacks sedating effects, do you see that?

                                                 Page 164

 1            A.      Yes.
 2            Q.      And somebody scratched it out,
 3 at least on this one, the twenty milligram?
 4            A.      I do not think so because if
 5 you look at the next one, it's not scratched out,
 6 so --
 7            Q.      But on this first page of the
 8 one for the twenty milligrams, it's scratched
 9 out, correct?
10            A.      That looks like that, yes.
11            Q.      Okay.  It goes on to say, in
12 agitated patients or patients suffering from
13 significant sleep disturbances, additional
14 application of a sedative is recommended at the
15 beginning of treatment.  Until antidepressive
16 actions become effective, patients are to be
17 observed sufficiently.
18            A.      That's what it says.
19            Q.      And again, this is the
20 information that goes to the German public
21 patient?
22            A.      Correct.
23            Q.      Did anybody from Indianapolis
24 tell you to take that part of the precaution that

                                                 Page 165

 1 says Fluctin lacks sedating effects out of the
 2 package insert?
 3            A.      No.
 4            Q.      Did they tell anybody at the
 5 German affiliate to take that language out?
 6            A.      I cannot speak to that but I
 7 was not told to take this out.
 8            Q.      Are you sure?
 9            A.      Pretty sure.
10             (PLAINTIFFS' EXHIBIT NO. 6 WAS
11              MARKED FOR IDENTIFICATION AND
12              RECEIVED IN EVIDENCE.)
13            Q.      Let me show you Exhibit 6,
14 Doctor.
15            A.      Okay, so obviously somebody
16 asked me, but you see the result.
17            Q.      All right.  There's no
18 question pending so let's take it one at a time,
19 okay.  This is a December 12, 1986 E-mail to you
20 from Doctor Wernicke in Indianapolis, correct?
21            A.      Yes.
22            Q.      And in there he is talking
23 about what we've just been talking about, your
24 submission to the BGA, including the package

                                                 Page 166

 1 inserts, correct?
 2            A.      Yes.
 3            Q.      And generally he thinks it's
 4 pretty good, correct, in fact he says excellent
 5 job, correct?
 6            A.      Yes.
 7            Q.      He goes on to say, I have only
 8 one suggestion, in patient information under
 9 precaution eliminate fluoxetine lacks sedating
10 effects, correct?
11            A.      Yes.
12            Q.      He also wants you to take this
13 statement out of your answer to the BGA, correct?
14            A.      That presumably would follow
15 although it's not stated here.
16            Q.      At the bottom, it says would
17 also delete this statement from page five of
18 answer to BGA, does he not?
19            A.      Okay, yes.
20            Q.      That's on the 12th, and on the
21 15th, the second page of the exhibit is an E-mail
22 to Doctor Weinstein from S. Heymanns in Germany,
23 correct?
24            A.      Uh-huh, yes.

                                                 Page 167

 1            Q.      Who is S. Heymanns?
 2            A.      Mrs. Heymanns was a regulatory
 3 manager or associate, anyway in regulatory.
 4            Q.      And she's referenced -- it's a
 5 she, correct?
 6            A.      Yes.
 7            Q.      She's referencing your telex,
 8 the one we just talked about, the one that Doctor
 9 Wernicke wrote to you on December 12th, correct?
10            A.      Yes.
11            Q.      And she says we would like to
12 take into consideration the suggestion of Doctor
13 Wernicke and write in the package insert,
14 physician's information and letter to the BGA at
15 page five, quote, in most patients Fluctin lacks
16 sedating effect, unquote, instead of Fluctin
17 lacks sedating effect, unquote, correct?
18            A.      It's written here.
19            Q.      And this is a little bit of
20 negotiating going on here, isn't there?  I mean
21 Doctor Wernicke wants the statement taken out and
22 S. Heymanns wants to leave something about it in
23 but has rewritten the sentence a little bit,
24 correct?

                                                 Page 168

 1            A.      Well, that's correct.
 2            Q.      She goes on to say that we
 3 think that such statement reflects study results,
 4 we also want to give by this statement a reason
 5 for our recommendation that agitated patients and
 6 those with sleep disturbances should get a
 7 sedative at the beginning of the therapy,
 8 correct?
 9            A.      Yes.
10            Q.      And then the next day Doctor
11 Weinstein writes back and says that it's okay to
12 use the revised statement on sedation, correct?
13            A.      Yes.
14            Q.      Did you talk to Doctor
15 Wernicke about his wanting to take out that
16 sentence in the package insert?
17            A.      I do not recall if we talked,
18 but presumably not, because we have this written
19 communication going on.
20            Q.      Do you know if S. Heymanns
21 talked to Doctor Wernicke?
22            A.      I don't know about that.  But
23 I see here another statement made about another
24 serotonin reuptake inhibitor called fluvoxamine

                                                 Page 169

 1 which is basically the same.
 2            MS. ZETTLER:  Motion to strike.
 3 There's no question pending and it's
 4 nonresponsive.
 5            Q.      Let's go back to Exhibit 5.
 6 At this point had you submitted or had Lilly
 7 submitted the information on patients who
 8 attempted suicide in the clinical trials to
 9 outside experts for review, at the time this was
10 written?
11            A.      This -- well, the expert
12 opinion which is referred to here was obtained a
13 little bit earlier.  But as far as I recall, the
14 final data set were the updated suicide incidents
15 was also made available to the experts.
16            Q.      The one that -- the updated
17 data?
18            A.      Yes.  Well, again I'm not a
19 hundred percent sure how that really was done but
20 we clearly consulted also on this.
21            Q.      Okay.  Doctor, do you know a
22 Doctor Winzenreed?
23            A.      Only his name and actually I
24 didn't really communicate with him, himself, it

                                                 Page 170

 1 was an old available expert opinion.
 2            Q.      Was that the expert opinion
 3 that was submitted to the BGA with this
 4 submission?
 5            A.      Well, all expert opinions we
 6 had been obtaining over the years or time and
 7 which had not been part of the very, very first
 8 submission were attached.
 9            Q.      There weren't any expert
10 opinions on suicide attached to the very, very
11 first submission, were there?
12            A.      Correct.  I just was saying in
13 general expert opinions, not knowing if there was
14 any.  But presumably all expert opinions were
15 going with this one.
16            Q.      Besides Doctor Winzenreed, who
17 else did Lilly use as an expert opinion on the
18 suicide issue?
19            A.      Basically Pulmeyer.
20            Q.      Did Doctor Winzenreed and
21 Doctor Pulmeyer look at information related to
22 each of the cases of suicide and suicide attempts
23 that had occurred in the clinical trials?
24            A.      Actually I don't recall how it

                                                 Page 171

 1 was specifically, I think Winzenreed looked more
 2 at it from a case oriented basis and Pulmeyer
 3 more as the overall base and putting this into
 4 relation of what is known about suicide,
 5 depression and overall incidence in the
 6 population.
 7            Q.      Did you review any cases of
 8 suicide or suicide attempt on fluoxetine?
 9            A.      Not more or less than I was
10 reviewing other adverse events.
11            Q.      Did you write up reports on
12 those cases?
13            A.      Well, not on the specific
14 cases.  I mean I was compiling the data also
15 attached here which resembled the actual status
16 upon submission.
17            Q.      Well, the reason Y asked is
18 recause attached also to this is your
19 documentation on suicide gestures in clinical
20 trials with fluoxetine, correct?
21            A.      Yes, that's what I'm referring
22 to.
23            Q.      Okay.  Now, attached to a
24 bunch of graphs and charts and, et cetera, are

                                                 Page 172

 1 towards the end some one or two paragraph
 2 descriptions of patients that had attempted or
 3 committed suicide in the clinical trials,
 4 correct?
 5            A.      Correct.
 6            Q.      Who wrote those?
 7            A.      Well, they were written --
 8 actually, I don't know the individuals but
 9 because they're from different countries, I
10 requested the other affiliates to prepare this
11 for me based on the data they had in-house,
12 because I couldn't access all the raw data.  They
13 did this for me and that's why you also see
14 different types of typewriters being used here.
15 So I just pasted this together.  The only case
16 which is from -- I don't know if it's the only
17 case from Germany, I think it's the only case.
18 This is actually done by myself I guess, yes,
19 which is the German study.  The -- are there
20 more?  Anyway, there is a case from --
21            Q.      Can you tell me which one it
22 is?
23            A.      Let me just browse through
24 that.  Anyway, if there had been German cases in

                                                 Page 173

 1 the in-patient study then I wrote it myself
 2 because that was during my responsibility for the
 3 product.  So for example on -- well, you know, on
 4 the right, number 242, which is fluoxetine versus
 5 amitryptiline in-patient study, this is clearly
 6 also you can see from the code, SG stands for
 7 Germany, so this is from this in-patient study.
 8 So without remembering this specifically, but
 9 this presumably has been written by me.
10            Q.      Okay.
11            A.      But this happened to be
12 amitryptiline.  So then the next one is -- all
13 the others are not from German trials, so they
14 had been compiled by somebody else and I
15 explained the mechanism to you.
16            Q.      Let me ask you about the one
17 that you wrote.  What did you use to compile this
18 information that's written here?
19            A.      The case report forms which
20 are available on each study patient.
21            Q.      Did you talk to any
22 investigator?
23            A.      I may have also talked to him
24 because it was unblinded.

                                                 Page 174

 1            Q.      Do you recall talking to the
 2 investigator?
 3            A.      I don't know the details about
 4 it.
 5            Q.      Okay.  It says sixty-four year
 6 old female patient suffering from -- and it's
 7 kind of blacked out so it's hard to read -- but I
 8 think you mean endogenous depression.
 9            A.      Presumably, yes.
10            Q.      Of retarded subtype was
11 enrolled on -- looks like 7-31-88 -- no, it can't
12 be, '85?
13            A.      No -- anything.
14            Q.      Into study.  On entry her
15 total Hamilton score was twenty-four out of
16 seventeen items.  Suicidality was rated four on
17 8-4-85.  She took two capsules -- two capsules
18 twice a day?
19            A.      Yes, b.i.d means twice a day.
20            Q.      According to protocol.  So
21 does that mean she was getting eighty milligrams
22 a day?
23            A.      No, we're talking about
24 amitryptiline.

                                                 Page 175

 1            Q.      Oh, you're right, okay.  How
 2 much would she have been getting then?
 3            A.      Oh, I don't know.  I think we
 4 gave a hundred fifty milligram a day, but I don't
 5 recall.  So twice seventy-five, but I'm not sure.
 6            Q.      In the evening of the same
 7 day, she scratched her wrists and her neck.  The
 8 surface wounds were treated by a surgeon.  After
 9 being back in the psychiatric department, she
10 tried to strangle herself with a stocking in the
11 same night at 1:00 a.m. on the following day.
12 She was given benzodiazepines parenterally.
13            A.      Parenterally, uh-huh.
14            Q.      Study was discontinued.  At
15 the bottom, it says that this case was unblinded
16 by Lilly and not reported on a 1639 because it
17 was determined to be amitryptiline and not
18 fluoxetine, correct?
19            A.      That's what it says here, yes.
20            Q.      To your knowledge, were all of
21 these reports on fluoxetine, the ones that are
22 listed in here, reported on 1639s?
23            A.      Well, I would say that these
24 are all reports from the studies which had been

                                                 Page 176

 1 in question or available, and unless otherwise
 2 mentioned, I guess they would have been
 3 fluoxetine.  They wouldn't exclude that -- no,
 4 see you're not -- it's not right, because the
 5 case on 244, or just by scanning over this, says
 6 it's Mianserin, which also is another compound.
 7            Q.      Right.  No, I'm talking about
 8 just the fluoxetine cases, okay.  Do you know if
 9 the people on fluoxetine, if one of these cases
10 involved somebody on fluoxetine, do you know
11 whether or not a 1639 was filed on each of the
12 fluoxetine cases?
13            A.      Oh, okay.  Well, I can only
14 talk about Germany and would say yes.  I of
15 course cannot say what has been done elsewhere --
16 excuse me.  It's of course depending on what the
17 outcome is because you know the criteria for a
18 serious event, and here we use the world wide,
19 the FDA criteria, it is either overdose or
20 hospitalization or death or kind of best to
21 qualify for serious, and then you would file
22 this.  Now that means if there is a suicide
23 attempt, not qualifying for any of those, it
24 would actually not fall into the grid provided by

                                                 Page 177

 1 the FDA, then it would appear only in the final
 2 study report.
 3            Q.      Okay.  Is it your
 4 understanding that one of the criteria for a
 5 serious adverse event according to the FDA is
 6 requiring treatment with prescription medication?
 7            A.      That as far as I'm informed
 8 was a criteria but was dropped by the FDA.
 9            Q.      Do you know when it was
10 dropped?
11            A.      I don't.
12            Q.      All right.  So as far as you
13 know these blurbs on the various patients that
14 were connected to the end of your suicide
15 analysis, were written by the people at the
16 various affiliates, whoever had responsibility
17 for these trails?
18            A.      These kind of things, yes.
19            Q.      I apologize, Doctor, my copy
20 came unstapled so I'm not sure whether I have
21 this in the right order, but still I'm doing my
22 best, okay.  To go back to the first pages of
23 your suicide analysis.
24            A.      Uh-huh.

