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: JOHN H. HEILIGENSTEIN, MD 15 16 DATE: APRIL 27, 1994 17 18 REPORTER: MARY KATHLEEN NOLD 19 20 *-*-*-*-* 21 22 23 KENTUCKIANA REPORTERS 730 WEST MAIN STREET, SUITE 250 24 LOUISVILLE, KENTUCKY 40202 (502) 589-2273 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 PAGE 3 WITNESS: JOHN H. HEILIGENSTEIN, MD 4 DIRECT EXAMINATION BY MS. ZETTLER 12 5 6 PLAINTIFF'S EXHIBIT NO. 1 95 7 8 QUESTION CERTIFIED 54 9 QUESTION CERTIFIED 184 10 QUESTION CERTIFIED 184 11 QUESTION CERTIFIED 186 12 QUESTION CERTIFIED 270 13 QUESTION CERTIFIED 272 14 QUESTION CERTIFIED 290 15 16 17 18 19 20 21 22 23 24 7 1 THE FOLLOWING DEPOSITION 2 OF JOHN H. HEILIGENSTEIN, MD, WAS TAKEN AT THE 3 OFFICES OF BAKER & DANIELS, 300 NORTH MERIDIAN 4 STREET, SUITE 270, INDIANAPOLIS, INDIANA, 46204, 5 ON APRIL 27 AND 28, 1994; SAID DEPOSITION TAKEN 6 PURSUANT TO NOTICE IN ACCORDANCE WITH THE RULES OF 7 CIVIL PROCEDURE. 8 *-*-*-*-* 9 A P P E A R A N C E S 10 11 NANCY ZETTLER COUNSEL FOR PLAINTIFFS 12 1405 WEST NORWELL LANE SCHAUMBURG, ILLINOIS 60193 13 14 15 PAUL SMITH COUNSEL FOR PLAINTIFFS 16 745 CAMPBELL CENTER 2 8115 NORTH CENTRAL EXPRESSWAY 17 DALLAS, TEXAS 75206 18 19 LAWRENCE J. MEYERS COUNSEL FOR ELI LILLY AND COMPANY 20 FREEMAN & HAWKINS 4000 ONE PEACHTREE CENTER 21 303 PEACHTREE STREET, N.E. ATLANTA, GEORGIA 30308-3243 22 23 24 8 1 APPEARANCES (CONTINUED) 2 CURTIS G. OLTMANS JAMES T. BURNS 3 ELI LILLY AND COMPANY LILLY CORPORATE CENTER 4 INDIANAPOLIS, INDIANA 46285 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: Nancy, before 2 we begin, just so the record is clear, Doctor 3 Heiligenstein's deposition, as I understand it, is 4 being taken in the same cases, I won't recite all 5 of them, that Doctor Wong, Doctor Fuller and 6 Doctor Talbott's depositions were taken in and 7 that it relates to Mr. Paul Smith and his state 8 court cases of Huslig which is in the state of 9 Kansas, and Biffle, Welch, Reves, Kung and Crosset 10 in the State of Texas. 11 Paul, you have stipulated 12 that the MDL confidentiality order of May the 22nd 13 of 1992 will govern these proceedings today, 14 right? 15 MR. SMITH: That's 16 correct. Additionally, I would like to add that 17 even though there's not been any notice issued in 18 connection with a particular case, I have, as of 19 yesterday, filed a notice of appearance in Cause 20 No. 92-037684, Patricia Boling, Individually, et 21 al., versus Eli Lilly and Company and Barry 22 Rosson, MD, pending in the 80th District Court in 23 Harris County, Houston, Texas. I'm going to hand 24 the court reporter a document with the style of 10 1 the case on it, and it is my intent with respect 2 to Eli Lilly and Company certainly to use this 3 deposition in that cause. 4 MR. MYERS: Right. My 5 recollection is that we have an agreed protective 6 order in that case, but whether we do or not, as 7 long as you are in agreement with my earlier 8 comments, I certainly have no problem with your 9 extending the use of that deposition to that state 10 court case as well. 11 MR. SMITH: Certainly, 12 and I will probably be filing a notice of 13 appearance in the Raymeyer case and should know on 14 that by the end of the day and will notify you 15 appropriately. 16 MR. MYERS: Right. 17 MR. SMITH: And if 18 there's a confidentiality order pending in that 19 case, certainly we'll be willing to abide by that. 20 MR. MYERS: I don't know 21 whether there is or not presently, but I suspect 22 that once that happens we can get that worked out 23 among ourselves as with these other cases. 24 MS. ZETTLER: Also, I 11 1 just filed a motion that will probably be filed 2 today in the Gardner versus Eli Lilly case pending 3 in the Circuit Court of Champaign County, 4 Illinois, motion for a substitution of counsel. 5 MR. MYERS: That has not 6 yet been granted though? 7 MS. ZETTLER: No. It's 8 my understanding that the judge pretty much 9 regularly signs them, so it may very well be 10 granted by the end of the day, but when the 11 appearance is filed, I intend to use this 12 deposition in that case too, and I'll stipulate to 13 using the protective order. 14 MR. MYERS: Once that 15 happens in both Raymeyer and Gordon we'll get that 16 worked out. 17 MS. ZETTLER: Fine. 18 *-*-*-*-* 19 JOHN HARRISON 20 HEILIGENSTEIN, MD, after having been first duly 21 sworn, was examined and deposed as follows: 22 23 24 12 1 DIRECT EXAMINATION 2 3 BY MS. ZETTLER: 4 Q Could you please state 5 your full name for the record? 6 A John Harrison 7 Heiligenstein. 8 Q Doctor Heiligenstein, 9 have you given a deposition before? 10 A Yes, I have. 11 Q On how many occasions 12 have you been deposed? 13 A Pardon? 14 Q On how many occasions 15 have you given a deposition? 16 A One occasion. 17 Q Have you given a 18 deposition in any Prozac cases? 19 A No, I have not. 20 Q When were you deposed the 21 one time you were deposed? 22 A Relative to my divorce. 23 Q When was that, the 24 deposition? 13 1 A 1991. 2 Q There are some ground 3 rules that we're going to need to follow to make 4 sure that the record is clear in the case, okay? 5 If there's any question that I ask you that you do 6 not understand, for any reason that you don't 7 understand it or you don't hear it properly or my 8 voice goes, please let me know and I'll either 9 repeat or rephrase the question so you can 10 understand it, okay? 11 A Sure. 12 Q You also have to answer 13 out loud. That's for the court reporter. She 14 can't take down a shake of head or uh-huh or 15 huh-uh, so you have to give verbal answers to the 16 questions. 17 A That's fine. 18 Q At any time you want to 19 take a break, let us know. We usually take a 20 break an hour, usually that is sufficient, but if 21 you feel you need to take a break for any reason, 22 let us know and we'll take a break, okay? 23 A That's fine. 24 Q What is your date of 14 1 birth? 2 A April 20, 1945. 3 Q And what is your current 4 address? 5 A XXXXXXXXXXXXXXXXXXXXXX 6 XXXXXXXXXXXXXXXXXXX. 7 Q How long have you lived 8 there? 9 A Two and one half years. 10 Q Do you have any current 11 plans to move? 12 A No, I do not. 13 Q And you said you are 14 divorced? 15 A That's correct. 16 Q Are you still single? 17 A Yes. 18 Q Do you have any kids? 19 A Two. 20 Q Could you give us their 21 names and ages, please? 22 A XXXXXXXXXXXXXXXXXXXXXXXX 23 XXXXXXXXXXXXXXXXXXXXXXXXXXX. 24 Q Except your divorce, have 15 1 you ever been involved in any litigation; have you 2 been sued or has somebody sued you? 3 A No. 4 Q You haven't sued anybody? 5 A Yes, I have. 6 Q Can you give us a little 7 idea of what that case was about? 8 A It's relative to the 9 divorce. 10 Q Something that's separate 11 and apart from the divorce? 12 A It's not related to my 13 ex-spouse in a sense. 14 Q I'm just trying to find 15 out if besides your divorce have you been involved 16 in any other litigation. 17 A Besides the divorce? 18 Q Right. 19 A Oh, no. 20 Q But you said you sued 21 somebody relative to the divorce? 22 A That's correct. 23 Q That in my mind, at 24 least, is two difference things, so I'm trying to 16 1 differentiate besides the actual divorce 2 proceedings, you have been involved in another 3 litigation? 4 A That's correct. 5 Q Can you tell me a little 6 bit about what that was about? 7 A A component of my ex- 8 spouse's testimony was lost in the transcription 9 at the time of her deposition. 10 Q So this is deposition 11 testimony, not trial testimony? 12 A That's correct. 13 Q And are you suing the 14 court reporter in that action? 15 A That's correct. 16 Q Is that case still 17 pending? 18 A It is. 19 Q When you say the 20 testimony was lost in transcription, what do you 21 mean? 22 A The audio tapes were lost 23 and the disk was dysfunctional and only a portion 24 of her testimony was available. 17 1 Q When you say her, you 2 mean your wife, your ex-wife? 3 A That's correct, yes. 4 Just a point of clarification of an earlier 5 question, the reporting firm is being sued as 6 well. 7 Q Okay. Besides that case, 8 have you been involved -- besides that and your 9 divorce, have you been involved in any other 10 litigation? 11 A None that I recall. 12 Q Have you ever served in 13 the military? 14 A I have. 15 Q Can you tell us about 16 that? 17 A From 1974 through 1976, I 18 was a Major in the United States Army, Chief of 19 Pediatrics at Fort Sheridan Army Health Center in 20 Fort Sheridan, Illinois. 21 Q Up in Highland Park? 22 A That's correct. 23 Q Were you Chief of 24 Pediatrics at Fort Sheridan from 1974 to 1976? 18 1 A That's correct. 2 Q I take it that's treating 3 family members of people in the service, correct? 4 You weren't treating people who were in the Army, 5 obviously. 6 A Dependents. 7 Q Was that an honorable 8 discharge? 9 A Correct. 10 Q Could you list for us 11 your education past high school? 12 A Okay. The years or just 13 the -- 14 Q The years, places and 15 degrees. 16 A It's long. 17 Q Okay. 18 A From 1963 to '67 I 19 attended the University of Illinois in Urbana; had 20 my Bachelor's Degree from that university. 21 From 1967 through 1971 I 22 attended Loyola University, Stritch School of 23 Medicine in Maywood, Illinois, from which I 24 obtained my MD. 19 1 From 1971 through 1973 I 2 was a pediatric resident at Children's Memorial 3 Hospital in Chicago, part of the Northwestern 4 family of hospitals. 5 From 1973 through 1974 -- 6 a year, July to July is usually the running dates 7 for residency programs -- I was a Fellow in 8 Neurology at the University of Kentucky Medical 9 Center in Lexington, Kentucky. 10 From '74 to '76, as I 11 mentioned, I was in the military. 12 From 1976 to 1978 I was a 13 Fellow and Chief Resident for the second year of 14 child, adolescent and family psychiatry at the 15 University of Virginia Medical Center in 16 Charlottesville, Virginia. 17 From 1978 through the end 18 of 1979, so for eighteen months, I was a resident 19 in general psychiatry at Cornell University 20 Medical Center, the White Plains campus. 21 Q I'm sorry, a resident in 22 what? 23 A General psychiatry. 24 Q Is that it? 20 1 A As far as education, 2 formal education, yes. 3 Q You said you got your 4 bachelor's at the University of Illinois, 5 Champaign, Urbana in '67. What was it, a 6 bachelor's in what? 7 A Zoology. 8 Q In the summer of '73 to 9 the summer of '74 you were a fellow in neurology 10 at the University of Kentucky in Lexington? 11 A That's correct. 12 Q It looks like your early 13 history in medicine was in pediatrics. Is there a 14 particular reason why you switched to psychiatry? 15 A I had always intended to 16 specialize within pediatrics. 17 Q So pediatric psychiatry 18 or psychiatry? 19 A My initial inclination 20 was towards child neurology, but I later made a 21 change to child and family psychiatry. 22 Q Why? 23 A It interested me. 24 Q Are you Board certified? 21 1 A Yes, I am. 2 Q In what areas? 3 A I have my Boards in 4 pediatrics, in psychiatry, and in child and 5 adolescent psychiatry. 6 MR. SMITH: Beg your 7 pardon? 8 A I have my Boards in 9 pediatrics, general psychiatry, and then my third 10 set of Boards is in child and adolescent 11 psychiatry. 12 Q How about neurology? 13 A No, I do not. 14 Q Did you take those 15 Boards? 16 A I was not eligible. 17 Q Why not? 18 A Three or four years are 19 required of neurology training. 20 Q How many years of 21 psychiatry training are required for the psych 22 Board? 23 A It has changed. At the 24 time I graduated from medical school I believe it 22 1 was three years. Currently I believe it's four 2 for general psychiatry. 3 Q And you obtained the 4 three years when you worked as a fellow at the 5 University of Charlottesville in child and 6 adolescent psych and then as a resident in general 7 psych at Cornell? 8 A That's correct. 9 Q Besides your formal 10 education, have you taken any seminars or other 11 continuing education type classes in psychiatry or 12 psychology? 13 A Yes, I have. 14 Q Could you list those for 15 us, please. As many as you can remember. 16 A I attend regularly the 17 child and adolescent psychiatry meetings, where 18 there are specific workshops and symposia 19 offered. In those meetings I have tended to focus 20 on disorders of childhood and then selected topics 21 in general psychiatry. 22 In addition, I have 23 attended the American Psychiatric Association 24 meetings on an irregular basis, and have attended 23 1 symposia and workshop at those meetings, very much 2 along the same lines. 3 Q Stressing mostly 4 adolescent psychiatry? 5 A In those arenas it was 6 primarily disorders of affect, anxiety spectrum 7 disorders, and to some extent psychotic disorders 8 of adults. 9 Q I'm sorry, anxiety what 10 disorders? 11 A Anxiety spectrum. I've 12 also attended others, if you're interested. 13 Q Sure. 14 A I've attended biological 15 psychiatry meetings where there are full day 16 symposium. I've attended the American College of 17 Neuropsychiatry meetings on an irregular basis. I 18 mean every couple of years I go usually, with the 19 opportunity to participate in similar such 20 workshops to those I described at the APA. 21 The Congress of 22 International neuropsychopharmacology meetings, 23 I've attended two or three of those. I've 24 attended some meetings of the American Society of 24 1 Adolescent Psychiatry and the International 2 Society of Adolescent Psychiatry, at least one 3 occasion for each of those, with again 4 participation as an attendee in workshops. 5 I attend fairly regularly 6 the NCDEU meetings which are held usually in June 7 in Florida. I've attended courses when I was in 8 practice that were offered through the American 9 Academy of Child and Adolescent Psychiatry. 10 Review courses, I've also 11 attended selected review course that are offered 12 through Harvard University, their program. 13 Q What is NCDEU? 14 A I don't know what all the 15 letters stand for, but it's a meeting that is 16 primarily sponsored by the National Institute of 17 Mental Health bringing together investigators, 18 physician researchers, to discuss study issues, 19 that sort of thing. 20 Q When you say study 21 issues, you mean the conducting of studies? 22 A The design of studies, 23 et cetera. 24 Q Does it have anything to 25 1 do with adverse event reporting? 2 A No, it does not; not to 3 my recollection. 4 Q Since 1979, when you 5 completed your residency at Cornell University, 6 have you been in private practice? 7 A I have been. 8 Q Can you tell us about 9 your private practice? 10 A I began private practice 11 in 1982 in Greensboro, North Carolina, and then I 12 returned to Charleston, South Carolina where I was 13 in private practice until September of 1986, when 14 I came to Lilly. 15 I left Lilly in July of 16 1987 and was director of a child inpatient unit at 17 Lutheran General Hospital in Parkridge, Illinois, 18 and then I returned to Lilly May the 3rd or 4th of 19 1988 and I have been here since. 20 Q What did you do from 1979 21 to 1982? 22 A I was an assistant 23 professor of pediatrics and psychiatry at the 24 Medical University of South Carolina in 26 1 Charleston, South Carolina. 2 Q In your private practice 3 in 1982 through September of '86, when you first 4 joined Lilly, was that psychiatric practice? 5 A That's correct. 6 Q General psych or 7 adolescent or child psych? 8 A I focused very heavily on 9 child and adolescent psychiatry, family 10 psychiatry. 11 Q I'm sorry, you said when 12 you were at Lutheran General you ran which 13 department? 14 A I was responsible for the 15 child inpatient psychiatry unit. 16 MR. SMITH: Is that in 17 Chicago? 18 MS. ZETTLER: Yes, it's 19 outside of Chicago in Oakridge. 20 Q (BY MS. ZETTLER) Why did 21 you leave Lilly in 1987? 22 A It was primarily for 23 domestic reasons. 24 Q When you say for domestic 27 1 reasons, can you give us a little more detail? 2 A My ex-wife was a medical 3 student at the University of Illinois in Chicago 4 and I was commuting and it was very difficult to 5 maintain the commute. 6 Q Why did you come back to 7 Lilly in May of '88? 8 A Pardon? 9 Q Why did you come back to 10 Lilly in May of '88? 11 A I really enjoyed what I 12 was doing when I was here, so I wanted to get back 13 into an active role in research and development of 14 compounds. 15 Q And you've been at Lilly 16 consistently to the present since May of '88? 17 A That's correct. 18 Q In your private practice 19 from 1982 to 1986, did you have occasion to 20 prescribe or give any patients fluoxetine 21 hydrochloride? 22 A I did. 23 Q Can you tell us about 24 those occasions? 28 1 A The window of opportunity 2 was limited given my return to Lilly in May of 3 1988. 4 Q Let me stop you. I meant 5 from when you started your private practice in 6 1982 until -- 7 A I'm sorry. 8 Q Another rule I forgot to 9 tell you, you have to let me finish my question 10 and I'll do my best to let you finish your answer. 11 She can't take us both down at once. 12 From 1982, when you first 13 began private practice, until September of '86 14 when you joined Lilly, did you have an opportunity 15 to administer fluoxetine to any patients? 16 A No, I did not. 17 Q Now, from when you left 18 Lilly in July of '87 until you came back to Lilly 19 in May of '88, did you prescribe fluoxetine to any 20 patients? 