1 NO. 90-CI-6033 JEFFERSON CIRCUIT COURT 2 DIVISION ONE (1) 3 *-*-*-*-* 4 JOYCE FENTRESS, ET AL. PLAINTIFFS 5 6 VS. DEPOSITION FOR PLAINTIFFS 7 8 SHEA COMMUNICATIONS, ET AL. DEFENDANTS 9 10 11 *-*-*-*-* 12 13 14 DEPONENT: PAUL STARK 15 16 DATE: JUNE 28, 1994 17 18 REPORTER: MARY KATHLEEN NOLD 19 20 *-*-*-*-* 21 22 KENTUCKIANA REPORTERS 730 WEST MAIN STREET, SUITE 250 23 LOUISVILLE, KENTUCKY 40202 (502) 589-2273 24 1 1 UNITED STATES DISTRICT COURT SOUTHERN DISTRICT OF INDIANA 2 INDIANAPOLIS DIVISION 3 IN RE ELI LILLY AND COMPANY ) Prozac Products Liability ) MDL Docket No. 907 4 Litigation ) 5 *-*-*-*-* 6 NO. 91-02496-A 7 JACKIE LYNN BIFFLE, ET AL ) IN THE DISTRICT ) COURT OF 8 V. ) DALLAS COUNTY, TEXAS ) 9 ELI LILLY & COMPANY AND ) 14TH JUDICIAL DISTA PRODUCTS COMPANY ) DISTRICT 10 *-*-*-*-* 11 NO. 92-14775-E 12 RICHARD HAROLD CROSSETT, JR., ) IN THE 13 CHAD H. CROSSETT, AMY MICHELLE ) DISTRICT CROSSETT AND KRISTEN ANN CROSSETT,) COURT OF 14 INDIVIDUALLY AND AS SURVIVORS OF ) AND ON BEHALF OF THE ESTATE OF ) 15 JOCQUETTA ANN CROSSETT, DECEASED ) ) 16 V. ) DALLAS COUNTY, ) TEXAS 17 ELI LILLY & COMPANY, DISTA ) PRODUCTS COMPANY, TEXAS ) 18 PSYCHIATRIC COMPANY, INC. ) D/B/A HCA WILLOW PARK ) 101st JUDICIAL 19 HOSPITAL, JAMES K. WITSCHY, M.D., ) DISTRICT AND DOUG BELLAMY, ED.D ) 20 *-*-*-*-* 21 22 23 24 2 1 NO. A-921,405-C 2 MARIA GUADALUPE REVES ) IN THE INDIVIDUALLY AND AS NEXT ) DISTRICT COURT 3 FRIEND OF GRANT JULIAN REVES ) OF A MINOR CHILD, AND ON BEHALF ) 4 OF THE ESTATE OF CHRISTIAN ) MARIE REVES, DECEASED ) 5 ) V. ) ORANGE COUNTY, 6 ) TEXAS ELI LILLY & COMPANY, DISTA ) 7 PRODUCTS COMPANY, RAVIKUMAR ) KANNEGANTI, M.D., HOSPITAL ) 8 CORPORATION OF AMERICA, A ) TENNESSEE CORPORATION, HEALTH ) 9 SERVICES ACQUISITION CORP., ) A DELAWARE CORPORATION, ) 10 HCA PSYCHIATRIC COMPANY, A ) DELAWARE CORPORATION, TEXAS ) 11 PSYCHIATRIC CO., INC., A/K/A ) AND/OR D/B/A HCA BEAUMONT ) 12 NEUROLOGICAL HOSPITAL, AND HCA) HEALTH SERVICES OF TEXAS, INC.) 128TH JUDICIAL 13 A/K/A AND/OR BEAUMONT ) DISTRICT NEUROLOGICAL HOSPITAL ) 14 *-*-*-*-* 15 16 17 18 19 20 21 22 23 24 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 *-*-*-*-* 12 SUPERIOR COURT OF THE STATE OF CALIFORNIA 13 FOR THE COUNTY OF LOS ANGELES 14 DR. MARIUS SAINES, etc., et al., ) Case No.: ) SC 008331 15 ) Plaintiffs, ) 16 ) vs. ) 17 ) ELI LILLY & COMPANY, a corporation;) 18 DISTA PRODUCTS COMPANY, a Division ) of Eli Lilly & Company; and DOBS 1-) 19 100, Inclusive, ) ) 20 Defendants. ) ___________________________________) 21 *-*-*-*-* 22 23 24 4 1 NO. 93-8792-D 2 DAVID KUNG, DALE KUNG COHEN ) IN THE DISTRICT ROBERT KUNG, AND TIMOTHY KUNG, ) COURT OF 3 INDIVIDUALLY AND AS SURVIVORS ) AND STATUTORY BENEFICIARIES ) 4 OF MAY YUN KUNG, DECEASED ) ) 5 VS. ) DALLAS, COUNTY ) TEXAS 6 ELI LILLY AND COMPANY, DISTA ) PRODUCTS COMPANY, AND MONIQUE ) 7 KUNKLE, PH.D. ) 8 *-*-*-*-* 9 IN THE DISTRICT COURT OF JOHNSON COUNTY, KANSAS CIVIL COURT DEPARTMENT 10 EUGENE HUSLIG, AS ADMINISTRATOR ) 11 AND EXECUTOR AND ON BEHALF OF ) THE ESTATE OF DEBORAH G. WEATHERS ) 12 HUSLIG, DECEASED, AND AS SURVIVING ) HUSBAND AND HEIR AT LAW OF DEBORAH ) 13 G. WEATHERS HUSLIG, DECEASED, ) AND IN HIS INDIVIDUAL CAPACITY AS ) 14 HUSBAND OF DEBORAH G. WEATHERS ) HUSLIG, DECEASED, AND RONALD C. ) 15 WEATHERS, SON OF DEBORAH G. ) WEATHERS HUSLIG, DECEASED, ) CASE NO.: 16 ) 94 C 192 PLAINTIFFS, ) 17 ) COURT NO. 7 VS. ) CHAPTER 60 18 ) MARY L. BILLINGSLEY, EXECUTOR OF ) 19 THE ESTATE OF THAD BILLINGSLEY, ) M.D., DECEASED D/B/A THE BENESSERE ) 20 CENTER, SUSAN C. JOHNSON, PH.D., ) BILLINGSLEY ENTERPRISES, INC., ) 21 F/K/A THAD H. BILLINGSLEY, M.D. ) CHARTERED, D/B/A THE BENESSERE ) 22 CENTER, ELI LILLY AND COMPANY, ) AND DISTA PRODUCTS COMPANY, ) 23 ) DEFENDANTS. ) 24 5 1 CAUSE NO. 93-04911-A 2 LINDA JILL WELCH, CARLINDA WELCH REX, CONNAN ROSS WELCH 3 AND CHAD MICHAEL WELCH, INDIVIDUALLY AND AS SURVIVORS 4 AND STATUTORY BENEFICIARIES OF CARL EUGENE WELCH, DECEASED PLAINTIFFS 5 V. 6 ELI LILLY AND COMPANY, DISTA 7 PRODUCTS COMPANY, NOE NEAVES, M.D., AND MINITH-MEIER 8 CLINIC, P.A. DEFENDANTS 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 6 1 I N D E X 2 WITNESS: PAUL STARK 3 DIRECT EXAMINATION BY MS. ZETTLER.............. 11 4 CROSS-EXAMINATION BY MR. SMITH................ 148 5 REDIRECT EXAMINATION BY MS. ZETTLER........... 188 6 RECROSS-EXAMINATION BY MR. SMITH.............. 189 7 WITNESS EXCUSED............................... 190 8 9 EXHIBITS MARKED: 10 STARK EXHIBIT NO. 1............................ 27 11 STARK EXHIBIT NO. 2............................ 29 12 STARK EXHIBIT NO. 3............................ 65 13 STARK EXHIBIT NO. 4........................... 118 14 STARK EXHIBIT NOS. 5 AND 6.................... 132 15 16 17 18 19 20 21 22 23 24 7 1 THE FOLLOWING DEPOSITION 2 OF PAUL STARK WAS TAKEN AT THE OFFICES OF BAKER & 3 DANIELS, 300 NORTH MERIDIAN STREET, SUITE 270, 4 INDIANAPOLIS, INDIANA, 46204, ON JUNE 28, 1994; 5 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 13 14 PAUL SMITH COUNSEL FOR PLAINTIFFS 15 745 CAMPBELL CENTER 2 8115 NORTH CENTRAL EXPRESSWAY 16 DALLAS, TEXAS 75206 17 18 JOE FREEMAN LAWRENCE J. MEYERS 19 COUNSEL FOR ELI LILLY AND COMPANY FREEMAN & HAWKINS 20 4000 ONE PEACHTREE CENTER 303 PEACHTREE STREET, N.E. 21 ATLANTA, GEORGIA 30308-3243 22 23 24 8 1 APPEARANCES (CONTINUED) 2 MARY HUFF ELI LILLY AND COMPANY 3 LILLY CORPORATE CENTER INDIANAPOLIS, INDIANA 46285 4 5 6 BEATRICE M. SMITH COUNSEL FOR BEAUMONT NEUROLOGICAL HOSPITAL 7 FRIEND & ASSOCIATES LLP 1301 MCKINNEY, #2900 8 HOUSTON, TEXAS 77010 9 10 BARTON BROWN COUNSEL FOR DOCTOR BILLINGSLEY 11 WALLACE, SAUNDERS, AUSTIN, BROWN & ENOCHS 10111 WEST 8TH STREET 12 PO BOX 12290 OVERLAND PARK, KANSAS 66282 13 14 15 ROBERT L. HARRIS COUNSEL FOR NOE NEAVES, MD 16 SIFFOLD & ANDERSON, LLP 6300 NATIONS BANK PLAZA 17 901 MAIN STREET DALLAS, TEXAS 75202 18 19 20 21 22 23 24 9 1 MR. MYERS: We'll use 2 again the same stipulation that we used in 3 Mr. Wood's case, the deposition in the same cases 4 as Larry made reference to in the letter. 5 MR. FREEMAN: Let me just 6 state at this time a little brief stipulation. 7 This is the deposition of Paul Stark taken on 8 behalf of the plaintiffs for purposes of discovery 9 and use at the trial on any of the cases 10 heretofore recited. The deposition of Mr. Stark 11 is taken by agreement of counsel and by notice in 12 the offices of Baker and Daniel in Indianapolis. 13 Objection will be made at 14 this time as to any leading questions that 15 Mr. Stark's own counsel may put to him or any 16 objection that any lawyer may have to the 17 witness's response to the questions propounded. 18 All other objections will be reserved until the 19 time of court hearing. 20 MS. ZETTLER: As well as 21 my Chicago cases? 22 MR. MYERS: As well as 23 yours. 24 * * * * * 10 1 PAUL STARK, called by 2 Plaintiffs, after having been first duly sworn, 3 was examined and deposed as follows: 4 5 DIRECT EXAMINATION 6 7 BY MS. ZETTLER: 8 Q Good morning, Doctor 9 Stark. I introduced myself a little earlier, my 10 name is Nancy Zettler and I represent a couple of 11 families in the Chicago area, as well as a group 12 of plaintiffs down in Louisville, Kentucky related 13 to actions against Eli Lilly for their drug 14 Prozac. 15 Are you familiar with the 16 Wesbecker case in Louisville, Kentucky? 17 A Not in particular. 18 Q What knowledge do you 19 have of the case? 20 A If you were to ask for 21 any detail, I would have to pass and say that you 22 just rang a bell that I had heard something, but 23 that's about it, I'm sorry. 24 Q You were no longer 11 1 employed at Eli Lilly at the time that incident 2 occurred, correct? 3 A No, I was not. 4 Q You left in '84, I 5 believe? 6 A That's correct. 7 Q Can you tell me what 8 month in '84, do you remember? 9 A July. 10 Q I understand that you 11 have given your deposition before, not just in 12 this case, correct? 13 A Yes, I have. 14 Q How many times have you 15 given a deposition, besides this case, if at all? 16 A Oh, once. 17 Q Was that related to your 18 work with Eli Lilly? 19 A No, it wasn't. 20 Q Was that related to 21 employment at all, or was that a personal matter? 22 A It had to do with breach 23 of contract with my company. 24 Q So you understand the 12 1 ground rules basically of a deposition, correct, 2 that you have to answer out loud so the court 3 reporter can take it down, and if you don't 4 understand my questions, ask me to repeat them and 5 I will, or try to clarify them so that you 6 understand them, is that fair? 7 A Yes. 8 Q Are you familiar with a 9 woman named Dorothy Dobbs? 10 A I'm not sure what you 11 mean, am I familiar with her; I know of her. 12 Q How do you know of her? 13 A She worked at Eli Lilly 14 for some of the time that I was there. 15 Q When did you first meet 16 Doctor Dobbs? 17 A I don't know precisely 18 when. 19 Q Was it during your 20 employment at Lilly? 21 A Oh, yes. 22 Q Were you working there 23 before Doctor Dobbs began working at Lilly? 24 A Yes, ma'am. 13 1 Q Did you work with Doctor 2 Dobbs while you were at Lilly? 3 A Not with her; she was 4 associated with the regulatory group, I believe. 5 Q Did you have any common 6 tasks while you were at Lilly with Doctor Dobbs? 7 A I interacted with her. I 8 can only recall vague as opposed to much detail at 9 this point in time. You are going back a 10 significant number of years. She was responsible 11 for filing documents with the FDA, and from time 12 to time she would make inquiry as to the items on 13 the case report forms and so on, fluoxetine 14 studies. In essence, I would attempt to find 15 someone who could give her the detailed answers as 16 opposed to any detailed interaction on my own. 17 Q Did you have any 18 responsibility while you were at Lilly working 19 with the international affiliates with regard to 20 Prozac? 21 A I interacted with them; 22 certainly the group in the UK, I guess, 23 primarily. And Lilly France, I just remembered 24 one. 14 1 Q How about Germany; did 2 you interact with that affiliate at all? 3 A No, I never had any 4 interaction with anyone over there. 5 Q I understand that you 6 left in mid '84, but were you involved at all in 7 any efforts to get fluoxetine hydrochloride 8 registered in any foreign country outside of the 9 United States for marketing in those countries? 10 A How do you mean was I 11 involved in trying to get them registered? 12 Q Did you interact with any 13 of the foreign regulatory agencies, for instance? 14 A No, I did not. 15 Q Did you help prepare any 16 documents to be submitted to foreign regulatory 17 agencies? 18 A No. 19 Q Did you consult with 20 anybody at Lilly's foreign affiliates with regards 21 to questions asked by regulatory agencies with 22 regards to the registration of fluoxetine? 23 A Not that I recall. That 24 was -- I was just going to say, just so you put it 15 1 appropriately in time, this was before 2 registration; I left before registration occurred. 3 Q Anywhere? 4 A Yes, so that I was 5 removed from the loop before significant 6 regulatory interactions took place. 7 Q What is your recollection 8 of what country Prozac was first registered in for 9 marketing? 10 A I don't have a 11 recollection. 12 Q You continued to work 13 with Lilly after you left, did you not, in some 14 capacity? 15 A Our company performed two 16 studies for Eli Lilly and Company. 17 Q Were you ever a member of 18 Lilly's psychiatric advisory panel after you left? 19 A Lilly's what? 20 Q Psychiatric advisory 21 panel? 22 A I don't know of one. 23 Q Did you consult with 24 Lilly in any way other than the two studies that 16 1 your company performed for Lilly? 2 A No, I did not. 3 Q When you say the two 4 studies, you mean fluoxetine studies, correct? 5 A Yes. 6 Q Did your company perform 7 any other studies other than on fluoxetine? 8 A Not yet. 9 MR. SMITH: Did you say 10 not yet? 11 THE WITNESS: I'm forever 12 hopeful. 13 Q (BY MS. ZETTLER) How 14 about registration in the United States, did you 15 have any responsibilities with preparing documents 16 to be submitted to the FDA in support of 17 registration here? 18 A No, I didn't. 19 Q You were a clinical 20 monitor? 21 A Yes, I was. 22 Q When did you become a 23 clinical monitor on fluoxetine? 24 A I can only guess, 17 1 about '79. 2 Q And you replaced Doctor 3 Slater, I believe? 4 A Yes. 5 Q In your role as clinical 6 monitor, did that include responsibilities with 7 regards to keeping track of adverse events that 8 occurred on the drugs during the clinical trials? 9 A I'm not sure what you 10 mean by keeping track. Do you mean being aware of 11 them? 12 Q Right. 13 A I was aware of them. 14 Q Okay. Was there a system 15 in place, say in the early '80s, where people 16 would report to you any adverse events or any 17 serious adverse events that occurred during 18 clinical trials on fluoxetine? 19 A Serious adverse events 20 were reported to me, brought to my attention. 21 Q What was that mechanism, 22 how did that happen? 23 A The serious adverse 24 events, to the best of my recollection, for the 18 1 most part, was by way of a telephone call that 2 came in, and we would forward the information to 3 the regulatory group so that they would notify the 4 FDA within the time constraints. 5 Q What mechanism was in 6 place back then to follow up on any adverse events 7 that occurred during the clinical trial? 8 A I can only speak for what 9 I did on our system, and what we did was we 10 immediately contacted the site and got further 11 information, and then followed up appropriately 12 with people visiting, as needed, or not visiting, 13 if that was deemed not necessary. If the patients 14 were hospitalized, we got all of the 15 hospitalization information, discharge summaries, 16 and the regulatory people then dealt with it. We 17 were, if you will, merely the hands, I guess, in 18 the process. 19 Q If a site visit was 20 necessary, who would go; would it be somebody from 21 your department or somebody from regulatory? 22 A I don't recall. To 23 answer a complete answer, there were occasions I 24 know when my CRA's went, clinical research 19 1 associates. We had people called clinical 2 research coordinators, they were covering 3 different regions, they would make visits. They 4 could be called upon. I can't give you the full 5 gamut of people who could be called upon. 6 Q What types of information 7 would be gathered in a serious event? 8 A Anything at all that 9 would be of any pertinence to what had 10 transpired. I can only give you some of the items 11 that I can recall. We'd always pick up the last 12 time the medication was taken, what dosage had 13 been taken, what concomitant meds had been taken, 14 any information with regards to admission, history 15 that had been gotten, discharge summaries. I give 16 you these as examples, but not as all- 17 encompassing. 18 Q Demographic information, 19 the person's age, sex? 20 A I can't specifically 21 answer you on that. 22 Q How about information 23 regarding the causal relationship between the use 24 of fluoxetine and the adverse event? 20 1 A I think those were 2 recorded on the case report forms in the 3 investigator's best opinion. 4 Q Was a suicide attempt 5 considered a serious adverse event back then? 6 A At that time it was, yes. 7 Q Do you recall a time when 8 it was no longer considered a serious adverse 9 event while you were at Lilly? 10 A I didn't recall that I 11 said that, that it ever was not considered a 12 serious adverse event. 13 Q You said at that time it 14 was, that's why I -- 15 A That's all I can speak 16 for, when I was there. 17 Q How about when you were 18 performing studies for Lilly after you left the 19 company? 20 A At that time, it was 21 still considered a serious adverse event. 22 Q When was the last time 23 that you were working on a study on fluoxetine for 24 Lilly? 21 1 A Approximately 1987. 2 Q When you worked for 3 Lilly, was suicide attempt considered an expected 4 adverse event? 5 A An expected adverse 6 event, because of what? 7 Q Because of the regulatory 8 definition. 9 A I'm not sure that I 10 follow you. Are you saying it's an expected 11 adverse event because of? Fill in the missing 12 word and I can answer you. 13 Q Were you familiar with 14 the regulatory requirements for adverse event 15 reporting when you were working for Lilly? 16 A Generally, yes. 17 Q When you were working for 18 Lilly, there was a regulatory definition of what 19 was considered a serious adverse event, correct? 20 A Yes. 21 Q There was also a 22 regulatory definition as to what would be 23 considered an unexpected or expected adverse event 24 for the purposes of reporting, correct? 22 1 A I follow your 2 questioning, but you're so general that, 3 unfortunately, it's not really going to be 4 accurate, so I will answer you in the manner that 5 I interpreted it. 6 Q That's fine. 7 A Mainly that if a suicide 8 were to occur because of the drug, I would 9 consider this an unexpected result. If a person 10 who were depressed were to attempt suicide, I 11 would not consider that an unexpected event from 12 the person spontaneously doing that. 13 Q Was an effort ever made 14 to differentiate between whether or not a 15 particular suicide attempt was caused by the drug 16 as opposed to the person's underlying condition? 17 A Not by me. I just 18 accepted all of them as serious adverse events and 19 then allowed that to be established later on by 20 the people in regulatory. We treated any 21 hospitalization and any suicidal attempt as a 22 serious adverse event, period. 23 Q What about as far as 24 expectancy was concerned? 23 1 A I didn't have anything to 2 do with the decision on that. 3 Q Was suicide considered an 4 adverse event when you were working with Lilly? 5 A I thought we just stated 6 that, it was a serious adverse event. I perhaps 7 misunderstood your question and my answer. 8 Q When did you first become 9 aware that there was an issue as to whether or not 10 fluoxetine caused or increased suicidal ideation? 11 A Could you repeat the 12 question? 13 Q You are aware that the 14 issue has been raised as to whether or not 15 fluoxetine causes someone to become suicidal or 16 worsens a suicidal ideation, correct? 17 A The question has been 18 raised by whom? 19 Q By us, for one. 20 A I think that's very 21 important because I've never heard it from the 22 scientific community. So, if you're saying your 23 point of view, I would be happy to entertain any 24 questions with regards to your question. 24 1 Q Have you ever become 2 aware of Doctor Teicher's article that was 3 published in early 1990? 4 A No, I've not been. 5 Q Do you know who Martin 6 Teicher is? 7 A No, I don't. 8 Q Is it your testimony that 9 other than these lawsuits, you are not aware if 10 the issue of whether or not fluoxetine as related 11 to suicidal ideation has ever been raised? 12 A By whom? 13 Q By anybody. 14 A Yes, I'm quite aware it's 15 been raised. 16 Q By whom? 17 A Paul Smith from Dallas, 18 Texas. 19 Q Anybody else? 20 MR. SMITH: And we'll 21 stipulate he's not a medical doctor. 22 A I have read in the lay 23 press that the question has been raised by various 24 law firms in various suits. I have to admit I've 25 1 not followed it in detail. 2 Q When did you first read 3 that in the lay press? 4 A Oh, God, I don't recall. 5 Q Before 1990? 6 A I don't recall. If I'm 7 going to give you an accurate answer, I would have 8 to answer you that. 9 Q How about by the German 10 government, are you aware that they raised the 11 issue as to whether or not fluoxetine was related 12 to suicidal ideation or increased suicidal 13 ideation as early as 1984? 14 A I'm not aware of the 15 detailed allegations by the German authorities. 