                                                 Page 178

 1            Q.      I think that starts at 229.
 2            A.      Yes.
 3            Q.      And you talk about how the
 4 various analyses that are connected to here are
 5 done, the patient years as opposed to the patient
 6 numbers, et cetera, do you see that, generally?
 7            A.      Yes.
 8            Q.      And then you talk about the
 9 comparator group that was put together to use in
10 the analysis, do you recall that?
11            A.      Yes.
12            Q.      And in there, you talk about
13 one of the comparators, placebo and then you have
14 comparator medications, and one of the other
15 pieces to the comparator group is the no drug
16 portion, do you see that?
17            A.      Can you help me where it is
18 exactly?
19            Q.      It's the fifth paragraph down
20 starting there have been reports.
21            A.      I'm sorry, I still don't have
22 it -- from the top, yes.
23            Q.      It says there have been
24 reports of suicide gestures although no drug was

                                                 Page 179

 1 actually given.  Do you see that?
 2            A.      Yes.
 3            Q.      This is due to the fact that
 4 investigators have been instructed to report all
 5 observations related to trial patients even after
 6 completion of the protocol?
 7            A.      Correct.
 8            Q.      So sometimes follow up
 9 information for weeks or even months was
10 available and documented.  In such cases the
11 suicide gestures were listed with fluoxetine if
12 the event occurred, I think it's within something
13 days after withdrawal of the drug, correct?
14            A.      Yes, yes.
15            Q.      My question is, who made the
16 decision to put into this comparator group
17 patients who had theoretically been off the drug
18 for, in some cases, a very long period of time?
19            A.      Well, I'm not -- well, let me
20 rephrase your question to make sure that I
21 understand.
22            Q.      Okay.
23            A.      So your question is, if the
24 patient who committed, whatever, suicide attempt,

                                                 Page 180

 1 was not on fluoxetine or not a drug, how could he
 2 end up to be reported as fluoxetine case?
 3            Q.      No.
 4            A.      No?
 5            Q.      Let me try again.  My
 6 understanding of how this reads and my
 7 understanding from looking at the analyses is
 8 that there were some people that were included in
 9 the other group.
10            A.      Yes.
11            Q.      And if you look at the first
12 thing on world wide totals on 231, it says other
13 with an asterisk, and asterisk says placebo, no
14 drug, comparator, okay?
15            A.      Yes.
16            Q.      The no drug, my understanding
17 of your definition in the first page of your
18 report was that patients who fit in that category
19 could have been off of the study and off of any
20 of the given drugs for a very long period of time
21 and still ended up in that no drug group?
22            A.      Well, but this -- isn't that
23 logical?
24            Q.      To me, it's not.

                                                 Page 181

 1            A.      Please explain why, because I
 2 mean if they have no drug --
 3            Q.      Let me ask my question.
 4            A.      -- then they have no drug.
 5            Q.      If you're talking about -- I
 6 mean theoretically under this definition,
 7 somebody who is out of the study for five years
 8 and commits a suicide or commits a suicide
 9 attempt can end up in this no drug portion of the
10 comparator, and not the fluoxetine.  Do you see
11 what I'm saying?
12            A.      Yes, well, I see what you're
13 saying.  But the point is that the system counted
14 as fluoxetine, and we had to take them out of
15 that group.
16            Q.      Why use them at all if they're
17 so far off the study?
18            A.      That's what you say but the
19 FDA sees it differently.
20            Q.      The FDA required you to do
21 this?
22            A.      In fact, you can argue about
23 the value of all this but it's in fact a medical
24 problem, but as long as the physician observed

                                                 Page 182

 1 the patients and, you know, the practical
 2 background is sometime for example you have five
 3 or ten patients in your institution that you put
 4 into one trial, and obviously that's not all at
 5 the same time, you start with patient one and
 6 finish the treatment and by the time you've
 7 finished treatment with patient ten, it stretches
 8 all being a study period, which means you are
 9 involved in the study, you are involved in the
10 reporting, you are involved in interacting with
11 the company.  Now when, whatever, one year later
12 while you treat patient ten, you happen to learn
13 that your patient one, who happened to be in the
14 study, whatever, commit suicide, it might easily
15 enter the records and then, yes.  So as long as
16 the study is ongoing, even not with this patient,
17 we basically report it.
18            Q.      On the other hand,
19 theoretically you could have a patient who is off
20 the fluoxetine arm of the study for two weeks
21 commit suicide and ends up in the other category
22 also, correct?
23            A.      Well, presumably not because
24 we cannot read it here, but there was a period

                                                 Page 183

 1 set where we said well even if he's sometime off,
 2 he would be counted f|uoxetine, which is a very
 3 conservative approach, because of course, each
 4 drug, I mean, you know, has a little bit of
 5 hangover, so we were very conservative in
 6 evaluating this and saying, okay, not immediately
 7 after taking off we would take them out of the
 8 group, but we included them even when they were
 9 not any more on fluoxetine, but given the certain
10 period of time, that's what we obviously cannot
11 read here.
12            Q.      I suppose it has to do with
13 how many days --
14            A.      It has to do with
15 pharmacokinetics.
16            Q.      Actually the half life of
17 fluoxetine or its metabolites can be up to weeks,
18 correct?
19            A.      That's exactly the reason why
20 we were thorough enough to include those
21 patients.
22            Q.      It depends.  If this in fact
23 says after two days, then that's not true.
24            A.      I'm sure it doesn't, I mean we

                                                 Page 184

 1 cannot read it.
 2            Q.      It doesn't say weeks here,
 3 does it?  It says days.
 4            A.      Where?
 5            Q.      I agree with you we cannot
 6 read this from this copy we were provided, we
 7 cannot read how many days they're talking about,
 8 but it says occurs looks like within days after
 9 the withdrawal of the drug, e.g. blank.
10            A.      That's correct.  Yes, but I'm
11 sure we considered the pharmacokinetic profile.
12            Q.      Okay.  So assuming that the
13 amount of time allowed relates to the true
14 pharmacokinetic profile of the drug, then that
15 would be in your opinion very --
16            A.      It doesn't necessarily relate
17 but in order to evaluate carefully you would need
18 to include in the analyzers, yes.
19            Q.      Aren't you risking skewing the
20 data by including too many people in the other
21 drug category as opposed to the people in
22 fluoxetine by including these patients not only
23 that attempted suicide within a short period of
24 time after stopping fluoxetine, but also

                                                 Page 185

 1 including those patients who attempted suicide
 2 long after they were off of any drug included in
 3 the study?
 4            A.      No, I don't think so, in terms
 5 of what the real question here was.
 6            Q.      Do you know how many of these
 7 people listed in the world wide total were
 8 patients who fell under that no drug category?
 9            A.      No, I don't remember what it
10 was exactly.
11            Q.      Because right now -- well,
12 when I say right now, I mean in this exhibit, the
13 world wide totals of suicide attempts assuming in
14 December of 1986 were sixty-three for Prozac and
15 fifteen for all three arms of the other category,
16 correct?
17            A.      So this is including
18 everything, it says sixty something fifteen,
19 that's right.
20            Q.      Okay.
21            A.      These are total numbers.  As
22 you know they have to be related to exposure.
23            Q.      Well, that's debatable but I'm
24 talking about the total numbers.

                                                 Page 186

 1            A.      Okay.
 2            Q.      Sixty-three fluoxetine
 3 patients committed either successfully or
 4 unsuccessfully suicides, and fifteen on all three
 5 of the other arms, in other words the placebo,
 6 the comparator and this no drug group that was
 7 devised.
 8            A.      Yes, that's what it says here.
 9            Q.      Is this across all indications
10 or is this just depression?
11            A.      Well, I guess it's only
12 depression because that was what we investigated.
13 Now there are subtypes of depression which might
14 be all included, so that's from all trials, all
15 experience that we have.
16            Q.      We're not talking about
17 obesity or bulimia trials or OCD trials or
18 anything like that, or are we?
19            A.      Actually I don't know.  I
20 would then however rather say I took what we had.
21 That means if at that time we had already such
22 trials ongoing, they would be included.  But the
23 number presumably was very small because that was
24 done much later.

                                                 Page 187

 1            Q.      You're trying to be as
 2 inclusive as possible.
 3            A.      Right.
 4            Q.      And use the largest amount of
 5 data possible, correct?
 6            A.      Exactly.
 7            Q.      You also included in here
 8 ongoing studies.
 9            A.      Yes.
10            Q.      Not just completed studies,
11 correct?
12            A.      All information I had.
13            Q.      And what you were trying to do
14 is get as much information to look at as
15 possible, correct?
16            A.      I think I did, I think that
17 was the right way to do.
18            MS. ZETTLER:  Let's take a break.
19            (A SHORT BREAK WAS TAKEN.)
20            Q.      (BY MS. ZETTLER)  Doctor, if
21 we could go back to Exhibit 5, back to the first
22 page of your suicide analysis, that's 229.
23            A.      Yes.
24            Q.      We're talking about that

                                                 Page 188

 1 sentence about when the patients were included in
 2 that no drug category, okay.  The last sentence
 3 of that paragraph says however they are listed
 4 with the control group if they occurred five
 5 weeks or more after the withdrawal of fluoxetine.
 6 Do you see that?
 7            A.      Yes.
 8            Q.      Even if the pharmacokinetics
 9 of the drug, it doesn't last in your system for
10 five weeks, at least to a therapeautic level or a
11 level that's going to have any effect on you,
12 does it?
13            A.      Yes.  So it does not last that
14 long.
15            Q.      And the reason that you
16 included the people in the clinical trials, I
17 want to make sure I understand this, who had been
18 off of the drug for five weeks or more, was
19 because they had to be reported to the FDA?
20            A.      Well, usually the point is I
21 mean if you don't know about it, obviously you
22 don't report.  But occasionally investigators
23 bring this to your attention under the
24 circumstances I was just describing and then yes,

                                                 Page 189

 1 I mean you would report that.  Anyway, the point
 2 here was, I didn't recall it but as it's
 3 described here that there were cases in the
 4 system listed in a certain category but by closer
 5 analysis could be found that in fact they had
 6 been so long off drug and that's why in order to
 7 make a proper analysis, they were getting into
 8 this different category.
 9            Q.      But if it was a patient on
10 fluoxetine in a clinical trial who after they had
11 been off the drug for at least five weeks
12 attempted suicide or some other event occurred,
13 okay, they would be listed in the reports to the
14 FDA as having been a fluoxetine patient, would
15 they not?
16            A.      That's correct.
17            Q.      And then why weren't they
18 included in the fluoxetine group then?
19            A.      Because they were not on
20 fluoxetine.
21            Q.      Okay.  So simply because they
22 were not on fluoxetine, they were still included
23 in the other?
24            A.      Clearly it's difficult to

                                                 Page 190

 1 understand.  Let me give you another example.  As
 2 long as a study is blinded and even -- let's take
 3 our case, amitryptiline, even if the suicide was
 4 on amitryptiline, as long as it's not unblinded,
 5 it runs as -- well, fluoxetine in the test drug,
 6 fluoxetine study, and it's reported as such to
 7 the FDA, just to --
 8            Q.      As an adverse event?
 9            A.      Yes, although it's not on
10 fluoxetine but it's just, you know, because the
11 regulation is whatever you see in the study, I
12 mean, you report.
13            Q.      But if somebody has a serious
14 adverse event, say an overdose, they're going to
15 be unblinded so they can see what drug they're
16 on, are they not?
17            A.      Sometimes yes, sometimes no,
18 depending on what the clinical situation
19 requires.
20            Q.      Do you know of any FDA
21 regulation under which unblinded patients have to
22 be reported as adverse events?
23            A.      No, that's -- I mean the
24 unblinding, the act of unblinding is just an

                                                 Page 191

 1 investigator or clinical decision.  If whatever
 2 you need to do for the patient requires to know
 3 which drug he's on, and that may be necessary,
 4 yes or no, now the only impact that has then is
 5 an impact on the study, because if you had a
 6 blinded study you would like to have it blinded.
 7 So that's why you usually do not easily unblind,
 8 not to compromise the study.  So there are two
 9 interests.  And however as long as it's not
10 unblinded, everything, regardless if it's test or
11 comparator drug, is reported to the FDA under the
12 test drug.  That's just a regulation.
13            Q.      Under what situation -- are
14 you saying adverse events if they occur when the
15 patient is still blinded, right, if they occur --
16 strike that.
17                    You're saying that adverse
18 events if they occur and the patient is still
19 blinded are reported to the FDA as adverse events
20 occurring on the study drug?
21            A.      That's correct.
22            Q.      Why, when?  Give me a
23 situation when that would happen.
24            A.      Well, I mean, in this case you

                                                 Page 192

 1 better ask the FDA.  But the point is that they,
 2 which I understand is -- or which I think is
 3 understandable, they want to know what is going
 4 on during the development of drugs.  That's why
 5 we have an IND system here in this country.  And
 6 again, as long as you don't know better, I mean
 7 as long as you do not know if it's A or B, but
 8 still so that they can find it in their system,
 9 you need to label it somewhat and it's just the
10 practice that you report it as the study what it
11 is, the study of the test drug.  And only after
12 unblinding, only after breaking the code and
13 everybody knows, okay, he was on amitryptiline,
14 she was on fluoxetine, only then you can make
15 this correlation.
16            Q.      I just want to make sure I
17 understand what -- you're not saying that an
18 adverse event is reported to the FDA on say a
19 fifteen day alert status or on a 1639 for a
20 serious report as fluoxetine-related if it's an
21 unblinded study, are you?  If you have a serious
22 adverse event --
23            A.      Yes.
24            Q.      And you have to report that to

                                                 Page 193

 1 the FDA within a certain period of time --
 2            A.      Yes.
 3            Q.      -- if it meets the criteria,
 4 right?
 5            A.      Yes.
 6            Q.      You're not saying that Lilly
 7 was reporting as fluoxetine patients, patients
 8 who had not even been unblinded if they had a
 9 serious event during the clinical trial, are you?
10            A.      That may happen.  Because
11 maybe for you it's difficult to understand, if
12 there's a serious event why at all can you keep
13 the blinding.
14            Q.      Right.
15            A.      But there are cases where
16 there's no problem to do that because the serious
17 classification is a very, you know, bucketwise
18 classification which does not correlate
19 necessarily to the clinical severity of the case.
20            Q.      Have you seen cases where
21 Lilly has reported an unblinded patient --
22            A.      Yes.
23            Q.      -- on a 1639 as a serious
24 adverse event?