21 A Yes. 22 Q Tell us about those 23 occasions. 24 A It was just one patient. 29 1 Q Is that patient an adult 2 or an adolescent? 3 A Child. 4 Q And what was the reason 5 that you prescribed the fluoxetine to that child? 6 A The youngster was a very 7 complicated child and had been unresponsive to a 8 number of medications and had a significant 9 affective component to his disorder and I chose to 10 try fluoxetine. 11 Q When you say the child 12 had a significant affective component, are you 13 talking about depression? 14 A Yes. 15 Q Was that treatment 16 successful? 17 A It was. 18 Q Did the child experience 19 any adverse events during the course of fluoxetine 20 treatment? 21 A None that I recall. 22 Q What was the dosage that 23 you administered to that child? 24 A As I recall, twenty 30 1 milligrams. 2 Q Daily? 3 A Yes, ma'am. 4 Q Was this child an 5 inpatient or an outpatient? 6 A He was an inpatient. 7 Q Any other opportunity to 8 prescribe fluoxetine in any of your patients from 9 1987 to 1988, when you returned to Lilly? 10 A No. 11 Q When you were not 12 employed in-house at Lilly, did you have an 13 opportunity to run or participate in any way in 14 any clinical trials on fluoxetine? 15 A No, I did not. 16 Q Do you know Doctor John 17 Davis? 18 A I know of him. 19 Q Can you tell me what you 20 know about Doctor Davis? 21 A Just to be sure, where 22 does he live? 23 Q Chicago. 24 A I wanted to be sure we're 31 1 talking about the same John Davis. I just know 2 that he is well thought of in the field of 3 psychiatry for his research, in his area of 4 research. 5 Q What is his area of 6 research? 7 A I believe, the best I 8 recollect, he's studied affective disorders and 9 possibly done some work in schizophrenia. 10 Q Are you aware that Doctor 11 Davis participated in a clinical trial on 12 fluoxetine as an investigator? 13 A I'm sorry, I didn't hear. 14 Q Were you aware that 15 Doctor Davis participated in a clinical trial of 16 fluoxetine as an investigator? 17 A I was not aware. 18 Q Have you ever spoken with 19 Doctor Davis about fluoxetine? 20 A Not that I recall. 21 Q How about Jan Fawcett, do 22 you know who Jan Fawcett is? 23 A Yes, I do. 24 Q Who is Jan Fawcett? 32 1 A Jan Fawcett is a 2 professor and psychiatrist at Rush Presbyterian 3 Hospital in Chicago, Illinois. 4 Q What school is he a 5 professor with? 6 A I believe that's the Rush 7 Medical School. 8 Q Have you ever spoken with 9 Doctor Fawcett? 10 A Yes, I have. 11 Q On what occasions? 12 A Usually while attending 13 various scientific meetings. 14 Q Have you spoken with 15 Doctor Fawcett about fluoxetine? 16 A Yes, as best I recall. 17 Q Are you aware that Doctor 18 Fawcett participated in at least one clinical 19 trial on fluoxetine? 20 A I recollect that. 21 Q Have you ever spoken with 22 Doctor Fawcett about that clinical trial? 23 A Not that I recall. 24 Q Have you ever spoken with 33 1 Doctor Fawcett about the issue of violent 2 aggressive behavior in patients on fluoxetine? 3 A Violent aggressive 4 behavior directed towards self? 5 Q Directed towards others. 6 A No, I have not. 7 Q How about directed 8 towards self? 9 A Yes. 10 Q On what occasion did you 11 speak with Doctor Fawcett about that topic? 12 A As best I recall, Doctor 13 Fawcett was a consultant that we engaged to help 14 us explore the issue of suicidality. 15 Q Was that before or after 16 the 1991 Drug Advisory Committee meeting? 17 A That would have been 18 prior to that meeting. 19 Q Where was this 20 conversation with Doctor Fawcett, where did that 21 take place? 22 A It would have occurred at 23 Lilly. 24 Q Did you have a one-on-one 34 1 conversation with Doctor Fawcett or was it a 2 meeting in which Doctor Fawcett participated? 3 A It was more in the format 4 of a formal meeting and discussion. 5 Q When did these meetings 6 with the consultants take place? 7 A That I don't recall. 8 Q Was it before or after 9 January of 1990? 10 A I believe it was after 11 January of 1990. 12 Q To your knowledge, has 13 Doctor Fawcett ever been a member of Lilly's 14 Psychiatric Advisory Panel? 15 A That's my recollection. 16 Q Would you tell us about 17 that panel? 18 MR. MYERS: What about 19 it? 20 Q Generally when it was 21 begun, how many times it met, things of that 22 nature. 23 A I don't know when it was 24 organized and I don't know with what frequency it 35 1 met. 2 Q Was it organized before 3 you came to Lilly in September of '86? 4 A As best I recall, it was. 5 Q How many members were on 6 the panel? 7 A I don't know. 8 Q More than ten? 9 A I don't know. 10 Q Did you ever attend any 11 meetings where the panel was convened? 12 A I have. 13 Q On how many occasions? 14 A Two or three. 15 Q What was the first one 16 that you attended? 17 A It would have been 18 sometime in 1986 or 1987. 19 Q Have you ever worked for 20 the FDA or any other governmental agency related 21 to psychiatry? 22 A No. 23 Q Have you worked for the 24 FDA or any other governmental agency in any 36 1 capacity? 2 A As a physician in the 3 United States Army. 4 Q When you were a physician 5 in the Army, did you participate in any way in 6 clinical trials on medications? 7 A I did not. 8 Q Other than providing 9 medical services to dependents of enlistees, what 10 were your job capacities, what were your duties, 11 outside your duties as a Major in the Army? 12 A My time with the Army was 13 spent providing care to those dependents. In 14 addition, during that time I had a faculty 15 appointment at the Medical College of Wisconsin in 16 Milwaukee where I volunteered my services on a 17 once or twice monthly basis to the child neurology 18 program. 19 Q You say once or twice a 20 month? 21 A That's correct. 22 Q And when you say you 23 volunteered your services, was that a teaching 24 position or a consulting position? 37 1 A Teaching and clinical. 2 Q Was that for the entire 3 two-year period? 4 A Yes, ma'am. I also, 5 during that time, did some moonlighting at a home 6 for retarded individuals in southern Wisconsin. 7 Q What did you do at that 8 home for retarded individuals? 9 A Essentially provided 10 evening coverage. 11 Q Medical care? 12 A Medical care. 13 Q Psychiatric care? 14 A Not to any significant 15 degree. 16 Q Have you worked for any 17 other drug companies besides Lilly? 18 A I have not. 19 Q Other than what you've 20 already told us, have you had any other positions 21 that involved psychiatry or psychiatric care of 22 patients? 23 A Would you repeat the 24 question? 38 1 Q Sure. Other than what 2 you've already told us about your work at -- for 3 instance the moonlighting at the home for retarded 4 individuals in southern Wisconsin and your faculty 5 appointment in the Medical College of Milwaukee 6 where you did clinical work and you were in 7 private practice, have you had any other jobs that 8 have entailed providing psychiatric care or 9 involved the practice of psychiatry in any 10 capacity? 11 MR. MYERS: Are you 12 including his residency program? 13 Q No, outside of your 14 formal education. 15 A For completeness sake, I 16 did provide supervision to residents at Loyola 17 University of Chicago in 1986 into -- I'm sorry, 18 1987 to 1988, as a volunteer. 19 Q That was in addition to 20 your work at Lutheran General Hospital? 21 A That was in addition to 22 my -- I apologize, 1986 to 1987. That's in 23 addition to my work here at Lilly. 24 Q Okay. I'm sorry, where 39 1 did you work during that period of time? 2 A Loyola University. 3 Q Loyola. 4 A And then I'm active 5 locally on the board of directors of a mental 6 health agency. 7 Q Which one? 8 A Tri-County Mental Health 9 Center. 10 Q Do you provide patient 11 care in that capacity? 12 A I do not. 13 Q Is that a paid position? 14 A It is not. 15 Q I take it you've 16 published some papers in the area of psychiatry, 17 have you not? 18 A I have. 19 Q Would you give us an idea 20 of how many papers you've published? Throughout 21 your career, not just at Lilly. 22 A That have been published 23 or in press? 24 Q Right. Let's start with 40 1 have been published. 2 A I would say somewhere on 3 the order of eight or nine. 4 Q Can you list as many of 5 those for us as you can remember? 6 A Sure. I published a 7 paper that involved a meta-analysis of events of 8 aggression occurring during clinical trials with 9 fluoxetine. A less extensive version of that 10 paper was also published, so there were two 11 publications related to the same topic. 12 I participated in the 13 publication of a paper relative to events 14 occurring with co-prescribing of fluoxetine and 15 monoamine oxidase inhibitors. 16 I've published relative 17 to the efficacy of fluoxetine in patients with 18 melancholia. There are two papers relative to 19 melancholia. 20 Q Both on efficacy of 21 fluoxetine in treating that condition? 22 A That's correct. I 23 participated in the publication of the paper 24 relative to suicidality, the analysis of the data. 41 1 Q Doctor Beasley's 2 meta-analysis article? 3 A The first publication. 4 Q The publication that 5 appeared in the British Medical Journal? 6 A That's correct. 7 Q How about the 8 republication and reprint? 9 A I do not believe, I 10 cannot recall participating in that. Those are 11 the ones that I can recall of. 12 Q Any others on violent 13 aggressive behavior and the use of fluoxetine? 14 A No, not that I recall. 15 Q Any others on suicidality 16 related to the use of fluoxetine? 17 A None that I recall. 18 Q All of these papers were 19 published, I take it, throughout your career at 20 Lilly? 21 A That's correct. 22 Q How about outside your 23 career at Lilly, have you published anything? 24 A I have not. 42 1 Q You said that there were 2 some papers that were currently in press? 3 A That's correct. 4 Q Can you tell us what 5 those papers are? 6 A One is a paper which I 7 coauthored on design strategy, and I believe that 8 will appear in the Journal of the American 9 Statistical Association. 10 An additional paper will 11 be published relative to the efficacy of 12 fluoxetine in patients who have a reduced rapid 13 eye movement latency. 14 Q Any others? 15 A There are others that 16 have been submitted or that are being reviewed. 17 Q When you say submitted 18 and are being reviewed, you mean submitted to 19 journals? 20 A That's correct, and have 21 not been accepted, but are currently under review. 22 Q Can you list those for 23 us, please? 24 MR. MYERS: Before you 43 1 answer, you can tell her what the subjects are, 2 but I'm not going to let you disclose what the 3 journals are that you've submitted to at this 4 point, but tell her the subject matter certainly. 5 MR. SMITH: Why? 6 MR. MYERS: Because 7 that's confidential information. 8 MR. SMITH: Confidential 9 in what respect? 10 MR. MYERS: Those 11 manuscripts are submitted, Mr. Smith, in 12 confidence to the publishers of the journals. 13 I'll let the Doctor disclose the subject matter, 14 the other authors on the papers, I'm not going to 15 let him tell you who the journals are. 16 Q (BY MS. ZETTLER) I'd 17 like to start with the subject matter of those 18 papers. 19 A There is submission 20 relative to patients -- a comparison of fluoxetine 21 and imipramine in patients with depression and 22 agitation. A submission of a paper comparing 23 fluoxetine placebo in the geriatric population. 24 Q Any others? 44 1 A Those are the only others 2 I can recall at this time. 3 Q Who are your coauthors on 4 the fluoxetine versus imipramine agitated 5 depressed paper? 6 A Doctor Tollefson, and I 7 believe Mary Sayler. 8 Q Mary Sayler is a 9 statistician, right? 10 A That's correct. 11 Q Is this a paper that's 12 pending on fluoxetine versus imipramine in the 13 treatment of agitated depressed individuals the 14 result of a clinical trial? 15 A That's correct. 16 Q When was that clinical 17 trial run? 18 A I don't recall the 19 specific dates. 20 Q Can you give me years? 21 A Approximate would be -- 22 maybe 1989 to 1990. 23 Q From 1989 to 1990? 24 A Somewhere in that range. 45 1 Q Why has it taken so long 2 to get this published? 3 MR. MYERS: Object to the 4 form assuming it has taken so long. I don't know 5 what your question assumes has happened between 6 the time the trial has been over and today, but 7 answer the question, if you can. 8 A It is not unusual for 9 papers to take a long time to be published given 10 reviewer's comments and possibly the need to 11 submit to several journals sequentially if the 12 first journal rejects the papers. 13 Q Has this paper been 14 submitted to other journals that have rejected it? 15 A I'm not sure of that. 16 Q When did you first begin 17 work on this paper, personally? 18 A Probably, the best I can 19 estimate, 1992. 20 Q Was this clinical trial 21 performed in the United States or outside the 22 United States? 23 A In the United States. 24 Q How many investigational 46 1 sites were used on that? 2 A Two. 3 Q Do you know if this 4 clinical trial was begun before or after January 5 of 1990? 6 A I can't recall. 7 Q What is the conclusion of 8 that paper? 9 A That fluoxetine and 10 imipramine were of comparable efficacy and that 11 the safety profile for the compound was 12 extraordinary. 13 Q Which compound? 14 A Fluoxetine. 15 Q Was extraordinary? 16 A Yes. 17 Q In what way? 18 A There were no events, as 19 best I recollect, of patients who were at baseline 20 depressed and agitated that required them to leave 21 the study because of either worsening of their 22 agitation or any kind of self or other directed 23 violent ideations. 24 Q Was this an inpatient or 47 1 outpatient study? 2 A It was outpatient. 3 Q Was serious suicidal risk 4 and exclusion criteria on that study? 5 A I don't recall. 6 Q Were concomitant 7 administration of sedatives allowed on that study? 8 A I can't recall. 9 Q How about chlorohydrate? 10 A That's a possibility, I 11 just don't recall specifically the wording of the 12 inclusion exclusion. 13 Q Who decided that the 14 clinical trial on agitation should be run? 15 A It was a decision that 16 was really generated within the medical. 17 Q Were you involved in that 18 decision? 19 A Yes, I was. 20 Q Who else was involved in 21 that decision? 22 A My colleagues within the 23 cluster who were working with fluoxetine. 24 Q Can you give us some 48 1 names? 2 A Doctor Beasley, Doctor 3 Wheadon. 4 Q When did Doctor Wheadon 5 leave Lilly? 6 A I believe he left in 7 February or March of 1992. 8 Q Do you know why he left? 9 A To take advantage of an 10 opportunity that had been offered to him with 11 another company. 12 Q What company? 13 A Smith Kline Beecham. 14 Q Do you know why he chose 15 to leave Lilly to go to Smith Kline? 16 A It was a promotion. 17 Q To your knowledge, had 18 anybody at Lilly tried to convince Doctor Wheadon 19 not to leave Lilly? 20 A I certainly did. 21 Q How about besides 22 yourself, anybody else? 23 A Not that I'm aware. 24 Q To your knowledge, was 49 1 Doctor Wheadon dissatisfied with the progress of 2 his career at Lilly? 3 A I think there was some 4 dissatisfaction. 5 Q In what way? 6 A Doctor Wheadon is 7 ambitious, he's bright, a very competent young 8 man, and I think that constellation of attributes 9 led him to want to move quickly within an 10 organization. 11 Q Do you know if he tried 12 to move up in the ranks at Lilly quicker than he 13 was able to? 14 A Could you rephrase that? 15 Q Was he denied a promotion 16 at Lilly, to your knowledge? 17 A No, I'm not aware that he 18 was denied a promotion. 19 Q How long had Doctor 20 Wheadon been at Lilly? 21 A I would estimate about 22 four and one-half years. 23 Q Why did you and your 24 colleagues decide that it was necessary to perform 50 1 a clinical trial comparing fluoxetine and 2 imipramine in agitated depressed patients? 3 A Because there was a sense 4 that some physicians felt uncomfortable in 5 prescribing fluoxetine to patients who had 6 significant agitation at baseline as a component 7 of their depression, and it was our judgment that 8 the best way to address this would be to embark 9 upon a clinical trial. 10 Q Did this study have a 11 placebo arm? 12 A It did not. 13 Q Why not? 14 A It was felt that it was 15 more important to compare the compound to another 16 active compound that would be one of the more 17 preferred compounds for patients with a baseline 18 depression and agitation. 19 Q Is imipramine a tricyclic 20 antidepressant? 21 A It is. 22 Q Were other serotonin 23 reuptake inhibitors available on the market at the 24 time the study was run? 51 1 A As I best recollect there 2 were none of the selective serotonin uptake 3 inhibitors available in this country. 4 Q Did the group consider 5 comparing other selective serotonin reuptake 6 inhibitors to fluoxetine in treating agitated 7 depressed patients? 8 A No, we did not. 9 Q You said earlier that 10 there were two sites that were involved in the 11 clinical trial -- 12 A That's correct. 13 Q You have to let me finish 14 my question. 15 A I'm sorry. 16 Q How many patients total 17 were involved in the study? 18 A As I recollect, a hundred 19 and twenty-four. 20 Q When you say a hundred 21 and twenty-four, you mean a hundred and 22 twenty-four completers? 