16 Q Did you do any work with 17 regards to the application submitted to the BGA 18 for the marketing of fluoxetine in Germany? 19 A I don't know when it was 20 marketed, but I'd bet my wife and children I had 21 left Lilly before that happened. I don't really 22 know when applications went in. I didn't think it 23 was marketed anywhere before I left the company. 24 Q But my question was, were 26 1 you aware that they raised the issue throughout 2 the process of Lilly attempting -- 3 A No, because I really 4 don't know when any documents were submitted. I 5 didn't know that anyone preceded the States in 6 actuality, if you were to ask me. If that shows 7 my ignorance, I apologize. 8 (STARK EXHIBIT NO. 1 MARKED FOR 9 IDENTIFICATION.) 10 Q Have you had a chance to 11 review Exhibit 1, Doctor? 12 A I'm sorry? 13 Q Have you had a chance to 14 review the exhibit? You can take your time and 15 look at it if you'd like. 16 A Oh, thank you, no, I just 17 looked to see the date and my name on it. 18 Q Why don't you go ahead 19 and take a look at it. 20 A Thank you. 21 Okay, I've looked at it. 22 I'll go back in more detail as you proceed, if I 23 may. 24 Q Do you recognize Exhibit 27 1 1? 2 A No. 3 Q Have you seen it before? 4 A Not that I recall. 5 Q You are listed as a main 6 recipient on that? 7 A I see this on here. I 8 can't tell you for sure, but I should draw your 9 attention that this is marked 6/26/84. 10 Q Uh-huh. 11 A And I was in Montecatini 12 and Florence for the symposium on fluoxetine and 13 got home like July 4th, round numbers, and 14 proceeded to give my notice at Lilly, and I was 15 out of there two weeks later. So how much I 16 interacted, I can't possibly tell you. I can 17 assure you my mind was somewhat elsewhere in that 18 two-week period. So, my name is on here, I'm sure 19 I received it. The probabilities are in that 20 two-week period that I looked at it; I have no 21 recollection of what I did about it. 22 Q Why did you leave so 23 quickly from Lilly? 24 A I decided to start my own 28 1 company. 2 Q Was it something about 3 your career path at Lilly that made you decide to 4 go out on your own, or was it just a desire to go 5 out on your own? 6 A No, I really wanted to be 7 an entrepreneur. For the record, I'm glad I did 8 it. 9 (STARK EXHIBIT NO. 2 MARKED FOR 10 IDENTIFICATION.) 11 Q Have you had a chance to 12 review Exhibit 2? 13 A I'm sorry. 14 Q Have you had a chance to 15 review Exhibit 2? 16 A Yes. 17 Q Do you recognize this 18 exhibit? 19 A No, I'm sorry. 20 Q Do you know who Hans 21 Weber is? 22 A I have a name, but I 23 can't tell you anything about the person and the 24 name combined. 29 1 Q Do you recall being asked 2 by Doctor Weber to meet with a professor of some 3 sort? It's hard to tell because the name is 4 blacked out on this. 5 A I don't recall. 6 Q Do you have any 7 recollection whatsoever regarding the German 8 government's response to Lilly's application for 9 marketing there? 10 A I'm sorry, I really 11 don't. 12 Q Let's go back to Exhibit 13 1 then. If you could look on the second page 14 under Point No. 7. 15 A Okay. 16 Q It says, "The BGA 17 explained their reservations regarding CNS side 18 effects," correct? 19 A That's what it says here. 20 Q Would it be fair to say 21 that CNS is the central nervous system, given the 22 text of the rest of the point under No. 7? 23 A I think that's a fair 24 supposition. 30 1 Q Okay. To your knowledge, 2 while you were at Lilly or afterwards, were you 3 ever aware of the issue being raised as to whether 4 or not fluoxetine causes central nervous system 5 stimulation? 6 A Would you define 7 stimulation for me? 8 Q Are you aware that 9 there's a school of thought that fluoxetine is a 10 stimulating as opposed to a sedating 11 antidepressant? 12 A I've not heard the term 13 stimulating used by any scientists. There are 14 other terms, but only legal people have tried me 15 on that one. 16 Q How about activating? 17 A No, I've not heard the 18 scientists refer to it as an activating compound 19 either. 20 Q What types of terms do 21 the legal people use? 22 A What you've just said, 23 activating and stimulating. Actually, I have only 24 met one significant individual in that area. 31 1 Q Point No. 10, would you 2 look under Point No. 10? Do you know Doctor 3 Johanna Schenk? 4 A Yes. 5 Q Is she a medical doctor? 6 A Yes. 7 Q Is she a psychiatrist? 8 A That I don't know. 9 Q Would you consider her a 10 scientist? 11 A I'd consider her a 12 physician. 13 Q Okay, you don't consider 14 her a scientist? 15 A I don't know her that 16 well to really say about her scientific acumen. 17 Q You certainly don't 18 consider her a lawyer, do you? 19 A No, I don't. 20 Q If you look under Point 21 No. 10 -- and this memo appears to have been 22 written by Doctor Schenk and Doctor Weber, 23 correct? 24 A Yes. 32 1 Q If you look under Point 2 No. 10, it says, "Comparative use of concomitantly 3 taken hypnotics and benzodiazepines in agitated/ 4 retarded fluoxetine patients versus agitated/ 5 retarded patients on comparators. Reason: BGA 6 suspects fluoxetine to be a stimulating/ 7 activating drug," do you see that? 8 A Yes. 9 Q Does this refresh your 10 recollection as to whether or not the issue of 11 whether fluoxetine is a stimulating or activating 12 antidepressant has been raised other than by us 13 legal types? 14 A Well, I see here a 15 statement. I don't know who raised this question 16 at the BGA even, so that I can't answer you. 17 Q So you're saying that it 18 may have been a lawyer at the BGA? 19 A I don't have any idea, 20 I'm not saying. What I'm telling you is I have a 21 document here and I believe every word of it 22 that's written, but I can't go beyond that, 23 especially when I can't even tell you that I 24 recall the document. I really would like you to 33 1 recognize we're going back ten years and I've not 2 really seen this in the passage of time. 3 Q Are you on any medication 4 today that would impair your ability to testify? 5 A Not that I'm aware of. 6 Q Because you've recently 7 had surgery, so I just want to make sure you 8 weren't on any painkillers of the like that might 9 be hampering your ability to remember facts. 10 A No, I'm afraid it's my 11 sixty-five years of age. 12 Q Could you look at Point 13 No. 14 on the third page of the exhibit? It says, 14 "As we already explained by our telex to Doctor 15 Zerbe of June 8, '84, we need a careful analysis 16 of suicides and suicide attempts," do you see 17 that? 18 A Yes, I do. 19 Q Do you recall this issue 20 being raised in June of 1984? 21 A No, I don't. 22 Q Do you recall ever 23 speaking with Doctor Zerbe about reviewing 24 database information in clinical trials with 34 1 regards to this question? 2 A No, I don't. 3 Q Did you have any 4 responsibility back then to oversee or somehow 5 supervise the analyses of any clinical trial data, 6 not just on the issue of suicidality? 7 A Supervise the analyses, 8 no. I was aware of analyses and participated in 9 examining data as they were generated. 10 Q What types of analyses do 11 you recall being done? 12 A The statistical group had 13 a constant input of the data, and they were 14 reviewed. Papers that we presented, we gave the 15 incidents of adverse experiences, side effects, we 16 presented at Montecatini and at Florence, in the 17 publications that David Hardison and I put out. 18 You're going to have to expound on what it is you 19 want me to tell you. I gave you -- 20 Q When you say that you 21 reviewed analyses, are you talking about analyses 22 of data from clinical trials that had been 23 performed? 24 A Yes. 35 1 Q And were those analyses 2 done at the end of the clinical trial to try to 3 assess whether or not the drug was shown to be 4 efficacious, for instance, on that trial? 5 A To see if it was 6 efficacious and to get a profile of the side 7 effects as well. 8 Q What type of side effect 9 profile did fluoxetine present when you were 10 working for Lilly? 11 A The detail I can't give 12 you, but I would refer you to the package insert. 13 Q What is your recollection 14 of what the profile was back then? 15 A I can recall some of the 16 major side effects, which included early insomnia, 17 disappearing over time, nausea early on, 18 disappearing over time, diarrhea, some agitation. 19 Those are the major ones that I can recall. 20 Q Nervousness? 21 A Yes, I can recall 22 nervousness, agitation being put together. 23 Q How about anxiety? 24 A Not of a great 36 1 significance; that doesn't stand out as a high 2 incidence at all. 3 Q How about irritability? 4 A I can't answer you. 5 Q Why not? 6 A Because I don't recall. 7 Q Are you aware that 8 protocols for a number of the clinical trials on 9 fluoxetine in the efficacy clinical trials allowed 10 for the concomitant use of benzodiazepines or 11 chloral hydrate during the studies for insomnia or 12 agitation? 13 A I don't remember the use 14 of benzos being allowed. I recall chloral 15 hydrate, but for sleep. 16 Q Were you involved in 17 making the decision as to whether or not to allow 18 the use of chloral hydrate for sleep in the 19 clinical trials? 20 A To not allow it to be 21 used? 22 Q To allow it; were you 23 involved in the decision to allow it? 24 A Yes. 37 1 Q Who else was involved in 2 that decision? Was there a particular committee, 3 for instance, that was charged with that decision? 4 A The Protocol Review 5 Committee, whomever that may have involved, had 6 the final say at the end. 7 Q Were you on the Protocol 8 Review Committee? 9 A No. I presented to them. 10 Q Were you for or against 11 the use of chloral hydrate on the clinical trials? 12 A I would have been for it; 13 I can't recall, but I would have been for it. 14 Q Why do you say that? 15 A Because I think one of 16 the most significant presenting symptoms in a 17 depressed patient is complaints of insomnia, and I 18 don't believe I know of any antidepressant drug 19 whose onset of action is immediate; therefore, it 20 is a means of giving symptomatic relief to a 21 depressed patient, and if you limit the length of 22 time that you allow the patient to be on chloral 23 hydrate, you can give them symptomatic relief, and 24 then you can assess the efficacy of your drug 38 1 because you don't allow them to stay on chloral 2 hydrate. 3 Q Because you do not allow 4 them? 5 A That's correct, you only 6 allow it for a limited period of time; I believe 7 my protocols so stated. 8 Q How long? 9 A I can't recall what I 10 said in those days. 11 Q Longer than three weeks? 12 A I'm sorry? 13 Q Longer than three weeks? 14 A I would have thought not. 15 Q Longer than two weeks? 16 A Longer than two weeks? I 17 don't know what I would have stated then. Just to 18 make life easy for you, in this day and age when I 19 help people put together protocols, I allow up to 20 two weeks from the time of the starting of the 21 double blind. So, if there is an one week washout 22 beforehand, that would allow up to three weeks. 23 Q Are you currently doing 24 work or have you done work in the past -- your 39 1 company I mean -- on other serotonin reuptake 2 inhibitors? You don't have to be specific as to 3 what. 4 A Yes, we have. 5 Q Do you generally allow 6 for the administration of chloral hydrate in 7 clinical trials that your company performs -- or 8 protocols that you write for clinical trials on 9 tricyclic antidepressants? 10 A Yes. 11 Q How about MAO inhibitors? 12 A Yes. 13 Q Is it your experience 14 that chloral hydrate is administered relatively 15 frequently during those types of clinical trials? 16 A Define frequently. 17 Q Let's say as much as it's 18 administered in a clinical trial on serotonin 19 reuptake inhibitors. 20 A Yes. 21 Q Have you authored papers 22 on other serotonin reuptake inhibitor clinical 23 trials besides fluoxetine? 24 A No, I have not. 40 1 Q Have you authored any 2 papers since leaving Lilly? 3 A Yes. 4 Q Are those papers related 5 in any way to clinical trials performed on drugs 6 other than fluoxetine? 7 A Yes. 8 Q Can you give me some of 9 those drugs? 10 A Wellbutrin. 11 Q Any others? 12 A That's all that I've 13 published on. 14 Q What type of drug is 15 Wellbutrin? 16 A It's an antidepressant. 17 Q In what class? Is it a 18 tricyclic? 19 A I don't think the 20 mechanism of action is known. 21 Q Does it have any 22 serotonin reuptake inhibitor properties? 23 A I don't think anything 24 significant. 41 1 Q There is a controversy as 2 to whether or not Wellbutrin caused a higher 3 incidence of seizures, was there not? 4 A That is correct. 5 Q Were you involved at all 6 in the FDA's deliberations on that issue, either 7 presenting data or consultant to the FDA? 8 A I was a consultant for 9 Burroughs/Wellcome. 10 MR. SMITH: When? 11 THE WITNESS: I'm sorry? 12 MR. SMITH: When were you 13 a consultant? 14 Q (BY MS. ZETTLER) When 15 were you a consultant for Burroughs/Wellcome? 16 A When? 17 Q Yes. 18 A If you will accept a 19 round number -- 20 Q To the best of your 21 recollection, Doctor. 22 A Five years ago. 23 Q Were you a consultant to 24 the FDA or Eli Lilly with regards to the 1991 Drug 42 1 Advisory Committee meeting that was held on the 2 issue of antidepressant use in suicide or violent 3 aggressive behavior? 4 A I was not. 5 Q Were you asked to be a 6 consultant? 7 A No. 8 Q Other than Lilly's 9 lawyers, have you ever discussed the issue of 10 whether or not fluoxetine causes or exacerbates 11 suicidality or violent aggressive behavior? 12 A No. 13 Q Have you discussed that 14 issue with Doctor Feighner? 15 A Did I? 16 Q Have you ever discussed 17 it? 18 A Not other than in a 19 passing vein. I don't know when, either, because 20 I speak with him so much about so many things, but 21 I'm sure it came up. 22 Q Do you recall generally 23 conversations in passing with Doctor Feighner 24 regarding those issues? 43 1 A Yes. 2 Q Generally, what did you 3 say and what did he say about the issue? 4 A If you'll accept it 5 indeed in a general vein, I think our consensus 6 was that it was not any different than any of the 7 other drugs with regards to eliciting or causing 8 any kind of suicidal behavior. 9 Q Are you of the opinion 10 that any other antidepressant on the market causes 11 or exacerbates suicidal or violent aggressive 12 behavior? 13 A You're going to have to 14 rephrase that one on a slower basis. 15 Q Are you of the opinion 16 that any other antidepressant on the market 17 causes, as least in a certain population of 18 people, suicidal ideation or exacerbates suicidal 19 ideation? 20 A Whether I'm aware of any 21 other antidepressant exacerbating suicidal 22 ideation, is that your question? 23 Q Yes. 24 A No, I'm not aware. 44 1 Q How about violent 2 aggressive behavior? 3 A What kind of behavior? 4 Q Violent aggressive 5 behavior? 6 A I'm not aware. 7 Q When you were a clinical 8 monitor on fluoxetine before you left in 1984, 9 were you aware of any suicides or suicide attempts 10 that occurred on any of the clinical trials on 11 fluoxetine? 12 A I am aware that it 13 happened, but I can't give you any detail, 14 unfortunately, at this point in time. 15 Q How about hostility or 16 violent aggressive behavior, are you aware of any 17 occurrences such as that? 18 A I can't recall any 19 incident of such significance that it stayed with 20 me. Whether I ever saw something on a case report 21 form -- I would have to guess the term "hostility" 22 would have to turn up, but I couldn't tell you if 23 it was on placebo, imipramine or fluoxetine, 24 as none of them caused it to remain on my mind to 45 1 pay attention to this. I know I'm not answering 2 your question, but it's the best I can do in an 3 honest way. 4 Q How about intentional 5 injury, do you recall any patient on fluoxetine, 6 or during the clinical trials any patients 7 intentionally injuring somebody else during the 8 clinical trials? 9 A You just asked me two 10 questions. 11 Q Are you aware -- 12 A You first said injuring. 13 Q Intentionally. 14 A And then you said someone 15 else. 16 Q Right. Let me ask it 17 again, I know it was a bad question. 18 Do you recall any 19 incidents where a patient on fluoxetine, or any 20 other drug during the clinical trials, 21 intentionally injured another person during the 22 clinical trials? 23 A No, I don't recall. 24 Q Do you recall any 46 1 instance where somebody from Lilly went to visit a 2 site or visited a patient who had become suicidal 3 while on fluoxetine, while you were there? 4 A Do I recall anyone from 5 Lilly visiting a patient or a site? 6 Q Right. An investigation 7 site. 8 A I don't recall either A 9 or B. 10 Q Okay. And I'm limiting 11 it just to suicidal patients. 12 A I don't recall is the 13 question, and I don't recall them visiting a 14 patient or a site, although -- you know, I can't 15 conceive of someone visiting a patient, anyone who 16 worked with me. 17 Q Have you ever discussed, 18 to the best of your recollection, with the 19 clinical investigator, whether or not a particular 20 adverse event -- 21 A I have to ask a favor of 22 you. 23 Q Sure. 24 A You're talking a little 47 1 too fast for me and I can't -- 2 Q That's a bad habit I 3 have, maybe it's because I was born on the East 4 Coast, I don't know. 5 A I want to follow what 6 you're saying and it just makes it difficult for 7 me. 8 Q Sure, that's one of the 9 ground rules, if you don't understand my question 10 for any reason, tell me. 11 Do you recall ever 12 discussing with the clinical investigator whether 13 or not any particular adverse event was related to 14 the use of fluoxetine and not the underlying 15 disease or some other reason? 16 MR. MYERS: Are you 17 talking about suicide? 18 MS. ZETTLER: No, I'm not 19 limiting to suicide or violent aggressive 20 behavior; any adverse event that you have heard 21 whatsoever. 22 A I can answer yes, but 23 unfortunately it's going to stop the conversation 24 because I can't tell you in particular to whom and 48 1 about what. 2 Q Okay. 3 A And I really can't 4 remember with whom and what, but I do recall that 5 there were conversations; I'd ask for 6 clarifications and stuff like that, but -- okay, 7 I've anticipated a question which I should not 8 have done. 9 Q That's okay, you make my 10 job easier. Do you know Doctor Burton Goldstein? 11 A Yes. 12 Q Who is Doctor Goldstein? 13 A He's in Florida, Miami. 14 Q How do you know him? 15 A He did a clinical trial 16 for us. 17 Q Why are you laughing? 18 A It was funny, like twenty 19 questions; what street does he live on, I don't 20 know. 21 Q He did a clinical trial 22 on fluoxetine? 23 A Yes. 24 Q And was that trial done 49 1 under Protocol 27, if you recall? 2 A I don't recall the 3 numbers at all. 4 Q Do you recall if it was a 5 fluoxetine-imipramine-placebo? 6 A No, I don't recall, it's 7 too far back. 8 Q Do you recall whether or 9 not Doctor Goldstein completed his clinical trial? 10 A (WITNESS MOVES HEAD FROM 11 SIDE TO SIDE.) 12 MR. MYERS: The answer 13 was no. 14 THE WITNESS: I'm sorry; 15 he shook his head gently from side to side. 16 Q (BY MS. ZETTLER) Have 17 you ever heard of a pre-NDA submission on 18 fluoxetine, or a mini-NDA on fluoxetine? 19 A No. 20 Q Are you aware of any 21 submissions that were made by Lilly to the FDA 22 prior to submitting the NDA, other than the IND? 23 A Other than adverse events 24 as well? 50 1 Q Right. 2 A No. 3 Q Do you remember a Charles 4 Prettyman, Prettyman? 5 A The name Prettyman rings 6 a bell. He's at the FDA? 7 Q Yes. Do you recall who 8 Mr. Prettyman was at the FDA? 9 A No. 10 Q How about Doctor Shedden, 11 do you recall Doctor Shedden? 12 A Yes. 13 Q Who is Doctor Shedden? 