                                                 Page 194

 1            A.      Yes.
 2            Q.      What cases?  Give me examples
 3 of the types of adverse events.
 4            A.      Well, that's, I mean, I just
 5 can't think of recent examples and they are
 6 related to drugs still under development and I
 7 think that's not necessary to mention yet.
 8            Q.      You don't have to tell me what
 9 drug it is, just give me the types of adverse
10 events.
11            A.      Well, see, if one criteria is
12 hospitalization.
13            Q.      Okay.
14            A.      And I mean for whatever reason
15 you get into the hospital, that may not be
16 necessarily a real big thing, but just for social
17 reasons even, for some reason, I mean, you're
18 admitted to the hospital, and just by that, you
19 qualify for serious, but maybe after some
20 examination you are discharged again, then just
21 because of that, you would qualify for serious
22 because even if it was just itching but because
23 you were hospitalized, it would qualify.  So
24 there are distinct differences.  To make it even

                                                 Page 195

 1 more complicated, you can have a myocardial
 2 infarction and for some reason nobody diagnoses
 3 it and you stay at home and actually it's not
 4 qualifying because you're neither hospitalized,
 5 if you don't die, it's not an overdose, it
 6 doesn't qualify.
 7            Q.      What about life threatening?
 8            A.      Well, life threatening usually --
 9 well, life threatening is a gray area but
10 basically it's understood that only if you are
11 really in acute danger of your life, because
12 there are many conditions which are potentially
13 life threatening, like a myocardial infarction,
14 but not necessarily, I mean, leading to the
15 death.  So usually it's understood only
16 conditions where you're at the immediate risk of
17 your life, where you're in the intensive care
18 unit and people are fighting for your life or
19 something like that.
20            Q.      Where do you get that
21 information, is that an FDA regulation
22 definition?
23            A.      Well, the life threatening is
24 clearly a judgment call, no officer can help you

                                                 Page 196

 1 with that.
 2            Q.      So that's something that you
 3 learned through Lilly?
 4            A.      That's a physician decision.
 5            Q.      There are other requirements
 6 under the FDA regulations that apply to whether
 7 or not an adverse event is reported via 1639 or
 8 within a certain period of time, are there not,
 9 like for instance expectedness?
10            A.      Yes -- well, I mean actually --
11 you're right.  Although I'm not a hundred percent
12 familiar being not directly subject to FDA
13 regulations, neither in Germany nor in Japan now,
14 that I do not know all the precise requirements.
15 I know the serious criteria, that's what we do to
16 put it in the corporate system.  Now what
17 corporate then does to report it to Washington is
18 a different story.
19            Q.      Okay, so you may report to
20 corporate --
21            A.      All serious --
22            Q.      Let me finish.  An adverse
23 event that occurs in a clinical trial where you
24 do not unblind the patient, correct?

                                                 Page 197

 1            A.      Yes.
 2            Q.      Okay.  Do you know for a fact
 3 that those are then reported by the corporation
 4 to the FDA as fluoxetine or whatever the study
 5 drug is involved?
 6            A.      Yes.
 7            Q.      As that study drug, even
 8 though you don't know if it was placebo,
 9 comparator or the study drug?
10            A.      Yes.
11            Q.      How do you know that?
12            A.      Well, I just know it because
13 sometimes these reports are sent back to be
14 informed to other regulatory authorities.
15            A.      Because if such thing happens,
16 for example, in Belgium, and they send it to
17 Indianapolis, and well, Indianapolis is
18 responsible for the FDA but they also according
19 to certain criteria, and here in fact
20 expectedness plays a role, comes into play, they
21 send it back to all affiliates, because it's not
22 only important for Belgium and Washington, it's
23 also important for other regulatory authorities,
24 and in order to enable that, I mean, you need to

                                                 Page 198

 1 have this flow back of information, and that's
 2 exactly what's happening.  So that's why I can
 3 see it occasionally.
 4            Q.      Forgive me, Doctor, because
 5 what you're describing to me just doesn't make
 6 sense from the position of being able to test the
 7 safety and efficacy of the drug, okay.  Let me
 8 finish.  If you have a situation where you have a
 9 comparator study going on, okay, or just a
10 placebo study drug study going on, how is the FDA
11 supposed to accurately assess the safety at least
12 of the drug if it's being flooded or it's being
13 given adverse events reported as the study drug
14 adverse event when it's something that's
15 happening on another drug or on placebo?
16            A.      That's a very good question
17 but I really must encourage you to ask the FDA
18 officer because it's hard to understand but it's
19 just done that way.  Obviously, I mean later when
20 the study progresses or is finished, I mean then
21 once it's unblinded it's sorted.
22            Q.      Are the majority of these
23 adverse events that are unblinded reported to the
24 FDA through mechanisms such as line listings in

                                                 Page 199

 1 safety updates or periodical updates that are
 2 reported to the FDA?
 3            A.      No, I think they can occur at
 4 any time.
 5            Q.      But I guess I'm just trying to
 6 understand it because it sure seems like it would
 7 confuse and confound and skew the data that is
 8 being submitted to the FDA to report an adverse
 9 event to it on a 1639 as a serious adverse event
10 without telling the FDA what drug the person was
11 on?
12            A.      Well, but of course it's --
13 you can take from this report that this is from a
14 study and this it's a blinded study so the FDA
15 presumably will, you know, assess it with
16 caution.  So you can see from the form that it's
17 a study report and a study which is blinded.
18            Q.      Have you seen regulations that
19 require, have you actually seen the regulations
20 that require that this type of reporting happen?
21            A.      No, I have not seen the
22 regulations, and again I have never worked
23 professionally within the United States, so I do
24 not know this precisely.  The only thing I can

                                                 Page 200

 1 say is that, you know, whatever happens during
 2 the study qualifying the serious criteria, you
 3 must report, and that there is no rule at
 4 occurrence to immediately unblind, as a result
 5 there may reports go in where you do not know
 6 which drug the individual is on.  But again, this
 7 is marked in the report, so I mean the agency
 8 does not assume falsely that this is related to
 9 one or the other drugs, so they know it can be
10 one or the other drug.
11            Q.      Do you know what the FDA does
12 with information that's reported to it on the
13 Form 1639?
14            A.      I don't know.
15            Q.      Is it your testimony that
16 adverse events occurring on comparator drugs or
17 placebo are reported as 1639s to the FDA, if you
18 know, if you know that it happens on, for
19 instance, your suicide attempt on amitryptiline,
20 was that reported to the FDA on a 1639?
21            A.      Well, obviously it says here
22 it was unblinded and that's why it was not
23 reported.  But, well, let's set the case it was
24 not unblinded, we would have reported, and only

                                                 Page 201

 1 at the end of the study would have learned it was
 2 amitryptiline.
 3            Q.      And then you would have
 4 notified the FDA that was not a fluoxetine
 5 adverse event, that was an amitryptiline adverse
 6 event?
 7            A.      That's presumably the way they
 8 would do it.  Again, I don't know how the
 9 colleagues do that here.
10            Q.      That's how you do it in
11 Germany?
12            A.      Well, there we don't report
13 such events.
14            Q.      In Germany, you do not report
15 blinded adverse events?
16            A.      We have a completely different
17 system in that regard.
18            Q.      But your understanding from
19 people here in Indianapolis is that the FDA does
20 require that kind of report?
21            A.      Yes, that's my understanding.
22            Q.      Who told you that
23 specifically, do you remember?
24            A.      Well, it's actually nobody

                                                 Page 202

 1 told me, it's just that we see these reports.
 2 And I said that these reports once entering the
 3 corporate system, I mean are fed back to the
 4 affiliates, particularly those that did not make
 5 the initial submission.
 6            Q.      Okay.  So you're in effect
 7 making the assumption because you've seen reports
 8 that come out of the corporate system that are
 9 not blinded or that are unblinded?
10            A.      Which are blinded.
11            Q.      Which are blinded, thank you.
12            A.      Right, I have seen such
13 reports, right.
14            Q.      And you are assuming that they
15 are, because they're on these forms, reported to
16 the FDA?
17            A.      Yes, because it's basically a
18 copy of those, yes.
19            Q.      But nobody from Lilly has told
20 you that this is a requirement or practice of the
21 FDA?
22            A.      Nobody directly told me but I
23 think it's easy to conceive because the FDA wants
24 to know what's going on during studies.

                                                 Page 203

 1             (PLAINTIFFS' EXHIBIT NO. 7 WAS
 2              MARKED FOR IDENTIFICATION AND
 3              RECEIVED IN EVIDENCE.)
 4            A.      Okay.
 5            Q.      Do you recognize Exhibit 7,
 6 Doctor?
 7            A.      Yes.
 8            Q.      Can you tell me what it is,
 9 please?
10            A.      Well, obviously this was as it
11 says here an update of the findings with
12 fluoxetine, especially in regard to safety, as I
13 see it here based on German study data.
14            Q.      Okay.  This is the safety
15 update you were talking about earlier, or this is
16 an example of a safety update you were talking
17 about?
18            A.      Well, all these kind of things
19 were done and finally included in this
20 submission, yes.
21            Q.      Was this actual document sent
22 to the FDA -- or to the BGA?
23            A.      Oh, I do not recall this.  It
24 may be not so because what we also were -- I do

                                                 Page 204

 1 not really recall when we made the resubmission.
 2 The point here is it says please find enclosed
 3 the actual safety update for Germany as promised.
 4 I would rather think that this is relating or
 5 providing information from Germany for the safety
 6 update to be prepared for the FDA here in
 7 Indianapolis, because it's basically following
 8 the format we usually are requested to have for
 9 that.  I cannot exclude that it has been also
10 attached to our resubmission but if the
11 resubmission was much later it would have
12 presumably added actual data.
13            Q.      Okay, so let me make sure I
14 understand it.  You recall that this is the
15 German portion of the safety update for
16 submission to the FDA, it's information on the
17 German studies that were done?
18            A.      It's definitely from German
19 studies and judging from how it's related here,
20 it's most likely determined to be used in the
21 U.S. safety update which has to be a world wide
22 overview.
23            Q.      This is not something that was
24 submitted to the BGA before what you submitted in

                                                 Page 205

 1 December, 1986?
 2            A.      This was presumably not
 3 submitted, I cannot exclude if it was also
 4 attached to the December documents.
 5            Q.      But it was not --
 6            A.      Not at the same time.
 7            Q.      Not an individual submission?
 8            A.      Not at the same time.
 9            MS. ZETTLER:  Let's change the tape.
10            MR. BOUR:  The time is 2:46, the start
11 of Tape 3.
12            Q.      (BY MS. ZETTLER)  The first
13 page of Exhibit 7 is a telecopy again written by
14 Barbara von Keitz in Bad Homburg to a number of
15 people, or at least it's written to Doctor Zerbe
16 in Indianapolis and it's copied to a number of
17 other people around the world, correct?
18            A.      Well, it's to Doctor Zerbe in
19 Erl Wood here at that time.
20            Q.      Okay, he's in Erl Wood, okay.
21 But Doctor Zerbe is originally from Indianapolis.
22            A.      He's an American, yes.
23            Q.      And it's back here in the
24 United States?

                                                 Page 206

 1            A.      Correct.
 2            Q.      And you're carbon copied on
 3 this, correct?
 4            A.      Yes.
 5            Q.      And it's dated March 7, 1986?
 6            A.      Yes.
 7            Q.      And the second paragraph from
 8 the bottom she states, during a telephone
 9 conversation with Doctor Wernicke, I got the
10 impression that in the safety update for the FDA,
11 the number of suicides and suicide attempts will
12 not be especially evaluated.  Did you know
13 anything about that?
14            A.      Well, it's stated here so I
15 knew about it but there's nothing surprising
16 about it.
17            Q.      Why is it that the FDA did not
18 especially evaluate the suicides and suicide
19 attempts by the FDA -- strike that.
20                    Why is it that Lilly did not
21 especially evaluate the suicides and suicide
22 attempts for the FDA?
23            A.      Well, so again it confirms
24 that the whole thing is basically for the U.S.

                                                 Page 207

 1 safety update, and, you know, there are
 2 presumably hundreds or even more individual
 3 observations that are listed according to certain
 4 criteria.  They are being -- there are
 5 regulations requiring which patients have to be
 6 described in more detail, for example those
 7 discontinued for safety issues, and those having
 8 died from that.  But other than that, they're
 9 basically listed as the format of the safety
10 update and unless there is a certain reason,
11 suspicion or whatever, concern, it's neither
12 necessary nor justified to evaluate each
13 individual case in this safety update, so that's
14 nothing unusual.  Now obviously from a German
15 point of view, where we received this question
16 from the BGA and we're working on this, it was a
17 little bit different.  So that's why, I mean,
18 this expresses it simply, I mean we understand
19 you are not going to do that in detail but we
20 need it so provide us with the data.  That's what
21 it means.
22            Q.      So it's your understanding
23 that for the FDA Lilly didn't do the -- at least
24 at this time, 1986, the indepth analyses of the

                                                 Page 208

 1 suicide attempts that they were doing or helping
 2 you do for the BGA, correct?
 3            A.      That's correct, and really
 4 looking on it on a case by case.
 5            Q.      Okay.  The last paragraph
 6 says, I also would like to mention that it is
 7 very important for us to get regular information
 8 on what is planned and done on this resubmission
 9 in the U.K., in order that we can consider this
10 in our plans for the answer to the BGA.  Why was
11 the U.K. submission so important at this point?
12            A.      Well, that's what I mentioned
13 earlier, that in particular in Europe also
14 authorities communicated with each other, and
15 that insofar it was always interesting to know
16 what concern another authority, in particular one
17 the U.K. might have, and |ast but not least also
18 to c 1 agencies in Europe?
 2            A.      Well, I don't have evidence
 3 for that but that's what people usually assume.
 4 Now today it's basically world wide network.
 5            Q.      Did it have anything to do
 6 with what you were talking about earlier that the
 7 U.K. didn't generally follow -- evaluate the drug
 8 on the U.S. package like everybody had until
 9 after you started working on Lilly?
10            A.      I don't know, in this case it
11 could have been France.  The reason why it's U.K.
12 is because obviously it went timewise more in
13 parallel.
14            Q.      So it's really a function of
15 the regulatory processes that were going on at
16 the same time?
17            A.      Right.  As you know at this
18 point in time, we could anticipate that during
19 the next months we would make our submission so
20 we were of course interested to know about that.
21            Q.      The second page is an E-mail
22 from you to Doctor Wernicke.
23            A.      Yes.
24            Q.      And you talk about -- it says,

                                                 Page 210

 1 please find enclosed the actual safety update for
 2 Germany as promised in my telex of March 27th.
 3 Then you go on under the report is organized as
 4 follows, overview -- under number two, overview
 5 of all projects by investigator and study title,
 6 indicating which information has already been
 7 submitted in the original September safety
 8 update.  Are you talking about the September FDA
 9 safety update?
10            A.      I'm sure I do that because
11 it's only the FDA requiring this type of regular
12 reports during review.
13            Q.      How often was Lilly submitting
14 safety updates to the FDA during this period of
15 time, do you know?
16            A.      I do not know how often we
17 actually did it, but I understand that the rule
18 is quarterly after NDA submission in America.
19 However the FDA can request any additional, when
20 it, you know, at its discretion.
21            Q.      The next page is entitled
22 Fluoxetine Safety Update, Germany, and talks
23 about retrospective reporting on trials that had
24 been completed before August of 1985.  Do you see