23 MR. MYERS: Let me object 24 to the form. When you say completers, what do you 52 1 mean? 2 Q People that completed the 3 entire study. 4 A That would have been a 5 hundred and twenty-four would have been 6 randomized, as I best recollect. 7 Q How many patients were 8 originally included before randomization? 9 A I don't recall. 10 Q How many patients 11 actually completed the entire trial? 12 A I don't recall. 13 Q What was your role with 14 regard to this clinical trial? 15 A I was the clinical 16 monitor for the trial. 17 Q Prior to this study, had 18 Lilly conducted any other clinical trials 19 regarding fluoxetine and the treatment of agitated 20 depression? 21 A None that I recall. 22 Q Tell us what your 23 responsibilities as a clinical monitor on this 24 study were. 53 1 A To begin, I was 2 responsible for the planning of the design of the 3 protocol and the preparation of the protocol. I 4 was also responsible for the selection of 5 investigators, for the implementation of the 6 study, for monitoring the study relative to safety 7 on a day-to-day basis, and then once the study was 8 completed, to facilitate the collection of the 9 data, the analysis of the data, and preparation of 10 a final report from the study. 11 Q Who were the clinical 12 investigators on the study? 13 MR. MYERS: Let me object 14 to the question and direct the witness not to 15 answer that question. That is a matter that has 16 been covered by several orders of both the 17 multi-district and the Fentress court, and we're 18 not going to disclose the information at this 19 time. So don't answer that, Doctor Heiligenstein. 20 Q Are you going to follow 21 your attorney's instructions and not answer the 22 question? 23 A Yes. 24 MS. ZETTLER: Certify it. 54 1 (QUESTION CERTIFIED.) 2 Q (BY MS. ZETTLER) Where 3 were those trials conducted? 4 MR. MYERS: Doctor, you 5 can tell her the cities they were conducted in. 6 A They were conducted in 7 Madison, Wisconsin and Minneapolis-St. Paul, 8 Minnesota. 9 Q Had these investigators 10 performed other clinical trials on fluoxetine for 11 Lilly to your knowledge? 12 MR. MYERS: You can 13 answer that. 14 A I believe that one had, 15 but I cannot be certain. 16 Q The one that you believe 17 that may have conducted another clinical trial, 18 was that physician from Madison or Minneapolis? 19 A From Madison. 20 MR. SMITH: What does 21 that mean? 22 MR. MYERS: What does 23 what mean? 24 MR. SMITH: When you do 55 1 this. 2 MR. MYERS: Just a 3 nervous habit. 4 MR. SMITH: I've noticed 5 it over several weeks here and maybe you can tell 6 us. 7 MR. MYERS: It's not a 8 signal, it's probably just one nervous habit that 9 I have. 10 MR. SMITH: I think it 11 would be especially appropriate for you to make an 12 analysis of that since you have training in child 13 psychiatry. 14 MR. MYERS: You don't 15 have to respond to that, Doctor. 16 MS. ZETTLER: Let's take 17 a break. 18 (SHORT BREAK TAKEN.) 19 Q (BY MS. ZETTLER) Doctor, 20 was the decision to perform the agitation study 21 made before or after September 1989? 22 A I can't recall. 23 Q Are you familiar with 24 Joseph Wesbecker? 56 1 A I am. 2 Q How are you familiar with 3 Joseph Wesbecker? 4 A I was familiar with 5 Mr. Wesbecker through the media accounts as well 6 as the information that we received here. 7 Q When you say we received 8 here, you mean Lilly received here in 9 Indianapolis? 10 A That's correct. 11 Q And what is your 12 understanding of acts committed by Mr. Wesbecker? 13 A It is my understanding 14 that he entered his place of employment or former 15 place of employment and wounded and killed some 16 individuals who were working at that time, and 17 then, as I best recollect, he shot himself. 18 Q Was the decision to 19 conduct the agitated depressed study comparing 20 fluoxetine to imipramine made before or after 21 Joseph Westbecker's acts? 22 MR. MYERS: Would you 23 tell him when that was? 24 Q September of 1989. 57 1 A I don't recall. 2 Q Had the issue of people 3 becoming agitated or agitation being exacerbated 4 in people who were agitated depressed been raised 5 at Lilly with the use of fluoxetine, had it been 6 raised at Lilly prior to Doctor Teicher's article 7 on suicidality and the use of fluoxetine? 8 A Could you repeat that 9 again, please? 10 Q Sure. I'm just trying to 11 get an idea of whether or not this agitated 12 depressed clinical trial was run before or after 13 the issues were raised regarding violent 14 aggressive behavior against oneself or others in 15 the use of fluoxetine, was it raised before 16 Teicher's article came out or before the events of 17 Joseph Wesbecker? 18 A I can't recall. 19 Q Is there any way we could 20 find that out? 21 A I think the one place 22 where one might find out is to look at the start 23 date of the study, and then most studies require a 24 minimum of six and possibly somewhat longer, nine 58 1 months of planning before they are actually 2 launched. 3 Q So earlier when you said 4 to the best of your recollection the study was run 5 in 1989 and '90, would that have included the 6 planning stage of the study or would that have 7 been the actual time that the study was performed? 8 A That may have included a 9 planning component as well. 10 Q Would documents 11 reflecting the date that this study was first 12 conceived be contained in your files? 13 MR. MYERS: When you say 14 conceived, are you referencing when it was 15 started? 16 MS. ZETTLER: No, he 17 testified already that he met with Doctor Beasley, 18 I believe, and Doctor Wheadon, and that they 19 decided to conduct the study on agitated depressed 20 patients and fluoxetine and I'm just wondering if 21 documents reflecting when that meeting at least 22 was held would be in your files. 23 A I don't know. 24 Q Do you usually keep 59 1 documentation like that in your files? 2 MR. MYERS: I'm sorry, 3 Nancy, but documentation like what, reflecting 4 that meeting or the starting of the study? 5 Q Both, reflecting the 6 meeting first; start with that first. 7 A I doubt that there would 8 be much or anything that I would keep from sort of 9 a discussion, brainstorming kinds of efforts. 10 Q How about when the 11 planning phase began, would you have documentation 12 of that, not necessarily the exact date when it 13 began, but documentation of the planning phase of 14 the study? 15 A I don't know. 16 Q What types of 17 documentation, what kinds of documents related to 18 any particular study that you were a clinical 19 monitor on would you keep in your files? 20 A That would be variable 21 depending upon the study. 22 Q How about the agitated 23 and depressed study, what types of documents would 24 you have kept on that study? 60 1 A I don't know. 2 Q Would you have kept 3 documentation on the contact between you and the 4 prospective clinical investigators? 5 A I don't know. 6 Q Would you have kept 7 enrollment documentation if there were people 8 enrolled in the study? 9 MR. MYERS: Him 10 personally? 11 MS. ZETTLER: Yes. 12 A I don't think so, but I 13 don't know. 14 Q Would you have kept site 15 audit information documentation? 16 A I don't know. 17 Q What types of 18 documentation do you recall keeping in your files, 19 generally? 20 MR. MYERS: With respect 21 to fluoxetine? 22 MS. ZETTLER: Right. 23 A That's a very broad 24 question. In general, with a study, I might have 61 1 kept early protocols that would then be -- would 2 evolve into more formal final protocol. In any 3 given study, but not necessarily so, I might have 4 kept specific information about study progress. I 5 may have kept some notes of phone conversations 6 with the investigators. 7 Q Anything else? 8 A I would have kept in most 9 instances a copy of the final report. 10 Q When you say the final 11 report, you mean the report submitted to the FDA? 12 A That's correct, the 13 report that we prepare once a study is completed. 14 Q The final report is 15 sometimes the basis of a manuscript that is 16 eventually published too, correct? 17 A That's correct. 18 Q How is it determined 19 whether or not the patients that were enrolled in 20 the study were suffering from agitated depression? 21 A Patients were required to 22 meet the DSM-3 revised criteria for major 23 depression, and in addition were required to meet 24 criteria for agitation based upon the research 62 1 diagnostic criteria, as best I recall, that had 2 been put together by what we call the St. Louis 3 group. 4 Q Who were the St. Louis 5 group? 6 A A group of academic-based 7 investigators, academic university-based 8 investigators who tried to systematize the 9 diagnosis of various psychiatric disorders 10 primarily for research purposes, and a great deal 11 of that effort was focused at Washington 12 University in St. Louis and were -- in some ways 13 would have been considered, as best I recall, the 14 forerunner of the DSM-2/3, criteria that are now 15 widely used. 16 Q You mean their 17 systemization is the basis for the DSM-3 criteria? 18 A It had an impact in terms 19 of a need for a systematic classification of 20 disorders. 21 Q Is this St. Louis group a 22 Lilly group? 23 A No, it's not; it's a 24 Washington University faculty in psychiatry. 63 1 Q Do you know any of the 2 members of that group? 3 A The one that was perhaps 4 most prominent was John Finer. 5 Q Anybody else? 6 A I recall that maybe 7 Robert Spitzer may have been a part of that, but 8 I'm not sure. 9 Q Anybody else? 10 A I can't recall other 11 names. 12 Q Is this group still 13 together? 14 A No. 15 Q When was this group 16 together? 17 A When they were 18 university-based. 19 Q Can you give me a year? 20 A I can't. 21 Q Before or after 1989? 22 A Before. 23 Q Before or after you 24 started at Lilly? 64 1 A Before. 2 Q So I understand this, is 3 it your testimony that this group worked to 4 categorize different types of depression, such as 5 retarded depression, agitated depression? 6 A It is my understanding 7 that there was a group of individuals that worked 8 to classify psychiatric disorders, of which one 9 would have been depression, and there was some 10 additional work in terms of trying to subtype 11 depression. 12 Q And this work had an 13 impact on the DSM criteria for various afflictions 14 on subtypes of afflictions, to your knowledge? 15 A I believe that it did. 16 Q Does the DSM have a 17 criteria for agitated and depressed individuals? 18 MR. MYERS: Which one? 19 MS. ZETTLER: III-R. 20 A Not that I recall. 21 Q The criteria that was put 22 together by the St. Louis group, was that 23 published? 24 A As I recall, it was. 65 1 Q Do you know where? 2 A No, I don't. 3 Q And this is criteria for 4 agitated depressed individuals? 5 A Uh-huh. 6 Q You have to say yes or 7 no? 8 A I'm sorry, yes. 9 Q Was this criteria used in 10 enrolling patients for the study, the agitated 11 depressed study? 12 A Yes, ma'am. 13 Q Would this criteria have 14 been in your file? 15 A I don't know. 16 Q Do you recall whether or 17 not you kept a copy of the protocol for the 18 agitated depressed study in your file? 19 A I'm not sure. 20 Q What is your best 21 recollection of whether or not you would have a 22 copy of that in your file? 23 A I just don't know. 24 Q You were the clinical 66 1 monitor on that study, correct? 2 A That's correct. 3 Q Would you have had to 4 refer to the protocol occasionally in your 5 capacity as clinical monitor on that trial? 6 A As a clinical monitor 7 during the course of the trial, yes. 8 Q Would you have kept a 9 copy of that protocol handy during the course of 10 that trial? 11 A I might well have. 12 Q What is your habit with 13 regard to what is done with protocols once the 14 study is completed? 15 MR. MYERS: Let me just 16 object to the form and ask what is done by what 17 person? 18 MS. ZETTLER: By him. 19 A As I recall, once a study 20 is completed, the protocol is incorporated into 21 the final report. 22 Q Not necessarily your copy 23 of the protocol, though? 24 A That's correct. 67 1 Q What I want to know is 2 what is your habit or what do you usually do with 3 the protocol once the study is completed? 4 A Once the final report is 5 completed, I usually do not keep my protocols 6 since a copy is incorporated into the final 7 report. 8 Q Occasionally over the 9 past few years you've been required to turn 10 documents within your files on fluoxetine over to 11 the legal department at Lilly, correct? 12 A Yes, ma'am. 13 Q And when you turn over, 14 they ask you to turn over all documents you have 15 in your possession at that time, at any given 16 time, to Lilly or the legal department at Lilly, 17 correct? 18 A That's correct. 19 Q Did they ever tell you 20 not to turn over copies of protocols? 21 A No. 22 Q Is it possible that 23 during the period of time that you were acting as 24 clinical monitor for the aggression study that you 68 1 would have turned over a copy of the protocol to 2 the Lilly legal department? 3 A It's possible. 4 Q Is it probable? 5 A It depends upon when the 6 study finished relative to when that request was 7 made. 8 Q When were you first 9 requested to start turning over documents to the 10 legal department on fluoxetine? 11 A I don't recall. 12 Q Before or after 1989? 13 A I don't recall. 14 Q And that's been done on a 15 quarterly basis since then, correct? 16 A To the best of my 17 recollection. 18 Q When was the last time 19 you turned documents over to the legal department 20 at Lilly? 21 A About a month to two 22 months ago. 23 Q What types of documents 24 did you turn over to them at that time related to 69 1 fluoxetine? 2 A I don't recall specifics. 3 Q Do you recall generally? 4 A It might have consisted 5 of -- well, anything that I received relative to 6 fluoxetine such as a publication, a communication, 7 would have been most likely part of that. 8 Q Are you working on any 9 studies at the present time with regard to 10 fluoxetine? 11 A Yes, I am. 12 Q Fluoxetine in the 13 treatment of depression? 14 A Yes, ma'am. 15 Q Okay, did you turn over 16 any documents related to those studies the last 17 time you turned over documents to the legal 18 department? 19 A The current studies? 20 Q Right. 21 A I don't recall if I have 22 or have not. 23 Q When you turn documents 24 over to the legal department, you don't turn over 70 1 your entire file every quarter, do you, or do you 2 turn over documents that you have not turned over 3 before? 4 MR. MYERS: When you say 5 your entire file, your entire file on what? 6 MS. ZETTLER: On 7 fluoxetine; anything he had related to 8 fluoxetine. 9 A I turn over what has not 10 been previously submitted. 11 Q How many documents 12 volume-wise did you turn over in the last 13 submission? 14 A Volume-wise, I have no 15 idea. 16 Q A box? 17 A I have no idea. 18 Q Do you have any 19 recollection whatsoever on what the volume was? 20 A I do not. 21 Q Did you physically turn 22 those documents over yourself? 23 A Can you specify -- 24 Q Tell me what the 71 1 procedure you went through the last time you 2 turned over a document was. 3 A Regularly, even more 4 often than quarterly, when I have a batch of 5 documents, I turn them over to my secretary, who 6 then is responsible for networking or giving them 7 to the correct people. 8 Q Is there an amount of 9 documents that you accumulate when you feel it's 10 necessary to turn them over to your secretary so 11 she could turn them over to legal? 12 A No. 13 Q When was the last time 14 that you did that, turned over documents to your 15 secretary to network? 16 A My best estimate would be 17 a month ago. 18 Q How many documents did 19 you turn over to her then? 20 A I don't recall. 21 Q More than ten? 22 MR. MYERS: Ten pages? 23 MS. ZETTLER: Ten 24 documents. 72 1 A Possibly. 2 Q More than a hundred? 3 A I doubt it. 4 Q Did you give her a stack 5 of documents or did you put them in some sort of 6 container? 7 A No, I give them to her. 8 Q Do you recall how big the 9 stack of documents that you turned over to her 10 was? 11 A I don't. 12 Q Were you able to carry it 13 all by yourself? 14 A Yes, ma'am. 15 Q Were you able to carry it 16 in one trip to your secretary? 17 A What I characteristically 18 do is when I get this much or this much, it 19 doesn't make any difference how much, I pass it on 20 to her. It could be a two-week interval 21 sometimes, it could be at a monthly interval. It 22 could be at the time of the quarterly request; I 23 then systematically go through my files and make 24 sure that all of the documents I have have been 73 1 submitted. 2 Q Have there been any 3 documents that you've been told not to turn over 4 to legal with regard to fluoxetine? 5 A Not that I recall. 6 Q Do you work on a 7 computer? 8 A Yes, ma'am. 9 Q Do you turn over any 10 disks with information to the legal department 11 with regards to fluoxetine? 12 A Disks? 13 Q Floppy disks. 14 A No. 15 Q Have you ever turned over 16 any floppy disks with information on it regarding 17 fluoxetine? 18 A Not that I recall. 19 Q Have you been asked to 20 download any information off of your computer and 21 turn it over to the legal department regarding 22 fluoxetine at any time? 23 A I put very little 24 information on disk. The only thing I put on disk 74 1 in my recent memory are manuscripts in 2 preparation. 3 Q That's not my question. 