14 A He was at Lilly, I don't 15 recall the ultimate position he had. I think he 16 was a vice president ultimately, but he was one of 17 the -- he was over my boss in the clinical group. 18 Q Do you know if he worked 19 on fluoxetine at all while you were there? 20 A He worked on it in the 21 sense that it was going on in his department, so, 22 yes. 23 Q Was he your boss, so to 24 speak? 51 1 A He was my boss's boss. 2 Q Your boss's boss? 3 A Yes. 4 Q Did you ever have any 5 discussions with Doctor Shedden regarding adverse 6 events occurring on fluoxetine? 7 A The answer has got to be 8 yes, but I don't recall what they were because 9 there's no way that I would be there and he would 10 be there and it wouldn't come up. 11 Q Were you charged with 12 reporting to Doctor Shedden on a regular basis, as 13 a part of your job description, regarding adverse 14 events on fluoxetine? 15 A No, that would probably 16 be more in regards, I would guess, to a guy named 17 Cecil Vendish. 18 Q He would report to Doctor 19 Shedden and you would report to him? 20 A He would report to 21 Shedden, I would report to him, and there would be 22 some meetings where everybody would be present so 23 you wouldn't have to say it over and over and over 24 again. I just recall these get-togethers in rooms 52 1 with tables. 2 Q Was Doctor Leigh Thompson 3 working for Lilly while you were there? 4 A Yes. 5 Q Was he there the entire 6 time you were there? 7 A Oh, no. My best 8 recollection is about the last couple of years I 9 was there. 10 Q While you were there, was 11 Doctor Thompson your superior? 12 A Who? 13 Q Doctor Thompson, Leigh 14 Thompson? 15 A Was he there? 16 Q Was he your superior? 17 A He headed up the group, 18 but he would not be my direct -- 19 Q Was he Doctor Shedden's 20 superior? 21 A You know, I don't recall 22 that those two guys were there at the same time. 23 Q Okay. 24 A I don't recall when one 53 1 left and another one came in. 2 Q Do you know when Doctor 3 Shedden left Lilly? 4 A No. I mean yes and no; 5 precisely, no. 6 Q How about approximately? 7 A Well, it would have been 8 after '79 and before '84. 9 Q So he left before you 10 did? 11 A Yes. I apologize to you, 12 but I really can't give you definitive dates on 13 that. 14 Q It's to the best of your 15 recollection, Doctor; that's all I'm asking for. 16 I understand it has been a while. 17 Do you know why Doctor 18 Shedden left Lilly? 19 A Yes, he got into some 20 trouble with flunoxaprofen, an inflammatory drug. 21 I don't know the details, I just know there was a 22 mutual agreement. 23 Q Mutual agreement between 24 Doctor Shedden and Lilly? 54 1 A Yes. 2 Q Is flunoxaprofen Oraflex? 3 A Yes. 4 Q In fact, he was indicted 5 along with Lilly with regards to that drug, 6 correct? 7 A I don't recall the 8 details, but I know that there was heap big 9 trouble. 10 Q Do you know where Doctor 11 Shedden went to after he left Lilly? 12 A He went to the UK. 13 Q Was he from there 14 originally? 15 A Yes. 16 Q Do you know if he's still 17 alive? 18 A No, I don't. 19 Q Did Doctor Thompson take 20 over for Doctor Shedden on fluoxetine? 21 A I knew you were going to 22 ask me that. I don't know. 23 MR. ZETTLER: If you 24 should think of any other questions I should ask, 55 1 let me know, because I know I'm going to miss 2 some. Let's take a quick break. 3 (SHORT BREAK TAKEN.) 4 Q (BY MS. ZETTLER) Doctor 5 Stark, do you know a doctor named Stewart 6 Montgomery? 7 A Yes, I do. 8 Q How did you come to meet 9 Doctor Montgomery? 10 A I first met Doctor 11 Montgomery when he was, I guess, a consultant for 12 Lilly. 13 Q Was that while you were 14 still working with Lilly? 15 A Yes. 16 Q What was Doctor 17 Montgomery a consultant to Lilly about? 18 A I know one of the things 19 he was a consultant on was with regards to Prozac. 20 Q In what way did he act as 21 a consultant to Lilly on Prozac? He's a 22 psychiatrist, correct? 23 A Yes, he is. 24 Q What issues did he 56 1 consult with Lilly on regarding Prozac? 2 A He was, A, an 3 investigator in the UK, and B, he attended 4 meetings at Erl Wood in the UK when we discussed 5 programs or studies to be conducted in the UK. 6 Q When you say discussed 7 programs, you mean seminars or symposia for 8 doctors? 9 A Protocols and so on, he 10 sat in and gave his, quote, expert opinion. 11 Q Do you consider Doctor 12 Montgomery an expert? 13 A If he can be an expert 14 and qualify, if I can disagree with him from time 15 to time, yes. 16 Q Have you had 17 disagreements with Doctor Montgomery regarding 18 Prozac? 19 A No. 20 Q Have you had 21 disagreements with Doctor Montgomery on 22 psychiatric issues? 23 A Yes. 24 Q What issues? 57 1 A Whether anxiety and 2 depression are one and the same illness. 3 Q Did you have those 4 discussions or debates back when you were working 5 for Lilly? 6 A No. 7 Q When did you have that 8 discussion or those discussions? 9 A Within the past couple of 10 years in Shepherd's Market. 11 Q Who thought it was and 12 who thought it wasn't one and the same? 13 A Well, he never was quite 14 adamant, he sort of thought that it was very much 15 like the same; I felt that they were very much 16 like not the same, but overlap. 17 Q But they could overlap? 18 A Yes, I think there's a 19 lot of violence, if you look at a Hamilton Anxiety 20 and a Hamilton Depression Rating Scale, you'll 21 find there is commonality. But then again 22 Hamilton wrote both of them, so -- 23 Q So there should be. 24 A Yes. 58 1 Q Were you ever at Erl Wood 2 when Doctor Montgomery attended meetings regarding 3 Prozac? 4 A Yes. 5 Q When is the first 6 occasion that you can recall that Doctor 7 Montgomery was at Erl Wood to discuss Prozac? 8 A Sometime after 1979. 9 Q And before 1984? 10 A Yes. 11 Q Do you recall, not the 12 date necessarily, but what the occasion of the 13 meeting was? 14 A In general, we were 15 discussing protocols and attempting to have 16 greater commonality; and in particular we were 17 discussing the Hamilton Depression Rating Scale. 18 In the UK they tended to use the first seventeen 19 items, whereas in the United States we tend to use 20 all twenty-one items. In order to have ability to 21 have more common data, we were discussing whether 22 it was feasible indeed to take all twenty-one of 23 the UK and they could still record their 24 seventeen, and indeed it turned out, yes, of 59 1 course. 2 Q So you ended up using the 3 twenty-one? 4 A Yes. 5 Q How about the MADRS 6 scale? 7 A At that time we were not 8 using the MADRS. 9 Q Is that Doctor 10 Montgomery's scale? 11 A Yes, Stewart Montgomery 12 and Marie Osgood. 13 Q Had it been developed at 14 that time, the MADRS? 15 A Yes. 16 Q Why didn't you use the 17 MADRS then? 18 A It was very, very early 19 on at that time and it hadn't really been 20 advocated and so on. You know, even today I think 21 in the United States, the Hamilton Depression is 22 still taken by the FDA as the primary rating 23 scale. 24 Q While you were at Lilly, 60 1 what studies had Doctor Montgomery performed or 2 was he working on? 3 A I don't recall 4 precisely. I would not have been so intimately 5 involved with his stuff accept I knew that he was 6 an investigator. I don't recall that he ever did 7 anything that could be considered a pivotal type 8 study or anything like that. 9 Q What's your definition of 10 a pivotal study? 11 A I consider a pivotal 12 study as that which has a large enough N, number 13 of patients, is placebo controlled, and may or may 14 not have a comparator drug in it, so that any data 15 that are generated from it would not be considered 16 chance, but of an adequate entity. If you do a 17 study with one patient, of course, you've got 18 perfect data, so -- 19 Q You said a large enough 20 end number of patients? 21 A N, as in number of 22 patients, number of subjects. 23 Q Oh, N, not E-N-D, N as in 24 Nancy. 61 1 Had any studies that you 2 would consider pivotal been performed at Lilly on 3 fluoxetine while you were there? 4 A Yes. 5 Q Can you tell me about 6 those studies generally? 7 A Most of the program that 8 I participated in. 9 Q But do you recall a 10 study, a large multicenter study being conducted 11 while you were there comparing placebo, imipramine 12 and fluoxetine? 13 A I recall that I did such 14 a study, yes. 15 Q Do you recall how many 16 sites participated in that study? 17 A (WITNESS MOVES HEAD FROM 18 SIDE TO SIDE.) 19 Q Do you recall if Doctor 20 Feighner was one of the clinical investigators on 21 that study? 22 A I don't know if he was on 23 that particular study, but Doctor Feighner 24 definitely did some studies for us. 62 1 Q How about Doctor Fabre? 2 A Yes. 3 Q Was he on that study? 4 A I don't know if it was 5 that study. I ran several protocols, so I can't 6 specifically tell you who did what. 7 Q Do you recall Doctor 8 Montgomery either writing for or performing a 9 study on fluoxetine using weekly dosing after 10 loading, early loading? 11 A All I recall is him 12 raising the question one time, in a conversational 13 scientific approach, could this be done, you know, 14 like because of the half life, is this feasible. 15 That's the extent of my recollection of anything 16 ever coming from it was that conversation taking 17 place. 18 Q To your knowledge, 19 was such a study considered by Lilly? 20 A If you mean considered, 21 did they listen and hear him, I'd say yes, because 22 I recall it just now when you asked me the 23 question. 24 Q How about was it debated 63 1 in committee or investigated, there was a protocol 2 drawn up? 3 A I can't answer that for 4 you, I don't recall. 5 Q What was your opinion on 6 whether or not such a study was feasible? 7 A My opinion was probably 8 not. 9 Q How come? 10 A Just because of the fact 11 that until such time as one can show that more 12 than just blood levels are the basis for the 13 activity, and the best example I can give you is 14 benzodiazepines where it must be taken on a 15 regular basis for its true axiolitic effect, even 16 though you can detect it in the blood days after a 17 single dose. But just empirically, there is 18 nothing that said that that would be so and you 19 would have to address that, even including some of 20 the tricyclics where regular dosing is considered 21 preferable. 22 Q Have you ever heard of 23 the phrase parasuicide? 24 A What? 64 1 Q Parasuicide? 2 A No, not that I recall. 3 (STARK EXHIBIT NO. 3 MARKED FOR 4 IDENTIFICATION.) 5 Q Before you read that, let 6 me ask you a couple of other follow-up questions 7 real quick. What other issues did Doctor 8 Montgomery consult with Lilly on regarding Prozac, 9 to the best of your recollection? 10 A I don't know; I just 11 don't know. 12 Q Do you recall attending 13 any other meetings at Erl Wood or here in the 14 United States, or anywhere else? 15 A I was never involved with 16 anything other than Prozac with Stewart. 17 Q I'm sorry? 18 A I was never involved with 19 Stewart in anything other than Prozac, that I can 20 recall. 21 Q But I mean with regards 22 to Prozac, do you recall any other areas that 23 Doctor Montgomery consulted with Lilly on, on 24 Prozac? 65 1 A Not while I was an 2 employee there. 3 Q Do you recall attending 4 any other meetings where Doctor Montgomery was 5 present regarding Prozac while you were an 6 employee? 7 A There was more than one, 8 but the one that I remember the most was that one, 9 because I remember that one at Erl Wood, and I 10 can't tell you where even. 11 Q Have you worked with 12 Doctor Montgomery on fluoxetine since leaving 13 Lilly? 14 A Not on fluoxetine with 15 Doctor Montgomery, no. 16 Q Have you worked with him 17 with regards to other drugs that your company has 18 worked with? You don't have to give me the names 19 of the drugs. 20 A It depends on how you 21 mean worked with him. 22 Q Has he run a clinical 23 trial under your direction? 24 A No, he's not been an 66 1 investigator for us in any of the studies we've 2 conducted. 3 Q Have you consulted with 4 him on psychiatric issues related to any other 5 drugs that your company has worked with? 6 A Yes; he is a part of our 7 company, actually. He is a senior consultant with 8 our firm in Europe. 9 Q Was he a senior 10 consultant for Feighner, before you became 11 involved with Feighner, Feighner's company? 12 A Not that I'm aware of; I 13 think they're peers. 14 Q Have you discussed 15 fluoxetine with Doctor Montgomery at any time 16 after you left Lilly? 17 A I would have to say I'm 18 sure I did, but I don't recall what, just because 19 of the fact we know each other and we've talked. 20 I don't know where the conversations go, but I'm 21 sure it happened; I just can't tell you what it 22 was or where it was or when it was. 23 Q Has Doctor Montgomery 24 been a consultant to any drug advisory committee, 67 1 FDA drug advisory committee that you are aware of 2 on drugs that you worked with, besides fluoxetine? 3 A Not that I recall that he 4 was on. Never on any advisory committees, did you 5 mean a consultant to or on the advisory -- 6 Q Right, consultant to. 7 A I would not know of that 8 very accurately, actually. 9 Q Did you attend the 1991 10 advisory committee meeting on fluoxetine and other 11 antidepressants and the occurrence of suicidal 12 ideations? 13 A No, I didn't. 14 Q Were you invited to? 15 A No. 16 Q Did you want to? 17 A Probably not. I was 18 probably too busy then, our company was busy 19 working. I only go to some meetings. 20 Q You just like to go to 21 the ones in Europe, right? 22 A Well, that's not bad. 23 MS. ZETTLER: Go ahead 24 and take a look at, I believe, Exhibit 3. 68 1 (SHORT BREAK TAKEN.) 2 Q (BY MS. ZETTLER) Have 3 you had a chance to review Exhibit 3? 4 A I'm sorry. 5 Q Have you had a chance to 6 review Exhibit 3? 7 A Partially, yes. 8 Q If you need to refer back 9 to it at any time to answer any of my questions, 10 that's fine, okay? 11 A Yes. 12 Q Exhibit 3 purports to be 13 meetings from the Clinical Projects Review 14 Committee? 15 A Yes. 16 Q Do you recall the 17 Clinical Projects Review Committee? 18 A I recall its existence, 19 yes. 20 Q What was its purpose, 21 other than the obvious purpose from the title? 22 A Well, it was primarily 23 management getting together to review ongoing 24 activity. 69 1 Q Exhibit 3 purports to be 2 minutes from a meeting held on October 4, 1983, 3 correct? 4 A Yes. 5 Q You are listed as a 6 recipient of a copy of the meeting minutes, 7 correct? 8 A That is correct. 9 Q Did you attend Clinical 10 Project Review Committee meetings? 11 A Some of them, yes. 12 Q For what purposes would 13 you attend a particular meeting? 14 A If they were discussing 15 fluoxetine, or that part of that meeting, because 16 usually there would be several items, you were 17 invited in. 18 Q Okay, and did you attend 19 all of the meetings where fluoxetine was 20 discussed, to the best of your knowledge? 21 A I can't -- I would guess 22 most. 23 Q What would be your 24 general purpose to be there during those meetings, 70 1 to give them information? 2 A To answer questions, if 3 they asked them. 4 Q Do you recall being at 5 this particular meeting in October of 1983? 6 A No. You would have never 7 gotten such a chuckle from me if I did. 8 Q On the first page of the 9 actual minutes, the second page of the 10 exhibit -- 11 A Yes. 12 Q -- it states that Earleen 13 Ashbrook briefly discussed special fluoxetine 14 studies by the CPRC, which is, I take it, the 15 Clinical Projects Review Committee? 16 A Yes. 17 Q And then under that is 18 Doctor Kusmierek? 19 A Yes, Jacque Kusmierek, 20 you refreshed my memory. 21 Q Concentrated on the 22 status and plans of the European clinical 23 programs, correct? 24 A That's what it says here. 71 1 Q Who is Jacque Kusmierek? 2 A He was a medical director 3 that -- 4 Q From Lilly France? 5 A Well, he came over to the 6 US, which is where I know him from. He was in 7 Lilly France for a while and then came over to 8 Indianapolis. 9 Q And, I take it, he was 10 medical director during this period of time? 11 A Well, I don't know. I 12 don't know what his role was -- at what time he 13 was where. He had both positions, though, in the 14 course of after '79 and before '84. 15 Q How about Doctor 16 Schulze-Solce; do you remember Doctor 17 Schulze-Solce? 18 A No. I don't recall him 19 is what I would rather answer you. Anymore, I'm 20 going to be very careful what I say. 21 Q After that introductory 22 paragraph, it says the discussion at the Clinical 23 Projects Review focused on the following points, 24 and lists nine points on the next two pages, or 72 1 that page and the next page, correct? 2 A Yes, several pages. 3 Q Point No. 4, it says, 4 blank, "is conducting a study in patients with 5 Major Depressive Disorder, giving fluoxetine 6 either once weekly or daily versus amitriptyline," 7 correct? 8 A That is correct. 9 Q Does that refresh your 10 recollection as to whether or not a study was 11 actually conducted, a weekly dose, in the study on 12 fluoxetine? 13 A Would you believe no? 14 Q Do you know, if such a 15 study was done, would there have been anybody but 16 Doctor Montgomery who would have performed it? 17 A I can't tell you. 18 Q If you turn to the fourth 19 from the last page of the exhibit, which would be, 20 if you look on the lower right-hand corner, Pz1124 21 910? 22 A I am there. 23 Q Okay. At the top of the 24 page it says "weekly dosing", correct? 73 1 A Yes. 2 Q Under that it says, 3 "Potential difficulties from positive Montgomery 4 result," do you see that? 5 A Yes, I do. 6 Q Would it be fair to say 7 that Doctor Montgomery is the one that was 8 performing the weekly dosing study that's referred 9 to on the second page of Exhibit 3? 10 A I would have to only go 11 so far as to say probably. The reason I'm saying 12 that is because, in all fairness, he does do 13 consulting for many firms and does review and 14 write up a summary report for them. I know that 15 he does that to this very day. So, whether he did 16 that for Lilly or did the study, I can't answer 17 you precisely. 18 Q What do you mean by a 19 summary report? 20 A Take the data and put it 21 together, and statistically and professionally 22 analyze the date generated. If Doctor Smith, a 23 cohort of his, did the study -- Smith, by the way, 24 is a fictional name, Paul excluded -- he might 74 1 then take the data and prepare it as a consultant 2 for a drug firm, so that's why I can't answer you 3 that you should or should not assume that he did 4 the study. 5 Q So he would do reports on 6 other people's studies as well as his own studies? 7 A That's correct. 8 Q For instance, if Doctor 9 Feighner performed a study on fluoxetine, Doctor 10 Montgomery would, in some cases -- just using 11 Doctor Feighner as an example -- could take the 12 data gathered during his study and put it in final 13 report form or manuscript form? 14 A That's exactly correct, 15 yes. 16 Q Did he do that on all of 17 his own studies, to your knowledge? 18 A I have no idea, I really 19 don't. 20 Q Do you recall any 21 situation where Doctor Montgomery was asked to 22 prepare such a report on studies performed on 23 fluoxetine? 24 A No, I don't recall such a 75 1 request. 2 Q But, to your knowledge, 3 it is his practice to do that on his own studies? 4 A I don't want to say it's 5 his practice; I know that he does do that. 6 Q Do you recall discussing 7 the results of a weekly dosing study at any time 8 during the time you worked at Lilly? 9 A No. 10 Q Do you recall discussing 11 whether or not it would be practical to perform 12 such a study on fluoxetine? 