                                                 Page 211

 1 that?
 2            A.      Yes.
 3            Q.      The second paragraph from the
 4 bottom, it says case summaries and CRFs are not
 5 submitted for all discontinuations due to adverse
 6 events, i.e. including lack of drug effect, but
 7 only for discontinuations due to side effects.
 8 What do you mean by that?
 9            A.      Well, this is a long time ago
10 but what I would think I meant was we -- the lack
11 of drug effect was, you know, regarded still also
12 as an event.  On the other hand, I mean, there --
13 each drug, I mean you have responders and
14 nonresponders, so also it's not really revealing
15 important safety information, and the point here
16 is that if there was a discontinuation due to an
17 event, you need to supply a case summary and also
18 the original case report form.  Now if we are --
19 when we are in Germany and need to provide this
20 for the FDA, we must undergo all the hassle to
21 translate this, so we usually try to reduce our
22 administrative burden.  And as long as it's not
23 definitely requested and presumably it's also in
24 most cases irrelevant, and that's what it means

                                                 Page 212

 1 here, we said okay, we are -- case summaries and
 2 CRFs but not for those cases which have been
 3 discontinued due to lack of efficacy, assuming
 4 that it's presumably not that relevant.  Mainly
 5 the background is that, yes, I mean if you think
 6 from a foreign affiliate, I mean it's sometimes
 7 very cumbersome to all get this from your local
 8 language to English, and sometimes case reports
 9 forms particularly in such trials are like this,
10 so we wanted simply to spare the translation.
11            Q.      What was your definition of
12 lack of drug effect?
13            A.      That's usually according to
14 the commands of the investigator in the case
15 report form, because they have to give a reason
16 why they discontinued the trial.
17            Q.      How does the investigator know
18 that it is lack of drug effect as opposed to an
19 adverse event?  For instance, the BGA was
20 concerned that fluoxetine actually increased some
21 symptoms or exacerbated some symptoms of
22 depression, correct?
23            A.      Yes, well, I would say it the
24 following, you know, these are all psychiatrists,

                                                 Page 213

 1 I mean people who I would expect know the
 2 diseases and the progression of the diseases, so
 3 when we asked them in our case report form what
 4 do you think is the reason for taking the patient
 5 out of the study, then I would simply trust the
 6 reason he's given me.  I think it's also not my
 7 duty to question that.
 8            Q.      Wouldn't it be more honest to
 9 say worsening of depression, for instance, as
10 opposed to a lack of efficacy?
11            A.      Well, it's the same, worsening
12 of depression.  But again, that's natural, we
13 know that no drug, including fluoxetine, works in
14 a hundred percent of the patients.
15            Q.      Let's turn to page 2057, it
16 says Fluoxetine Safety Update, Table 3.
17            A.      Which page, please?
18            Q.      2057 in the bottom right-hand
19 corner.
20            A.      Yes.
21            Q.      It says, Table 3, Table of All
22 Discontinuations By Project?
23            A.      Yes.
24            Q.      And you list about two pages

                                                 Page 214

 1 worth of discontinuations, correct?
 2            A.      Yes.
 3            Q.      And the vast majority of them
 4 it appears to me without counting each one of
 5 them up is lack of efficacy, is it not?
 6            A.      Yes.
 7            Q.      Then you go on here and I'm
 8 assuming that it's very difficult to match these
 9 up because the patient numbers are blocked out
10 even though there are patient numbers that are
11 left in on the first couple of pages, but you go
12 on to talk about case summaries from patients who
13 discontinued because of adverse events.  Do you
14 see that?
15            A.      Yes.
16            Q.      Were any of these summaries on
17 patients who were dropped because of lack of
18 efficacy?
19            A.      Well, we would need to go
20 through that and we can determine it.
21            Q.      Here, let's do it this way:
22 Four pages back at 2062, Doctor Schenk talks
23 about a sixty-one year old female patient with
24 unipolar depression, retarded subtype, who was

                                                 Page 215

 1 discontinued from the study because of moderate
 2 gastric distress and dizziness, as well as lack
 3 of efficacy, do you see that?
 4            A.      I've got the case but where's
 5 the line you're talking about?
 6            Q.      The very last line, on
 7 8-11-84, discontinuation because of moderate
 8 gastric distress.
 9            A.      Yes, I see that.
10            Q.      Would this person have been
11 reported as having discontinued because of lack
12 of efficacy or because of dizziness or gastric
13 distress?
14            A.      I actually don't know, I mean
15 here you see how difficult it is to make
16 judgment, so you have it in one or the other
17 table, maybe depending on what the investigator
18 had listed as the primary reason, as we cannot
19 correlate the numbers, this was done by Doctor
20 Schenk, I really don't know, it could be both,
21 what was the leading symptom.
22            Q.      It depends on what the leading
23 symptom was?
24            A.      Uh-huh.

                                                 Page 216

 1            Q.      The page before that is a
 2 summary written by you, at least it looks like it
 3 was written by you.
 4            A.      Yes, I signed it.
 5            Q.      Is that your signature at the
 6 bottom?
 7            A.      It is.
 8            Q.      And it's at page 2061,
 9 correct?
10            A.      Yes.
11            Q.      It says, a forty-three year
12 old woman suffering from endogenous depression,
13 of retarded subtype, received fluoxetine, three
14 days forty milligrams, and then sixty milligrams
15 a day, on July 11, '84 after three days of a
16 placebo run in period.  She had a history of
17 three depressive phases which had been treated in
18 the hospital.  Before admitted this time, she had
19 received amitryptiline, two hundred fifty
20 milligrams and thioridazin?
21            A.      Yes.
22            Q.      Sixty milligrams since two
23 months without any success.  It says she --
24 before receiving this study medication which we

                                                 Page 217

 1 know is fluoxetine, she had a thirty-two of
 2 twenty-one on the Hamilton score and on five days --
 3 let's see, on July 16th, she received a
 4 cotrimoxazol?
 5            A.      Cotrimoxazol, yes.
 6            Q.      For a urinary tract infection.
 7 On 7-25-84 promethazine twenty-five milligrams
 8 was added due to nervousness.  She was
 9 discontinued due to lack of efficacy on 7-31-84
10 on investigator's decision.
11            A.      Yes.
12            Q.      Her HAMD was thirty-three of
13 twenty-one.  After withdrawal of the study, she
14 was treated with thymoleptic infusion and
15 improved.
16                    She's given a concomitant
17 medication because of nervousness, yet she was
18 discontinued from the study because of a lack of
19 efficacy judgment.  Does that seem appropriate to
20 you, Doctor?
21            A.      Absolutely, that can happen,
22 in particular when you see the the history of
23 this patient and its HAMD score.
24            Q.      And when you have her as

                                                 Page 218

 1 retarded subtype depression, right?
 2            A.      Well, wasn't amitryptiline and
 3 another thioridazin before.
 4            Q.      But it doesn't say she became
 5 nervous on either one of those, does it?
 6            A.      Well, but she didn't respond
 7 to treatment, it says.
 8            Q.      She also had nervousness that
 9 was serious enough for the doctor to feel that he
10 had to prescribe concomitant medication, correct?
11            A.      Well, so what?
12            Q.      It seems to me, Doctor, that
13 if you have somebody who's receiving a
14 prescription medication in response to an event
15 that's occurring on a study drug, that that
16 should be reported as an adverse event and not a
17 discontinuation due to lack of efficacy?
18            MR. LORE:  It's not a question.
19            Q.      Do you know if that
20 nervousness was reported in addition to the
21 discontinuation?
22            A.      I would think so.
23            Q.      Do you know where it would
24 have been reported?

                                                 Page 219

 1            A.      Well, it's obviously in the
 2 study report, otherwise it wouldn't have been
 3 mentioned here.
 4            Q.      If you look at what is written
 5 here, we don't know anything about this person's
 6 nervousness, do we, under Table 3 of
 7 discontinuations?
 8            A.      No, presumably we don't.
 9            Q.      When is the determination as
10 to whether or not the patient is being
11 discontinued as to lack of efficacy made by the
12 investigator, before or after they're unblinded?
13            A.      Excuse me, say again, when or
14 how?
15            Q.      When is it determined by the
16 investigator that a patient is being discontinued
17 due to lack of efficacy, before or after the
18 investigator is unblinded?
19            A.      I mean, of course, I mean when
20 he's still blinded, depending on what kind of
21 study it is.  I mean, there are also open
22 studies, there are also controlled studies, but
23 if it's blinded of course he stays still blinded.
24            Q.      Fluoxetine was rejected again

                                                 Page 220

 1 in 1988, was it not, by the BGA?
 2            A.      No, I think it was earlier.
 3            Q.      Pardon?
 4            A.      That must have been earlier.
 5            Q.      Than 1988?
 6            A.      Yes.  By the way, it was never
 7 rejected.  You mean intention for rejection or
 8 what are you referring to?
 9            Q.      Well, I have a document here
10 that says that it was officially rejected in
11 1988.
12            A.      Well, that's internal.
13            Q.      Do you want to take a look at
14 it?
15             (PLAINTIFFS' EXHIBIT NO. 8 WAS
16              MARKED FOR IDENTIFICATION AND
17              RECEIVED IN EVIDENCE.)
18 
19            A.      Okay.
20            Q.      Exhibit 8 is another E-mail by
21 Claude Bouchy to a number of people including
22 yourself and a couple of people in Indianapolis,
23 correct?
24            A.      Correct.

                                                 Page 221

 1            Q.      It's dated April 29, 1988, is
 2 it not?
 3            A.      Yes.
 4            Q.      He says, Fluoxetine
 5 Registration In Germany-Confidential.  We have
 6 had yesterday a bad surpryse.  We received an
 7 official letter from the BGA officially rejecting
 8 our application for registration, exclamation
 9 point.  Of course we have, in agreement with
10 Gerhard, tried to understand what was going on
11 with the help of Straeter.  Correct?
12            A.      It's written here.
13            Q.      Who's Gerhard?
14            A.      Myer.
15            Q.      Okay.  Who was Gerhard Myer at
16 the time?
17            A.      President of Europe.
18            Q.      Pardon?
19            A.      President of the Lilly
20 operations in Europe.
21            Q.      And again you employed Mister
22 Straeter to help you find out what was happening,
23 correct?
24            A.      Yes.

                                                 Page 222

 1            Q.      And Mister Straeter is the
 2 former BGA lawyer who was consulting with Lilly
 3 and other drug companies on regulatory issues
 4 with the BGA, correct?
 5            A.      Yes.
 6            Q.      The letter or the E-mail goes
 7 on to say, and this is what we have been able to
 8 learn since last evening when we received the
 9 letter.  By the way -- strike that.
10                    Did you know about this, did
11 you know that it had been rejected in 1988?
12            A.      Well, that's why I was saying
13 it's not rejected because there are explanations
14 to that.
15            Q.      Well, you received a letter
16 rejecting the application, correct?
17            A.      Well --
18            Q.      Whether or not somebody
19 retracted it is a different question.  You did
20 get a letter --
21            A.      I simply didn't recall this
22 because at the end and what the whole process
23 shows, because with a rejection we would have
24 needed to resubmitted fully, which we never did.

                                                 Page 223

 1            Q.      Okay.  My question is, in
 2 April of '88, you received an official rejection?
 3            A.      That's what Claude Bouchy says
 4 here and as I read it it comes to my mind and
 5 again there's an explanation to that, and
 6 basically in paragraph two.
 7            Q.      The answer to my question is
 8 yes, in April of '88, you received an official
 9 rejection of the product license or registration
10 in Germany?
11            A.      In that context, yes.
12            Q.      And this is what we have been
13 able to learn since last evening when we received
14 the letter.  Frau Gundert Remy, head of the
15 clinical review department knew nothing about it.
16 Somebody contacted Professor Remy, correct?
17            A.      Obviously, yes.
18            Q.      Two, it is most probably due
19 to an action developed by the administration
20 people of the BGA.  They are being criticized at
21 the moment for not making decisions and they are
22 apparently looking at the status of all
23 applications.  Since we were supposed to answer
24 the deficiency list before the end of December of

                                                 Page 224

 1 '86, and since we have not delivered the total
 2 in-patient study from blank, the administration
 3 saw here a clear case where a rejection decision
 4 could be made.  These people obviously were not
 5 aware of our verbal agreement with Doctor Elias.
 6            A.      Presumably Elbers, but anyway --
 7            Q.      Pardon?
 8            A.      Presumably Elbers.
 9            Q.      Elbers, okay.  And Frau
10 Gundert.  Who is Doctor Elbers?
11            A.      He was also BGA officer.
12            Q.      What position is Doctor
13 Elbers?
14            A.      I don't know exactly, I just
15 recall his name.  He's presumably also in the
16 department of -- or maybe separate department.
17 Anyway, I mean he's a BGA guy.
18            Q.      Okay.  Did this E-mail suggest
19 that you didn't in fact answer the intent to
20 reject letter in December of 1986 like the
21 document that we have shows?
22            A.      Well, the point is that
23 apparently from an administrative point of view,
24 strictly speaking, the deadline was not respected

                                                 Page 225

 1 and so on administrative grounds presumably it
 2 would have been correct to say that, and that's
 3 also the reason why I first said there was never
 4 a rejection because for me it's only important in
 5 terms of by content, and this finally was worked
 6 out to be something, just an administrative
 7 misunderstanding, evidenced by the fact that we
 8 never made an official resubmission, but that
 9 this was further discussed and resulted finally
10 in the approval.  But as yes, you can read here,
11 and yes, I mean, I did not really recall it,
12 there was this kind of thing, but obviously done
13 not with the knowledge of the head of the
14 department, Professor Gundert Remy, and as it --
15 well, it states here, just to, you know, they
16 have piles of registrations and if they can lower
17 those piles, I mean of course they're interested
18 in doing that and they look at just formal kind
19 of incompleteness and throw everything out that
20 is formally incomplete, overlooking, you know, on
21 the troops level here that we have this
22 agreement.
23            MS. ZETTLER:  Motion to strike as
24 nonresponsive.