4 My question is have you ever been asked by anybody 5 in the legal department in Lilly to download 6 information off of your computer and give it to 7 them related to fluoxetine? 8 MR. MYERS: Downloaded 9 from the computer onto a disk or -- 10 MS. ZETTLER: Right, or 11 to any -- 12 MR. MYERS: I don't speak 13 computerese. 14 A The instructions were to 15 provide, you knew, information on all documents 16 that we would have had to legal. 17 Q So answer my question, 18 okay? Have you ever been asked to download any 19 information off of your computer, put it on floppy 20 disk or transfer it to another file, a computer 21 file, or in any way move information off of your 22 hard drive on your computer to any other format 23 related to fluoxetine and transfer it in some way 24 to the legal department at Lilly? 75 1 MR. MYERS: Does that 2 include to print something too? 3 MS. ZETTLER: No. 4 MR. MYERS: Just 5 downloading. 6 MS. ZETTLER: No, just 7 talking about -- 8 A I don't recall. 9 Q Okay, how about E-mail 10 messages? 11 A Yes. 12 Q You've been asked to take 13 those off and give them to the Lilly legal 14 department? 15 A That's correct. 16 Q What medium did you use 17 to transfer those E-mail messages to the legal 18 department? 19 A Hard copy. 20 Q So they asked you to 21 print them all out? 22 A That's correct. 23 Q Do you have a file on 24 your hard drive where you store E-mail messages? 76 1 A I do not. 2 Q How is it that you 3 retrieve those E-mail messages to give to the 4 legal department? 5 A What I do is I print any 6 message I receive relative to fluoxetine. 7 Q As it comes in? 8 A As it comes in. 9 Q So you have a file that 10 you keep? 11 A I do not keep a file. I 12 get the message, print it off and turn it over to 13 my secretary. 14 Q Does your secretary 15 generally maintain your files for you on 16 fluoxetine? 17 A No. 18 Q Has she kept copies of 19 all the documents that you turned over to the 20 legal department related to fluoxetine? 21 A It is my understanding 22 that those documents are copied and then returned 23 to us. 24 Q Do you know if your 77 1 secretary then keeps the copies that are returned 2 to you? 3 A I don't know. 4 Q What is her name? 5 A Melanie Baker. 6 Q How long has she been 7 your secretary? 8 A A little over a year. 9 Q Who was your secretary 10 before Melanie? 11 A Jana Hall. 12 Q How long was she your 13 secretary? 14 A Approximately a year. 15 Q Is she still with the 16 company? 17 A She is. 18 Q Where is she now? 19 A I believe she's in Human 20 Resources. 21 Q Was your system with Jana 22 the same as it is with Melanie as far as turning 23 over periodically your documents and fluoxetine 24 for her to network? 78 1 A Yes, as I recall there 2 was an individual who was assigned to retrieve 3 those documents from staff and to forward those to 4 the legal department. 5 Q My question is, though, 6 was your procedure similar with Jana as it was the 7 procedure you just described to us that you do 8 with Melanie where you turn over periodically 9 documents on fluoxetine and then Melanie turns 10 them over to legal or in some way transfers them 11 to legal? 12 A Yes. 13 Q Were there any adverse 14 events that were recorded from the agitated 15 depressed study on fluoxetine, any whatsoever? 16 A There were events 17 recorded. 18 Q What types of events were 19 recorded? 20 A I don't recall 21 specifically. 22 Q How about your paper, 23 does it list any events that were recorded? 24 A It does address some 79 1 events. 2 Q Which events? 3 A Specifically, as I 4 recall, two patients developed suicidal ideations 5 during the course of the trial. 6 Q Were those patients on 7 fluoxetine or imipramine? 8 A Imipramine. 9 Q Was there a placebo 10 washout period in this trial? 11 A Prior to randomization. 12 Q Did anybody suffer 13 adverse events related to suicidal ideations 14 during the placebo washout phase of the trial? 15 A Suicidal ideation is not 16 an adverse event. 17 Q Why not? 18 A It's a component of the 19 illness. 20 Q Doctor, is it your 21 testimony that nobody has ever become suicidal 22 because of the use of fluoxetine? 23 A In my estimation, to the 24 best of my knowledge, no. 80 1 Q Nobody has ever become 2 suicidal because of using fluoxetine? 3 A To the best of my 4 knowledge. 5 Q How about hostile or 6 violent, has anybody ever become hostile or 7 violent because of using fluoxetine? 8 A To the best of my 9 knowledge, no. 10 Q Do you recall personally 11 ever making a determination that an instance of 12 suicidal ideation or suicide attempt or suicide 13 was reasonably related to the use of fluoxetine? 14 A Yes. 15 Q What is the difference 16 between that and somebody becoming suicidal? 17 A In making those 18 assignments, one, I chose to be very conservative, 19 so although I may not think that, I may have 20 assigned so, so that the report would have been 21 filed and brought to the notice of a regulatory 22 body. 23 Q Meaning the FDA? 24 A Correct. 81 1 Q Are you saying that you 2 made that determination so a particular adverse 3 event would be reported as an alert event? 4 A If the event was serious. 5 Q You would do that if you 6 felt the event was serious? 7 A We assign causality if 8 the event is serious, meets the criteria for 9 severity. 10 Q Meaning an outcome of 11 death, hospitalization, overdose, cancer, 12 congenital anomaly, correct? 13 A Those are some of those 14 criteria. 15 Q What are the other 16 criteria? 17 A They have varied. I 18 think there's been some variation, but other 19 reasons, serious, I think permanent disability may 20 be one of those criteria. 21 Q What categories come 22 under other reason, serious? 23 A If there is a degree of 24 specificity or severity to the event as it has 82 1 been reported, one can assign other reasons, 2 serious. 3 Q What do you mean when you 4 say a degree of specificity? 5 A I think what I wanted to 6 say was that relative to expectancy for the degree 7 of severity, one for specificity that is, so that 8 if an event occurs which is serious -- and I'm 9 diverging here a bit to clarify the point I made 10 earlier -- if in the estimation of the monitor it 11 is of sufficient specificity relative to what is 12 available in a package labeling, then one can 13 change expectancy to make it an unexpected. 14 Q Give me an example with 15 regard to suicidal ideation where an event would 16 be of such specificity that you would consider it 17 unexpected? 18 A There are really none. 19 We did have some guidelines that any death 20 reported with fluoxetine, whatever the nature of 21 the event, would be reported as unexpected. 22 Q How many people have died 23 within clinical trials related to the use of 24 fluoxetine? 83 1 A I don't know. 2 Q More than a hundred? 3 MR. MYERS: Let me just 4 ask for clarification. When you say related, you 5 mean in fluoxetine clinical trials where that was 6 one of the drugs? 7 MS. ZETTLER: He answered 8 it, Larry, he understood it. 9 MR. MYERS: I object to 10 the form. 11 MS. ZETTLER: Doctor 12 Heiligenstein knows that if there is something 13 that he is not clear about in one of my questions, 14 that he has the right to ask me to clarify it or 15 repeat it. He answered the question, he 16 understood it. 17 A I would clarify that. 18 Q Pardon? 19 A Can I clarify that? 20 Q Sure. 21 A Because I think I 22 really -- the way you worded the question, I 23 think, is -- I would respond differently. 24 Q How did I word the 84 1 question, tell me what your understanding of the 2 question is. 3 A I'm sorry, you said 4 related. I'm not aware of any deaths that I can 5 recollect that are related to fluoxetine. 6 Q Not one single death 7 related to the use of fluoxetine? 8 A None that I can recall. 9 Q How about people using 10 fluoxetine in combination with MAO inhibitors? 11 People have died using that combination of the 12 drug, have they not? 13 MR. MYERS: In a clinical 14 trial? 15 MS. ZETTLER: Yes. 16 A I do not recall that 17 occurring during clinical trials. 18 Q How about outside the 19 clinical trials? 20 A There have been deaths 21 reported when monamine oxidase inhibitors and 22 fluoxetine have been used in close proximity. 23 Q With close proximity of 24 each other? 85 1 A That's correct. 2 Q How many people have died 3 from that situation? 4 A I don't recall. 5 Q Do you recall any deaths 6 whatsoever during clinical trials on fluoxetine? 7 A Do I recall deaths 8 occurring during clinical trials? 9 Q Yes. 10 A Yes. 11 Q How many? 12 A I don't recall. 13 Q Can you give me an 14 approximation? 15 MR. MYERS: In patients 16 on fluoxetine or just in trials? 17 MS. ZETTLER: In trials, 18 let's start with in trials. 19 A I don't recall. 20 Q More than a hundred? 21 A I don't know. 22 Q How about people in 23 clinical trials on fluoxetine who have committed 24 violent acts, are you aware of any such situation 86 1 where somebody in a clinical trial has become 2 violent or committed a violent act? 3 A Well, I participated in 4 an analysis of the data from the clinical trials. 5 Q I know that. 6 A So in that process, we 7 sought to identifying individuals who would have 8 met criteria to have been violent towards others. 9 Q So what's the answer to 10 my question, are you aware of anybody who has 11 become violent during a fluoxetine clinical trial? 12 A I recollect that there 13 were patients who may have become violent during 14 clinical trials. 15 Q What criteria did you use 16 when you reviewed the databases? 17 A It's very long. 18 Q What is the criteria, 19 Doctor? 20 A To give you the criteria, 21 I would like to go through the process. 22 Q Sure. 23 A We wanted to address this 24 particular issue as scientifically as possible 87 1 with the search of the database remaining blinded 2 to those individuals responsible for the 3 leadership of the meta-analysis, which primarily 4 resided in my domain, so I was primarily 5 responsible for that. 6 Q So you were blinded is 7 what you're saying? 8 A That's correct. In 9 discussing this with several individuals, we first 10 went through the post marketing adverse events, 11 and what we did is we looked through the 12 dictionary listing, that meaning either the ELECT 13 or the Co-Start dictionaries, whatever dictionary 14 we used during the course of those clinical 15 trials. 16 Q Wait, let me interrupt 17 you. First you said you went through the post 18 marketing adverse events? 19 A I'm sorry -- 20 Q So are we in post 21 marketing or clinical trials? 22 A We're in post marketing. 23 Q Okay. 24 A We didn't want to look at 88 1 the clinical trial database until we knew how best 2 to look at that clinical trial database. So as 3 best I recollect, we went through the dictionary 4 and selected all those terms that could possibly 5 have incorporated as a component of that event a 6 violent expression toward another. 7 Q Okay. 8 A We selected all those 9 events and then ran an output from post marketing 10 reports. 11 Q The DEN database? 12 A That's correct, of all 13 such events that had been reported to us. We then 14 reviewed each of those reports and we 15 established -- we identified from clinical trials, 16 as I best recall, eight or ten such occurrences. 17 We then selected from the larger pool of events 18 those that would most likely -- and this is to the 19 best of my recollection -- those that would most 20 likely have incorporated an adverse event of 21 violence towards another or an event of violence 22 towards another, where there may be that event 23 embedded in it, in the event as reported. 24 Q What do you mean when you 89 1 say the event embedded in it? 2 A Well, may I give you an 3 example? 4 Q Sure. 5 A Antisocial personality. 6 If someone struck another person, a reporter, in 7 reporting that to Lilly, or in our internal review 8 mechanism, the event may have been assigned to 9 antisocial personality. It might not have fallen 10 into something that was readily captured for that 11 particular event, and at that time, as best I 12 recall, the dictionaries were somewhat limited in 13 sort of capturing specifically that type of event, 14 although, as you might well expect, how one 15 defines violence can be very broad in terms of 16 verbal, nonverbal, et cetera. So, I wanted to be 17 sure that if such an event occurred and it had 18 been assigned to antisocial personality, that we 19 would capture that event. 20 So, from this process we 21 developed a list of approximately twenty events 22 that we then applied blindly to the clinical trial 23 database to capture any such events, and it was a 24 very sort of exhaustive look that led to that 90 1 point, and from that we received specific events 2 of patients who may have had their event coded as 3 antisocial personality or some other such event. 4 Q Let me make sure I 5 understand this. You went through the Co-Start 6 and ELECT dictionaries and gleaned from those 7 dictionaries event terms that you felt were 8 related in some way to violent aggressive 9 behavior? 10 A That could have 11 incorporated violent or aggressive behavior, and 12 that was a process that involved more than just 13 myself. 14 Q When I say you, I mean 15 the people you were working with. 16 A Exactly. 17 Q When I say you, I mean 18 Lilly generally, the people who were responsible, 19 okay? 20 A Okay. 21 MR. MYERS: At least for 22 this series of questions. 23 MS. ZETTLER: Right. 24 Q So you went through, just 91 1 went through and looked at event term to event 2 term, down the line to see what was listed that 3 you felt may have incorporated violent aggressive 4 behavior, for instance, like you said, antisocial 5 personality and things of that nature? 6 A We went event by event, 7 correct. 8 Q Then you ran those event 9 terms in the DEN database? 10 A That's correct. 11 Q And you pulled the 1639 12 printouts of those event terms, correct? 13 A That's correct. 14 Q And then you went through 15 and looked at those 1639's to see if somebody had 16 actually committed harm or tried to commit harm to 17 somebody else? 18 A That's correct. 19 Q Okay. And of those cases 20 where somebody tried to commit harm to somebody 21 else, what did you do? How did it impact, how did 22 the fact that they tried to commit harm to 23 somebody else impact on your analysis? 24 A Then what we did is we 92 1 made a decision as to which of those many events 2 that were initially sort of screening types of 3 events would seem to have been most likely to 4 capture an event. 5 Q Where somebody committed 6 harm towards somebody else? 7 A That's right, where that 8 sort of allegation had been made, and at that 9 point we had no idea if this would have been 10 verbal or nonverbal or just a perception, other 11 than it being reported, and so we took -- were 12 able to identifying roughly twenty key event terms 13 that we then applied blindly to the database. 14 MR. SMITH: The clinical 15 trial database? 16 THE WITNESS: That's 17 correct. 18 Q Were the events where 19 people -- let's say for instance hostility was 20 reported but the person who was hostile had not 21 made an actual aggressive act or move, were those 22 considered also? 23 A Yes. 24 Q Or was it just adverse 93 1 events where somebody had actually committed an 2 injurious act to somebody else used? 3 A Our efforts were to be as 4 inclusive as possible, and so where there was any 5 possibility that an event term, even though it had 6 only identified in the initial screening verbal 7 aggression, we would have been -- we would have 8 included that in our effort to be inclusive. 9 Q So it was verbal 10 aggression, physical aggression. Any other types 11 of aggression towards others? 12 A I suppose one could say 13 perceived aggression; that is where a reporter 14 said he or she seemed hostile or whatever in a 15 post marketing would have been something that we 16 would have looked at very careful as well, so that 17 we wanted again to be as inclusive as possible. 18 So there are certainly -- in life in general there 19 are specific occurrences of nonverbal hostility or 20 aggression and there are specific instances of 21 verbal -- no, verbal hostility and aggression, and 22 then there would be what you and I might perceive 23 as hostile or aggressiveness that might not be in 24 the eyes of another, so it would be our 94 1 perception. 2 Q What is the aggression 3 cluster of events? 4 A As best I recall, those 5 were those key events that we identified that we 6 would apply to the clinical trial database. 7 Q Okay, and that wasn't 8 seventeen events, though, correct, or twenty 9 events? 10 A I don't recall. 11 Q You narrowed down the 12 number of events that you decided were to be the 13 aggression cluster of events, correct? 14 A We narrowed those, but as 15 best I recall, that was still a rather sizeable 16 number of events. 17 (EXHIBIT NO. 1 MARKED FOR 18 IDENTIFICATION.) 19 Q Have you had a chance to 20 review exhibit one, Doctor? 21 A I have. 22 Q Do you recognize this 23 exhibit? 24 A I do. 95 1 Q Tell me what it is. 2 A These are events, as best 3 I recall, that we selected from the ELECT 4 dictionary that would most likely have 5 incorporated verbal and nonverbal aggression. 6 Q Intentional injury isn't 7 on here, is it? 8 A It's not. 9 Q Is that one that you 10 recall having used? 11 A As best I recall, that 12 was not a term that was in the ELECT dictionary. 