13 A I don't recall that we 14 did. But if your question is do I recall 15 discussing whether it was practical, almost 16 anything is practical if you use enough 17 imagination, but, no, I don't recall. 18 Q Do you recall ever 19 discussing the pros and cons of doing such a study 20 from a marketing point of view? 21 A I don't recall discussing 22 it. I recalled to you before that the 23 conversation had come up, but I can't give you any 24 kind of detail. I just can't conjure it up for 76 1 you. 2 Q If such a study were 3 performed in the United States, you would have 4 been a clinical monitor on that study, would you 5 not? 6 A Before 1984, yes. 7 Q And if such a study was 8 performed in Europe, would you have been a 9 clinical monitor on that? 10 A No. 11 Q If such a study was 12 performed in the UK, who would have been the 13 clinical monitor back then? 14 A I can picture him, but I 15 can't recall his name. 16 Q Patrick Keohane? 17 A No. Black straight hair, 18 about six foot tall. 19 Q English accent? 20 A Absolutely. 21 Q Regardless, it appears 22 that a study on weekly dosing was conducted on 23 fluoxetine during this period of time, whether or 24 not it was completed at this time or not is -- 77 1 A This document would 2 suggest that. 3 Q Back when you were 4 working for Lilly between 1979 and 1984, was it 5 Lilly's practice to submit to the FDA final 6 reports on all studies it conducted on fluoxetine? 7 A I can't answer. 8 Q Did you have any 9 responsibility with preparing final reports on 10 clinical trials to be submitted to the FDA? 11 A No. 12 Q Who would have done that 13 back then? 14 A Someone in regulatory. 15 Q Would you have 16 responsibility to help them gather, analyze data 17 to be used in those final reports? 18 A Probably certain aspects 19 of it I would be asked questions of, like you 20 asked me of my relationship with Dottie Dobbs, I 21 think she may have come into my office or I would 22 have walked into hers and she asked a question. 23 Did I sit down and was part of a group, no. 24 Q Do you know, did Doctor 78 1 Dobbs leave before or after you left Lilly? 2 A I can't recall 3 precisely. It was really very close around there, 4 but I can't recall precisely when she left. 5 Q Do you recall ever having 6 any disagreements with Doctor Dobbs as to any 7 aspects of the work being done by Lilly on 8 fluoxetine? 9 A Ask me the question 10 again. 11 Q Do you recall having any 12 disagreements with Doctor Dobbs regarding the work 13 being done by Lilly in preparation for submitting 14 the fluoxetine NDA, for instance? 15 A No, because I didn't 16 participate in much of it. I participated only in 17 day-by-day type things that went on, and I've had 18 disagreements with everybody, never -- I had very 19 few quarrels. 20 Q Do you recall Doctor 21 Dobbs having any quarrels, to use your word, with 22 anybody at Lilly with regards to Lilly's work on 23 fluoxetine? 24 A No. 79 1 Q Other than Doctor 2 Montgomery, who was a consultant to Lilly on 3 fluoxetine during the time that you worked there? 4 A John Feighner. That was 5 near the latter part. 6 Q Anybody else? 7 A I just can't recall 8 people who were consultants at that particular 9 point in time. You know, a lot of stuff -- I'm 10 sorry, but a lot of stuff does just merge 11 together. In '84, when I left, also I worked with 12 a whole bunch of pharmaceutical firms and everyone 13 had different groups, and that's all I can give 14 you that I can recall. 15 Q Okay, but Doctor Feighner 16 and Doctor Montgomery you do recall? 17 A Yes. 18 Q How about Doctor Winokur? 19 A He's in Iowa. 20 Q Right. 21 A But I don't recall that 22 he was a consultant for Lilly. I only know of 23 him, and I've been at meetings with him, but I 24 don't recall him as a consultant. 80 1 Q How about Jan Fawcett? 2 A Chicago. I don't know if 3 he was a consultant. 4 Q Have you met Doctor 5 Fawcett? 6 A Oh, yes, I know him; 7 still know him to this day. 8 Q Do you recall -- I know I 9 interrupted your answer, and I apologize, but do 10 you recall Doctor Fawcett being a consultant for 11 Lilly while you were there? 12 A I don't recall him as a 13 consultant. 14 Q How about David Dunner? 15 A I don't recall him as a 16 consultant for Lilly while I was there. 17 Q Do you know where he 18 lives? 19 A Yes, Seattle. 20 Q How about Doctor 21 Goldstein, was he ever a consultant for Lilly 22 while you were there? 23 A No. 24 Q How about Professor 81 1 Herrmann from Germany? 2 A Who? 3 Q Professor Herrmann. We 4 don't have his first name, unfortunately. 5 A I don't recall at all. I 6 don't even recall the name. 7 Q What types of things did 8 Doctor Feighner consult with Lilly about while you 9 were there? 10 A Specifically, I can't 11 really recall. 12 Q Generally is fine. 13 A In generalities, we'd 14 discuss patients, his experience with his 15 patients, global impressions, which is a very 16 important evaluation if you have a good 17 psychiatrist. PGI is very important, or the CGI 18 is very important in their patient, and globals. 19 You know, he's been in the business for more years 20 than he cares to admit, and so he's had an awfully 21 lot of empiric experiences that he can relate to. 22 He's looked at a very significant number of drugs 23 for pharmaceutical industries. He's a smart guy. 24 Q And he lives in -- 82 1 A San Diego. He's my 2 partner. 3 Q I know that. When you 4 say he consulted about his patients and the global 5 impressions, the PGI and the CGI, are you talking 6 about with regards to his specific patients or PGI 7 and CGI generally? 8 A I can't answer you 9 specifically. I just -- you just specified your 10 question and I got tripped up. 11 Q So you don't recall 12 whether or not he consulted with Lilly regarding 13 the PGI and CGI outside of his own patients? 14 A No, I don't. 15 Q How about what scales to 16 use in the protocols, like the HAMD or PGI or CGI, 17 did he ever consult with Lilly on which scales 18 should be included in the clinical trials? 19 A I consulted with him 20 before we started the program, but that's about 21 the extent of it. 22 Q What did you and Doctor 23 Feighner discuss before you started the program? 24 A When is too much too 83 1 much, too many scales; you start getting 2 inaccurate answers if you go too far. 3 Q What is too much? 4 A Well, when a physician 5 and a patient would keep going and going. A good 6 example I can give you is the SCL-56 is more 7 popular than the SCL-90. People started finding 8 that after about the sixtieth question the 9 patients just check them all the same and say I'm 10 done. So, the SCL-56 could accurately give you an 11 answer and the patient's attention would be 12 maintained. 13 Q So, it's not so much the 14 number of scales that are administered, but the 15 length of the scales themselves? 16 A Yes, and also there are 17 an infinite number of scales that one can use, but 18 if they don't really tell you something, are you 19 merely padding data being generated. 20 Q Do you recall 21 consideration being given to including a scale 22 specific to suicidal ideation? And I mean outside 23 the HAMD-3. 24 A No, I have to admit that 84 1 at that time I don't recall that there was 2 anything that one could very specifically use 3 other than the HAMD series test for suicidal 4 ideation, you know, as to how much they went on 5 and so on. 6 Q Are you saying you don't 7 recall if any other scales existed at that time? 8 A I don't recall of any at 9 that time at all. 10 Q How about the Beck? 11 A The Beck? 12 Q Yes. 13 A I only know the Beck 14 scale that was used in general, but not in 15 particular. 16 Q How about the Adult 17 Suicidal Ideation Questionnaire, to your knowledge 18 was that in existence? 19 A I was not familiar with 20 it at that time at all. 21 Q Other than discussing 22 when is too much too much with Doctor Feighner, do 23 you recall any other discussions you had with him 24 with regards to putting together the protocols? 85 1 A We discussed inclusion, 2 exclusion type of criteria, make sure that when 3 you write things down had you addressed all the 4 things that ought to be done. One has to address, 5 if you have a tricyclic together with a serotonin 6 reuptake inhibitor, the inclusion, exclusion 7 criteria has to be broadened somewhat. As an 8 example, for narrow angle glaucoma, you wouldn't 9 want to have such patients not addressed if you 10 use tricyclic antidepressants. 11 Q Do you recall bipolar 12 patients being excluded from the major depressive 13 disorder trials? 14 A From some of them. 15 Q Do you know why that was 16 done? 17 A I'm sorry? 18 Q Why was that done? 19 A Well, at that particular 20 time, we wanted to know whether we were doing a 21 major depressive disorder, but I did conduct a 22 study in bipolar patients though. 23 Q Is that the study that 24 was done by Doctor Cohn? 86 1 A You asked me a question I 2 thought I was going to answer you Dunner. 3 Q Dunner? 4 A Yes, but at this point in 5 time I trust you more than I trust me on 6 recollection. 7 Q No, I think Joe and Larry 8 told you not to do that. Really, it is the best 9 of your recollection. 10 A Yes. Actually, both 11 those sites could very well have been enveloped, 12 for all I know. I had lots of combinations. We 13 did do a bipolar study, though. 14 Q What were the results of 15 that study, do you recall? 16 A In generalities only, I 17 can recall that it did relieve the depressive 18 symptomatology, there did not appear to be any -- 19 as I recall, any particular exacerbation of any 20 conditions whatsoever. 21 Q Like mania? 22 A Yes, like mania, I guess 23 if that's what you would like me to say, but to 24 the best of my recollection, that did not occur. 87 1 We allowed and did not allow in some cases 2 concomitant lithium to get some impressions. It 3 was not a remarkable study; it was a reinforcing 4 study in the sense you felt good you did it. 5 Q Allowing concomitant 6 lithium, you said you did that in some, but you 7 did not do that in others? 8 A I can't recall. It seems 9 to me that partway through the study there was a 10 modification, but I can't tell you for sure, 11 because I remember many of the physicians or 12 people who went to visit said this is so common, 13 you really want to allow it. 14 Q What was so common? 15 A The use of lithium in 16 bipolar type patients, so we allowed it. 17 Q Did you find any evidence 18 of an interaction between fluoxetine and lithium? 19 A Not that I can recall. 20 Q Was there a problem with 21 mania in the trials where the investigators wanted 22 to use lithium? 23 A No. To the best of my 24 recollection, they had patients who were taking 88 1 lithium and wanted to know if they could be 2 entered because their depressive symptomatology 3 was still there. 4 Q So is it your 5 recollection that people who were on lithium were 6 not excluded, or was it -- was the administration 7 of lithium allowed after the person started on 8 fluoxetine? 9 A I can't recall for you. 10 Q How about -- 11 A In actuality, I know the 12 protocol is a public document, so you could really 13 get all the details. 14 Q But I want to know what 15 you remember about it. 16 A Okay. I'm not hiding it 17 from you, I just don't recall. 18 Q How about serious 19 suicidal risk; why were people who were at a 20 serious risk of suicide excluded from the trials? 21 A Well, because I think 22 that's common practice. It's common practice that 23 you do not allow patients into outpatient studies 24 if they have serious suicidal ideations, because 89 1 if they do have that, serious suicidal ideation, 2 they ought to be on an inpatient study to start 3 with. 4 Q What's your definition of 5 serious suicidal ideation? 6 A I think that becomes a 7 clinical judgment that the patient is at 8 significant risk of attempting suicide, and the 9 other thing, of course, is any recent serious 10 attempt at it. 11 Q What would you consider a 12 recent serious attempt at suicide? 13 A I'm sorry? 14 Q What would you consider 15 recent, when you say recent serious attempt? 16 A That varies usually from 17 company to company; it varies from six months, 18 usually, to one year. 19 Q How about at Lilly, what 20 was considered recent while you were there? 21 A I don't recall. 22 Q How about serious attempt 23 at suicide, what was considered a serious attempt 24 at suicide while you were at Lilly? 90 1 A Serious attempt or 2 serious suicidal -- 3 Q Serious attempt at 4 suicide. We are talking about a serious attempt 5 within six months or a year. 6 A I can't give you complete 7 details, but rather in generalities, any real 8 attempt as opposed to a discussion of. 9 Q So an actual act as 10 opposed to just talking about it? 11 A Yes. 12 Q Would a determination be 13 made as to whether a given act was a suicidal 14 gesture as opposed to, say, a plea for attention? 15 A The psychiatrist would 16 make that determination. 17 Q Were there any guidelines 18 given to the psychiatrists by Lilly with regards 19 to making that determination? 20 A Not to the best of my 21 recollection. 22 Q If you go back to the 23 second page of Exhibit No. 3, Doctor, and Point 24 No. 4. 91 1 A Yes. 2 Q It says, "A validation 3 program is to be discussed by Doctors Bandak, 4 Kusmierek, Lemberger, and Stark." Do you see 5 that? 6 A Yes. 7 Q Do you recall ever having 8 such a discussion with Doctors Bandak, Kusmierek, 9 and Lemberger? 10 A No, I don't. 11 Q Do you know what they 12 mean here when they say "validation program"? 13 A No, I don't. 14 Q Who was Doctor Bandak? 15 A He is from Canada, Lilly 16 Canada. 17 Q How about Doctor 18 Lemberger? 19 A He ran the Phase 1 unit 20 here at the Lilly clinic. 21 Q Do you recall having 22 discussions with Doctor Lemberger about whether or 23 not fluoxetine acted as a stimulating/activating 24 drug as opposed to a sedative drug? 92 1 A No, I don't recall having 2 such conversations. 3 Q The last point in the 4 beginning of the exhibit on the third page, No. 9, 5 it says, "CPR recognizes that fluoxetine will need 6 careful post marketing surveillance on the first 7 10,000 patients." Do you see that? 8 A Yes. 9 Q Do you recall that being 10 an issue while you were there? 11 A No, I don't recall it 12 being an issue. 13 Q Do you recall a post 14 marketing surveillance study being conducted by 15 Lilly or started by Lilly while you were there? 16 A No, I just recall the 17 fact that this was considered as a possibility. 18 This related to the zimelidine. Fifteen thousand 19 patients, I think, were run by people with 20 zimelidine. They were trying to establish whether 21 or not the zimelidine syndrome was for real. 22 Q So fifteen thousand 23 patients were run on zimelidine? 24 A Yes. 93 1 Q Not on fluoxetine? 2 A That's correct. 3 Q Do you know if a post 4 marketing surveillance study was ever done on 5 fluoxetine to look at the zimelidine syndrome 6 question? 7 A No, it would be -- to 8 some extent, it would be illogical to have done 9 that, to look for the zimelidine syndrome since we 10 did run patients who had responded to zimelidine. 11 By showing the symptom, they were switched off 12 successfully, so that there was no reporting of it 13 and patients who had manifested it were 14 successfully treated with fluoxetine without 15 manifesting it, so -- 16 Q But there were at least a 17 couple of patients where the situation was 18 reversed? 19 A There were some, yes. 20 Q In fact, Doctor 21 Montgomery had a couple, didn't he? 22 A That I can't tell you 23 who. 24 Q Back to Page 2. 94 1 A I'm there. 2 Q Would you look under 3 Point 5? 4 A Yes. 5 Q Okay. Do you know if 6 Doctor Montgomery ever did rechallenge those 7 patients on fluoxetine? 8 A No, because I don't 9 recall the thing happening, so -- 10 Q Even though it says the 11 details were to be worked out by Doctors Stark and 12 Kusmierek? 13 A Yes. You're making fun 14 of me now, aren't you? 15 Q No, I'm trying to help 16 you remember, Doctor. 17 A I don't. 18 Q On the next page, under 8 19 it says fluoxetine versus amitriptyline, studies 20 are of little value in the US, do you see that? 21 A Under 8. 22 Q Right. 23 A Am I on the wrong page? 24 Q On Page 894? 95 1 A Yes. 2 Q It says under No. 8, 3 "Doctors," blank, "the intended investigators for 4 the adult dose ranging study ... are unwilling to 5 use a placebo control but would study fluoxetine 6 versus amitriptyline." 7 A Yes. 8 Q "Such studies are of 9 little value in the US." 10 A Okay. 11 Q Do you take that to mean 12 dose ranging studies versus placebo or versus 13 amitriptyline? 14 A Neither. 15 Q Okay. 16 A The absence of placebo 17 would be of little use. 18 Q I see. So if it's just 19 strictly amitriptyline comparing -- 20 A It's interesting, but has 21 no meaning. The FDA wouldn't -- 22 Q You can't use it as 23 pivotal study? 24 A That's correct. 96 1 Q Do you know if a 2 fluoxetine-placebo-amitriptyline study was ever 3 conducted here in the United States? 4 A I don't know so, but I 5 believe so. 6 Q On the next page it says 7 special fluoxetine studies, do you see that? 8 A Yes. 9 Q The first study listed is 10 MDD, no code break, do you see that? 11 A Yes. 12 Q What is the no code break 13 study? 14 A I can't answer you for 15 sure. 16 Q Give me the best of your 17 recollection. 18 A Not even to the best of 19 my recollection, it would be a presumption. There 20 were -- when we had extensions, at the end of the 21 first six-week period, there would be a code break 22 after the physician told you what the patient's 23 Hamilton depression scale was at the start and 24 what it was at the end, because if they had had a 97 1 response, they were allowed to continue on open 2 label, a humanitarian type of thing. Then the 3 question came up, Paul Leber said, well, you know, 4 these guys could remember all their patients for 5 the past year and you might be able to be telling 6 them something like this, I don't like you guys 7 doing this code break thing, he said I don't think 8 it's a true double blind, so we said, yes, sir. 9 And as I recall, we then just said we're not going 10 to do any code breaks, and one of the things that 11 was done is we just maintained the blind for a 12 while and allowed them whatever they were on, they 13 stayed on, but I think we eventually just 14 discarded those as being a unwieldy monster. 15 That's to the best of my recollection, I do want 16 to qualify that for you, because I've done so many 17 of these protocols, since even, that I don't know 18 who belongs to what. 19 Q Do you recall Doctor 20 Leber becoming at some point satisfied that the 21 blind was not broken on the other studies? 22 A Yes, I think -- to the 23 best of my recollection, I really don't want you 24 guys doing this, I'm not going to throw anything 98 1 out, and to the best of my recollection nothing 2 was thrown out, because those were some of my 3 original pivotal studies and they stood up after I 4 left the company. I know they stood up because 5 they went in and the drug was approved, but I 6 bumped into this afterwards, and I'm quite 7 familiar, all of the other drugs firms had to 8 address that question later on. 9 Q To make sure I 10 understand, at some point in time after you 11 started the no code break study, Doctor Leber said 12 you don't have to do it and I'm convinced now that 13 the blind is true and the pivotal studies -- 14 A I don't think he ever 15 made such a statement. 16 Q Okay. 17 A Paul Leber has never made 18 a mistake in his life. 19 Q Okay. 20 A I think that we just -- I 21 think the industry, in general, has stopped 22 breaking code under any circumstances and just 23 find other ways of doing it, of doing the studies. 