                                                 Page 226

 1            Q.      My question is, and was, that
 2 it appears from this memo that you did not submit
 3 the response to the intent to reject letter in
 4 December of 1986, as the documents that we
 5 reviewed earlier show, okay.  Do you know what
 6 they're talking about here?  I'm not asking for a
 7 long diatribe about how, you know, what happened
 8 here, we'll get into that in a minute.  What I
 9 want to know is --
10            A.      I'm not sure if the December
11 '86 is correct, but anyway the point is we missed
12 the deadline if you want to know this, yes.
13            Q.      Do you know if you submitted
14 it by April of 1988?
15            A.      I don't recall when the
16 submission date was, maybe so.
17            Q.      Because it appears from here
18 that you didn't, it appears from this that it
19 says since we were supposed to answer the
20 deficiency list before the end of December, 1986,
21 and since we have not delivered the total
22 in-patient study from blank, the administration
23 saw here a clear case where rejection decision
24 could be made.

                                                 Page 227

 1            A.      Yes, okay, you're right.  So
 2 obviously we didn't do that, okay.
 3            Q.      Who made the verbal agreement
 4 with Doctor Elbers and Frau Gundert?
 5            A.      I don't know.
 6            Q.      Do you know what that verbal
 7 agreement was?
 8            A.      I can only speculate and you
 9 touched on it earlier yourself because we
10 definitely were extending the time frame usually
11 granted to respond to questions.  We took a
12 longer time, but the general agreement I guess
13 was made because everybody was understanding, to
14 conduct and evaluate an in-patient trial would
15 exceed the three months.
16            Q.      By about nine months, correct?
17            A.      Well, it took even two years
18 and that's not unnormal for such a trial.
19            Q.      But you had verbal -- is it
20 your understanding that you had a verbal
21 agreement with Doctor Elbers and Frau Gundert to
22 deliver the data in two years?
23            A.      It was not me personally
24 because when the initial issues all were coming

                                                 Page 228

 1 in, I wasn't in charge of that, so I assume that
 2 that was at that time agreed, but between whoever
 3 represented the company and BGA officials.
 4            Q.      Is it normal for the BGA to
 5 allow an application to sit there basically for a
 6 couple of years as opposed to rejecting it as
 7 they stated in their intent to reject letter?
 8            A.      Well, maybe it's not normal,
 9 but obviously it happened.
10            Q.      Is it unusual for a drug
11 company to make a verbal request as opposed to an
12 official written request for more time as this
13 document implies was done here?
14            A.      It's difficult to judge from
15 that what is more appropriate.
16            Q.      Okay.  Mister Bouchy goes on
17 to say it is still embarrassing to have an
18 official letter here in house rejecting our
19 application for registration based on specific
20 efficacy and safety deficiencies, some of them
21 are new.  Do you know what new issues are raised?
22            A.      I would need to see the old
23 versus the new list, I don't recall it
24 specifically.

                                                 Page 229

 1            Q.      We haven't been given the new
 2 one here, this is the first indication we've
 3 gotten that this was rejected again in '88.
 4                    Here is the action plan -- it
 5 goes on to say, here is the action plan we are
 6 proposing.  We have the possibility to appeal
 7 officially within one month and Straeter thinks
 8 we have a good chance to be successful because
 9 the decision of the BGA breaks our gentleman
10 agreement, correct?
11            A.      It stands here.
12            Q.      Should we decide not to
13 appeal, then we still have the possibility to do
14 the EEC route.  What's the EEC route?
15            A.      Well, it's possible these days
16 in Europe that you apply for registration by
17 other country which actually have approved.  In
18 other words, which was the fact there, if all
19 countries in Europe basically have approved the
20 compound and the BGA has not, then I mean it
21 would go via Brussels and the BGA basically
22 wouldn't need to say what their concerns were and
23 if they could substantiate them, of course it
24 would be discussed, and if not the drug would be

                                                 Page 230

 1 approved against even the BGA.  That's the easy
 2 route.
 3            Q.      So it was still possible for
 4 the drug to be approved for the use in Germany
 5 through other country?
 6            A.      Well, you have -- they're easy
 7 because we have the EC now and the EC is more and
 8 more coming to a stage to be one country, and I
 9 mean it just doesn't make sense that whatever
10 London and Paris and everybody says, I mean okay,
11 that's good for our people, and somebody else
12 says not, then at least it must be discussed and
13 unless there are very good reasons then it would
14 be ruled by Brussels, okay, it must be approved.
15            Q.      But from earlier documents we
16 talked about, we talked about today, the U.K.
17 wasn't all that far off the line from what the
18 BGA wanted to do, was it?
19            A.      Well, that may be true but
20 there were enough countries in Europe where it
21 was approved, otherwise it wouldn't be mentioned
22 here.  And in the end also they approved earlier.
23            Q.      The strigency of the approval
24 process varies by country, does it not?

                                                 Page 231

 1            A.      The what, please?
 2            Q.      The stringency, the strictness
 3 of the approval process.
 4            A.      Well, I agree that there might
 5 be differences between Greece and London or
 6 Berlin, but they have very good authorities also
 7 reviewing the package in Europe.
 8            Q.      Such as Sweden and Norway?
 9            A.      Well, I don't know about
10 Sweden, the only thing I know is what we're
11 talking about was not a subject there.
12            Q.      What do you mean what we're
13 talking about is not a subject in Sweden?
14            A.      Well, I mean, we talk about
15 for hours about basically the same thing.
16            Q.      The suicide and the agitation
17 issue?
18            A.      Yes, obviously.
19            Q.      The activation issue, you know
20 that for a fact it was not raised as an issue in
21 Sweden?
22            A.      I don't know it for a fact.
23            Q.      Somebody told you that though,
24 right, Doctor?  Did somebody tell you that the

                                                 Page 232

 1 issue was never raised in Sweden?
 2            A.      Maybe I shouldn't go on, I
 3 obviously not in Sweden so I don't know what
 4 really discussions have been there.  I just was
 5 told by my colleague that this was not impacting
 6 the registration process.
 7            Q.      That the issue being raised by
 8 Germany was not -- the issue of suicidality or
 9 the issue of activation or agitation was not
10 impacting the Swedish registration process?
11            A.      Correct.
12            Q.      Which colleague told you that?
13            A.      Obviously the one who had been
14 in charge there at that time.
15            Q.      Do you remember that
16 colleague's name?
17            A.      A small affiliate, actually I
18 don't know.
19            Q.      Did you write the response to
20 the 1988 rejection by the BGA?
21            A.      Well, I think so, I think
22 there was a document we have already seen.
23            Q.      The 1988 rejection, the one we
24 just talked about?

                                                 Page 233

 1            A.      Oh, this one?
 2            Q.      Right.  Did you write the
 3 response to that?
 4            A.      I'm not sure if we made a long
 5 response, I think it was more dealt with from an
 6 administrative point of view.  No?
 7            Q.      Well, I'm not sure, let me see
 8 if we can find out.
 9             (PLAINTIFFS' EXHIBIT NO. 9 WAS
10              MARKED FOR IDENTIFICATION AND
11              RECEIVED IN EVIDENCE.)
12            A.      Okay.  I mean I think there's
13 no need to go through this in detail.  So there
14 was a response to that, yes.
15            Q.      And this also gives us some
16 insight even though we don't have the official
17 rejection letter as to what the issues they
18 raised were in that letter, does it not?  Like,
19 for instance, on the second page of the exhibit,
20 it says Response 1, efficacy and safety of the
21 preparation in severe depression, especially in
22 inpatients have not been proven, correct?  Look
23 towards the bottom of the page.
24            A.      Oh, I see a bipolar -- can you

                                                 Page 234

 1 say which line, please?
 2            Q.      At the very bottom of page
 3 1550.
 4            A.      Oh, page 1.
 5            Q.      I'm sorry, I thought you were
 6 on the same page.
 7            A.      1550, yes.
 8            Q.      And at the bottom of it says,
 9 our detailed statements against the reasons for
10 denial of the approval are as follows.
11            A.      Have not been proven, yes, I
12 see that.
13            Q.      So does this appear to you to
14 be at least a draft of the response to the 1988
15 rejection by the BGA?
16            A.      Again, as I say, that may well
17 be.
18            Q.      Okay.  And Doctor Straeter was
19 consulted when you put this together, was he not,
20 when this was put together?
21            A.      In terms of the form, it may
22 also be.  Definitely not in terms of the content.
23            Q.      How often did you guys consult
24 with Doctor Straeter?

                                                 Page 235

 1            A.      It depended.
 2            Q.      Did you personally consult
 3 with him on any occasions?
 4            A.      Well, he was to the office,
 5 yes, and I also was frequently talking to him.
 6            Q.      Did he have an office at the
 7 affiliate?
 8            A.      No, he didn't.  Not an office,
 9 no, but he was private practicing, he had his own
10 office, and not in the same city either, he was
11 traveling a lot and so, you know, maybe once or
12 twice a month.
13            Q.      You would talk to him once or
14 twice a month?
15            A.      Talk to him maybe more
16 frequently, but that he just passed by when
17 coming to Bad Homburg.
18            Q.      Did you consult with Mister
19 Straeter regarding drugs other than fluoxetine?
20            A.      Yes.
21            Q.      Do you use him generally with
22 all the registration processes you were going
23 through with all the drugs?
24            A.      In general, BGA affairs, yes.

                                                 Page 236

 1            Q.      Okay.  In 1988, they still
 2 hadn't seen enough evidence that the efficacy and
 3 safety of Prozac had been established at least in
 4 severe depression, correct?
 5            A.      Well, it's not surprising
 6 because we actually did not submit any new data
 7 and that's why also understand was the surprise
 8 to receive this rejection which I mean actually
 9 was not in response to the new data we were
10 comparing, which confuses me really to make this
11 clear, because there was -- I'm always referring
12 to a final submission which had then all the data
13 and all the deliberations following -- that's
14 also what we talked earlier today, so this was a
15 kind of thing in between that really slipped from
16 my mind.  But obviously yes, we prepared a short
17 response, but because there were no new data, it
18 wasn't surprising that they had the same
19 concerns.
20            Q.      Do you know if the BGA made
21 the decision to withdraw its rejection of the
22 drug based on this letter?
23            A.      On this one.
24            Q.      To withdraw its rejection.

                                                 Page 237

 1 Remember you said that --
 2            A.      Okay.
 3            Q.      -- you were under the
 4 impression it was never rejected?
 5            A.      Correct.  Well, if this was
 6 this one or if there were other people following
 7 up on the gentleman agreement, I don't know,
 8 again the only thing I know is that we never made
 9 a full package resubmission.  We basically
10 submitted the data which were generated in
11 addition.  In other words, the only thing which
12 was re-reviewed again was the clinical dossier,
13 you know, the chemical part, the preclinical part
14 was never reviewed again.
15            Q.      Okay.  Did anybody from Lilly
16 Indianapolis ever ask -- talk to you about the
17 definition or what the BGA meant by the terms it
18 used in any of their communications to you or
19 anybody else at the affiliate in Germany?
20            A.      What terms do you mean?
21            Q.      For instance, severe organ
22 damage.
23            A.      Did anybody in Indianapolis
24 ask what that means?

                                                 Page 238

 1            Q.      Do you recall anybody asking
 2 that?
 3            A.      Not specifically, what the
 4 word damages mean.  Also I think in Indianapolis
 5 receiving communication from all parts of the
 6 world, including very exotic ones, they're
 7 trained to read, you know, between the lines and
 8 I think they were more looking at what was
 9 following specifically and yes, we discussed all
10 of that, I mean phospholipidosis, suicide risk,
11 and the in-patient data.
12            Q.      Are you confident that the
13 personnel in Indianapolis was familiar with what
14 the BGA meant when it said that the drug side
15 effect profile showed unacceptable damaging
16 effects?
17            A.      I think it's difficult for me
18 to judge, I think there was people who better
19 respond to that.
20            Q.      Do you recall the issue of
21 severe organ damage being raised by the BGA with
22 regards to fluoxetine?
23            A.      Yes, well, I mean we talked
24 about this, we talked about this specifically,

                                                 Page 239

 1 but I really don't understand the -- what is your
 2 question.
 3            Q.      Well, there just seems to be
 4 some confusion between Germany and Indianapolis
 5 as to what the BGA meant by certain things.
 6            MR. LORE:  Wait a minute.  I object to
 7 the form of that question.  If you have something
 8 to show him -- but not about what we discussed
 9 today, certainly, so I object to the form as not
10 being in evidence for the doctor to understand
11 the question.
12            MS. ZETTLER:  I'll show him something
13 but I need a stapler.
14             (PLAINTIFFS' EXHIBIT NO. 10 WAS
15              MARKED FOR IDENTIFICATION AND
16              RECEIVED IN EVIDENCE.)
17            Q.      Have you had a chance to
18 review Exhibit 10?
19            A.      Review what?
20            Q.      Exhibit 10?
21            A.      Yes, I have seen it.
22            Q.      Have you seen this before
23 today?
24            A.      No, I have not seen this

                                                 Page 240

 1 before.
 2            Q.      Exhibit 10 is a letter signed
 3 by Max Talbott or somebody on behalf of Max
 4 Talbott, looks like Sam Robinson, to the FDA
 5 dated December 4, 1987, correct?
 6            A.      Yes.
 7            Q.      And it talks about a follow up
 8 conversation between members of the FDA and
 9 Doctor Wernicke, Doctor Masica and Earlene
10 Ashbrook at Lilly Indianapolis, correct?
11            A.      Yes.
12            Q.      And the purpose of the meeting
13 was to review the foreign regulatory actions on
14 fluoxetine, correct?
15            A.      Yes.
16            Q.      And the next paragraph says,
17 Doctor Laughrens and Kapit noted that the BGA in
18 Germany seemed to hold the opinion that
19 fluoxetine was hepatotoxic, correct?
20            A.      Yes.
21            Q.      In May of '84, the BGA made
22 the following request, quote, please explain the
23 significance of lab chemical and enzymatic
24 abnormal deviations and resulting severe organ

                                                 Page 241

 1 damage, unquote.
 2            A.      Yes.
 3            Q.      Do you see that?  It was never
 4 made clear what the BGA meant by severe organ
 5 damage, do you see that also?
 6            A.      Yes.
 7            Q.      You knew what the BGA meant by
 8 severe organ damage, did you not, Doctor?
 9            A.      Well, in terms of severe
10 damage to the liver, I don't really know what
11 they meant.
12            Q.      You knew it had to do with
13 transaminases, right?
14            A.      Yes, but, you know --
15            Q.      And you also knew it had to do
16 with the liver, correct?
17            A.      If you would drink a few
18 whiskeys tonight and I take your transaminases
19 tomorrow, you might have them elevated.  So it
20 depends on what the real history context and the
21 amount is and frequency of occurrence, and I
22 think our early conclusions have been really
23 confirmed by the drug being taken, whatever,
24 millions of times.