13 Q How about Co-Start? 14 A As best I recall at the 15 time this analysis was done, it was not in 16 Co-Start. 17 Q Is it your testimony that 18 that term has since been incorporated into the 19 Co-Start dictionary? 20 A I believe it has been. 21 Q When was this analysis 22 done? 23 A This analysis was done -- 24 I believe it was done in 1989. 96 1 Q Do you see any event 2 terms that were pulled from the ELECT dictionary 3 that you recall that is not on this list? 4 A None that I recall. 5 Q Was this project done in 6 1989 before or after the Wesbecker incident? 7 A After Wesbecker. 8 Q Do you recall this being 9 done specifically in response to the Wesbecker 10 incident? 11 A Yes. 12 Q Which of these event 13 terms were then used to search the clinical trial 14 database? 15 A I can recall several, but 16 I don't recall all. 17 Q Okay. 18 A The two that come to mind 19 most immediately are hostility and antisocial 20 reaction. As I recall, there were several others 21 as well. 22 MR. SMITH: What are 23 they? 24 THE WITNESS: I don't 97 1 recall which of these others would have been part 2 of that cluster. 3 Q (BY MS. ZETTLER) Is the 4 cluster defined in your article? 5 A It is. 6 Q If I told you there was 7 three events that are listed in the article, would 8 that surprise you, to make up the cluster? 9 A No. 10 Q Why weren't all of these 11 events run on the clinical trial database? 12 A Because in looking at 13 these -- in pooling the events from post 14 marketing, there were not events that we could 15 identify where the individual, apart from, let's 16 say, another medical or neuropsychiatric illness, 17 engaged in aggressive verbal and nonverbal 18 behaviors towards another. 19 Q What do you mean when you 20 say apart from another psychiatric illness? 21 A Well, for instance, an 22 individual can experience delirium as part of a 23 metabolic illness such as thyroid disease and can 24 be aggressive towards another, and that -- the 98 1 most likely explanation is the fact that the 2 individual is experiencing the delirium. 3 Q Would that information be 4 listed on the 1639, that they're suffering from a 5 thyroid disorder? 6 A Oftentimes it was, yes. 7 Q I guess I'm a little 8 confused. Were all of these people being treated 9 for depression with fluoxetine that you reviewed? 10 A I don't know. 11 Q Did you limit it to the 12 treatment of depression? 13 A Post marketing? 14 Q Your search, right. 15 A The post marketing 16 search? 17 Q Right? 18 A No. 19 Q Do you recall, was it 20 broken down in any way with regards to people who 21 were suffering from depression that suffered these 22 adverse events as opposed to some other 23 indication? 24 A I do not believe we split 99 1 out where there was an indication listed and where 2 there wasn't an indication, and within that 3 indication, when an indication was noted, whether 4 we -- I don't recall that we did that. 5 Q Okay. I want to get an 6 understanding of how this process actually 7 worked. After you gleaned the event terms from 8 the ELECT dictionary, you then asked the systems 9 department to run a search on the DEN database for 10 these ELECT terms, correct? 11 A That's correct. 12 Q And how long did that 13 search take, do you know? 14 A I don't recall. 15 Q Was it months? 16 A No. 17 Q Weeks? 18 A I can't be sure. 19 Q Okay. What was the 20 result of that, was that a printout of the actual 21 adverse events or was it the 1639's that were 22 turned over as a result of this search? 23 A 1639's. 24 Q Okay, so eventually your 100 1 group got a stack of 1639's, correct? 2 A That's correct. 3 Q As a result of this 4 search of all of these adverse event terms? 5 A That's correct. 6 Q And then you physically 7 went through those 1639's? 8 A That's correct. 9 Q Do you recall how many 10 1639's you were given? 11 A I don't. 12 Q Did everybody review all 13 of the 1639's, everybody in your group, or were 14 they split up between you? 15 MR. MYERS: Is the 16 question were the reports reviewed by more than 17 one person? 18 MS. ZETTLER: Yes. 19 A As best I recall, I 20 reviewed every event. Where there was any 21 question about how to classify an event, then I 22 had a point person colleague who, as I recall, 23 assisted me with reaching a final judgment. 24 Q Who was that? 101 1 A Doctor Beasley. 2 Q I want to know what 3 happened to the original stack of 1639's that the 4 Systems Department came and gave to you and said 5 here's the result of your inquiry regarding these 6 event terms. Did you review every single 1639? 7 A I did. 8 Q And what did you do in 9 the process, tell me about that process? 10 A I went through and 11 reviewed each one and sought to identify any event 12 that involved, in a very inclusive way, aggression 13 towards another. 14 Q What determined in your 15 mind whether or not an event included aggression 16 towards another? 17 A As best I recall, what I 18 tried to do in that process, in reading each of 19 those carefully, was to ascribe whether the event 20 occurred in either a verbal or nonverbal fashion 21 directed towards another, and any attenuating or 22 additional information that would shed light on 23 that specific event. 24 Q What other information? 102 1 A Such as illnesses, other 2 illnesses that could possibly have precipitated 3 the event. 4 Q Where in the 1639 would 5 other illnesses be listed? 6 A As I recall, it could 7 have been in -- it might have been in the comments 8 section. That's where the initial report is 9 recorded. Occasionally it was -- it may have been 10 mentioned in the section that deals with 11 concomitant medications. So it would be the text 12 or concomitant medications is where one might see 13 that. 14 Q Now, in every case where 15 there appeared to be another illness that could 16 account for the person's behavior, did you 17 discount that adverse event? 18 A I did not. 19 Q What did you do? 20 A I reviewed it with my 21 colleague. 22 Q Doctor Beasley? 23 A Yes. 24 Q Did he make the decision 103 1 on whether or not to include that adverse event or 2 discount it because of another illness? 3 A We did that together, so 4 it was not -- if there was any question in my 5 mind, I visited that question to Doctor Beasley, 6 and then in collaboration we would say is this an 7 event that looks as if we have no other 8 attenuating circumstances that we can clearly 9 identify based upon this report. 10 Q Other than reviewing the 11 1639's, did you do any investigation on any 12 individual adverse event? 13 A Such as? 14 Q Call the investigator or 15 the person reporting the adverse event. 16 A Not that I recall. 17 Q Why not? 18 A Well, I'm not sure that 19 we didn't, but I can't recall. But if -- it may 20 have been that the event would have been rather 21 straight forward, that there may have been 22 sufficient information, or that we felt in our 23 clinical and scientific judgment that we could 24 make that decision. 104 1 Q That another disease was 2 more likely the cause of the adverse event as 3 opposed to the fluoxetine? 4 A No, that the other 5 disease might have been associated with the event 6 rather than causative, but that it was more likely 7 a component of that illness rather than the 8 illness for which fluoxetine is being prescribed. 9 MR. SMITH: You need to 10 correct that; I don't think you meant to say that. 11 (ANSWER READ ALOUD.) 12 Q (BY MS. ZETTLER) Are you 13 comfortable with that response? 14 MR. MYERS: Is that what 15 you intended to say? 16 A I guess what I'm trying 17 to capture is that there are events that occur -- 18 let me think of something that would be an 19 example. Let's take an LSD psychosis. An 20 individual with depression may be treated with an 21 antidepressant. If that individual happens to 22 take LSD, that individual may or may not become 23 violent. In such a situation, one would say that 24 it was most likely that the event of violence 105 1 would have occurred in the context of the 2 ingestion of the LSD rather than necessarily even 3 been a part of his or her core illness, and in my 4 estimation would bear no relationship to 5 fluoxetine. 6 Q How about Joseph 7 Wesbecker, did you review his 1639 as part of this 8 search? 9 A That was the post 10 marketing event that led to this exercise. 11 Q Okay, but did you review 12 his 1639? 13 A Oh, yes. 14 Q Did you make the 15 determination as to whether or not you thought it 16 was reasonably causally related to the use of 17 fluoxetine? 18 MR. MYERS: Let me object 19 to the form because I don't know that he's 20 testified that that's the exercise he was going 21 through. Are you asking this as a separate 22 question? 23 MS. ZETTLER: Right. 24 A I see, okay. I don't 106 1 know who ascribed causality, so I'm not sure I can 2 answer that question in terms of -- 3 Q You did not ascribe 4 causality? 5 A I don't know that I did 6 or I didn't, I don't recall. 7 Q Did you sign off on the 8 working form for his 1639? 9 A I don't know that either. 10 Q How about in this 11 exercise where you reviewed the 1639's that were 12 gleaned from the DEN as a result of the search of 13 these adverse events, did you review 14 Mr. Westbecker's 1639 as part of that? 15 A It would have been the 16 nodal event that led to this exercise so that we 17 would have reviewed it with what information we 18 would have had available at that time. 19 Q Where would 20 Mr. Westbecker's 1639 have fallen as a result of 21 your search, would it have been included in one of 22 the events that you thought was relevant to your 23 search of the database or would it have been 24 removed from that group? 107 1 A If, for instance, that 2 event had not been the nodal event, it would have 3 depended upon what dictionary term would have been 4 ascribed to the event as to whether one of these 5 events would have captured it. I would have every 6 reason to believe that that event would have been 7 captured with these terms. 8 Q As far as using that 9 event as part of your determination as to which 10 ELECT terms to search the clinical trial database 11 with, how would his 1639 have been incorporated? 12 In other words, would he have been marked under 13 the category -- if he fell under one of these 14 adverse events, would another check be put under 15 like the hostility category, that you found 16 another adverse event under hostility where 17 somebody was injurious towards another person? 18 A As I recall, we did have 19 a numerical count of events with each of these, as 20 I best recall. Some of these, of course, would 21 have been duplications, so more than one event 22 could have been ascribed to a given individual's 23 behavior, actions, et cetera, so that it is 24 possible that we would have had a numerical count, 108 1 as best I remember. 2 Q So did you have a cutoff 3 as to did you say well, ninety percent of these 4 fall under the hostility category, so we're going 5 to choose hostility as an adverse event to run in 6 your clinical trial database? 7 A No, what we tried to 8 identifying were those events, based upon this 9 review, that would most likely have captured those 10 events in the clinical trial database. 11 Q What do you mean by those 12 events in the clinical trial database? 13 A Those instances of 14 aggression, of aggressivity. So not necessarily 15 capturing events at that point, we had to use 16 events to try and capture occurrences. 17 Q I guess what I'm getting 18 confused at here is why didn't you run all of 19 these ELECT terms through the clinical trial 20 database? 21 A One could have done that 22 except that it would not have been scientifically 23 correct. 24 Q Why? 109 1 A Because many of these 2 events here reflect disorders or events that would 3 bear no relationship in our best estimation of a 4 relationship to the use of fluoxetine. 5 Q Somebody thought they did 6 because they reported them as adverse events 7 related to the use of fluoxetine, didn't they? 8 MR. MYERS: I object to 9 the form. Let me object to the form only to the 10 extent you used the term related to the use of 11 fluoxetine. I don't know what you're trying to 12 say, that it was caused or that it occurred when 13 the patient was on the drug. 14 MS. ZETTLER: Related. 15 Q (BY MS. ZETTLER) Do you 16 understand what the word related means, Doctor? 17 A I think people use it 18 differently. As I would reflect upon your 19 question, my thought would be that these were 20 events that were reported to us by, for the most 21 part at that point in time, prescribers, 22 occasionally a family member, very likely by our 23 sales force who heard of a physician in his office 24 or her office say something to the effect of by 110 1 the way, I have this patient, and our sales force 2 were instructed to, as you well know, report 3 everything they heard, so we had collected a lot 4 of data. It does not necessarily imply 5 relatedness or causality, it's a report. 6 Q But somewhere somebody 7 connected up the use of fluoxetine and the 8 occurrence of an adverse event, whether or not 9 they thought it was directly causally related, 10 somewhere in their mind there was a relationship 11 between the occurrence of the event and the use of 12 fluoxetine, correct? 13 MR. MYERS: I'll object 14 to the form because that would cause him to 15 speculate as to what some bunch of reporters 16 related or didn't relate. 17 Q Would a physician doctor 18 who prescribed fluoxetine to somebody and knew 19 that that person then took a hit of LSD and then 20 became psychotic, would they necessary report that 21 to Lilly as an adverse event on fluoxetine? 22 A They might. They might 23 also mention in passing to a sales force person, 24 though, who then, because of their obligations, 111 1 would alert us to that. 2 Q So if a doctor said to 3 one of your sales force people, "God, I had Joe 4 Blow on fluoxetine and then the fool went out and 5 took a hit of acid and jumped off a building," 6 they would report that adverse event, they would 7 report that jumping off a building to you? 8 A Yes, they would. 9 Q Why? 10 A Because they were 11 instructed that if they heard of any event 12 occurring while a patient was being treated with 13 fluoxetine -- to the best of my knowledge this is 14 the communication that was given to our sales 15 force personnel -- they were to report that event 16 to our DEN system, to our DEU component. 17 Q So if somebody was on 18 fluoxetine and wasn't having a problem with the 19 drug but they walked out in the street and got hit 20 by a car, that accident would be reported as an 21 adverse event? 22 A We have those reports in 23 individuals who had never even taken fluoxetine 24 but where it had been prescribed and not actually 112 1 filled. 2 Q Why do you report such 3 events to the FDA? Doesn't that skew the 4 reporting system? 5 A That's a judgment I can't 6 make. What I can tell you is that in my 7 responsibilities and as I understood the 8 responsibilities of our sales force is that we had 9 to be as diligent as possible in reporting events, 10 and ours was not to make a decision as to whether 11 an event should be reported or recorded or not, 12 but that it was to be done. 13 Q Do you personally agree 14 with reporting events of people who were given a 15 prescription of fluoxetine who never took the drug 16 and then were injured or killed by some sort of 17 accident as an adverse event on a drug, do you 18 agree with that? 19 A I don't know that it's my 20 position to agree or disagree because I'm not in 21 the position of a Federal regulatory body, whether 22 it would be here in the United States, to 23 determine how best to monitor the safety of a 24 compound. 113 1 Q I'm asking for your 2 personal opinion as to psychiatrist, Doctor. 3 A Well, prior to being in 4 the industry, I would have said why. Having been 5 in the industry and having the knowledge that I 6 have now, it does help keep things in perspective. 7 Q Helps keep things in 8 perspective or helps bury the true adverse event 9 profile of a drug? 10 MR. MYERS: Let me object 11 to the form of the question. That's awfully 12 argumentative. 13 Q Wasn't it easier for a 14 company like Lilly to point to a few hundred 15 thousand reports of adverse events that are 16 unrelated to a drug and say look, this guy wasn't 17 even on fluoxetine when he was hit by a car and 18 bury something that may be related such as 19 something like a Joseph Wesbecker where he became 20 more agitated and angry and mentally ill when he 21 was on the drug? 22 MR. MYERS: Same 23 objection. Go ahead and answer it, if you can. 24 A I would think that we 114 1 would be more vulnerable not to report simply 2 because there would be attorneys, whatever, who 3 would want to make the accusation that we did not 4 report events which were reported to us and that 5 we were trying to avoid the reporting requirement. 6 Q I'm not talking about 7 that were reported to you, I'm talking about 8 events like you described earlier where your sales 9 force was instructed to report any occurrence 10 whatsoever on fluoxetine that they heard about. 