24 Q Okay. 99 1 A But he never -- he just 2 never threw out the other stuff. It was a 3 preference, we did adhere to it, and everyone 4 still adheres to it to this day, and that was it. 5 Q So nobody breaks blinds 6 anymore? 7 A Not until the end of a 8 study, or else what you do today is you carry all 9 your patients on. 10 Q Just keep them on 11 whatever drug they're on if they're responding 12 without breaking the blind? 13 A That's correct. Or the 14 other way today is to just, at the end of the 15 study, if a patient is a nonresponder, they're 16 given the opportunity to go on the new drug if 17 they choose to, so that they didn't draw a short 18 straw, so to speak. 19 Q How do you then compile 20 data for the final report on efficacy if you never 21 break the blind, for instance? 22 A We don't do it until the 23 very end of the study. 24 Q Right, but if you're at 100 1 the end of, say, the six-week period study and you 2 want -- 3 A Oh, at the end of that 4 time, that doesn't matter. Once the last patient 5 has completed and is finished, then you just go 6 ahead and proceed and do your analysis on that, 7 and it's done prospectively. Your protocol says 8 that this is a six-week study. 9 Q So at the end of six 10 weeks, the study is over, you break the blind, and 11 then you can do your analysis? 12 A That's correct. 13 Q And that was what you 14 were doing before, was it not? 15 A We broke the blind as the 16 patients completed before the whole study was 17 completed, before every patient had finished. As 18 the patient's turn came up, you couldn't just drop 19 them and let them sit around for three months, and 20 so they would be Patient No. 27 -- 21 Q I see. So if you'd have 22 Patient No. 1 through 10 would start on, say, July 23 1st, and they would run for the next six weeks, 24 but then you would have other patients who would 101 1 be started on the drug a month later -- 2 A So the physician then 3 would call you and give you the starting HAMD, the 4 baseline, the concluding one, if the response was 5 appropriate, then by consensus they were allowed 6 then to continue or to get the new drug, or they 7 were offered a chance to switch. 8 Q Doctor Leber's concern 9 was if you are breaking the blind on the earlier 10 patients, then you would get kind of an insight as 11 to what type of side-effect profile or -- 12 A His concern wasn't with 13 the pharmaceutical industry, his concern was with 14 the investigator, that he would remember, of the 15 hundred and twenty patients, what the other -- he 16 would think of what the others might be getting. 17 You never questioned the integrity of the drug 18 firms, he assumed they were blinded. 19 Q But I just want to make 20 sure I understand what his concern was. His 21 concern was if you broke the blind on Patients 1 22 through 10 before Patients 11 through 20 were 23 completed, then the investigator would have some 24 sort of insight as to -- 102 1 A He might have some 2 biases, correct. 3 Q Please let me finish my 4 question. She can't take us both down at the same 5 time. 6 A I apologize. 7 Q I'm trying to slow down 8 and now it's going to take longer for me to get my 9 question out. 10 Just so I understand, 11 Doctor Leber was concerned that if the 12 investigator broke the blind on Patient 1 through 13 10, then he or she would have some sort of insight 14 as to what drugs Patient 11 through 20 may be on 15 because of looking at the data collected on 16 Patients 1 through 10 with regards to efficacy, 17 side effects, whatever, is that fair? 18 A That's close. He felt 19 that they might; he recognized the fact that that 20 was farfetched, in all fairness to him. 21 Q But now, or at least when 22 you left Lilly -- and you know the industry 23 because you work in the industry still -- now 24 everybody in the industry waits until everybody is 103 1 completed before you break the blind? 2 A That's correct. 3 Q And this was all changed 4 because of Doctor Leber's preference? 5 A Yes, ma'am. 6 Q He's a very powerful man, 7 isn't he? 8 A Yes, ma'am. 9 Q Is he as powerful as 10 Doctor Temple? 11 A Oh, that's his boss, so, 12 you know. 13 Q How about Carl Peck, who 14 is Carl Peck? Have you ever heard of Carl Peck? 15 A Yes, Bruce Peck at Lilly, 16 Carl Peck was at FDA. 17 Q Were they related? 18 A I don't think so. 19 Q At one time did Doctor 20 Dobbs hold the same position as Doctor Leber holds 21 now with the FDA? 22 A Oh, I don't know. I 23 don't believe so. She worked at FDA, but I think 24 Ron Karzinel came before Paul Leber. 104 1 Q She did work in the 2 psychopharmacological division, did she not? 3 A I can't even say for 4 sure, but considering her background, I would have 5 to guess so, but I know she was at the FDA. 6 That's as much as I can say precisely. 7 Q Is it your understanding 8 that before Doctor Leber's edict came down about 9 the no code break, that the industry would allow 10 further code breaking on earlier patients across 11 the board, or was it just a Lilly practice? 12 A I don't know the answer. 13 MS. ZETTLER: Let's take 14 a break. 15 (SHORT BREAK TAKEN.) 16 Q (BY MS. ZETTLER) On 17 either of the studies that you performed on 18 fluoxetine after you left Lilly, did you include 19 any scales to measure suicidal ideation other than 20 the HAMD-3? 21 A Not that I recall. 22 Q How about any scales 23 specifically to measure violent aggressive 24 behavior, hostility, and things of that nature? 105 1 A I don't recall having any 2 special scales for that. 3 Q Would you look at Page 4 Pz1124 898? It looks like it's about five or six 5 pages there. 6 A 890? 7 Q 898? 8 A Oh, 898. 9 Q I think it's closer to 10 the front. If it helps you, it's Page 6 of the 11 meeting minutes, it's up at the top. 12 A Yes, ma'am. 13 Q What is the core 14 protocol? 15 A To the best of my 16 recollection, those were the efficacy and safety 17 in major depressive disorder, and other variations 18 on it, just the basic efficacy for pivotal 19 studies. 20 Q In major depressive 21 disorder? 22 A Correct, to the best of 23 my recollection. 24 Q Would those be -- the 106 1 core protocol, would that be considered the 2 pivotal studies protocol? 3 A That, to the best of my 4 recollection, would be essentially it. 5 Q So you would have a 6 fluoxetine placebo arm at least, and then if you 7 had a comparator, you could actually plug in the 8 comparator, correct? 9 A That's correct. 10 Q Did you develop that 11 protocol? 12 A I developed the protocols 13 that were used between '79 and '84. 14 Q And since this is October 15 of '83, can we assume that you developed what 16 they're referring to as the core protocol? 17 A In the United States, 18 yes. 19 Q Do you know a Doctor 20 Menarini, M-E-N-A-R-I-N-I, in Italy? 21 A No. 22 Q Does that ring a bell, a 23 Doctor Menarini? 24 A No. 107 1 Q Do you recall discussions 2 of any kind about conducting a clinical trial on 3 patients who were suicidal and fluoxetine? Not 4 because of fluoxetine or anything like that 5 necessarily, but any study at all that you can 6 recall while you were at Lilly being discussed 7 where fluoxetine was to be given to, for instance, 8 somebody who was actively suicidal? 9 A I can only answer you 10 generically because I can't recall when the 11 inpatient study was or was not run. If an 12 inpatient study was run, then the patients may be 13 seriously suicidal. 14 Q So that was not 15 necessarily an exclusion criteria in the inpatient 16 study? 17 A For an inpatient study, 18 that would not have been. I can't place whether 19 it was fluoxetine or some other drug that I did 20 this after I left, I'm terribly sorry. 21 Q But other than the 22 possibility of seriously suicidal patients being 23 included in an inpatient study -- or not excluded 24 I guess would be a better phrase. 108 1 A Okay. 2 Q Do you recall any studies 3 being discussed at Lilly, while you were there, to 4 study the treatment of suicidality with 5 fluoxetine, for instance? 6 A I do not recall such 7 discussions. 8 Q If you could look at the 9 last page of Exhibit 3. 10 A Okay. That's your 11 parasuicide, isn't it? 12 Q Uh-huh. It says other 13 trials at top of the page, do you see that? 14 A Yes. 15 Q Do you recall studies 16 being discussed relating to suicide or parasuicide 17 as it's written on the page? 18 A No. I still don't know 19 what parasuicide is, actually. 20 Q How about anxiety, do you 21 recall any studies being discussed to treat 22 patients who were suffering from anxiety with 23 fluoxetine? 24 A I think that was a 109 1 discussion as another perhaps potential use for 2 the drug. That's all that I recall at that 3 particular time. I'm sure you know that from the 4 data, and I'm sure it has to do with the overlap, 5 but the anxiety component diminished in the 6 depressed patients, as well as their depression. 7 I can't tell you whether that was because of 8 commonality and overlap or not, but I do recall, 9 when I presented the data in Montecatini, that 10 that was an observation. 11 Q Do you recall Lilly 12 wanting to list in the package insert that 13 fluoxetine was indicated for use in treating 14 depression as well as anxiety related to 15 depression? 16 A I recall that discussion. 17 Q Do you recall any 18 disagreement by the FDA with regards to listing 19 the depression related anxiety or the anxiety that 20 may be occurring with depression as an indicated 21 use for fluoxetine? 22 A I can't place it in time, 23 but generically the FDA has opposed that, as well 24 as for anxiolytics to be used for depression. The 110 1 best example I can give you is an Upjohn product 2 where they had not bad data with depressed 3 patients. 4 Q So that the FDA is 5 against using anxiolytics for treatment of 6 depression? 7 A If they do an individual 8 study on individual patients and exclude the 9 others, and I don't know that anyone has quite 10 mastered that as yet, but the fact is there was a 11 diminution in the anxiety component of the SCL and 12 one other factor on patients, depressed patients, 13 and it -- the fact of the matter is, the anxiety 14 component in depressed patients did diminish. So, 15 I don't find that an unreasonable thought. I 16 don't know what happened after I left, but that 17 concept strikes me as purely logical. 18 Q Do you recall a 19 disagreement by the FDA that the anxiety actually 20 did diminish with fluoxetine as opposed to 21 increase? 22 A I don't recall that. 23 Q Do you differentiate 24 between agitation and anxiety? 111 1 A Do I? 2 Q Yes. 3 A Yes, I do. I don't know 4 if anyone else does. 5 Q Fair enough. How do you 6 define anxiety in a patient? 7 A You're getting into now a 8 very personal type of thing that is without 9 medical foundation since I do not have an MD. 10 Q Right, I'm asking for 11 your opinion within your qualifications as a 12 relative lay person as far as psychiatry goes. 13 A I think a person can be 14 anxious without being agitated. 15 Q Can a person be agitated 16 without being anxious? 17 A Yes, I get agitated 18 oftentimes. 19 Q How do you define 20 it? Like today, right? Or at least when Paul 21 asks you questions. 22 A Yes, it wasn't you at 23 all, it was Paul. 24 Q Thank you. What is your 112 1 definition of anxiety? 2 A To me, anxiety is 3 comprised of a variety of things. I think the 4 Hamilton Scale does very well on that in the sense 5 that -- since I'm allowed lay terms, they feel 6 relatively antsy. 7 Q Okay. 8 A I think the person feels 9 a degree of apprehensiveness, oftentimes with 10 intestinal type of problems associated with it, 11 even, if you will, tightness in the stomach, the 12 reporting of insomnia, and that's -- you asked me 13 the term nervousness, agitation, you tried tying 14 me into those, and you really can't because, you 15 know, it's a very subjective type of thing. I 16 don't know what you feel, but I can have a degree 17 of nervousness without being agitated at all, 18 feeling belligerent. I can't speak for you, of 19 course. 20 Q We haven't known each 21 other long enough, have we? 22 A We'll work at it. 23 Q What is your definition 24 of agitation? 113 1 A It is a mixed component, 2 in my mind, of anger, activity, if you will, 3 inability to stay put because of the anger, 4 upsetedness. It could be upsetedness as well as 5 anger, I suppose, I try to be subjective about it. 6 Q Irritability? 7 A My guess is if you're 8 agitated, you would be irritated, but I think 9 irritability has a rather broad potential 10 interpretation, and I wouldn't presume to try to 11 define it precisely. 12 Q Okay. Earlier I think 13 you said that you felt that agitation and 14 nervousness were similar? 15 A Uh-huh. 16 Q Do I remember that 17 correctly? 18 A It could be. 19 Q Is it fair to say that 20 one doctor may look at a patient who is exhibiting 21 symptoms and call it agitation, and another doctor 22 may look at that same patient and call it anxiety? 23 A As you phrased the 24 question, the answer is yes; you asked if it was 114 1 possible. 2 Q Do you find that that 3 happens? 4 A Well, it's my impression 5 that if you have competent, experienced 6 psychiatrists, that they usually ask enough 7 questions before they make up their mind as to 8 what symptom they would presume it to be, and I'm 9 sure that varies from psychiatrist to 10 psychiatrist, and therefore, in answer to your 11 question, yes, it's possible. I think it's more 12 likely that they'll have a greater degree of 13 agreement than disagreement, but I'm sure there's 14 got to be some disagreement. I think it's 15 impossible any other way on a theoretical basis. 16 Q How about a general 17 practitioner? 18 A I think a practitioner 19 may use terms more interchangeably than a 20 psychiatrist. I think their training is such that 21 that is not a focus as much. There's a much 22 broader attention given to the patient as opposed 23 to a psychiatrist who doesn't have to address very 24 much the potential of some organic disease. 115 1 Q So, if I understand your 2 testimony, you don't have any idea what 3 parasuicide means, as least as reflected in 4 Exhibit 3? 5 A I can honestly tell you 6 I'm sorry, I don't. 7 Q Studies that you 8 developed protocols on, were they Phase 2 or Phase 9 3 studies, or both? 10 A I did both. 11 Q And the imipramine- 12 placebo-fluoxetine comparator studies, would those 13 be considered Phase 2 or Phase 3? 14 A They could be considered 15 either one, depending on time basis and the 16 criteria and so on. I can't recall the -- again, 17 I couldn't in Fort Meyers and I can't here either, 18 because you refreshed my memory by handing me the 19 protocol, I think Bremner's study was the Phase 2, 20 because then we moved into a much broader scale, 21 and I can't recall if that was fluoxetine versus 22 placebo, fluoxetine versus imipramine. I don't 23 think it was a three-arm study because there were 24 too few patients. My memory says it was twenty 116 1 and twenty in each arm. 2 THE WITNESS: Do you 3 recall, Paul? 4 MR. SMITH: I was just 5 thinking. You did the geriatric study, too, 6 didn't you? Wasn't there a geriatric study that 7 you designed? 8 THE WITNESS: There was a 9 geriatric study that we ran also. 10 MR. SMITH: All right, I 11 just don't recall. 12 THE WITNESS: That was a 13 separate one, though. 14 Q (BY MS. ZETTLER) Would a 15 Phase 2 trial be used as a pivotal to support 16 efficacy? 17 A Well, actually it could 18 be. I don't think it's precluded. I think the 19 biggest question becomes is the N large enough. N 20 like in Nancy, that's what they say in Chicago. I 21 think usually the N's tend to be smaller in a 22 Phase 2, but they're not necessarily so. But if 23 the N is large enough that it really has 24 statistical meaning and it comes out very 117 1 statistically significant, it can be more than 2 just supportive, it can actually be one of the 3 pivotals. 4 Q Do you recall if this 5 study that -- the studies that were submitted to 6 the FDA in support of the NDA -- 7 A Yes. 8 Q -- the efficacy studies, 9 were those Phase 2 or Phase 3 studies? 10 A To the best of my 11 recollection, they were all Phase 3. 12 (OFF-THE-RECORD DISCUSSION HELD.) 13 14 15 (STARK EXHIBIT NO. 4 MARKED FOR 16 IDENTIFICATION.) 17 Q (BY MS. ZETTLER) I'm 18 really just going to ask you about -- I wanted to 19 use this as a reference. You're free to look at 20 the entire document if you like, but I'm most 21 interested in the third from the last page of the 22 document. 23 A Then why don't we go to 24 that, I can always go back to the others later on. 118 1 Q Fine. 2 A Okay. 3 Q My understanding of what 4 this document is, Doctor, and feel free to look 5 back at anything you want to verify it, but it's 6 in essence a review of the NDA that was submitted 7 here in the United States for use by either the 8 Swiss regulatory authority or the affiliate, the 9 Lilly affiliate for Switzerland, that handles 10 Switzerland. 11 A I don't know of that. I 12 didn't know the NDA went in until after I left 13 Lilly. 14 Q That's what I thought, 15 too, but it says review of the NDA on here, so I 16 don't know if that necessarily means that it's 17 just what was being prepared or what. Really all 18 I wanted to use this for is to try to refresh your 19 recollection as to what studies were done under 20 what we know to be Protocol 27, which was the 21 imipramine-fluoxetine-placebo multicenter study? 22 A Okay, yes. 23 Q If you look up at the top 24 of the page there, it lists, I believe, eight 119 1 studies, six of which look like they had patients 2 that were randomized to fluoxetine, imipramine, or 3 placebo; do you see that? 4 A The last six? 5 Q Right. 6 A Yes, I don't recall 7 whether Fabre and Rickels did them or did not, but 8 I don't know if that's a blank because it wasn't 9 done or they didn't have it; I don't know where to 10 really look. 11 Q Do you recall the 12 fluoxetine-imipramine-placebo multicenter study at 13 all? 14 A At all, sure. 15 Q Okay. 16 A Yes, there were three 17 compounds in them. I don't know that I will have 18 detail, but feel free to ask. 19 Q Okay. Did you develop 20 the protocol for that study? 21 A I would have to see it, 22 but if it was the one that was submitted to the 23 NDA, yes. 24 Q Were you aware when you 120 1 wrote that protocol that Lilly intended to do a 2 multicenter study using that protocol, for 3 submission as a pivotal study? 4 A Yes. 5 Q Okay. Were you aware 6 that the multicenter study that was conducted 7 under that protocol was, in fact, submitted to the 8 FDA as the main multicenter study that was 9 conducted in support of efficacy? 10 A No, I'm not aware of it; 11 I'm going to presume it. 12 Q Because as far as you 13 know, it was submitted after you left Lilly? 14 A That's correct. 15 Q Are you aware of any 16 other multicenter studies of the magnitude of the 17 study that was done under Protocol 27 -- if you'll 18 take my word for it on this one -- other than that 19 multicenter study; are you aware of any other 20 multicenter studies that were performed on major 21 depressive disorder and fluoxetine? 22 A There were other studies 23 conducted, I don't recall all of them. As an 24 example, I know a bipolar study was run, a 121 1 geriatric study was run. I started -- it was not 2 completed -- an adolescent depression study at the 3 Royal Ottawa Hospital. There were other studies, 4 I don't know all of them. 5 Q As far as a multicenter 6 study, though, conducted under a single protocol 7 such as Protocol 27, are you aware of any other 8 studies of this magnitude as far as the number of 9 patients and sites? 10 A I'd have to tell you this 11 isn't quite jibing with my recollection. 