                                                 Page 242

 1            Q.      But the FDA was asking for an
 2 explanation of what the BGA meant, not whether or
 3 not the drug caused it, they were asking for what
 4 the --
 5            A.      Wait a minute, the FDA noted
 6 that the BGA seemed to hold the opinion that
 7 fluoxetine was hepatotoxic, and the BGA made the
 8 following request, not the FDA, please explain.
 9            Q.      Right, it was never made clear
10 what the BGA meant by severe organ damage.
11            A.      That's what Doctor Talbott
12 refers to obviously quoting Doctor Wernicke and I
13 have just said I basically think the same.  I
14 mean we never have quite understood why the BGA
15 based on the very few laboratory abnormalities
16 which were found came to this conclusion.  And as
17 far as I recall we even obtained an expert
18 opinion on this later when we resubmitted and
19 basically that was --
20            Q.      How about unacceptable
21 damaging effects, clearly they defined that,
22 didn't they?
23            A.      They do that.
24            Q.      Huh?

                                                 Page 243

 1            A.      They do that obviously or they
 2 have done this.
 3            Q.      I'm talking about the BGA.
 4            A.      Yes, yes.
 5            Q.      The BGA defined it, correct?
 6            A.      Right, let them define this,
 7 but I also mentioned frequently today that on
 8 certain findings there are different ways of
 9 conclusions or interpretation, and if the
10 reviewer at the BGA for example concludes this,
11 it's not necessarily the collected wisdom of all
12 of the world.  So yes, they have thought this and
13 they have written this and their list of concerns
14 but that does not automatically mean that's
15 there.  I mean that's their view of the things.
16 In this particular case, I mean with the
17 hepatotoxicity, I mean I really also don't
18 understand how they ever could come to this
19 conclusion.
20            Q.      Let's talk about the
21 unacceptable damaging effects, okay, Doctor?
22            A.      Yes.
23            Q.      The FDA was asking questions.
24            A.      That's normal, it's an update,

                                                 Page 244

 1 what's happening outside.
 2            Q.      All right, I agree, it's
 3 normal for the FDA -- in fact, it's their job to
 4 ask questions, isn't it?
 5            A.      Yes.
 6            Q.      In fact, it's their job to
 7 find out what's going on in other regulatory
 8 agencies all over the world, correct?
 9            A.      Good.
10            Q.      Now it's Lilly's job to be
11 honest with them and inform them exactly what was
12 going on, isn't it?
13            A.      I think they did this.
14            Q.      You do?  Where do they say
15 anything about suicide with regards to
16 unacceptable damaging effects?
17            A.      How do you know that they
18 didn't say it?
19            Q.      In this letter, there's no
20 mention in this letter.  Where in this letter
21 does it say anything about the fact that the BGA
22 considered an unacceptable damaging effect of
23 fluoxetine an increased risk of suicide?  It
24 doesn't, does it?

                                                 Page 245

 1            A.      It does not say in this
 2 letter.
 3            Q.      Where in this letter does it
 4 say that the BGA considered an unacceptable
 5 damaging effect, the increased incidence of
 6 agitation or activation?
 7            A.      It doesn't say that.
 8            Q.      So if we're just looking at
 9 this letter, we don't know really what the BGA
10 was talking about, do we?  In fact this letter
11 says that the BGA never defined it, doesn't it?
12 Doesn't it, Doctor?
13            A.      Well, they are clearly
14 referring to the effects on the liver.
15            Q.      I'm talking about unacceptable
16 damaging effects in 19 -- it says here, quote, in
17 February, 1985 in a response to this submission,
18 the BGA alluded to, quote, unacceptable damaging
19 effects, unquote, this phrase was not defined,
20 period.  Do you see that?
21            A.      That's what they say here.  So
22 what, what shall I say about this?
23            Q.      That's not true, was it, it
24 was defined, wasn't it?

                                                 Page 246

 1            A.      Well, but I mean they had the
 2 translation of the letter.  Actually it's really
 3 not my job to talk what my colleagues have talked
 4 to the FDA.  I mean you can ask me what's written
 5 here and I say yes, but I cannot judge on not
 6 everything which is not written here because
 7 nobody knows if it's been set, yes or no.
 8            Q.      Is it your testimony that this
 9 is an accurate portrayal of what happened between
10 Lilly and the BGA with regards to the issue of
11 unacceptable damaging effects of fluoxetine?
12            A.      I don't comment on that
13 because the way you posed the question I think is
14 not really --
15            Q.      I'm just talking about this
16 letter, we're not talking about whether or not
17 somebody else reported something else to the FDA.
18 I'm talking about Doctor Talbott's December 4,
19 1987 letter to the FDA.  If we're looking at this
20 letter and this letter alone, it is not true.
21            A.      In terms of severe organ
22 damage, yes, because suicidal behavior and
23 activation has nothing to do with organ damage.
24            Q.      I'm talking about unacceptable

                                                 Page 247

 1 damaging effects, now, Doctor, it's two different
 2 catagories.
 3            A.      Yes, well, basically I think
 4 it's a well written letter.  If it's appropriate,
 5 yes or no --
 6            Q.      That's not my question,
 7 Doctor.  Please answer my question.
 8            MR. LORE:  If you can.  She's
 9 beginning to harrass you.
10            A.      I think I cannot respond to
11 this question.
12            Q.      Why?  What is it you can't
13 respond to?
14            A.      Well, I just don't find the
15 whole question appropriate the way you ask it.
16            Q.      I think it's very appropriate,
17 Doctor.  You have a letter here saying that the
18 BGA never defined unacceptable damaging effects,
19 correct?  Isn't that what this letter says?
20            A.      Yes, but I was not at the FDA,
21 it's not my job to report to the FDA.  The fact
22 that's referring to organ damage which has
23 nothing to do with suicidal behavior and nothing
24 to do with activation does not necessarily

                                                 Page 248

 1 demonstrate to me that this is all inadequate.
 2            Q.      I'm not talking about --
 3            A.      Well, then, I don't know what
 4 you mean.
 5            Q.      I'm talking about the
 6 unacceptable damaging effects, Doctor, which you
 7 testified to extensively what that meant and what
 8 the BGA meant when they raised that issue back in
 9 1985, correct?
10            A.      Okay, what, to say this phrase
11 was not defined, maybe not okay, but so what?
12            Q.      It's inaccurate, isn't it?
13            MR. LORE:  I object to the form, the
14 characterization of it being inaccurate.  If you
15 can answer the question, Doctor, go ahead.
16            A.      Well, obviously there is a
17 list of issues in the deficiency list of the BGA
18 which is referred to as unacceptable effects and
19 as a matter of fact, I think on this list
20 actually hepatotoxicity even doesn't appear, but
21 the issues we have been talking about are not
22 listed here, and if you ask if it's accurate or
23 no, in a literal sense, it's not accurate.
24            Q.      It doesn't list suicide, does

                                                 Page 249

 1 it?
 2            A.      Insofar it's not accurate, but --
 3            Q.      And it doesn't list
 4 phospholipidosis, does it?
 5            A.      It does not list that.
 6            Q.      And it doesn't list an
 7 apparent increase in the symptomatology of
 8 depression that the BGA at least related to the
 9 use of the drug, does it?
10            A.      This letter does not list
11 that.
12             (PLAINTIFFS' EXHIBIT NO. 11 WAS
13              MARKED FOR IDENTIFICATION AND
14              RECEIVED IN EVIDENCE.)
15            A.      Okay, I see that.
16            Q.      Have you ever seen this
17 document before, Doctor?
18            A.      This one here, no, I have not.
19            Q.      We received this document in
20 response to a Freedom of Information Act request
21 to the FDA, okay, and it's a memo dated December
22 8, 1987 written by R. M. Kapit of the FDA and it
23 talks about the December 4, 1987 conversation
24 that Doctor Talbott talks about in his letter.

                                                 Page 250

 1            A.      Yes.
 2            Q.      He says, on December 4, 1987,
 3 a letter from M. W. Talbott relayed Doctor
 4 J. Wernicke's response to a teleconference with
 5 Doctor T. Laughren and this reviewer regarding
 6 comments made by the German regulatory
 7 authorities, the BGA, on the safety of Prozac,
 8 correct?
 9            A.      Yes.
10            Q.      The letter asserted that the
11 German authorities never defined or documented
12 the phrases severe organ damage or unacceptable
13 damaging effects.  That's not necessarily
14 correct, is it, they certainly documented it,
15 didn't they?
16            A.      Yes, they said damaging
17 effects according to the translation, yes.
18            Q.      Which were used in their
19 communications to the company.  The letter denies
20 any such organ damage has ever occurred in
21 fluoxetine-treated patients.  The company asserts
22 that all information available to the BGA has
23 been made available to the FDA and to their
24 knowledge, the FDA has used more sophisticated

                                                 Page 251

 1 analyses in reviewing the data.  Do you see that?
 2            A.      Yes.
 3            Q.      I get the impression from this
 4 memorandum, Doctor, that the BGA is in effect
 5 linking the two phrases together, severe organ
 6 damage and unacceptable damaging effects, are
 7 they not?
 8            A.      That's what I tried to
 9 understand here, the point is that as we have
10 discussed earlier, the organ damaging -- no, no,
11 no, the unacceptable damaging effect is followed
12 by the listing of activation, suicidal and this
13 pulmonary changes, phospholipidosis.  It does not
14 here refer anywhere to this hepatic findings,
15 it's just that at the end of this very early
16 letter from the BGA, it's reflected in the
17 proposed recommendation.  On the other hand here
18 clearly is always the talk about organ damage and
19 the recommendation relates to the liver in fact
20 was seen as a kind of organ damage because again
21 as we would agree activation and suicidal
22 behavior cannot be really seen as an organ
23 damage, so that's clearly a confusion here.
24            Q.      Okay.

                                                 Page 252

 1            A.      And whatever have caused this,
 2 but that's --
 3            Q.      Doctor Talbott's letter
 4 doesn't do much to help them with their
 5 confusion, does it?
 6            A.      Doctor Talbott's letter was
 7 before this one here.
 8            Q.      Right.  It sure doesn't
 9 explain the difference between severe organ
10 damage and unacceptable damaging effects, does
11 it?
12            A.      It does not.
13            Q.      Okay.  Now the conclusion that
14 this reviewer at least draws from the
15 conversation in the letter that he received is
16 that the BGA comments do not appear to reflect
17 clinical events since no such events have been
18 reported to the FDA, and according to the
19 company, we have received all information
20 submitted to the BGA.  Again it seems like he's
21 talking about one set of specific events,
22 correct?
23            A.      You're talking now about the
24 Exhibit 11, the FDA letter?

                                                 Page 253

 1            Q.      Right.
 2            A.      And again which line?
 3            Q.      The conclusion.
 4            A.      Conclusion.  They appear to
 5 reflect clinical events since no such events have
 6 been reported to the FDA and, yes, I see this
 7 here.
 8            Q.      Do you think the BGA's
 9 concerns about increased risk of suicide or
10 activation or agitation would have been relevant
11 information for the FDA to look at for approving
12 the drug here, regardless of whether or not the
13 company thought it was legitimate?
14            A.      Well, I think the FDA had the
15 same information as the BGA.
16            Q.      But I mean the fact that the
17 BGA was concerned about this, do you think that
18 would have been relevant to the FDA's analyses?
19            A.      Well, maybe, but again I'm not
20 sure as what had been talked or not been talked.
21            Q.      Are you sure the FDA has the
22 same information that the BGA has, have you seen
23 the actual submission to the FDA?
24            A.      I cannot give my oath on this

                                                 Page 254

 1 because obviously I have not submitted it, but
 2 it's usually our company policy, so I would
 3 assume that.
 4            Q.      Do you make it a habit of
 5 looking at submissions to other countries other
 6 than the country you're working in?
 7            A.      Well, I mean the point is that
 8 I'm talking about the data.
 9            Q.      So am I.
10            A.      Not necessarily -- well, that
11 means of course the full package in terms of
12 formal report which goes in in German, is not
13 necessarily all literally translated, but I mean
14 the data.  So the essence of it is the same, so
15 that means also studies we produced in Germany or
16 data are also actually informed to the FDA, not
17 necessarily in the original form, as a literal
18 translation of the report, but definitely the
19 outcomes and the results.
20            Q.      Well, that's kind of an
21 assumption on your part considering you've never
22 seen the NDA submission to the FDA, have you, on
23 Prozac at least?
24            A.      Excuse me, the NDA submission.

                                                 Page 255

 1 I have never seen the NDA submission.
 2            Q.      To the FDA.
 3            A.      Of course, I have not.
 4            Q.      Based on this information,
 5 Doctor Kapit recommends in Exhibit 11 that the
 6 comments by the BGA should not affect the FDA's
 7 conclusion on whether or not fluoxetine is
 8 approvable, correct?
 9            A.      That's what it says here, yes.
10            Q.      Doctor Weinstein contacted you
11 on December 4th, the same day that Doctor Talbott
12 wrote his letter to ask you what the definition
13 or what the BGA meant by severe organ damage,
14 didn't he?
15            A.      Maybe so, so I don't recall
16 the details.
17            Q.      Did you tell him what it
18 meant?
19            MR. LORE:  I object to the form.  He's
20 already said he doesn't recall the details.
21             (PLAINTIFFS' EXHIBIT NO. 12 WAS
22              MARKED FOR IDENTIFICATION AND
23              RECEIVED IN EVIDENCE.)
24            A.      Yes, I see this.