11 A For all the years -- I'm 12 speaking personally -- that I've been in practice, 13 I have thought that information was power, and 14 that the more information you have, the more 15 helpful you can be. I think that's true in this 16 situation as well. It seems at times, from a 17 personal perspective, tedious, but it's in the 18 interest of safety, and in this particular 19 situation, I find it helpful and important. 20 Q That's assuming the 21 information is adequate and accurate, doesn't it? 22 A That's a very broad 23 question. I don't know how I could answer that 24 except to say that one can -- I think one could 115 1 argue what is adequate and what is inadequate to 2 make the necessary call. 3 Q You said that in your 4 opinion information is power, correct? 5 A That's correct. 6 Q That's assuming that that 7 information is accurate information, does it not? 8 A That's correct. 9 Q If information is power, 10 Doctor, why didn't you run all of these adverse 11 events in the clinical trial database at least to 12 get information on how many of these events were 13 reported in the clinical trial database? 14 A Because we wanted to -- 15 what we didn't want to be doing is running a large 16 number of adverse events that then post facto we 17 would be saying, well, we shouldn't really include 18 this because it really doesn't pertain to the 19 possibility of, you know, the occurrence of the 20 event with fluoxetine, but rather we wanted to do 21 it as scientifically correct as possible to sort 22 of in some ways separate the wheat from the chaff, 23 so to speak. 24 Q How can you know whether 116 1 or not a particular adverse event pertains to the 2 use of fluoxetine if you hadn't taken a look at 3 that particular adverse event? 4 A You mean relative to the 5 analysis of the clinical trial database? 6 Q Any. I mean, how can you 7 make a determination without even looking at an 8 adverse event saying that it is termed delusions, 9 how can you make a determination without even 10 looking at an adverse event that's termed delusion 11 without looking at that adverse event? 12 MR. MYERS: Before he 13 answers, let me object to the form of the question 14 because you are mischaracterizing his testimony 15 and mischaracterizing what the process was in 16 terms of why they were looking at the event. 17 Q You didn't run all these 18 adverse events in the clinical trial database, 19 correct? 20 MR. MYERS: He's answered 21 that; it's been asked and answered. Answer it 22 again, Doctor. 23 A Not that I recollect. 24 Q And the reason you didn't 117 1 run all of these was because of what? 2 MR. MYERS: He's answered 3 that already. Answer it one more time. 4 A Because we developed from 5 the initial review of adverse events from post 6 marketing data what we felt was scientifically, 7 and to do it in a blinded fashion and to be, I 8 think, scientifically correct, we identified 9 terms, the aggression cluster that we felt would 10 be most likely to capture those events, and 11 applied that to the database without anyone 12 knowing what the outcome would be. 13 Q Would you agree with me, 14 Doctor, as a psychiatrist, that a number of these 15 events represent risk factors as to whether or not 16 somebody is going to become aggressive towards 17 another person? 18 A Some of these effects 19 might very well reflect an individual who would be 20 at some vulnerability for that kind of an 21 expression. 22 Q Okay. You mean the 23 reason you picked these from the ELECT dictionary 24 is because you felt as a psychiatrist, you and 118 1 your colleagues felt as psychiatrists that these 2 were the event terms that would most likely 3 indicate some sort of aggressive event or some 4 sort of aggressive attitude on the person's part, 5 correct? 6 A That's correct. 7 Q And just because somebody 8 doesn't actually commit a violent act towards 9 others or verbalize a violent act towards others 10 doesn't necessarily mean that they are not hostile 11 or violent aggressive, does it? 12 MR. MYERS: At what point 13 in time? 14 MS. ZETTLER: At any 15 point in time. 16 MR. MYERS: I object to 17 the form. 18 A Could you rephrase that, 19 please? 20 Q Sure. A person could be 21 feeling hostile towards somebody and not act on 22 that hostility, correct? 23 A That's correct. 24 Q Somebody could be feeling 119 1 hostile towards others and not verbalize that 2 hostility, correct? 3 A That's correct. 4 Q So as risk factors, 5 you're looking at these various adverse event 6 terms to try to make a judgment or at least a 7 determination from to the post marketing adverse 8 events as to whether or not people who were listed 9 as suffering from these adverse event forms were 10 in fact acting or verbalizing aggression towards 11 others, correct? 12 A That's correct. 13 Q My question is then how 14 are you so sure that people in the clinical trial 15 database who were listed as having these adverse 16 events were not suffering from some sort of 17 increase or development of aggression just because 18 they didn't verbalize it or act on it? 19 MR. MYERS: The ones that 20 they did not search? 21 MS. ZETTLER: Right. 22 A In our best estimation, 23 and again addressing it from a scientific 24 perspective, we wanted to go into that database 120 1 with a cluster of events that we would then not 2 have to retrieve and peel away with other 3 explanations such as the occurrence of delirium 4 with whatever or a manic episode, that sort of 5 thing, so it was the cleanest way, in our 6 estimation, to look at that database for those 7 events of aggression directed towards others. 8 Q Wouldn't it have been 9 more thorough to look at every adverse event that 10 occurred in the clinical trial database that fell 11 under one of these event terms to make a 12 determination, number one, if that person was 13 suffering either the development of aggression or 14 the increase in aggressive feelings as opposed to 15 just picking two or three adverse event terms and 16 looking at those? 17 A I think scientifically 18 one would argue that the way we proceeded in terms 19 of an epidemiologic study was the most scientific. 20 MR. SMITH: We object to 21 the continuing response in connection with the 22 term scientifically, we object to the word 23 scientifically because in fact it mischaracterizes 24 what was actually done, it was actually not 121 1 scientific. 2 MR. MYERS: That comment 3 need not concern you, Doctor. That's just an 4 objection that Mr. Smith makes. 5 Q (BY MS. ZETTLER) How 6 many 1639's did you review from the initial review 7 of the DEN database with these ELECT terms? 8 A I don't recall. 9 Q More than a hundred? 10 A From the DEN database, 11 possibly, but I don't recall. 12 Q How long did it take you 13 to complete your review of the 1639's? 14 A I don't recall. 15 Q More than a week? 16 A As best I recall, to 17 expedite the process, I was given those in 18 batches. 19 Q Over what period of time? 20 A I would say a week, maybe 21 two weeks, I just can't be sure. 22 Q What do you mean to 23 expedite the process you were given them in 24 batches? 122 1 A They would pool -- when 2 they got a batch of adverse events from any one of 3 these terms, they would pool and bring it to me so 4 I could combine the review process. 5 Q So you would look at the 6 acute brain syndrome adverse events at one time 7 and then the hostility adverse events at another 8 time? 9 A As best I recall, the 10 events were organized in that fashion. 11 Q By event term? 12 A By event term. 13 Q Do you recall any cross- 14 over between 1639's? 15 A Crossover meaning? 16 Q In other words, did you 17 see a 1639 that fell under the acute brain 18 syndrome adverse event group and the same one 19 falling in the hostility adverse event group? 20 A I don't recall that 21 specifically, but it's possible. 22 Q Was there anything done 23 to prevent that crossover into various event term 24 groups? 123 1 A No, we would not have 2 done that. 3 Q Do you recall from this 4 list any adverse event that wielded a greater 5 number of 1639's than another? 6 MR. MYERS: You mean just 7 in an aggregate count? 8 MS. ZETTLER: Uh-huh. 9 A I don't recall. 10 Q I'm a little confused, 11 Doctor. Let me see if I understand what you guys 12 did. You pulled the 1639's in which, for 13 instance, acute brain syndrome was listed as an 14 adverse event, correct? 15 A That's correct. 16 Q From the DEN? 17 A That's correct. 18 Q Okay. And then you 19 reviewed those 1639's to see if there was some 20 other reason or something else that contributed to 21 or could have contributed to this person suffering 22 the adverse event of acute brain syndrome other 23 than the use of fluoxetine? 24 A I don't recall that being 124 1 the next step in the process. 2 Q Okay. 3 A What I recall is that I 4 first sought to identifying with this specific 5 1639, this specific patient report, whether there 6 was behavior suggestive of aggressivity. 7 Q So you looked at the 8 acute -- let's just say Patient A, okay? Patient 9 A, you were given their 1639, okay? 10 A Okay. 11 Q And as an adverse event, 12 acute brain syndrome is listed on that 1639, 13 okay. 14 A Okay. 15 Q Then you looked to see if 16 there is something in that report that indicates 17 that Patient A was either physically or verbally 18 hostile towards other people, not necessarily 19 anybody in general or in particular, correct? 20 A As best I recall. 21 Q Now, if you determined 22 that there was a verbal or physical act indicating 23 hostility towards others or injurious intent 24 towards others, what did you do with that 1639? 125 1 A As best I recall, that 2 event would have been identified as an event for 3 joint review. 4 Q Okay. What did you do if 5 Patient A did not, at least as far as the 1639 was 6 concerned, exhibit verbally or physically 7 injurious intent towards others, what was done 8 with that 1639? 9 A With that particular 10 1639, it would have been separated into a separate 11 pile of like events. 12 Q And what happened to that 13 separate pile of like events, what happened to 14 those 1639's? 15 A Physically? 16 Q Yes. 17 A I don't recall. 18 Q What happened to them 19 within this process, were they then considered in 20 any way, any further, or were they just excluded 21 from the group at that point? 22 A As best I recall, they 23 were excluded. 24 Q Okay. So the first 126 1 criteria for inclusion in this was whether or not 2 the 1639 from the DEN system indicated that there 3 was a verbal or physical act of aggression? 4 A As best I recall, that 5 would characterize the initial step. 6 Q Now, if it fell into that 7 category where it indicated in your judgment a 8 verbal or physical act of aggression, it was then 9 reviewed by Doctor Beasley and yourself? 10 A As best I recall. 11 Q Was this procedure 12 written down anywhere? 13 A I don't recall. 14 Q Who determined this 15 procedure? 16 A There was a discussion 17 that included several individuals, some of whom I 18 can recall, others that I cannot recall. 19 Q Okay, who can you recall? 20 A I can recall Doctor 21 Beasley being a component of that, and I recall 22 Doctor Kotsanos being a component of that early 23 process. 24 Q Anybody from the legal 127 1 department? 2 A No. 3 Q Anybody from marketing? 4 A Oh, no. 5 Q Anybody from upper 6 management? 7 A No. 8 Q How about Doctor Leigh 9 Thompson? 10 A He was not a part of that 11 discussion. 12 Q How many other people 13 were involved in that? 14 A In that discussion? 15 Q Yes. 16 A There may have been 17 several others. 18 Q Was this one particular 19 discussion where this formula was devised? 20 A I don't recall it being a 21 formal meeting, but rather a process that began 22 with the question how does one address the issue, 23 the analysis of the clinical trial database, and 24 that was a process of discussion because we were 128 1 all in such close proximity, that is Doctor 2 Beasley, myself, Doctor Kotsanos, possibly several 3 others who had been peripheral players in that 4 initial discussion. We kind of had these less 5 formal types of discussions. 6 MR. SMITH: How many 7 people would have been in the clinical trial 8 database, how many patients at that time? 9 THE WITNESS: As I 10 recall, it was a rather substantial number because 11 we did the analysis across all indications as 12 opposed to limiting it just to depression. 13 Q (BY MS. ZETTLER) Was it 14 even limited to data from double blind control 15 studies? 16 A It was. 17 Q Why were the other 18 studies excluded? 19 A As best I recollect, when 20 one embarks upon such a process, one needs to have 21 some basis for making comparisons, and the effort 22 was to insure that the data that was reviewed 23 would have been part of a double blind controlled 24 study. 129 1 MR. SMITH: But how many 2 patients were analyzed? 3 THE WITNESS: I don't 4 recall specifically the number, several thousand I 5 would guesstimate. 6 Q (BY MS. ZETTLER) Is it 7 listed in your paper? 8 A I believe it is. 9 Q Prior to 1989, when this 10 project was begun, did you have any particular 11 expertise in violent aggressive behavior in 12 depressed patients? 13 A Could you define what 14 particular expertise would mean? 15 Q Did you focus in on that 16 type of behavior in depressed patients prior to 17 1989, in any of your work? 18 A As a clinician, I was 19 aware of individuals who were depressed who would 20 develop thoughts, ideations, at times take action 21 of wanting to harm themselves or others. My 22 expertise, given my clinical and academic 23 experience, would have been significant, but not 24 in terms of embarking on any unique studies. As I 130 1 mentioned earlier, I had not been involved in 2 research prior to coming to Lilly. 3 Q And prior to starting 4 this project in 1989, did you have any particular 5 interest in the phenomena of violent aggressive 6 behavior in mentally ill patients in general? 7 A Directed towards others 8 or self? 9 Q Directed towards others 10 for now. 11 A I don't recall that I had 12 a particular interest in that area, I would have 13 to say no. 14 Q Okay, so the second step 15 after your review of the 1639's from the DEN 16 database was to rereview the 1639's that you felt 17 indicated a verbal or physical act of aggression 18 or feeling of aggression with Doctor Beasley, 19 correct? 20 A As best I recall. 21 Q And he reviewed those 22 1639's to make his own determination as to whether 23 or not he felt those 1639's indicated aggression 24 on behalf of the patient either verbally or 131 1 physically? 2 A As best I recall. 3 Q Do you recall him 4 disagreeing with you on any 1639's that you felt 5 were evidence of a verbal or a physical act of 6 aggression? 7 A I don't recall that there 8 were any disagreements. 9 MS. ZETTLER: Let's take 10 a break for lunch. 11 (LUNCH BREAK TAKEN.) 12 Q (BY MS. ZETTLER) Doctor, 13 I think before lunch we had left off where you had 14 taken the 1639's from the DEN database that you 15 felt reflected aggressive or hostile behavior 16 towards others, injurious behavior towards others, 17 either through a physical or verbal act, is that 18 your recollection? 19 A That's my recollection. 20 Q And those were taken to 21 Doctor Beasley and then Doctor Beasley reviewed 22 those 1639's to see if he agreed with your 23 determination as to whether these 1639's in fact 24 reflected hostility or injurious behavior towards 132 1 others, either verbally or physically, correct? 2 A As best I recollect, I 3 was very inclusive in that sorting-out process, 4 and so that he and I independently then went 5 through and looked at each of those, and then 6 melded the process or the exercise in terms of 7 these are the events that most likely reflect 8 other directed behavior, aggressive behavior. 9 Q But I mean did you go 10 through them first and make your initial 11 determination and then give the group that you had 12 culled out to Doctor Beasley or did Doctor Beasley 13 look at every single 1639 also? 14 A Not that I recall. As I 15 recall, I did some sorting out in advance of that. 16 Q So my understanding is 17 clear, he looked at the group that you initially 18 reviewed and determined were indicative of 19 injurious behavior towards others, either 20 physically or verbally? 21 A He looked at that group, 22 the all-inclusive group, and then from that 23 process there was a sorting out as well. 24 Q So did he cull out some 133 1 that he felt or disagreed with you about in your 2 all-inclusive determination were in fact related 3 to evidence of verbal or physical hostility 4 towards others? 5 A In my process, I was 6 inclusive to the extent that anything that even I 7 would not have included where someone else might 8 have judged that as a possibility, I included that 9 pile so that we both extracted from that initial 10 separation, as I recall, the events, that we then 11 said do we agree that this is one that captures 12 certain event terms that we should then apply to 13 the clinical trial database. 14 Q I know I'm probably 15 getting confused, but let's walk through this one 16 step at a time. My understanding is -- let's just 17 use an example the number one thousand just for an 18 example purpose. You were presented with one 19 thousand 1639's that were culled from the DEN 20 database as a result of running these event terms 21 that are listed in Exhibit 1, correct? 22 A That's correct. 