12 Q Okay. 13 A It seems to me that with 14 all these sites that you have here, this was the 15 pooling of several studies. I think that 16 beforehand -- I can only give you a for instance, 17 so this is not what actually happened, but let's 18 look at this thing here. Like Feighner and Cohn 19 would be one study, Bremner and Dunner is another, 20 Gosser and Abuzzahab is another. I have no idea 21 if those were the combinations. But they were set 22 up beforehand, prospectively, not retrospectively, 23 as comprising a study, a multicenter study to 24 stand on their own with an adequate number of 122 1 patients. The paper that I presented in 2 Montecatini was a pooling of all the placebo, 3 imipramine, and fluoxetine studies, but I don't 4 believe that the pooled data were submitted as a 5 single study, but rather this was broken out to 6 stand alone or break it. If there was like a 7 hundred and twenty patients in a study, that would 8 be a stand-alone study, forty in each arm as an 9 example. And so I don't recall how many of those 10 are involved in what you are putting together here 11 and calling a multicenter study. There was a 12 multicenter study, but each by themselves may have 13 been a stand-alone or a multicenter in a sense 14 that more than one site comprised a study. 15 Q Were the protocols that 16 were used in these studies, as you described 17 them -- granted that it's not necessarily Dunner 18 and Bremner, et cetera -- were they all conducted 19 under the same protocol? 20 A I can't recall. 21 Q Could they be pooled if 22 they weren't? 23 A If there was -- the only 24 way they could be pooled is if there were no 123 1 significant differences between them. 2 MR. SMITH: You mean 3 between the protocols or between the results? 4 THE WITNESS: No, between 5 the protocols. They self-destruct if the results 6 are different, and the best example of that is 7 Cohn. 8 Q And Doctor Cohn's results 9 were different than the rest? 10 A Marvelous. 11 Q The best thing since 12 penicillin, a miracle drug. 13 A It was so marvelous that 14 they had to be taken and put by themselves to be 15 in proper perspective. 16 Q Why do you think that 17 happened? 18 A I'd dealt with him for 19 years while he was still alive, I've dealt with 20 him for years since, and I think every once in a 21 while, five times out of a hundred, you'll have a 22 busted study that should have been a good study, 23 or you'll have something that's real remarkable 24 the other way. And, you know, I made the 124 1 statement at Montecatini, and Lilly I think was 2 quite content with it, his data showed and should 3 only be interpreted that fluoxetine was at least 4 as good as imipramine. 5 Q But his actual data 6 didn't show that? 7 A It was significantly 8 statistically better than imipramine even, but the 9 fact is he was the only one who showed that; 10 therefore, you ought not to believe it. 11 Q Have you ever seen data 12 that pooled his results with the results of the 13 rest of the fluoxetine-imipramine-placebo studies? 14 A No. 15 Q Do you think it would be 16 appropriate to do that? 17 A To pool his with them? 18 Q Right. 19 A It depends. When you do 20 it with and without, if his impact doesn't change 21 anything, yes. But I think to take his study and 22 say look what we got, I think, no, because it was 23 an exception. 24 Q When you say when you 125 1 take his study and say look at what we got -- 2 A If someone were to try to 3 capitalize and say look at that, it is superior to 4 imipramine. 5 Q That's like for instance 6 if he tried to publish a manuscript or something 7 like that based on his -- 8 A No, you can publish it, 9 it just has to be -- I'm sure he would have. I 10 don't recall it to be -- probably his study was 11 actually published in some proceedings that came 12 from Montecatini thing. But when everyone was 13 there and looked at the data and said are you 14 serious, I made a little speech after lunch and I 15 said no, the fact is that's all you can contribute 16 to that, and I think in fairness that's the way it 17 should be. I think Jay felt the same way, he 18 thought look what I got by what I did, but I know 19 where it stands. 20 Q Doctor Cohn passed away 21 recently? 22 A Yes, he did. 23 Q Do you know what he died 24 of? 126 1 A I heard carcinoma of some 2 sort. 3 Q He never got the pleasure 4 of meeting Paul? 5 A It would have been a 6 unique experience for you. He was quite a guy, 7 you know, he got his JD really late in life, and 8 that was among his proudest achievements actually. 9 Q Really? 10 A Oh, God, he insisted on 11 practicing some law or it would be a total waste. 12 Q Do you have your JD? 13 A Yes, I do. 14 Q Is it one of your most 15 proudest experiences? 16 A No, it's just something 17 that was accomplished for a purpose, so -- 18 Q A lot of doctors seem to 19 be getting JD's so they know what their lawyers 20 are talking about when they're being represented 21 in cases. 22 Have you ever seen the 23 remainder of the fluoxetine-imipramine-placebo 24 studies pooled? 127 1 A The remainder? 2 Q Right, without Cohn. 3 A I don't recall if I saw 4 them with or without because, you know, the paper 5 I gave in Montecatini, I don't recall if he was in 6 it or out of it. I do know that we separated it 7 out with an asterisk, but I don't recall whether 8 it was all together or not. 9 Q My recollection is that 10 it was not. 11 A Okay. 12 Q Then again -- 13 A It probably ought not to 14 be because I probably would have wanted to make 15 the statement that there was no significant 16 difference between sites, and if I had him in 17 there, I couldn't have made the statement. 18 Q Does this refresh your 19 recollection as to whether these studies were done 20 under Protocol 27? 21 A No, I really -- I would 22 probably have to see the documents that I know you 23 have, so you really could tell me where it is. 24 Q And we also have the 128 1 impression that Doctor Goldstein did conduct a 2 study under 27, or at least started a study under 3 27. Do you have any recollection of that at all? 4 A No, I really -- you know, 5 Burt started and stopped one study, he had a hard 6 time deciding whether he wanted to participate or 7 wanted to renegotiate things, and so on. I just 8 recall that he and I bumped heads, we got 9 together, got it all resolved, and I don't recall 10 what happened. There was a guy, Roberto 11 something, who was involved with him down there. 12 Q Roberto? 13 A Domingues, he's a 14 co-investigator, so you should have him. If you 15 don't, you missed it. 16 Q Lots of times we don't 17 get to see all the investigators' reports. 18 A He was not the PI, but 19 Burt was. 20 Q Is Doctor Goldstein still 21 around? 22 A I think so. I have not 23 done studies with him in many, many, many years 24 now. 129 1 Q Was Roberto Domingues a 2 doctor? 3 A Yes, he's an MD. 4 Q Psychiatrist? 5 A Yes. 6 Q Do you know where he is 7 now? 8 A Not for sure. Florida, I 9 don't know. 10 Q Is it your recollection 11 that the individual studies of fluoxetine- 12 imipramine-placebo, other than Doctor -- well, we 13 know Doctor Cohn's did, but the rest of them 14 showed fluoxetine to be at least as efficacious as 15 imipramine, each on their own? 16 A As efficacious as 17 imipramine? 18 Q Right. 19 A I don't recall. 20 Q Do you recall in that 21 paper that you presented at Montecatini being the 22 results of the pooled data from those studies? 23 A I presented the pooled 24 data because I think the individuals, as I recall, 130 1 presented their individual studies at that 2 particular time. 3 Q Have you ever heard the 4 phrase pure pool with regards to fluoxetine? 5 A What. 6 Q Pure pool? 7 A I don't recall. 8 Q Do you recall there being 9 a controversy with the FDA as to the use of 10 concomitant benzodiazepines and chloral hydrates 11 in the fluoxetine-imipramine-placebo studies? 12 A I have to say no because 13 to the best of my recollection we did not allow 14 the concomitant use of benzos, chloral hydrate, 15 but -- you know, you're taking me back too far 16 now. 17 Q I have a document in here 18 somewhere, but I can't find it right now, so let's 19 take a second and we'll look for it and see if it 20 refreshes your recollection. 21 A I remember we used to use 22 chloral hydrate, five hundred milligrams to a 23 thousand milligrams, but I don't recall the benzo 24 stuff, though. 131 1 THE WITNESS: You know 2 you're taking me back fifteen years. I hope this 3 burdens you to do such a harsh thing to a man my 4 age. 5 MS. ZETTLER: Does it 6 make you feel any better that I was up until 1:00 7 o'clock in the morning Friday looking through 8 documents in preparation for your deposition? It 9 burdens me, trust me, more than you'll ever know. 10 (SHORT BREAK TAKEN.) 11 (STARK EXHIBIT NOS. 5 AND 6 MARKED FOR 12 IDENTIFICATION.) 13 Q (BY MS. ZETTLER) Have 14 you had a chance to review Exhibit 5? 15 A Yes. 16 Q Do you recall seeing this 17 document before? 18 A No. 19 Q Does this refresh your 20 recollection as to the issue raised by, I believe 21 it was, Hilary Lee -- 22 A Yes. 23 Q -- related to the use of 24 concomitant medications on fluoxetine clinical 132 1 trials? 2 A It doesn't refresh my 3 memory. It certainly does raise questions that I 4 know you have the answers to, or you should. The 5 last paragraph is what you're referring to? 6 Q Right. 7 A When I read this, I 8 didn't know whether she was stating that they were 9 allowed to, or if this was a rescue medication, 10 that patients had to have a benzo given 11 afterwards, so I don't know what did happen. I'm 12 not capable, unfortunately, of differentiating 13 existing protocols in the past ten years of my new 14 life versus the time before that. Certain 15 medications, to date, have an affinity for the 16 benzo receptors, other drug firms absolutely don't 17 allow it just so they don't confuse the issue as 18 to competition for receptors. So, the allowance 19 and nonallowance of benzos I'm on the fence on. 20 One thing I remember very well was chloral hydrate 21 because it tends to have the least ability to have 22 an effect on affect. 23 Q Okay. 24 A So that's the basis for 133 1 using it, and whereas the benzos would be 2 different than that. 3 Q So you don't recall what 4 percentage of patients on these trials may have 5 used benzodiazepines? 6 A I don't really recall 7 that it was in the protocol that it was even 8 allowed -- if that was the basis for having an 9 unevaluable patient, unfortunately. 10 Q That was the basis for 11 having an -- 12 A I don't know if it was 13 because I would have to see a protocol, just as 14 you're looking at or have looked at. I truly 15 don't recall that. 16 Q Okay. Oxazepam, 17 O-X-A-Z-E-P-A-M. 18 A Oxazepam? 19 Q Yes. What is that? 20 A It's a benzo. Do you 21 know -- there's different protocol numbers here. 22 Q Uh-huh. 23 A Was that a different 24 number assigned to the same overall protocol, do 134 1 you know, or don't you know? 2 Q Which are you referring 3 to? 4 A I see Protocol 19, 24, 5 22, 20, 22, 23, 26, 27. Are these all the same 6 protocols or are these all different protocols in 7 actuality? 8 Q I believe they're all 9 different protocols. For instance, Protocol 27, 10 it's our understanding that that's the fluoxetine- 11 imipramine-placebo protocol. 12 A Okay. 13 Q And then I believe one or 14 two of these others, 19 may be the fluoxetine- 15 imipramine studies without the placebo. 16 A Okay. We can try to 17 talk. 18 Q Okay. It's my 19 understanding that this document was submitted, at 20 least to the FDA, after you left Lilly, about six 21 months after, right? 22 A Yes. 23 Q Does this refresh your 24 recollection as to what psychotropics were allowed 135 1 and what were not? 2 A I'm looking at this here 3 and this, without a doubt, states that allowed 4 psychotropics include a wide range of the benzo 5 family. That's interesting. 6 MR. SMITH: What's 7 interesting? 8 THE WITNESS: Just 9 looking at the complete list of disallowed and 10 allowed. 11 MR. SMITH: Some of those 12 allowed drugs do have an effect on affect, don't 13 they, Doctor Stark? 14 THE WITNESS: Well, 15 sure. 16 Q (BY MS. ZETTLER) Okay, 17 the disallowed psychotropics, I'm assuming they're 18 talking about concomitantly with fluoxetine as 19 opposed to individually, correct? For instance, 20 imipramine, we know that imipramine was used as a 21 study drug? 22 A That's correct, but it 23 would not have been allowed as an additional drug 24 in the course of the study, only the blinded 136 1 materials would have been in. In other words, 2 they couldn't add to that imipramine. 3 Q If it wasn't in a study 4 where imipramine was being used as a comparator, 5 why could you not also give imipramine with, say, 6 fluoxetine? 7 A Well, I can't tell you 8 what the thinking was then, but the logical answer 9 would be why would you give an antidepressant if 10 you're trying to evaluate the efficacy of an 11 antidepressant in a clinical trial. I think 12 that's what they're primarily used for. 13 Q The reason I asked is 14 because during Doctor Dunner's deposition, he 15 testified that in a certain percentage of his 16 patients he has prescribed a concomitant tricyclic 17 antidepressant in low doses with fluoxetine to 18 counteract some of the agitation effects. 19 A If I could hear what he 20 said, I would know what he was talking about. My 21 immediate reaction, just gut-wise, is since I 22 can't relate to this, if I saw such data, I'd call 23 that an excluded patient, nonqualified. 24 Q I'm not talking about on 137 1 his protocols, I'm talking about in his practice. 2 A Oh. Well, Dave can do as 3 he likes. The fact of the matter is I'm sure many 4 physicians do, in practice, different types of 5 things, so I can't answer you at all. 6 Q Do you have any 7 reservation or problem with administering 8 concomitant sedatives with fluoxetine, at least 9 for the first few weeks of treatment on 10 fluoxetine? 11 A Do I personally? 12 Q Right. 13 A Not for the first two 14 weeks, I wouldn't really. 15 Q Okay. 16 A I guess the only 17 reservation I would have is a personal type of 18 thing, is I would try not to do a Hamilton 19 Depression Rating Scale the next morning when they 20 took it. That's the only reservation I would 21 have. 22 Q How about generally 23 treating patients, not necessarily in a clinical 24 trial, but generally treating them in a private 138 1 practice setting, would you have a problem with 2 administering a concomitant benzodiazepine with 3 fluoxetine for the first couple of weeks if a 4 person is suffering from anxiety or agitation? 5 A Let me answer you from a 6 pharmacological point of view. 7 Q Sure. 8 A I would not have a 9 problem from a drug interaction point of view, 10 from what I know. What I don't know may, of 11 course, be something all together different. 12 Q You are a 13 psychopharmacologist, correct? 14 A Yes. And I think at the 15 present time, studies are conducted in which 16 benzos are allowed as a nighttime sleep inducer 17 for the first week, sometimes two weeks. 18 Q But let's limit our 19 discussion just to fluoxetine. 20 A Okay. I would have no 21 problem -- with what I know today, have a problem 22 with the concomitant use of a benzo as a bedtime 23 hypnotic. 24 Q Okay. On the fourth page 139 1 in Table No. 1, do you see that? 2 A Yes. 3 Q Protocol 19. We know 4 what chloral hydrate is. What is Eskatrol? 5 A I'm not positive. We 6 would have to use a PDR. I believe it's 7 classified as an antipsychotic. 8 Q And we know that the 9 oxazepam is a benzodiazepine? 10 A Yes. 11 Q Does this indicate to you 12 that in Doctor Fabre's Protocol 19 study, 13 benzodiazepines were allowed concomitantly with 14 fluoxetine on the study? 15 A Only for the reason that 16 there's no X under disallowed. 17 Q Okay. So if we go by 18 this chart, it looks like they were allowed? 19 A That would be my 20 interpretation. 21 Q Okay. How about 22 diphenhydramine? 23 A I believe you're talking 24 about an antihistaminic. 140 1 Q Okay. Flurazepam? 2 A That's a benzo. 3 Q I always get these 4 confused, is that Halcion or is that triazolam or 5 whatever? 6 A I don't recall which is 7 which. 8 Q And amitriptyline, at 9 least in this case, was allowed? 10 A It was? I thought it has 11 an X beside it here. 12 Q Oh, I see, there's an X 13 in the allowed for the chloral hydrate and an X 14 for disallowed for the amitriptyline? 15 A Yes. 16 Q Okay. It also looks like 17 benzodiazepines were allowed on Doctor Rickel's 18 study done under Protocol 25, does it not? 19 A Yes. You know, when I 20 went through this thing, I didn't see any of them 21 where they weren't in here. 22 Q Where the benzodiazepines 23 were not allowed? 24 A Yes, not that I could 141 1 see. 2 MR. SMITH: I think he's 3 afraid you would go through every one of those. 4 MS. ZETTLER: I've been 5 known to do that. 6 Q (BY MS. ZETTLER) Are you 7 familiar with the studies done under these various 8 protocols, whether or not they're pivotal studies 9 that were submitted to the FDA? 10 A No. I'm taking your word 11 that 27 was one of the pivotal protocols. 12 Q Earlier I believe you 13 testified that you didn't feel it would be 14 appropriate to allow the administration of a 15 benzodiazepine during the clinical trial. Do you 16 still believe that? 17 A With the same stipulation 18 you would have to avoid -- two things. You would 19 have to avoid a long-acting one, and you should 20 not do a HAMD the next morning. I write that into 21 some of my protocols even today when I write them. 22 Q If that were to happen, 23 you have a long-acting benzodiazepine or you 24 administered a HAMD the day after the person took 142 1 the benzodiazepine, would that render the data 2 unevaluable, in your opinion? 3 A If it went through the 4 whole study, I think it would taint the evidence. 5 It would probably taint placebo more than drug. I 6 know you're familiar with the HAMD. The HAMD, if 7 you know, has three questions with regards to 8 sleep, and since that, therefore, plays such a 9 significant role in the Hamilton Depression Rating 10 Scale, if you alleviated that, you get the 11 impression they're doing perhaps better, and as a 12 consequence placebo patients would look much 13 better in that type of scheme of things. I think 14 also because presumptively, when I say this, 15 absolutely a drug will help more depressed 16 patients than will a placebo, and so as their 17 depression goes away, their sleep improves, but if 18 you help the placebo patients with a benzo -- so 19 that's why I think the limitation is for two weeks 20 as well as; at least everybody stands alone on 21 their own. 22 Q But not all these people 23 who received the benzodiazepines in these studies 24 were on placebo? 143 1 A They hadn't responded as 2 yet to the drug. I think that's the basis for the 3 limitation for how long they can take a hypnotic. 4 Q As far as the 5 benzodiazepines are concerned, you're assuming 6 that they were only allowed for the first two or 7 three weeks of the trial, right? 8 A That is indeed a 9 presumption I'm making. 10 Q It could be that they 11 were allowed throughout the entire clinical trial 12 since you don't recall them even being allowed at 13 all, right? 14 A That's correct. 15 Q Benzodiazepine is going 16 to affect symptoms other than insomnia in a 17 person, is it not? 18 A Yes and no. 19 Q Okay, what do you mean by 20 that? 21 A Well, your question is 22 very much like have you stopped beating your wife. 23 Q That's what I get paid 24 for, Doctor. 