                                                 Page 256

 1            Q.      Do you recall that
 2 conversation?
 3            A.      No, I don't recall this
 4 conversation because I mean we talked frequently,
 5 but I mean it's obviously properly reflected
 6 here.
 7            Q.      It's a December 4, 1987 E-mail
 8 from Allan Weinstein to Joe Wernicke, correct?
 9            A.      Yes.
10            Q.      And he's referring to the
11 letter that we just discussed that was ultimately
12 under Doctor Talbott's signature, correct?
13            A.      Yes.
14            Q.      And he says, Joe, the letter
15 looks fine to me.  I have confirmed with Nick
16 Schulze-Solce that the, quote, severe organ
17 damage, unquote, referred to the rare patients
18 with elevated transaminases, correct?
19            A.      Yes.
20            Q.      Do you have any explanation
21 why Lilly Indianapolis didn't simply tell the FDA
22 that that's what the BGA meant when it said
23 severe organ damage in that letter of December 4,
24 1987?

                                                 Page 257

 1            A.      No, I don't.
 2            MS. ZETTLER:  Okay.  Let's take
 3 another quick break and I think I'm almost done.
 4             (A SHORT RECESS WAS TAKEN.)
 5             (PLAINTIFFS' EXHIBIT NO. 13 WAS
 6              MARKED FOR IDENTIFICATION AND
 7              RECEIVED IN EVIDENCE.)
 8            Q.      (BY MS. ZETTLER)  Doctor, I've
 9 handed you Exhibit 13, would you please take a
10 look at it?
11            (WITNESS REVIEWS DOCUMENT.)
12            Q.      Do you recognize Exhibit 13,
13 Doctor?
14            A.      Pardon?  I've seen 13, yes.
15            Q.      It's -- the first page of 13
16 is an E-mail dated September 6, 1989 from you to
17 Allan Weinstein and Claude Bouchy, correct?
18            A.      Yes.
19            Q.      And in there you discuss a
20 meeting you had with Mister Straeter, correct?
21            A.      Yes.
22            Q.      This is a couple of weeks
23 approximately after that Commission A debate
24 where Professor Moeller and Professor Kleinsorge

                                                 Page 258

 1 challenged Doctor Karkos' wishes to
 2 contraindicate, or use contraindications with
 3 fluoxetine, correct?
 4            A.      Yes, it appears so.
 5            Q.      In the letter, or in the memo
 6 to Doctor Weinstein, you discuss new package
 7 insert drafts on the contraindication and
 8 indication sections of the package insert for
 9 Germany, correct?
10            A.      Yes.
11            Q.      And you say, I have just
12 returned from my meeting with Straeter.  Our
13 discussion resulted in the following action.  I
14 shall prepare eventually two options for the
15 indication and contraindication section of the
16 product information.  I shall add some comments
17 explaining our thoughts and position and send the
18 whole stuff as a letter to Straeter, correct?
19            A.      Correct.
20            Q.      Straeter will try to use this
21 in his discussion with Professor Elbers of the
22 BGA who is responsible for the coordination of
23 the further process and someone with good
24 relations to Straeter.  So you're -- correct?

                                                 Page 259

 1            A.      Correct.
 2            Q.      You're hoping that Doctor
 3 Straeter will leave this letter with Professor
 4 Elbers at the BGA, correct?
 5            A.      That is apparently the case.
 6            Q.      Do you recall doing that?
 7            A.      Well, obviously we did this, I
 8 mean I made this proposals.
 9            Q.      Do you feel uncomfortable with
10 doing that?
11            A.      No.
12            Q.      Why not?
13            A.      Because to discuss and
14 wordsmith the wording of labeling or package
15 inserts is an absolutely normal thing in all
16 countries.
17            Q.      Who's the wordsmith?
18            A.      Well, with everything you say
19 obviously I mean there's a certain connotation
20 and so the instructions for use and all the
21 information you give about the product, in order
22 to be balanced with regard or relation to the
23 data you have, is a very important thing, and
24 there are always different opinions everywhere

                                                 Page 260

 1 and that's why, I mean from the first draft to
 2 the final labeling there's always a discussion
 3 process between company and regulatory
 4 authorities and even within company or within the
 5 regulatory authorities.
 6            Q.      Okay.  Why do you go on to say
 7 Straeter will try to use this in discussion with
 8 Professor Elbers of the BGA who is responsible
 9 for the coordination of the further process and
10 someone with good relationship to Straeter.  He
11 may even leave our letter to Straeter as
12 mentioned above with Elbers.  Thus we will not
13 officially submit a new draft, but have the
14 opportunity to get some information about our
15 position into the agency.
16            A.      Yes.
17            Q.      If this is such a routine
18 thing, why did you do it on the sly, why didn't
19 you just make a formal submission?
20            MR. LORE:  I object to the
21 characterization of doing it on the sly.  You
22 can go ahead and answer it if you understand it.
23            A.      Well, actually, I don't
24 understand what means on the sly.  But the point

                                                 Page 261

 1 is that for the purpose of the thing, it's much
 2 better or more adequate to discuss it that way,
 3 simply also because in this particular case, we
 4 could let know what options or what positions we
 5 have, when in an official letter we would have to
 6 decide for one or the other.
 7            Q.      You couldn't give them more
 8 than one option in the official letter?
 9            A.      No, usually the BGA wants the
10 company to make up their mind.  It's just for
11 actually having the better discussion on what,
12 you know, really the options are, and it is --
13            Q.      So it's more appropriate in
14 your opinion for you to write a letter to
15 Straeter knowing that Straeter is going to
16 deliver that letter to Elbers and leave that
17 there in the hopes that it may at least at best
18 inform Professor Elbers as to what your positions
19 may be?
20            A.      Yes, in this case it was
21 really the more appropriate thing to do.
22            Q.      Appropriate according to who,
23 Lilly?
24            A.      Well, I think even the

                                                 Page 262

 1 reviewer, who was not Professor Elbers.
 2            Q.      Karkos?
 3            A.      Yes.
 4            Q.      Karkos thought this was
 5 appropriate?
 6            A.      I don't have evidence for
 7 that, but I mean simply how the process further
 8 went and what through Straeter I heard from him,
 9 I think so.  Now to use a go-between may
10 absolutely sound whatever strange from an
11 American point of view because here it's quite
12 common that you go in and out the agency and
13 that's depending on the reviewer, not necessarily
14 the case at the BGA.  So I found this was offered
15 by somebody who knew the people very well, so I
16 don't see something bad in that.
17            Q.      Is it your testimony that
18 Doctor Karkos knew that Lilly wrote a letter to
19 Straeter knowing that the purpose of writing the
20 letter was to give it to Doctor Elbers to inform
21 Doctor Elbers unofficially of what they may or
22 may not do with this package insert?
23            MR. LORE:  I object to the form of the
24 question.  You may answer.

                                                 Page 263

 1            A.      I don't know what he actually
 2 thought or knew or whatever.
 3            Q.      How can you say that it was
 4 appropriate?
 5            A.      Just from the further course
 6 of the things, how they developed and what we
 7 finally received from the BGA and what was
 8 obviously decided.
 9            Q.      A package insert much less
10 restrictive than what Doctor Karkos wanted,
11 correct?
12            A.      Maybe compared to his initial
13 thoughts, yes.
14            Q.      You go on to say, in this
15 draft we will not mention the other sections for
16 two reasons:  As far as we know about the
17 suggested changes with regards to adverse events,
18 interactions, et cetera, it is either peanuts or
19 we could totally agree.  Secondly by addressing
20 all this in the inofficial new draft, we would
21 disclose that we had insight in the reviewer's
22 statement to be presented to the Commission.
23            A.      Yes.
24            Q.      If this is appropriate, why do

                                                 Page 264

 1 you have a problem with letting people know that
 2 you had insight into the reviewer's statement to
 3 the Commission?
 4            A.      Well, it's useful information
 5 to make good decisions and it happened to be
 6 available.  That's all I can say.
 7            Q.      What's useful information,
 8 insight into the statement to be presented to the
 9 Commission?
10            A.      Well, as I said, I mean
11 unfortunately, and I really must emphasize
12 unfortunately, it's not possible like here to
13 walk into the agency and talk to the agency like
14 we have here evidence of the letter you have been
15 showing to me, unfortunately not.
16            Q.      Unless of course you're Mister
17 Straeter.
18            A.      Pardon?
19            Q.      Unless, of course, you're
20 Mister Straeter, then you can walk in and talk to
21 Mister Elbers, can't you?
22            A.      Yes, exactly.  Well, I mean I
23 had also contact with the BGA offices, however
24 now the case is depending on the BGA officer.

                                                 Page 265

 1 But it's not a routine or even required practice
 2 as it is here.  On the other hand, and so far I
 3 think it's very valuable here, it's very
 4 important that regulators and companies have the
 5 opportunity also to directly talk because things
 6 are not that straightforward always.  So that's
 7 why, I mean this information is useful, I do not
 8 hesitate to call it useful.
 9            Q.      You're not directly talking to
10 the BGA here though, are you, you're using a go-
11 between?
12            A.      Yes.
13            Q.      You're using Mister Straeter,
14 who used to be a member of the BGA to deliver a
15 message?
16            A.      Yes.
17            Q.      In effect to the BGA that is
18 covered up as a letter to Doctor Straeter,
19 correct?
20            A.      Yes.
21            Q.      That is no wheres near direct
22 contact, is it?
23            A.      No, that's what I'm not
24 saying.

                                                 Page 266

 1            Q.      It's not even an attempt at
 2 direct contact, is it?
 3            A.      No, it's an indirect one, I
 4 didn't deny that.
 5            Q.      With regards -- you go on to
 6 say, with regards to the two options, we felt
 7 basically two approaches to be most adequate,
 8 either to follow straightforward the U.K. line
 9 where this no sedation required comes from, i.e.
10 have the indication restricted but then abandon
11 too specific contraindications, as U.K., or stay
12 with our old indication claim and then have
13 contraindications and precautions.  So you're
14 talking there about the various options you have,
15 correct?
16            A.      Yes.
17            Q.      You can recommend either, you
18 can say, okay, we'll take the limited indication,
19 which I believe was that it was Doctor Karkos'
20 indication where people who required sedation
21 should not be given the drug, correct?
22            A.      I don't know if it was exactly
23 this but I mean there are always two ways, you
24 limit the indication, or if not that, I mean then

                                                 Page 267

 1 somewhere else you put the message in to exercise
 2 recommended caution.
 3            Q.      Let's look at your drafts,
 4 which are also attached hereto, the forth page on
 5 enclosure one.  And these are your drafts,
 6 correct?
 7            A.      Yes.
 8            Q.      Okay.  It starts on page 230.
 9 Enclosure 1, fluoxetine package insert, possible
10 version I, and then you have, in parens,
11 essentially U.K. version, close paren, right?
12            A.      Yes, and this is -- I mean
13 just to answer to your previous question, first
14 of all I didn't know what really Karkos wanted,
15 but it's definitely not what he wanted as we were
16 talking about this morning.
17            Q.      Okay, but you say the
18 indications here --
19            A.      This is much broader to say
20 that.
21            Q.      Your version is much broader
22 than Doctor Karkos's, correct?
23            A.      Again, I mean, when you say --
24 I mean you said this morning that all patients at

                                                 Page 268

 1 risk for suicide should be contraindicated, I
 2 mean that's not what it says here.
 3            Q.      Okay.  So the answer to my
 4 question is yes, this is much broader than what
 5 Doctor Karkos wanted?
 6            A.      If that was Doctor Karkos'
 7 proposal, yes.
 8            Q.      Okay.  It says, indications,
 9 fluoxetine is suited for treatment of depressive
10 diseases, especially if sedation is not required.
11            A.      Yes.  When it says essentially
12 U.K. version, obviously that's still the approved
13 package in the U.K.
14            Q.      Okay.  So it's your testimony
15 that the U.K. package insert says something to
16 the effect of it's suited for treatment of
17 depressive diseases especially if sedation is not
18 required, correct?
19            A.      Obviously there must have been
20 some relation to that, yes.
21            Q.      And then according to your
22 note to Doctor Weinstein, in this case, if you
23 use the restricted indication that we just talked
24 about, you wouldn't have to use contraindications

                                                 Page 269

 1 about co-medication, et cetera, correct?
 2            A.      Yes.
 3            Q.      Okay.  And then the other
 4 option was to say that Prozac was to be used for
 5 the treatment of depressive diseases, and then
 6 list precautions or contraindications within the
 7 package insert related to sedation, correct?
 8            A.      Yes.
 9            Q.      So the second option is laid
10 out in the first page of Exhibit 13, stay with
11 our old indication claim and then have
12 contraindications and precautions.  In both cases
13 we might leave it open if co-medication shall be
14 recommended or even required.  In view of our
15 discussion yesterday, I think you will
16 particularly appreciate the last point.  It was
17 interesting that Straeter as a lawyer brought up
18 the point why not leave it completely out.  He
19 means why not leave the contraindication or the
20 recommendation of co-medication completely out of
21 the suggested package insert, correct?
22            A.      I guess that's what it refers
23 to.
24            Q.      Or was it the letter that you

                                                 Page 270

 1 were to write to him?
 2            A.      I don't know, I would also
 3 interpret this as referring to this
 4 recommendation.
 5            Q.      Okay.  So the drafts that you
 6 were going to submit as part of your letter, he
 7 recommended that you leave out the co-medication
 8 issue all together?
 9            A.      Yes, apparently.
10            Q.      Okay.  You go on to say, I'm
11 looking forward to your comments to my letter to
12 Straeter early next week, but do not expect major
13 concerns because of what we have discussed so
14 far.  Generally, I shall keep you informed about
15 every new information and situation.  Clearly we
16 are approaching the last battle.  If we win we
17 should have letter of approval in the fourth
18 quarter.  If we lose, there will be a new war
19 will last a bit longer.  The registration is as
20 good as granted, however on which conditions.
21 Correct?
22            A.      That's what it says here.
23            Q.      Then attached to that is the
24 letter, at least a draft of the letter to Mister

                                                 Page 271

 1 Straeter, correct?
 2            A.      Yes.
 3            Q.      And you state, according to
 4 the opinion of our company and of German experts
 5 whom I have consulted about this subject,
 6 fluoxetine, in principle, is an agent for the
 7 treatment of depression, i.e. all forms of
 8 depression.  Of course it must be noted, that
 9 certain issues have to be taken into
10 consideration and precautions to be observed
11 respectively when administering fluoxetine to
12 some patients groups, correct?
13            A.      Correct.
14            Q.      Okay.  Then you go on to say:
15 When I look at our draft for the package insert
16 as of July, 1989, which has also been submitted
17 to the Federal Health Agency, paren, BGA, close
18 paren, and compare it with the wording of the
19 information of other countries, there are, in
20 general, two ways to describe the application of
21 fluoxetine adequately, correct?
22            A.      Correct.
23            Q.      Which other information from
24 other countries, which other countries did you

                                                 Page 272

 1 look at?
 2            A.      I cannot recall the specific
 3 countries but definitely U.K., U.S., France,
 4 well, basically the countries where it was
 5 approved, and where I had an English translation.
 6            Q.      The first way -- you go on to
 7 say:  The first way orientates to the wording of
 8 the English data sheet and slightly restricts
 9 indications, does, however, not provide any
10 further contraindications or precautions on
11 agitation, sleep disturbance, et cetera, right?
12            A.      Yes.
13            Q.      My interpretation of the U.K.
14 version is that fluoxetine in monotherapy is
15 especially suited for cases which do not require
16 sedation.  Those who require sedation would need
17 a co-medication.  Do you agree with that
18 statement today?
19            A.      Those who require sedation
20 would need a co-medication, yes, those who
21 require.
22            Q.      Those who require sedation as
23 a result of their reaction to fluoxetine?
24            A.      No, that what doesn't say.