23 Q You went through and 24 then, say, made a determination that two hundred 134 1 of those did not, in your opinion -- and again I'm 2 just using two hundred as an example -- did not in 3 your opinion show evidence of injurious behavior 4 towards others, either verbally or physically? 5 A To the best of my 6 recollection, there was a group that I could very 7 comfortably say this is not something that should 8 be considered in the next step of the process. 9 Q So the ones that you 10 culled out were then set aside and you gave the 11 ones that you felt were in your all-inclusive 12 review indicative of injurious behavior towards 13 others to Doctor Beasley to then review? 14 A What I did was where 15 there would be any question of the information 16 available that there might be some -- that they 17 might be one of the final reports to be selected 18 from that process. So that number going from X 19 became Y, and then in the final effort between 20 Doctor Beasley and myself became Z. 21 Q Right, but I'm trying to 22 take this step by step, so please listen carefully 23 to my question, okay? The group that you took 24 from X to Y, Y is the group that you gave to 135 1 Doctor Beasley, you didn't give him the ones that 2 you felt were definitely not includable in the 3 group that ended up being Y? 4 A As I recall, that's the 5 way it proceeded. 6 Q So you made an initial 7 paring down in effect of the number of 1639's 8 before you gave them to Doctor Beasley? 9 A To the best of my 10 recollection, yes, that's correct. 11 Q Then Doctor Beasley 12 reviewed the ones that you had given him, the 13 Group Y, right? 14 A We each reviewed those 15 again. He reviewed them and I reviewed them 16 again. 17 Q And there was another 18 paring down as a result of your agreeing that a 19 certain number of the Y group were not includable 20 as far as indicating injurious behavior towards 21 others, right? 22 A That's correct. 23 Q Do you recall how many 24 1639's were included in the original group that 136 1 you reviewed? 2 A No, I do not. 3 Q Do you recall, can you 4 give me a percentage that were culled out in your 5 initial review? 6 A No, I can't. 7 Q More than a third? 8 A I can't be sure. 9 Q Can you give me an 10 estimate? 11 A It would be speculation, 12 no, I couldn't really. 13 Q How about the group that 14 resulted from you and Doctor Beasley reviewing the 15 1639's together, the Group Z, can you give me a 16 percentage of the total initial number of 1639's 17 that that was? 18 A I can't. I don't recall 19 what percentage. I can't recall the 20 denominator -- yes, the denominator that we looked 21 at initially and then narrowed it down to, so I 22 can't -- 23 Q Less than half of the 24 original? 137 1 MR. MYERS: To the final 2 number? 3 MS. ZETTLER: The final 4 number. 5 A I would expect. 6 Q Yes, less than half? 7 A Well, to the best of my 8 recollection, it would be less than half. 9 Q Less than a quarter? 10 A I can't say. I would 11 think so. 12 Q You would think so? You 13 have to say yes or no, you would think that it 14 would be less than a quarter of the original 15 number? 16 A To the best of my 17 recollection, yes. 18 Q Do you recall the number 19 of 1639's that were left after the entire review 20 was done of this section of the 1639's? 21 A As best I recall -- and I 22 believe that is in the paper -- it was somewhere 23 between nine and eleven. 24 Q From the DEN review? 138 1 A As I recall, uh-huh. 2 Q After you and Doctor 3 Beasley did your co-review or your each individual 4 review of those 1639's that you had gleaned from 5 the original group that you felt were indicative 6 of injurious behavior towards others, what 7 happened with the 1639's that ended up being in 8 these nine or eleven final patients, what did you 9 do with those 1639's? 10 A I don't know what 11 happened to the original 1639's, but what we did 12 with that is we extracted the information and put 13 them in what we call line listing, which is 14 patient identifier, age, sex, so on and so forth, 15 with as much information in a summary fashion as 16 we could ascertain. 17 Q Now, did Doctor Beasley, 18 when he reviewed the 1639's that you gave him, 19 review them both from the perspective as to 20 whether or not the events or the events listed in 21 the information given indicated that the person 22 was suffering from injurious behavior towards 23 others and whether or not it could be attributable 24 to some other factor like a disease, or just 139 1 whether or not the 1639's indicated injurious 2 behavior towards others? 3 A We were very consistent, 4 and as I recall at the very start of this process, 5 we delineated a plan of action, Step X would be to 6 Step Y, to Z, to A, to B, to C, and so that in 7 that process we put our best thinking together, 8 mapped a plan and stuck to that plan, and part of 9 that process was trying, prior to this review, to 10 come up with some sort of sense between the two of 11 us or a definition of what other directed 12 aggression would consist of. 13 Q Again, that doesn't 14 really respond to my question. Let me ask you 15 this first: Was this plan put in writing? 16 A I can't recall that it 17 was. It may have been taken in a note form, but 18 I'm not sure it was put in a formal plan. Some of 19 this would be included, I suspect in the 20 methodology section of the paper, but probably not 21 all of it. 22 Q Okay. Now, my original 23 question was did Doctor Beasley review the 1639's 24 from only the perspective of determining whether 140 1 or not the 1639 indicated injurious behavior 2 towards others, or did he also review it from the 3 perspective as to whether or not there was 4 something else like your example earlier, another 5 disease process that may be contributing to this 6 person's condition like delusion or hostility? 7 A As best I recollect, we 8 agreed to the latter, that once we began that 9 process, we culled out, let's say, individuals 10 whose aggressivity may have very well been likely 11 or would most likely have been due to a condition 12 that developed related to another disease process. 13 Q How about the disease 14 process for which they were being administered 15 fluoxetine, for instance depression, was that ever 16 thought to be a cause of the aggressive behavior? 17 A Well, it was thought -- 18 you know, I think in our estimation, a certain 19 percentage of patients, and I can't quote you a 20 percentage, would be prone to self or other 21 directed aggressivity as part of the core illness, 22 but we did not -- that was not one of those 23 eliminations. 24 Q Okay, what other factors 141 1 were taken into consideration that possibly 2 contributed to the person's aggressivity? You 3 already listed, for instance, another disease 4 process like thyroid, hyperthyroidism or something 5 along those lines. What other types of factors 6 were taken into consideration? 7 A Apart from another 8 illness? 9 Q Right. 10 A As best I recall, that 11 was the only factor. 12 Q Another disease process? 13 A As best I recall. 14 Q What about in like, say, 15 the obesity trials that you reviewed, was 16 depression thought to be another illness? 17 A We didn't -- at that 18 point, we were not reviewing trials. 19 Q Okay, but certainly some 20 people who you had 1639's on were being given 21 fluoxetine for things such as obesity or bulimia, 22 right? 23 A That's possible, yes. 24 Q In those cases, if 142 1 somebody was termed as, say, suffering from 2 depression or if it was thought that somebody was 3 suffering from depression in addition to bulimia, 4 was depression considered as another disease 5 process sort of like hyperthyroidism where that 6 could be contributing to the person becoming, for 7 instance, hostile? 8 A No, it was not. 9 Q Okay. 10 A So those would have been 11 included. 12 Q So when you say that the 13 final number was probably less than twenty 14 percent -- twenty-five percent, I'm sorry -- less 15 than twenty-five percent of the original that you 16 started out with having been gleaned from the DEN 17 database, are you saying that in all of those 18 cases either it was the opinion of you and Doctor 19 Beasley that the 1639 did not indicate violent or 20 injurious behavior towards others or there was 21 another disease process going on that in your 22 minds contributed to the violent and aggressive 23 behavior towards others besides fluoxetine, 24 something besides fluoxetine? 143 1 A That's two questions. 2 Q Right. 3 A Could you just repeat the 4 first one? 5 Q I'm just trying to get an 6 idea of why -- I mean, you started out with, at 7 least in your figures, up to forty-four instances 8 just from the DEN database running all of these 9 adverse event forms down to nine or eleven, okay, 10 depending on -- you don't know the exact figures, 11 I understand that, but from your estimates, it 12 could be as high as forty-four initial 1639's that 13 you reviewed. I want to know what factors, if it 14 was just -- was it either that you didn't feel 15 that the 1639 reflected aggressive behavior or 16 injurious behavior towards others, was that the 17 most predominant reason, or was another disease 18 the more predominant reason? 19 A The vast majority of 20 those had no report of any kind of aggressivity as 21 part of the report. 22 Q And again, the adverse 23 events themselves, like for instance acute brain 24 syndrome or aggravation reaction, weren't in and 144 1 of themselves considered evidence of somebody 2 becoming injurious towards others? 3 A No. 4 Q Now, from the line 5 listings of information that you just told us 6 about that was gleaned from the remaining or the 7 resulting 1639's, from those line listings it was 8 determined to use the aggression cluster of events 9 to run on the clinical trial database? 10 A As a part of that 11 process, yes, we arrived at a cluster of events to 12 apply to a clinical trial database. 13 Q And those were events 14 that were listed in the 1639's that resulted from 15 your and Doctor Beasley's review of the DEN 16 database? 17 A That's correct. 18 Q So am I accurate when I 19 assume that the 1639's that resulted, the eleven 20 or so 1639's that resulted listed adverse events 21 of hostility, antisocial reaction, and the other 22 adverse events that were termed the aggression 23 cluster of events? 24 MR. MYERS: I'm sorry, 145 1 are you asking him what the terms were or were 2 those among the terms that were used? 3 Q My understanding is that 4 the, quote, unquote, aggression cluster of events 5 were three adverse event terms that were finally 6 gleaned from your review of the DEN database; is 7 that your recollection? 8 A That's correct. 9 Q Okay. Now, am I correct 10 in assuming that those three event terms appeared 11 in these eleven 1639's that were finally culled 12 from the DEN database? 13 A Well, to the best of my 14 recollection; I would have to look at those. 15 That's to the best of my recollection, yes. 16 Q Antisocial reaction, 17 hostility and personality disorders, does that 18 refresh your recollection as to the aggression 19 cluster of events? 20 A It does. 21 Q Now, these three events 22 alone were then run on the CT database, right? 23 A Across all double blind 24 clinical trials for all indications where that 146 1 trial was conducted in a double blind fashion. 2 Q But these were the only 3 events that were run: Hostility, personality 4 disorder and antisocial reaction? 5 A That's correct. 6 Q Do you call this a 7 meta-analysis, your paper on violence or 8 aggression? 9 A Yes, because it's over 10 multiple clinical trials and it is over multiple 11 indications. 12 Q Did you use some sort of 13 scientific model to pattern this analysis after? 14 A Me, specifically, no. We 15 had the expertise of an epidemiologist who 16 assisted us in planning the methodology, as well 17 as, of course, our statistical component, prior to 18 initiating the project itself. 19 Q Who is the 20 epidemiologist? 21 A Doctor Kotsanos. 22 Q He said he wasn't an 23 epidemiologist. Is it your understanding that 24 Doctor Kotsanos is an epidemiologist? 147 1 A That's my understanding. 2 Q Can we agree just for the 3 rest of the questioning about your aggression 4 paper that the aggression cluster of events are 5 hostility, personality disorder and antisocial 6 reaction instead of having to ask about them 7 individually? 8 A We can agree. 9 Q Okay. Then after you 10 determined what the cluster of events would be, 11 those events were run on the clinical trial 12 database across all indications, correct? 13 A That's correct. 14 Q Now, what information was 15 gleaned from the clinical trial databases as a 16 result of that computer analysis? 17 A Those events as they 18 occurred or reported in the trial were then 19 identified, and each of those reports were 20 reviewed and each of those reports were included 21 in the final analysis. 22 Q Now, when you say the 23 reports, do you mean the clinical report forms 24 themselves? 148 1 A Yes. 2 Q So you went and manually 3 reviewed the clinical report forms for those 4 patients who reported adverse events that fell 5 within the aggression cluster? 6 A As I recall, I did that, 7 yes. 8 Q The entire clinical 9 report form or just that -- 10 A As I recall -- 11 Q Let me finish my 12 question. The entire clinical report form or just 13 those visits in which the event was reported? 14 A As I recall, I did the 15 entire clinical report form from start to finish. 16 Q So if the trial lasted 17 six weeks and they had six or seven visits within 18 that six-week period, you reviewed every piece of 19 paper related to that trial? 20 A Yes, that's my 21 recollection. 22 Q Now, again so I'm clear, 23 when you say you reviewed the clinical trial 24 database, you reviewed the information gleaned 149 1 through double blind controlled studies across all 2 indications and no other studies? 3 A That's correct, as I 4 remember it. 5 Q Did it make a difference 6 whether or not the study had a placebo arm or not? 7 A It did only in the sense 8 that we did an analysis for a comparative, active 9 comparator controlled trials, and a separate 10 analysis for placebo controlled trials. 11 Q Why did you do the 12 separate analysis? 13 A That plan was part of 14 what was, you know, detailed initially in terms of 15 how we would look at the data, and it would be of 16 interest to the scientific community as to 17 breaking that out in terms of placebo and 18 comparator uniquely. As I recall, there may have 19 been a third component in the analysis, and that's 20 where there was a comparator and placebo in the 21 trial as well as fluoxetine, so as I recall there 22 may have been three separate analyses, but they 23 were not -- as best I recall, there was no lumping 24 of those studies all together before they were 150 1 treated independently. 2 Q You said you were blinded 3 as to what patient was on what drug or active drug 4 or placebo, correct? 5 A (WITNESS MOVES HEAD UP 6 AND DOWN.) 7 Q You were blind as to what 8 substance the person was on, right? 9 A Methodologically our 10 decision was that whichever of these events would 11 be captured in that process would be included in 12 the analysis, that regardless of the content of 13 event, that event would be included. 14 Q Okay, but again, Doctor, 15 that's not my question. My question is you were 16 blinded as to what substance the person was 17 taking, be it placebo, fluoxetine or comparator, 18 correct? 19 A As I recall, once the 20 event was pulled and identified, then we had the 21 information as to which category they would fall 22 into for analysis purposes of course. 23 Q What do you mean when you 24 say once it was pulled and identified? 151 1 A When all those event 2 terms were captured from the clinical trial 3 database, from a blinded clinical trial database, 4 we then pulled those case report forms. We also 5 had identifiers about the patient even from the 6 computer search, and so we would know at that 7 point in time what medication the patient was on, 8 and then I hand searched, as I recall, each of 9 those case report forms from start to finish of 10 the patient's participation in the study. 11 Q So at what point were you 12 blinded? 13 A We were blinded all the 14 way up to the point that those were pulled. 15 Q Pulled from where? 16 A Pulled and put into the 17 data set that would be used for the analytic 18 process. 19 Q What type of analysis did 20 you do on the clinical report forms that were 21 pulled as a result of the search of the aggression 22 cluster term? 23 A I read them for 24 informational purposes to obtain details of the 152 1 specifics of the event as described by the 2 investigator. There was no formal analysis of 3 that; they were already included. The decision to 4 include the analysis was made a priority. 5 Q So they weren't culled 6 out like they were with the 1639? 7 A No. 8 Q Every single adverse 9 event that was listed within the clinical trial 10 database that fell under one of the aggression 11 cluster of events was included in the final 12 analysis that was reported in your paper? 13 A That's correct. 14 Q Why bother blinding? 15 A Initially? 16 Q Right. 17 MR. MYERS: Hold on, 18 blinding what, the trials or his review? 19 MS. ZETTLER: His 20 review. 