144 1 A Let me answer your 2 question in a fair way. I think a benzodiazepine 3 can alleviate symptomatology associated with 4 anxiety, but I think in order to do that, it has 5 to be given at an adequate dosage and with an 6 appropriate frequency. To the best of my 7 knowledge, and my recollection, any hypnotics, 8 whether they included the benzos or not, could 9 only be given at bedtime, but not throughout the 10 course of the day. And so I think from a 11 pharmacological point of view, and a logical point 12 of view, you would have to say that the impact on 13 other parameters would be minimal, if at all, 14 other than sleep. 15 Q Again, you're assuming 16 that the benzodiazepines were given in a certain 17 regimen, correct? 18 A That is correct, that's 19 my presumption. 20 Q Earlier I think you 21 testified that a person who is agitated -- and if 22 I'm wrong, please -- like I said, bad memory is 23 not a function of age, as far as I'm concerned -- 24 A Okay. 145 1 Q Part of your definition 2 of agitation was insomnia. Do you recall that, 3 the inability to sleep? 4 A No, I don't think so. 5 Q Is anxiety? 6 A I think manifestations of 7 anxiety and depression can be insomnia. 8 Q And you don't necessarily 9 agree that depression and anxiety are one and the 10 same, like Doctor Montgomery does? 11 A I tend to be a little bit 12 further from that pole. 13 Q Okay. If a 14 benzodiazepine is used to treat agitation -- 15 A Uh-huh. 16 Q -- what symptoms within 17 agitation would it be treating? 18 A I think the benzos, any 19 of the benzodiazepines, given at an appropriate 20 frequency and dosage, if they were working, and 21 not all patients who are anxious patients, who are 22 agitated patients or nervous patients or whatever 23 class you would be treating, would respond and 24 have a diminution if they were responders to 146 1 agitation, if they were to take it appropriately. 2 I think taken at bedtime alone, unless you have a 3 compound whose activity was so sustained that 4 you -- the dosing regimen normally is once a day, 5 and you would have to sustain that therapy 6 throughout. I would guess that whatever you saw 7 would be only the early portion, but not the later 8 portion. So, the first two weeks, if that is the 9 period of time of double blind therapy, where 10 concomitant medication was allowed, you would 11 probably see an improvement in sleep, and only on 12 a theoretical basis would you see an impact on 13 other symptomatology. If it was taken throughout 14 the course of a day, as well as at bedtime, one 15 should predict that sixty percent of the patients 16 taking it in that manner should have a decrease in 17 the symptomatology, such as agitation or 18 nervousness and so on. 19 MS. ZETTLER: Okay. 20 Let's take a break. 21 (SHORT BREAK TAKEN.) 22 * * * * * 23 24 147 1 CROSS-EXAMINATION 2 3 BY MR. SMITH: 4 Q Doctor, you're leaving, 5 as I understand it, to go back out of the country? 6 A True. 7 Q Are you going to Europe? 8 A France. 9 Q On business? 10 A No. 11 Q You used the term, in 12 talking with Ms. Zettler, in connection with some 13 of these concomitant medications, the term rescue 14 medication; did I hear you correctly? 15 A Yes. 16 Q What is that, is that a 17 particular term or phrase used by people in the 18 clinical trial business or in pharmaceutical 19 companies? 20 A I don't know if that's 21 got that connotation, I learned of it in the 22 course of people discussing how they treat a 23 patient who has not responded and/or is having a 24 particular problem of some sort, and that's where 148 1 I've heard the expression used. 2 Q Well, is the term rescue 3 medication used in any protocols, in any trials of 4 any medication of which you're aware? 5 A Not that I'm aware. 6 Q Does the Food and Drug 7 Administration use -- have you ever seen that term 8 used by them, rescue medication? 9 A I don't recall having 10 seen that, Paul. 11 Q Do you mean by rescue 12 medication, a medication that is administered by 13 an investigator who is also the physician treating 14 a patient during a particular clinical trial for 15 some adverse experience that might be observed 16 during that trial? 17 A I've heard it used in two 18 ways. 19 Q All right. 20 A I've heard it used to 21 treat an adverse experience, and I've heard it 22 used in a means of treating patients before the 23 onset of efficacy of an antipsychotic drug, 24 patients who were being treated for schizophrenia. 149 1 Q All right, in other 2 words, they would be having some type of manic 3 reaction or something of that nature and they 4 might be given some antipsychotic medication? 5 A I haven't heard the 6 expression in treating of a manic experience. 7 I've heard it used for a person who was difficult 8 to control. If you're waiting for the onset of an 9 antischizophrenic, it's called rescue medication. 10 Q We've just not heard that 11 term, rescue medication, used by any other 12 witnesses in this litigation. 13 A I would be happy to 14 retract it if you'd allow me to. 15 Q No, I was just hoping 16 that you could enlighten us in connection with 17 what you meant by that. 18 A That's the extent of it. 19 Q As I understand it, from 20 what you've said, it's a medication that can be 21 used for relief of treatment emergent adverse 22 events or reactions that might occur during the 23 clinical trial at the discretion of a particular 24 investigator? 150 1 A Well, there's usually a 2 limitation. 3 Q I understand that. 4 A If it interferes then 5 with the furtherment of the study, that becomes 6 the therapy of the patient and the physician and 7 the role of the study. 8 Q And that might require 9 the patient be withdrawn from the study, is that 10 right? 11 A That's correct. The 12 dropped patient then is a treatment failure, not 13 just from a lack of efficacy, but because of an 14 adverse experience. 15 Q Would it be a treatment 16 failure or a treatment discontinuation or an early 17 discontinuation? 18 A I think it's an early 19 discontinuation. 20 Q Is there such a term as 21 treatment failure used in the clinical trial 22 business? 23 A Uh-huh, yes. 24 Q In what circumstances is 151 1 that term used? 2 A To the best of my 3 knowledge, Mr. Smith, it is either for lack of 4 response for efficacy or for intolerability of the 5 compound. 6 Q By intolerability of the 7 compound, would that include a particular serious 8 adverse experience? 9 A Yes, it could be a 10 serious adverse event, it could even be just an 11 adverse event. 12 Q Doctor Burton Goldstein, 13 in Miami, Florida -- you referred to him earlier. 14 A Yes. 15 Q And he was an 16 investigator for some of the clinical trials for 17 Lilly on Prozac, was he not? 18 A You used the plural, and 19 I don't recall whether it was one or more. 20 Q And his trial was 21 discontinued and then restarted, did I understand 22 that? 23 A No, he was -- his 24 willingness to participate was a stop, start; his 152 1 agreement to participate, and then he decided to 2 not, and then he decided he really would like to 3 if we could find a place for him. 4 Q What were the reasons for 5 that? Why did he decide to discontinue and then 6 start and stop again? 7 A He had heard rumors that 8 perhaps some of his peers were receiving some very 9 large sums of money, and then when he investigated 10 it and found that it wasn't so, he wanted to know 11 if he could join his peers again, he talked to 12 some of his peers after that. 13 Q You mean his peers that 14 were also running Prozac clinical trials? 15 A They were going to be 16 running clinical trials. 17 Q And he didn't think he 18 was getting paid as much as the other 19 investigators? 20 A That's correct. 21 Q And you and he, I think 22 you used the term, butted heads? 23 A Yes. 24 Q Over that, the payment 153 1 issue? 2 A Yes, if you like the term 3 butted heads. 4 Q Isn't that the term you 5 used? 6 A I did indeed. Thanks, 7 Paul. 8 Q Did you have any other 9 disagreements or instances in which you and Doctor 10 Goldstein disagreed? 11 A Not really. Not that I 12 can recall. I do have to qualify the statement, 13 not that I recall. 14 Q Do you recall some 15 dissatisfaction on your part at the rate of 16 sign-ups that Doctor Goldstein had, as far as 17 speed? 18 A Mr. Smith, it's too far 19 back, I just can't recall those things. 20 Q Do you recall -- and I'm 21 trying to help you, and it's all right if you 22 don't recall. Do you recall that there was a 23 problem that you had with the particular quality 24 of patient that Doctor Goldstein was enrolling? 154 1 A I don't recall, Paul. 2 Q Do you, as the medical 3 monitor, make the decision that a particular 4 investigator's trial should be discontinued? 5 A Probably the preliminary 6 such decision; it would not be consummated 7 unilaterally by me without discussion with my 8 management, my bosses. 9 Q Did you make that 10 determination in connection with Doctor 11 Goldstein's study, that it should be discontinued? 12 A I don't recall, Paul. 13 Q Who would have been your 14 management at that time that would have 15 participated in a decision such as this, if such a 16 decision were made by you? 17 A Possible people would be 18 Cecil Vendish -- I'm going through my mind -- Bob 19 Zerbe. I don't remember if I ever reported to 20 Jacque or not when he came over to this country 21 from France. Conceivably Jacque Kusmierek. 22 Q Do you recall 23 discontinuing or suspending any studies? 24 A Yes. 155 1 Q All right, which studies 2 were those? 3 A As you recall, when we 4 were down in Florida, I mentioned to you about 5 Fenerty and Goldberg, we spoke about them? 6 Q I don't recall it. 7 A I'll refresh your memory. 8 Q Thank you. 9 A Fenerty and Goldberg in 10 the Boston area conducted a study for Eli Lilly 11 and Company, and we had reason to suspect the 12 possibility of ghost patients, and I believe the 13 company notified the FDA that we were terminating 14 that study and the safety data would be listed, 15 but efficacy would not be pursued from that site, 16 and they were given a letter to that effect. 17 I also arranged to have 18 notification sent to the FDA with regards to a 19 study here in Indianapolis that I told you about 20 with Joyce Small, where we felt that inappropriate 21 patients were being entered, and that was it. I 22 have no idea what came of either of those 23 notifications, but we did that. 24 Q Who was it that would 156 1 have been in regulatory that would have made that 2 notification to the Food and Drug Administration? 3 A Whoever the head was, it 4 could have been Chris Christensen or Bruce Peck, 5 depending on the time frame of when things 6 happened. 7 Q Would Doctor Dorothy 8 Dobbs have been involved in that? 9 A I don't recall her being 10 there at that time, but I can't say for sure to 11 you. Fenerty and Goldberg, they were one of the 12 earlier ones. 13 Q Do you recall at any time 14 while you were the medical monitor on Prozac, the 15 difference in the number of patients that were 16 involved in clinical trials in the United States 17 versus outside the United States? 18 A Ask the question again, I 19 guess I missed it. 20 Q Do you recall at any time 21 while you were the medical monitor of Prozac -- 22 A Yes. 23 Q -- what the differences 24 were in the number of patients enrolled in 157 1 clinical trials in the United States versus the 2 number of patients that were enrolled in clinical 3 trials outside the United States? 4 A No. 5 Q Do you have a 6 recollection of whether or not there were more 7 patients or less patients outside the United 8 States than inside the United States? 9 A I don't have a 10 recollection, Mr. Smith. 11 Q Who was it again that was 12 responsible for overseeing the outside United 13 States clinical trials while you were the medical 14 monitor? 15 A A tall six-foot guy with 16 black straight hair, an English accent. 17 Q But you still can't 18 remember his name? 19 A No, I truly can't, Paul. 20 Q I believe you. In other 21 testimony, specifically in testimony with Doctor 22 Heiligenstein -- did you know Doctor 23 Heiligenstein? 24 A Oh, I recall the name. 158 1 He came after my time. 2 Q In testimony with 3 Mr. Wood and Doctor Perelman, there were 4 statements concerning the intent of the clinical 5 trials on Prozac, and that the clinical trials on 6 Prozac were not intended to assess suicidality. 7 Would that be your judgment also, that the 8 clinical trials, as far as you were concerned, 9 when you drafted the protocols, were not intended 10 to assess suicidality? 11 A I would say that that is 12 mostly true, in that suicide attempts or 13 suicidality, if it occurred, was reported as a 14 serious adverse event, and therefore it was 15 recorded, but the design of the study was for 16 efficacy and safety, and that was one aspect of 17 safety, so that I think that's the extent that I 18 can answer your question. 19 Q But as I understand it 20 from your conversations and during your deposition 21 in Florida, you were of the opinion throughout the 22 time that you were the medical monitor of Prozac, 23 that suicides that occurred were not the result of 24 ingestion of the drug Prozac, but were the result 159 1 of the underlying disease? 2 A That was my 3 interpretation of the data that was generated and 4 the results. 5 Q Therefore, when you, as 6 the medical monitor of Prozac, during those 7 periods of years, from 1979 to 1984 -- 8 A Uh-huh. 9 Q -- when you saw instances 10 of suicides or attempted suicides in connection 11 with Prozac, your judgment was that the reason 12 that you were seeing that was because depressed 13 people more tended to be of higher incidence of 14 suicidality than nondepressed individuals, is that 15 correct? 16 A Based upon the incidence 17 of suicides or attempted suicides from the 18 studies, including patients on all the 19 medications, and the failure to discern any trends 20 with the data that were generated, the frequency 21 of the occurrence, it was my interpretation that 22 what we saw was a manifestation of patients 23 failing to respond to treatment. 24 Q Yes. The point I'm 160 1 making is, though, is you assumed when you drew up 2 the protocol, and then you assumed when you saw 3 instances of suicidality, that what you were 4 seeing was just part of the core disease of 5 depression, correct? 6 A I'm left with an 7 uncomfortable feeling with your use of the words I 8 assumed. 9 Q How about you went in 10 with the scientific judgment that when you saw 11 these instances of suicidality, and when you 12 drafted the protocols, that if you saw instances 13 of suicidality, that it would most likely be the 14 result of the fact that you would see suicidality 15 at a higher degree in depressed individuals than 16 nondepressed individuals? 17 MR. FREEMAN: He's 18 already been asked and answered that. 19 A You're really wondering 20 around an awfully lot on that, Mr. Smith. I had 21 no presumptions. I had an open mind. I think 22 one, however, would very appropriately presume 23 that suicidality would have a greater incidence 24 and probability in depressed patients than in 161 1 nondepressed patients. 2 Q All right. And did that 3 continue throughout the time that you were the 4 medical monitor on Prozac? 5 A The statement that I just 6 made was accurate and nothing occurred to change 7 my opinion. 8 Q All right. You said, in 9 speaking with Nancy, that Paul Leber hasn't ever 10 made a mistake in his entire life. It sounds to 11 me like you've had, in the clinical trial business 12 that you're in now, several experiences with 13 Doctor Leber, is that correct? 14 A I have been present at 15 several meetings, and that was probably a slight 16 exaggeration that he's never made a mistake, but 17 my feeling is that he does not likely acknowledge 18 them. 19 Q Do I take it from your 20 statement that -- and I assume when you made that 21 statement, you were making that statement tongue 22 in cheek? 23 A That he never has made a 24 mistake? 162 1 Q Yes. 2 A Yes. 3 Q And that it was his 4 judgment he had never made a mistake in his life? 5 A I think that that was the 6 facetiousness of the statement. 7 Q The point is, is Doctor 8 Leber an individual who, in your experience, seems 9 to take a position and stick with that position 10 pretty steadfastly? 11 A Well, I think he is a 12 very bright and very sharp individual, and I think 13 what he does not particularly do is go to the 14 confessional box, but the fact is if you can 15 refute his position with logic, he will very 16 discretely not do anything about it and not 17 acknowledge the change -- not acknowledge the 18 errors, but allow the change to take place. 19 Q But he's slow to 20 acknowledge his errors? 21 A I think he's slow to 22 publicly state his errors. 23 Q All right. How often 24 have you dealt with Doctor Leber? 163 1 A From a scientific 2 position, I've been present probably a dozen 3 times. 4 Q How about on a 5 nonscientific? 6 A Probably half a dozen 7 times. 8 Q What were those 9 nonscientific occasions that you would see him, 10 what would be the reason for those? 11 A We know each other 12 personally. 13 Q How is your -- is it a 14 friendship or -- 15 A Yes. 16 Q -- an acquaintance? 17 A His grandmother knew my 18 grandmother in Montreal, and that's a fairly 19 strong bond. 20 Q Is that true, his 21 grandmother knew your grandmother in Montreal? 22 A That's correct. 23 Q When did you learn that 24 his grandmother knew your grandmother? 164 1 A In the course of talking 2 one time and he found out that I was raised in 3 Montreal. 4 Q And he was, too? 5 A No, he was in the states, 6 but he had family there and he went there 7 frequently, and we started delving into who lived 8 where and we found we had a mutual bond that tied 9 us together for life. 10 Q I take it you're friends 11 and do you see each other socially? 12 A We see each other at 13 meetings, usually we make it a point to get 14 together and chat for a little bit. 15 Q Has he ever been to your 16 place down in Sanibel? 17 A No. 18 Q Have you been to his 19 home? 20 A No. 21 Q Where does he live, in -- 22 A Somewhere up near the 23 FDA. It's strictly at scientific meetings we make 24 it a point to get together and see each other and 165 1 say hello, go for dinner sometimes, not very 2 often. It's tough because he's on a per diem and 3 makes me eat a hamburger. 4 Q You don't want to eat a 5 steak while he's eating a hamburger? 6 A My guilt beats me to 7 death. 8 Q Your company, Feighner 9 Research Institute International -- 10 A That's not my company. 11 Q What company, then, are 12 you employed by now? 13 A I'm president and CEO of 14 International Clinical Research Corporation. 15 Q That's right, they're two 16 separate -- we went into that ad nauseum in 17 Florida. 18 A Yes. 19 Q Some company performed 20 two studies for Lilly on Prozac after you left, 21 right? 22 A That's correct. 23 Q Was that ICR or Feighner 24 Research? 166 1 A International Clinical 2 Research ran the program. Feighner Research was 3 one of the sites that was used. 4 Q I'm sorry? 5 A Feighner Research was one 6 of the sites that was use. 7 Q Were those studies on 8 Prozac? 9 A Those two studies that I 10 left? 11 Q Yes. 12 A Those were two of the 13 studies that I have conducted since I left Lilly. 14 Q And were they on 15 depressed individuals? 16 A Yes, they were, sir. 17 Q And when were those 18 studies done? 19 A One started in '84, and 20 then when it was completed, the data were analyzed 21 and another study was run, I would have to only 22 guesstimate for you, but I would have to say 23 maybe '86. 24 Q Do you remember the 167 1 protocol number of that study? 2 A No, sir. 3 Q Do you remember the 4 purpose of those studies? 5 A They were fixed dose 6 studies to establish the minimal effective dose. 7 Q To establish the minimal 8 effective dose? 9 A Yes, sir. 10 Q What does that mean? 11 A It was the lowest dose at 12 which one finds a statistically significant 13 difference from placebo in efficacy in treating 14 depression. 