                                                 Page 273

 1 Those who require sedation can be also typical
 2 for the natural cause of the type of the disease.
 3 That's what I'm not saying.  I'm just saying
 4 those patients who require sedation would need a
 5 co-medication, and that's what would I sign
 6 today, and that's logical.
 7            Q.      Isn't it true, Doctor, that
 8 some patients react to fluoxetine in such a way
 9 that they need coadministration of a
10 benzodiazepine or another drug with sedating
11 properties to counteract that reaction?
12            A.      Yes, well, I have not denied
13 that there are such patients.  But there are also
14 patients who do not react to fluoxetine but just
15 as the course of the disease require sedation,
16 it's possible.
17            Q.      Do other antidepressant
18 package inserts or prescribing information used
19 in the U.K. have a recommendation that the doctor
20 may want to use a co-administered sedative with
21 the drug?
22            A.      If other antidepressants --
23            Q.      All of them?
24            A.      I don't know about them.

                                                 Page 274

 1            Q.      Can you point to any one that
 2 is not a serotonin reuptake inhibitor?
 3            A.      I simply don't know about the
 4 effects.
 5            Q.      It's not your testimony that
 6 this is something that's in every antidepressant
 7 package insert as a rule, a general rule, is it?
 8            A.      No, it's definitely not in
 9 every antidepressant's package insert, but I mean
10 still you may coadminister benzodiazepines to
11 amitryptiline patients if they require it.
12            Q.      Do you know if the
13 amitryptiline package insert suggests that?
14            A.      Presumably not.  I'm not sure
15 but presumably not.
16            Q.      That's because amitryptiline
17 is basically a sedating tricyclic-type
18 antidepressant?
19            A.      It may be also due to the fact
20 that it has been approved much earlier.
21            Q.      Are you saying that in Germany
22 if something comes up with the drug postmarketing
23 that they don't change the package insert to
24 reflect the use of the drug?

                                                 Page 275

 1            A.      There are only very peculiar
 2 rules to change it, not necessarily.
 3            Q.      In your opinion, should that
 4 package insert recommend the use of a concomitant
 5 sedative, because of the drug's effects?
 6            A.      Well, I don't see in the whole
 7 thing such a problem as you see and I have said
 8 that I find it's an acceptable wording which is
 9 just appropriate, which to some extent could be
10 also in a textbook for standard treatment, but to
11 my knowledge it's not in the package insert and I
12 could live without it, maybe you could even live
13 without it for fluoxetine, it depends on from
14 which angle you look.
15            Q.      But that's not my question.
16 Once again, Doctor, please listen to my question.
17 My question is, in your opinion as a physician,
18 do you think that the package insert for
19 amitryptiline in Germany should include a
20 recommendation like the fluoxetine package insert
21 has that because the drug is not sedating, the
22 doctor may want to put certain types of patients
23 on a concomitant sedative?
24            MR. LORE:  Object to the form of the

                                                 Page 276

 1 question.  If you understand it, Doctor, you can
 2 try to answer it.
 3            A.      Those who require sedation
 4 would need a co-medication, that's the proper
 5 statement.
 6            Q.      So is it your testimony that
 7 in your opinion as a physician every
 8 antidepressant package insert should have such
 9 language in it?
10            A.      These who require sedation,
11 why not?
12            Q.      Okay.  What about that the
13 drug isn't sedating, like in the package insert
14 for fluoxetine?
15            A.      Well, that's not a particular
16 problem because you don't want to have always
17 sedation apart from that.
18            Q.      Isn't it true that the
19 majority of antidepressants on the market today
20 have sedating-type properties as opposed to
21 activating properties like fluoxetine?
22            A.      Well, I'm not sure if this is
23 so expressed, on top of that, I mean if you look
24 into that in terms of comparative data, could not

                                                 Page 277

 1 be that well substantiated.
 2            Q.      Name for me besides serotonin
 3 uptake inhibitors, other antidepressants that do
 4 not generally have sedating effects?
 5            A.      Well, I would think that there
 6 are differences between imipramine and
 7 amitryptiline in that regard.
 8            Q.      Imipramine and what?
 9            A.      Amitryptiline.
10            Q.      So you're saying imipramine is
11 not as sedating as amitryptiline or vice-versa?
12            A.      That's what I say, yes.
13            Q.      Does the imipramine package
14 insert in Germany have a recommendation?
15            A.      As far as I know, no.
16            Q.      You go on to say this is not
17 only true for general practice but was also the
18 case in all our studies, namely that restlessness
19 and sleep disturbance were concomitantly treated
20 with benzodiazepines or chloral hydrate, correct?
21            A.      That's correct.
22            Q.      At the bottom of the
23 paragraph, you said the use of sedating
24 co-medication in particular - also in the German

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 1 studies in comparison with amitryptiline - did
 2 not differ between the fluoxetine group and the
 3 reference group, correct?
 4            A.      They did not differ between,
 5 yes, that's said here.
 6            Q.      Did -- why did you continue to
 7 use -- strike that.
 8                    Is the German studies -- were
 9 any of the German studies in-patient studies?
10            A.      Basically the majority of the
11 data submissions were in-patient data, that's
12 what we were requested to do.
13            Q.      Why did you continue to use
14 concomitant sedative drugs in the in-patient
15 German studies when the BGA had raised the issue?
16            A.      I tried to explain earlier
17 that it's not so easy to implement this in
18 practice, and that the physician simply requested
19 that and that also this is not that much of a
20 problem if you stratify the data, and that's what
21 we did.
22            Q.      If you have somebody under
23 your control in the hospital, isn't it much
24 easier to do a clinical trial where you don't

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 1 coadminister sedatives on the second trial?
 2            A.      If the patient complains about
 3 sleep disturbances, I mean you would like to do
 4 something for that as a doctor.
 5            Q.      If the drug is working, they
 6 shouldn't be complaining about sleep
 7 disturbances, should they?
 8            A.      No, that's simply not true
 9 what you say.  First of all because sleep
10 disturbance is also part of the disease and it
11 takes some time until this resolves.  It's not
12 only drug related.
13            Q.      But if the drug is working, it
14 should resolve, shouldn't it?
15            A.      You can read that it takes I
16 mean over all three weeks until even all active
17 drugs on the market today discriminate from
18 placebo.  So you have some reduction in the
19 symptoms of the first week, but it doesn't
20 resolve within a couple of days.
21            Q.      How long were the patients on
22 placebo kept on co-administered sedatives?
23            A.      Placebo, we didn't have any
24 controlled study with placebo.

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 1            Q.      How about amitryptiline, how
 2 long were the patients on the amitryptiline arm
 3 kept on co-medication generally?
 4            A.      I don't know, simply.
 5            Q.      Theoretically if the drug is
 6 working and is not causing any sleep disturbance
 7 or agitating effects, the patient shouldn't need
 8 a co-administered sedative, should they?
 9            A.      That's in theory true.
10            Q.      You go on to say:  The second
11 way would start from the general indication
12 depression and would list the restriction under
13 contraindications and relative contraindication
14 or precautions, correct?
15            A.      Yes.
16            Q.      This way would include the
17 draft of our present suggestion.  In my opinion,
18 it should be prefered since it is clear for the
19 physician, correct?
20            A.      Correct.
21            Q.      So you felt that it was clear
22 for the physician to allow the use of fluoxetine
23 in depression across the board and then indicate
24 in certain situations you may want to add a

                                                 Page 281

 1 concomitant sedative?
 2            A.      Yes, that was my opinion.
 3            Q.      Then you say:  Enclosed please
 4 find two drafts of possible wording, correct?
 5            A.      Yes.
 6            Q.      For the products information.
 7 Do you know if this letter actually made it to
 8 Doctor Elbers?
 9            A.      I don't know it for sure but I
10 assume yes.
11            Q.      Do you feel that this letter
12 had an impact on what was eventually approved as
13 far as the prescribing information for
14 fluoxetine?
15            A.      Difficult to judge, I mean we
16 can compare the final wording and this one.
17            Q.      You said earlier that you
18 thought that it had an impact at least on Doctor
19 Karkos, correct?
20            A.      Well, I mean Doctor Karkos is
21 the reviewer, but still they have their meetings
22 at the BGA to finally, I mean, reach concensus
23 before they sign off.  So this would include
24 Doctor Gundert Remy and maybe fellow reviewers,

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 1 so that's why it's a little bit more complex and
 2 that's why I'm saying it's rather or better to
 3 compare this with the very finally approved
 4 version, that may be then the answer.
 5            Q.      If you look at the first page
 6 of enclosure two, it starts the second from the
 7 last page on the exhibit, 232.
 8            A.      Yes.
 9            Q.      Your recommended wording at
10 the bottom of the page is, fluoxetine does not
11 have a sedating effect.  Fluoxetine should be
12 used with special caution in patients with states
13 of agitation or severe sleep disturbance.
14 Correct?
15            A.      Yes.
16            Q.      Concomitant medication should
17 perhaps be mentioned.  So that's an indication by
18 you there that this is where you think
19 concomitant medication should be discussed, if it
20 is discussed?
21            A.      Yes, yes.
22            Q.      Then you go on to say:
23 Patients must be observed satisfactorily until
24 the onset of antidepressant action, especially if

                                                 Page 283

 1 patients are in danger of suicide, correct?
 2            A.      Yes.
 3            Q.      Did somebody ask you to meet
 4 with Straeter and write this letter to him or did
 5 you do this on your own?
 6            A.      I think there was not really
 7 asking, I mean in this process, we of course had
 8 many discussions, and as I mentioned Straeter was
 9 visiting our office, usually he visited, I have
10 never visited his office.
11            Q.      Whose idea was it for you to
12 write a letter to Straeter that would be then
13 passed on to Doctor Elbers?
14            A.      I can't recall, but it could
15 well have been the idea of Straeter.
16            MS. ZETTLER:  I have nothing further,
17 Doctor.  Thank you.
18 
19             (THE WITNESS WAS EXCUSED.)
20 

                                                 Page 284

 1 
   COMMONWEALTH OF KENTUCKY        )
 2                                 :  ss
   COUNTY OF JEFFERSON             )
 3 
 4       I, MARY KATHLEEN NOLD, A NOTARY PUBLIC IN
 5 AND FOR THE STATE OF KENTUCKY AT LARGE, DO HEREBY
 6 CERTIFY THAT THE FOREGOING TESTIMONY OF
 7              DR. H. N. SCHULZE-SOLCE
 8 WAS TAKEN BEFORE ME AT THE TIME AND PLACE AS
 9 STATED IN THE CAPTION; THAT THE WITNESS WAS FIRST
10 DULY SWORN TO TELL THE TRUTH, THE WHOLE TRUTH,
11 AND NOTHING BUT THE TRUTH; THAT THE SAID
12 PROCEEDINGS WERE TAKEN DOWN BY ME IN STENOGRAPHIC
13 NOTES AND AFTERWARDS TRANSCRIBED UNDER MY
14 DIRECTION; THAT IT IS A TRUE, COMPLETE AND
15 CORRECT TRANSCRIPT OF THE SAID PROCEEDINGS SO
16 HAD; THAT THE APPEARANCES WERE AS STATED IN THE
17 CAPTION.
18       WITNESS MY SIGNATURE THIS THE 9TH DAY OF
19 OCTOBER, 1994.
20       MY COMMISSION EXPIRES MARCH 10, 1996.
21 
   
22 
   
23                _________________________
                  MARY KATHLEEN NOLD
24                COURT REPORTER AND NOTARY PUBLIC
                  STATE OF KENTUCKY AT LARGE

                                                 Page 285

 1               E R R A T A   S H E E T
 2 
   
 3 STATE OF                      )
                                 : SS
 4 COUNTY OF                     )
   
 5 
 6            I, DR. H. N. SCHULZE-SOLCE, THE
 7 UNDERSIGNED DEPONENT, HAVE THIS DATE READ THE
 8 FOREGOING PAGES OF MY DEPOSITION AND WITH THE
 9 CHANGES NOTED BELOW, IF ANY, THESE PAGES
10 CONSTITUTE A TRUE AND ACCURATE TRANSCRIPTION OF
11 MY DEPOSITION GIVEN ON THE 16TH DAY OF SEPTEMBER,
12 1994 AT THE TIME AND PLACE STATED THEREIN.
13 PAGE NO.     LINE NO.     CHANGE          REASON

                                                 Page 286

 1 PAGE NO.     LINE NO.     CHANGE          REASON
   
 2 
   
 3 
   
 4 
   
 5 
   
 6 
   
 7 
   
 8 
                    _____________________________
 9                  DR. H. N. SCHULZE-SOLCE
   
10            SWORN TO AND SUBSCRIBED BEFORE ME THIS
11 _____ DAY OF __________, 1994.
12            _____________________________
              NOTARY PUBLIC, STATE OF
13            AT LARGE

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