15 Q What were the results of 16 that study? 17 A The first study we found 18 that twenty, forty, sixty, and eighty milligrams 19 were approximately equally effective, but I can't 20 give you the exact data because this was hearsay, 21 we did not do the analyses of the data. 22 Q Who did that? 23 A Lilly. The next study, 24 we ran doses of five, twenty and forty, and I 168 1 can't give you the precise results on that because 2 we did not do the analyses then either. 3 Q What's your general 4 recollection? 5 A Twenty and forty was 6 repetitious of what we had conducted before, and I 7 can't recall what I heard about the five 8 precisely. I can't recall whether -- 9 Q Generally. 10 A In my mind, it sticks 11 that I thought it was not significant, but I can't 12 tell you for sure. 13 Q Not significantly 14 different in efficacy -- 15 A From placebo. 16 Q -- from twenty and forty? 17 A No, from placebo. 18 Q Do you know if the lowest 19 effective dose was established by virtue of your 20 study? 21 A As far as I know, at this 22 point in time, twenty represents the lowest dose 23 that I was involved in. I don't know what other 24 studies may have been conducted by Lilly. I know 169 1 many studies have gone on since I left, so I 2 couldn't tell you. 3 Q Do you know that Prozac 4 is now being manufactured in ten milligram 5 pulvules? 6 A Do I know it? 7 Q Yes. 8 A Yes. Your timing is 9 perfect, I just found out about it recently; I 10 wasn't aware of it until recently. 11 Q When did you find out 12 about it? 13 A Within the past week, I 14 had spoken with the group at Lilly and they told 15 me that there's a ten milligram one now. 16 Q What group did you speak 17 with? 18 A I spoke with the legal 19 group. 20 Q The legal group? 21 A Yes. 22 Q Ms. Huff and her cohorts? 23 A Yes. 24 Q Have you talked with 170 1 Doctor Leigh Thompson since you left Lilly? 2 A No. 3 Q Have you talked with 4 Doctor Robert Zerbe since you left Lilly? 5 A Yes. 6 Q Have you talked with 7 Doctor Zerbe concerning Prozac? 8 A No. 9 Q Have you approached 10 anyone at Lilly since this latest clinical trial 11 that you did with the five, twenty and forty 12 dosage, to do another clinical trial? 13 A Yes. 14 Q And I'm taking about with 15 Prozac. 16 A No. 17 Q All right. Have you 18 approached -- 19 A That's not true, no, 20 that's not true. 21 Q Tell me the truth. 22 A I'm trying my best, sir. 23 Yes, I did. 24 Q All right, when? 171 1 A Within the past three 2 years. Is that close enough? 3 Q Uh-huh. What type of 4 study did you propose? 5 A I didn't propose any, I 6 approached them to do studies with any of their 7 ongoing programs. 8 Q Their ongoing Prozac 9 programs? 10 A Whatever program; yes, 11 they had Prozac ongoing studies, or interests 12 anyway. I keep hearing of things by way of the 13 grapevine, so I make sure I get my dibs in. 14 Q You're only doing studies 15 on psychotropic medications, aren't you? 16 A Central nervous system, 17 complete. 18 Q You're not doing studies 19 on gastrointestinal drugs? 20 A No. 21 Q Musculoskeletal drugs? 22 A Well, it depends on what 23 you mean by that. 24 Q As opposed to some that 172 1 might affect the musculoskeletal system by virtue 2 of a CNS effect? 3 A Yes, we do that. We're 4 doing studies right now on ALS. 5 Q What studies were you 6 aware of within the last three years that Lilly 7 was involved in, in connection with Prozac? 8 A Nothing in particular 9 other than that they were talking about additional 10 uses, applications, and so on, of Prozac, and I 11 make it a point to always make sure people know 12 we'd be very pleased to service them. 13 Q Who would you approach in 14 that connection? 15 A At that particular 16 aspect, I spoke with Doctor Tollefson. 17 Q Have you approached 18 others at Lilly concerning this? 19 A Yes, I spoke with the 20 person who takes care of dealing with contract 21 research organizations. 22 Q Who is that? 23 A His name is Gary 24 Lightfoot, but he has since left the company, and 173 1 he's with a competitor of mine now. And I've 2 spoken with Mr. Steve Link, who has replaced Gary 3 Lightfoot, and I've expressed interest in doing 4 studies in all areas, including Prozac. I've 5 broadened my horizons. 6 Q Not out of the CNS 7 category? 8 A Not out of the CNS area. 9 Q Have you ever done a 10 prospective study to determine a particular issue 11 in connection with a CNS drug? 12 A Yes. 13 Q Give me an example of 14 some prospective studies that you've done to 15 examine an issue with respect to a CNS drug. 16 A I guess almost every 17 study I have done. I can't recall of any 18 retrospective ones that I've conducted. I guess 19 we can take all the Lilly protocols that I've done 20 were prospective. 21 Q In other words, a 22 prospective study, as far as you're concerned, is 23 a study where you would identify a particular 24 subject to be examined by the clinical trial, is 174 1 that correct? 2 A That's correct, where the 3 objective is spelled out on the first or second 4 page of the protocol. 5 Q You have an objective of 6 the trial, and then you draw up a protocol that 7 will set forth the scientific basis that you're 8 going to use to examine the particular product to 9 get to that objective, is that right? 10 A No, I don't think so. 11 Q Then tell me. 12 A I think what it says is a 13 prospective study lays out the objective of the 14 study, it does not necessarily spell out a 15 scientific basis in that portion of it. The 16 scientific basis is deduced from the introduction 17 and discussion of the study. 18 Q All right. 19 A Now, you should 20 understand that a prospective study does not 21 preclude a retrospective analysis. 22 Q Of data? 23 A Yes. One does not 24 necessarily preclude the other from happening. 175 1 Q Both prospective and 2 retrospective studies, though, do indeed each have 3 scientific value? 4 A Well, you can't really 5 design a retrospective study. 6 Q Okay. So that's an 7 advantage -- 8 A All studies are 9 prospective, but retrospective analyses may take 10 place. 11 Q So that's an advantage of 12 a prospective study, correct? 13 A All studies almost have 14 to be prospective. I don't think you can have an 15 objective that states I'm going to look backwards 16 on something that I didn't do. 17 Q Would that be a criticism 18 of a retrospective study? 19 A A study only results in a 20 retrospective analyses of data. 21 Q Okay. 22 A But you can't design a 23 retrospective study. I mean, it's an oxymoron. 24 Q Well, are you saying that 176 1 a retrospective analysis of a study has some 2 limitations? 3 A It can. 4 Q All right. 5 A But it is not necessarily 6 so. 7 Q But if you made a 8 retrospective analysis of a study to get the 9 answer to a particular question, and that study 10 didn't ask that question, then that retroactive 11 analysis isn't going to do you any good, is it? 12 A That's not true. 13 Q Tell me how it's 14 incorrect. 15 A Let's take an ultra- 16 simplistic approach, Paul. 17 Q That will help with me. 18 A Okay. If you set out to 19 do a study, and you got your answers, but sitting 20 there were data that were available that you 21 didn't anticipate and spell out as the objective 22 of the study, you could generate very, very useful 23 data that could be looked at and analyzed 24 retrospectively. You have your choice of saying 177 1 but I did get some information that was useful, or 2 you can say I can't see this data, I don't care 3 how good it is. That's really in essence what you 4 just said, that it's no good. It ain't 5 necessarily so, Paul. 6 Q I'll buy that. 7 A Okay. 8 Q But will you agree that 9 you are more likely to get an accurate answer to a 10 specific question if you do a prospective study 11 that addresses that specific question than if you 12 make a retroactive analysis of -- 13 A Retrospective or 14 retroactive? 15 Q -- retrospective analysis 16 of another study that didn't directly ask that 17 question? 18 A No, I would not 19 necessarily say that. 20 Q Would logic follow that 21 that could be a benefit of a prospective study 22 over a retrospective analyses? And I'm not trying 23 to hold you to any specific point on any 24 particular study, but just as a generality. 178 1 A In a generality, I am 2 disagreeing with you. 3 Q Okay, that's fine. 4 A I think that both are 5 possible, and even probable. 6 Q Did you mention a 7 document earlier where you were asked to do some 8 type of rechallenge study in connection with a 9 particular issue? 10 A Try me again, I missed 11 that. 12 Q You were asked to do a 13 rechallenge in connection with a particular 14 issue. 15 A It's written in there 16 that I was. 17 Q You didn't remember it? 18 A That's right. I think 19 that's the zimelidine syndrome type thing. 20 Q Yes. It's Exhibit 3, 21 Page 2. 22 A Yes. 23 Q Paragraph 5, Clinical 24 Projects Review Committee. 179 1 A Wait, wait, wait. Yes, 2 okay. 3 Q It says, "Montgomery 4 wanted to rechallenge with fluoxetine. CPR 5 recommended rechallenge only under carefully 6 controlled conditions. The details were to be 7 worked out by Doctors Stark and Kusmierek." 8 As I understand it, you 9 don't have any recollection of doing a particular 10 rechallenge study in connection with that 11 particular issue? 12 A Well, actually, I don't 13 remember the conversation even. 14 Q Okay. Have you done any 15 rechallenge studies, in your experience, since you 16 left Lilly? 17 A Yes. 18 Q All right, in what 19 instances did you do those rechallenge studies? 20 A They weren't studies, 21 they were rechallenge incidents is what it is. If 22 you notice here, I don't think -- what is it, two 23 patients? I think two patients is not a study. 24 Q Whether it be study or -- 180 1 A Incidents, episodes, and 2 when you have an adverse experience sometimes that 3 the investigator really is not sure whether it was 4 due to the drug or not, the patient had been doing 5 particularly well, the investigators will ask and 6 the sponsor will usually allow a rechallenge under 7 carefully controlled conditions to see whether it 8 was just some episode or if it was actually due to 9 the drug. 10 Q All right. Do I 11 understand it then that those instances in which 12 you have done rechallenge in investigating drugs, 13 in your business of investigating drugs per 14 contract basis, that you did that when you had an 15 adverse experience with a drug and you wanted to 16 make a determination concerning whether or not the 17 adverse experience was indeed scientifically 18 caused by the drug? 19 A I don't know about 20 scientifically caused by it, but -- 21 Q Or caused by the drug? 22 A Yes, that's okay. 23 Q All right. And you 24 employed a rechallenge? 181 1 A A rechallenge was 2 permitted by the sponsor. 3 Q All right. And is the 4 theory that if the drug is given again and the 5 particular experience occurs again, that there's a 6 greater likelihood that the experience was a 7 result of the drug? 8 A I think it's presumed 9 that if it recurs in that same patient, that that 10 patient's adverse experience was due to the drug, 11 and it's presumptive, even if it's not a hundred 12 percent proved, of course. 13 Q And you've done that on 14 how many occasions since you left Lilly and have 15 been in the clinical trial business? 16 A I couldn't tell you; not 17 that often. I would have to say fewer than six 18 times. 19 Q Okay. Would you say more 20 than five times? 21 MR. FREEMAN: Why don't 22 you just say six times, then? 23 MR. SMITH: Because he 24 said fewer. 182 1 A Let's be very specific; 2 more than once and less than six times. 3 Q Let's be more specific 4 than that. Can you say more than four times and 5 less than six times? 6 A I don't recall, you see, 7 because I really can't tell you, Paul. 8 Q Would it be closer to six 9 than one? 10 A Paul, I can't tell you. 11 Q Where did you get the 12 thinking of six? 13 A That was to my best guess 14 and judgment. 15 Q That's fine. Then 16 approximately six would suit me just fine. You 17 know how we lawyers are. 18 A I sure to do. 19 Q When was Stewart 20 Montgomery hired by your company as a senior 21 consultant? 22 A ICR Corporation formed 23 ICR Limited in -- I believe it was 1991, '90 24 or '91, I can't recall which year, and we hired 183 1 Stewart to act as an advisor and consultant to our 2 group when we started operations in the UK and 3 Europe, in general. 4 Q Is ICR Limited a 5 corporate entity designed to do business outside 6 the US? 7 A Yes, in particular with 8 offices in the United Kingdom. 9 Q Do you actually have an 10 office in London? 11 A Sure. We have employees, 12 too; real live people. On August 31, 1992, we 13 merged with Quintiles. 14 Q Q-U-I-N-T-I-L-E-S? 15 A Uh-huh. And Stewart 16 Montgomery retained his relationship with ICRL, 17 but became a senior consultant to Quintiles in the 18 transition type of thing, and he remains that to 19 this day. 20 Q What is Quintiles? 21 A What is it? 22 Q Uh-huh. 23 A Well, it's primarily a 24 data handling processing statistical group, 184 1 although it has now moved into other areas as well 2 of conducting clinical trials such as we do, 3 except not in the central nervous system area. 4 Q But is Quintiles related 5 to ICR Limited? 6 A They took it over, it 7 became a part of Quintiles on August 31, 1992. 8 Q Did you all sell ICR 9 Limited to Quintiles? 10 A We had what's called a 11 pooling of interests for tax purposes. 12 Q Did ICR or any of the 13 principals in ICR, or ICR Limited, get or obtain 14 any ownership interest, stock interest in 15 Quintiles? 16 A Yes, we had a pooling of 17 interest, we exchanged stock. 18 Q And Doctor Montgomery is 19 a senior consultant for Quintiles? 20 A Yes, that's the title I 21 think he has. 22 Q Is he paid on a salary 23 basis regularly, or is he just paid for strictly 24 per-job consulting work? 185 1 A He's paid on an annual 2 basis. 3 Q Is he an officer of the 4 company? 5 A No. 6 Q You don't know of any 7 study that Doctor Stewart Montgomery did for Lilly 8 using Prozac and examining the issue of whether or 9 not Prozac and suicidality are related? 10 A I do not. 11 Q You and he have never 12 discussed that? 13 A The only thing we have 14 ever discussed, as I stated to Ms. Zettler, we 15 discussed whether or not this was different or not 16 different from what is seen with other drugs, and 17 our conclusion was no. 18 Q But when you had that 19 discussion with him was when? 20 A I don't recall. These 21 are -- you see, they were never planned detailed 22 scientific type things. This is nothing more -- I 23 can't give it any other heading to make it more 24 important for you, Paul, other than in the course 186 1 of a conversation that would have come up, so I 2 can't tell you where or when because it never had 3 that importance. 4 Q Is Doctor Montgomery 5 prohibited from consulting for entities other than 6 Quintiles? 7 A No, he's not. 8 Q Do I understand it that 9 you have done, since you left Lilly, these dosage 10 studies in 1984 and 1986 on Prozac, is that 11 correct? 12 A Yes. 13 Q But you have done other 14 studies for other companies of other 15 antidepressants, correct? 16 A Yes. 17 Q And would that include 18 specific serotonin reuptake inhibitors? 19 A Yes, it would. 20 Q And do you know whether 21 or not there was a suicide inventory used in any 22 of those studies on other antidepressants? 23 A There was not in the 24 other studies that we had conducted. 187 1 Q Are you aware that there 2 are studies or scales in existence now that are 3 designed specifically to measure increases or 4 decreases in serious suicidal ideations? 5 A I've heard recently that 6 firms are thinking of questions, but I do not know 7 of any appropriate scale that gives the answer 8 other than the existing scales, such as MADRS and 9 Hamilton Depression, HAMD and MADRS. 10 MR. SMITH: No further 11 questions. 12 * * * * * 13 REDIRECT EXAMINATION 14 15 BY MS. ZETTLER: 16 Q Have you ever read Doctor 17 Beasley's meta analysis? 18 A No. 19 Q Did Doctor Feighner 20 coordinate the multicenter studies that were done 21 under Protocol 27 that we were talking about 22 earlier? 23 A No. 24 Q The coordination was done 188 1 out of Lilly? 2 A Yes. 3 Q That fixed dose study 4 that I believe you and Doctor Feighner worked on 5 together -- is that correct, worked on the fixed 6 dose study together? 7 A He was one of our sites. 8 It was multiple sites, though, for that, too. It 9 was a multi-site study. 10 Q Do you recall how many 11 patients were intended to be enrolled in that 12 study? 13 A Yes, the original study 14 was intended to have six hundred patients, and as 15 I recall, somewhere in the vicinity of six hundred 16 and fifty total were probably enrolled, plus or 17 minus a small number. 18 MS. ZETTLER: That's all 19 I have, thanks. 20 * * * * * 21 RECROSS-EXAMINATION 22 23 BY MR. SMITH: 24 Q Just to make sure my 189 1 assumption is correct, you're not a medical 2 doctor, are you, Doctor? 3 A No, that's correct. 4 (WITNESS EXCUSED.) 5 * * * * * 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 190 1 STATE OF KENTUCKY ) ) SS. 2 COUNTY OF JEFFERSON ) 3 I, MARY KATHLEEN NOLD, a Notary Public within 4 and for the State at Large aforesaid, do hereby 5 certify that the foregoing is a true, correct and 6 complete transcript of the deposition of PAUL 7 STARK, taken at the time and place and for the 8 purpose set out in the caption hereof; that the 9 witness was duly sworn before giving said 10 deposition; that the said deposition was taken 11 down by me in stenotype and afterwards transcribed 12 on a computer under my direction; that the 13 appearances were as set out in the caption hereof; 14 and that a request was made by counsel that the 15 deposition be submitted to the witness for reading 16 and signature. 17 GIVEN my hand as notary aforesaid, this 18 __________ day of ___________________, 1994. 19 My commission expires March 10, 1998. 20 21 ________________________________ MARY KATHLEEN NOLD 22 COURT REPORTER AND NOTARY PUBLIC STATE OF KENTUCKY AT LARGE 23 24 191 1 STATE OF___________________) ) SS: 2 COUNTY OF__________________) 3 I, PAUL STARK, do hereby certify that I have 4 read the foregoing deposition given by me on June 5 28, 1994, and that the answers contained therein 6 are true and correct to the best of my knowledge 7 and belief. 8 9 10 ______________________________ PAUL STARK 11 12 13 ______________________________ (DATE) 14 15 16 Subscribed and sworn to before me this day by 17 PAUL STARK. 18 My commission expires______________________. 19 20 ___________________________________ 21 NOTARY PUBLIC 22 23 ______________________________ 24 192 1 STATE OF____________________) ) SS: 2 COUNTY OF___________________) 3 I, PAUL STARK, do here certify that I have read 4 the foregoing deposition given by me on June 28, 5 1994, and that the answers contained therein are 6 true and correct to the best of my knowledge and 7 belief, with the following corrections: 8 PAGE/LINE CORRECTION REASON FOR CORRECTION 9 __________________________________________________ 10 __________________________________________________ 11 __________________________________________________ 12 __________________________________________________ 13 __________________________________________________ 14 _________________________________ PAUL STARK 15 _______________________________ (DATE) 16 17 18 Subscribed and sworn to before me this day by 19 PAUL STARK. 20 My commission expires_____________________. 21 22 ________________________________ NOTARY PUBLIC 23 24 ________________________________ 193