21 A Initially? 22 Q Right. I mean, if you 23 are going to go in and you are going to use every 24 single adverse event reported in a clinical trial 153 1 to do the analysis, why do you need to blind 2 yourself until the analysis is actually done? 3 MR. MYERS: Are you 4 asking him why did they blind it up to the point 5 that they got all these things when they did the 6 search? 7 MS. ZETTLER: I'm asking 8 him why they had a blind portion of the clinical 9 trial database review. 10 A Scientifically that would 11 be most correct. 12 Q According to who? 13 A According to our best 14 judgment of what is good science. 15 Q So it's Lilly's best 16 judgment as to what is good science? 17 A Not Lilly's, it's 18 physician scientists. 19 Q Physician scientists 20 within Lilly? 21 A That's correct. 22 Q Did the physician 23 scientists within Lilly have anything from the 24 outside to rely on as to what was the best 154 1 scientific method to use? 2 A There were individuals 3 who had their training and experience apart from 4 Lilly that they brought to Lilly that helped guide 5 that decision. 6 Q Such as who? 7 A Doctor Kotsanos, Doctor 8 Dornseif, Doctor Beasley. 9 Q Did Lilly use any outside 10 consultants in putting together this project? 11 A We engaged -- I don't 12 believe we used any outside consultants in the 13 initial component of the project, not that I 14 recall. 15 Q Did you use any 16 consultants at all throughout this project? 17 A Yes. 18 Q Who? 19 A Doctor Emil Carcaro. 20 Q Anybody else? 21 A Not that I recollect. 22 Q What was Doctor Carcaro's 23 role? 24 A Doctor Carcaro, once 155 1 we -- upon completion of the analysis of the 2 database and plan to publish the data, we invited 3 Doctor Carcaro to participate in that process. 4 Q What process? 5 A Publication process. 6 Q You asked him to help you 7 get it published? 8 A Not to help us get it 9 published, but to provide his expertise relative 10 to the science of impulsive aggression and 11 aggression. 12 Q Is he listed as an author 13 on your paper? 14 A He is. 15 Q And his contribution to 16 the paper had nothing to do with your analysis up 17 to the point where the analysis was completed, 18 correct? 19 A Not that I recall. 20 Q Did he contribute his 21 expertise in violent aggressive behavior in 22 general? 23 A Yes, he did. 24 Q Did he have an opinion as 156 1 to whether or not fluoxetine could cause violent 2 aggressive behavior in people taking it? 3 A Not that I recall. As I 4 recall, Doctor Carcaro, based upon the science of 5 the compound and what is known about impulsive 6 aggression in and of itself apart from any other 7 disease, felt that compounds such as fluoxetine 8 would be a very good compound to use, had studied 9 the compound in individuals who had the propensity 10 to be impulsive and aggressive. 11 Q But are the results of 12 any of his studies in that regard included in this 13 paper? 14 A I don't recall if his -- 15 I believe he has published and I'm not sure that 16 publication was available at the time this 17 manuscript was prepared. 18 Q When was Doctor Carcaro 19 first contacted to contribute to this paper? 20 A I don't recall. 21 Q Before or after the 22 analysis was done? 23 A I don't recall. 24 Q Did he have any input 157 1 into the conclusions gleaned through the analysis? 2 A Could you rephrase that? 3 Q Did he have any input 4 whatsoever into the analysis of the data itself? 5 A If you're asking did he 6 have any impact on the methodology, to my 7 recollection, he did not. 8 Q Did you submit any of the 9 1639's that you and Doctor Beasley had culled out 10 of the initial group produced as a result of 11 running these ELECT terms set out in Exhibit 1 for 12 his opinion as to whether or not he agreed with 13 your determinations as to whether the events 14 indicated violent aggressive behavior? 15 A Not that I recall. 16 Q Why not? 17 A Because the methodology, 18 the process had been set in place prior to 19 engaging Doctor Carcaro in the publication 20 process. 21 Q Is Doctor Beasley an 22 expert in violent aggressive behavior, as far as 23 you know? 24 MR. MYERS: Before he 158 1 answers, let me just object to the form only to 2 the extent your use of the term expert may have 3 some sort of legal significance. If you have a 4 professional view on that subject, but if you're 5 using it in the legal sense that us lawyers use 6 it, I object to the form. 7 MS. ZETTLER: I'm talking 8 to a doctor here. 9 Q You're not a lawyer, are 10 you, Doctor? 11 A No. 12 Q I'm talking to you as a 13 doctor, okay, assuming that you are a doctor and 14 I'm asking for your opinion as a doctor. 15 A Could you define expert 16 for me, though, because that's where I was having 17 difficulty -- 18 Q Sure, does he specialize 19 in studying violent aggressive behavior? 20 A Not that I'm aware. 21 Q Does he have any 22 experience outside of this project that you know 23 of specifically geared towards violent aggressive 24 behavior? 159 1 A Having trained in 2 psychiatry, I would assume that he has had 3 considerable experience. 4 Q Outside the general 5 training of a psychiatrist, has he sought out any 6 additional training in violent aggressive 7 behavior, as far as you know? 8 A No, not that I'm aware. 9 Q How about Doctor 10 Kotsanos, is he a medical doctor? 11 A Yes, he is. 12 Q As far as you know, does 13 he have any specialized training in violent 14 aggressive behavior? 15 A Not that I'm aware of. 16 Q Has he ever held himself 17 out to be an expert or a specialist in the field 18 of dealing with patients who are violent 19 aggressive? 20 A Not that I'm aware of. 21 Q How about Doctor 22 Dornseif, is he a medical doctor? 23 A He is not. 24 Q So to your knowledge, he 160 1 does not also hold himself out as an expert in 2 patients suffering from violent aggressive 3 behavior, does he? 4 A That would be correct. 5 Q Do you consider yourself 6 an expert in violent aggressive behavior? 7 A No. 8 Q So why is it that you 9 felt comfortable putting together a meta-analysis 10 of violent aggressive behavior without the use of 11 somebody such as Doctor Carcaro to guide you with 12 regards to determining what is in fact violent 13 aggressive behavior? 14 A First of all, I do bring 15 certain expertise to the table in these pursuits. 16 Secondly, there is literature readily available on 17 aggressivity. That literature was reviewed, and 18 with the internal expertise we had, the most 19 critical component or one of the more critical 20 components is the methodology of how you structure 21 your look at the data. 22 Q Since you were 23 comfortable with the expertise that you as well as 24 your colleagues brought to the table in putting 161 1 together this study, why did you feel like you had 2 to bring in Doctor Carcaro after the fact? 3 A Because a component of 4 the paper was a review of the basic science and to 5 some extent the relatively sparse clinical 6 literature relative to the issue of aggressivity, 7 and Doctor Carcaro has published in this area and 8 is, I would consider, one of our leading figures 9 in terms of thinking through the biochemical 10 mechanism and the literature reported to date. 11 Q So, in other words, it 12 was to lend credibility to the paper? 13 A No, it was to enhance the 14 scientific component or the scientific review of 15 the literature. 16 Q After the review was 17 done, after the analysis was completed? 18 A I cannot recall at what 19 point we engaged Doctor Carcaro relative to the 20 issue of aggressivity. 21 Q To your knowledge, did 22 Doctor Carcaro have any comments with regards to 23 either the methodology that was used to analyze 24 the data or the results of the analysis itself? 162 1 A I do not recall specific 2 comments. As I recall, there were no issues with 3 the methodology of the analysis. 4 Q Again, once the clinical 5 report forms from the review of the clinical trial 6 databases were pulled, what was done besides 7 reviewing those clinical report forms, were they 8 categorized in some way? 9 A No, they were not. 10 Double blind clinical trial reports, you're 11 speaking of once we pulled those from the 12 database, they were not formally categorized. Of 13 course, they were read and they were interesting. 14 Q From what perspective? 15 A From the perspective that 16 they were relatively benign events and did not 17 capture, as I recall, significant other directed 18 aggression in terms of direct physical injury. 19 Q Were you surprised by 20 that, Doctor? 21 A No, I was not. 22 Q Why not? 23 A Because, like many 24 others, I felt that a drug like fluoxetine, that 163 1 is a specific and selective serotonin uptake 2 inhibitor, would perhaps prevent the occurrence of 3 such events in some individuals. 4 Q Why? 5 A Because the data from 6 animal and some limited human studies suggested 7 that these drugs decreased impulsive aggressivity. 8 Q What animal studies? 9 A I would have to refer you 10 to the paper. There are a number of citations 11 that have been published in the basic science 12 literature. 13 Q Any studies outside of 14 Lilly? 15 A Outside of Lilly? 16 Q Right. 17 A Most of those were 18 outside of Lilly. Not ninety-five percent of 19 them, a huge number of them were not studies here 20 in-house. 21 Q Were studies that were 22 done on animals and fluoxetine? 23 A Exactly. There were some 24 animal studies with fluoxetine, as I recall. 164 1 Q But the studies that you 2 are referring to that are outside of Lilly were 3 not studies that were done with fluoxetine? 4 A No, as I recall, they 5 were not. 6 Q I'm talking about animal 7 studies done with fluoxetine; where did you find 8 those studies? 9 A In literature review. 10 Q Okay, and were those 11 studies with animals and fluoxetine, were those 12 in-house Lilly studies or were they outside of 13 Lilly? 14 A I can't recall. 15 Q What human studies are 16 you referring to? 17 A I cannot recall specific 18 publications. I recall there were some limited 19 publications in some individuals who had a 20 propensity towards impulsive aggressivity that may 21 have been in the literature at that time. 22 Q Are you talking about 23 people who were given fluoxetine? 24 A That's correct. 165 1 Q And what were the results 2 of those studies? 3 A Favorable in terms of the 4 occurrence of impulsive aggression decreased in 5 these individuals from baseline. 6 Q Were those studies that 7 were commissioned by Lilly? 8 A Not that I recall. 9 Q These are all listed in 10 the bibliography of the paper? 11 A Those would be in the 12 bibliography. 13 Q I guess I'm still a 14 little confused as to why you were blinded with 15 regards to the clinical report forms that were 16 pulled from the CT database search. At what point 17 did you become unblinded? 18 A I don't recall 19 specifically at what point I became unblinded in 20 that process. 21 Q Were you blinded during 22 the search of the 1639's or review of the 1639's 23 from the DEN database? 24 A I became unblinded once 166 1 the data, the 1639's were reviewed or were brought 2 to me and I reviewed them. 3 Q So when you reviewed the 4 1639's, you'd know whether or not the person was 5 on fluoxetine? 6 A Yes. 7 Q Okay. And when you 8 reviewed the clinical report forms from the 9 clinical trial database, you knew whether or not 10 the people were on fluoxetine or a comparator or 11 placebo, correct? 12 A As best I recall, that's 13 correct. 14 Q And all of the clinical 15 report forms that were pulled or all of the 16 patients that were flagged, so to speak, through 17 the CT database review of the aggression cluster 18 of events, they were all included in the analysis? 19 A Yes. To the best of my 20 recollection, yes. 21 Q Who did the actual search 22 of the clinical trial databases? 23 A That's a computerized 24 search. 167 1 Q And what did you get as a 2 result of the computerized search? 3 A Initially, I suspect -- I 4 can't really recall exactly, probably a number and 5 patient identifiers. 6 Q So they would point you 7 to what trial to go to and which patient within 8 each trial? 9 A That's correct. 10 Q How long did it take to 11 get that information from systems analysts? 12 MR. MYERS: This initial 13 set of numbers? 14 MS. ZETTLER: Right. 15 A I don't recall. What I 16 do recall is that process beginning from the start 17 to completion that we had that data by the end of 18 the year. 19 Q 1990? 20 A 1889. 21 Q 1989? 22 A That's correct. That's 23 the best of my recollection. 24 Q So beginning with pulling 168 1 the event terms from the ELECT dictionary to 2 getting the patient identifiers and studies 3 indicating where you could find the CRF's on the 4 patients pulled from the clinical trial database 5 search of the aggressive cluster of events was 6 done by the end of 1989? 7 A As best I recall. 8 Q Do you recall how long 9 after the Wesbecker incident it was before this 10 project was developed? 11 A I cannot recall 12 specifically. 13 Q Was the analysis of the 14 data completed by the end of 1989 also? 15 A I don't recall. I do not 16 think it was. 17 Q When was the paper 18 finally published? 19 A As best I recall, 1991 20 maybe. 21 Q Before or after the '91 22 Drug Advisory Committee meeting? 23 A I don't recall. 24 Q Was any information from 169 1 this analysis used during the Drug Advisory 2 Committee meeting? 3 A I don't recall. I seem 4 to recall that it was, but I cannot be certain of 5 that. 6 Q Were you at that meeting? 7 A Yes, I was. 8 Q What was your role at 9 that meeting? 10 A My role was sort of an 11 information resource. 12 Q In what area? 13 A For both the suicidality 14 analysis, as well as, I believe, the aggression 15 analysis. 16 Q So it would have had to 17 have been done for you to be able to be an 18 information resource, correct? 19 A Advisory Committee -- 20 MR. MYERS: When you say 21 it done, the analysis of the paper published? 22 MS. ZETTLER: The 23 analysis. 24 A The analysis was done. 170 1 I'm not sure that the paper was published at that 2 time. 3 Q I'm talking about the 4 information that was gleaned from the process as 5 well as the analysis. Was that information and 6 the results of that analysis used at the 1991 7 Advisory Committee meeting? 8 A I believe they were made 9 available to the Advisory Committee. I'm not sure 10 that there was -- I can't recall there being a 11 discussion at the formal meeting of the Advisory 12 Committee. 13 Q Did you make a 14 presentation at that meeting? 15 A I did not. 16 Q Were you asked any 17 questions during that meeting? 18 A I was not. 19 Q Were you asked to give 20 any written information to anybody at that 21 meeting, during the meeting itself? 22 A I was not. 23 Q Were you asked to give 24 any information, written information to the 171 1 committee after the meeting? 2 A I was not. 3 Q Where was the violent 4 aggression paper published? 5 A I don't recall. 6 Q Do you recall it being 7 submitted to like the Journal of the American 8 Medical Association and being rejected? 9 A As I recall, we did make 10 a submission to another journal and it was 11 rejected. 12 Q Do you know why it was 13 rejected? 14 A I don't recall. 15 Q What was Don Masica's 16 role in the paper? 17 A At that time, Doctor 18 Masica would have been the division director and 19 he would have had some input in terms of a 20 supervisory role of how we had planned the 21 methodology component, and then he participated 22 in, as I recall, helping edit the manuscript to be 23 submitted for publication. 24 Q Doctor, in your opinion, 172 1 does agitation impact in any way on a person with 2 respect to violent aggressive behavior? 3 A Are you referring to 4 agitation occurring uniquely without any other 5 disorder, or are you talking about depression and 6 agitation? 7 Q Is there a correlation 8 between, say, increased agitation and increased 9 hostility? 10 MR. MYERS: In a 11 depressed patient? 12 MS. ZETTLER: Yes. 13 MR. MYERS: In a 14 depressed patient? 15 MS. ZETTLER: Yes, let's 16 start with that. 17 A I don't know. I don't 18 know. 19 Q Did Lilly use any outside 20 consultant in regards to the agitation study you 21 were talking about earlier? 22 A I do not recall in a 23 formal sense engaging an outside person. I may 24 have had, as best I recollect, one or two 173 1 conversations with individuals in search of an 2 instrument, that is a questionnaire that would 3 capture the occurrence of agitation, but I do not 4 recall that specifically. 5 Q To be used in the study? 6 A To be used in the study. 7 Q Are you using any 8 questionnaires in the study or have you used any 9 questionnaires in the study? 10 A Yes. 11 Q What questionnaires? 12 A We used the research 13 diagnostic criteria for agitation that I referred 14 to earlier and put that into a questionnaire 15 format. 16 Q The criteria developed by 17 the St. Louis group we're talking about? 18 A That's correct. 19 Q And you put it in -- you, 20 meaning Lilly, put it into a questionnaire form? 21 A That's correct, in 22 consultation with our investigators. 23 Q The clinical 24 investigators that performed the study? 174 1 A That's correct. 2 Q They helped you develop 3 this questionnaire from the criteria set up by the 4 St. Louis group? 5 A As best I recollect, yes. 6 Q Was this questionnaire 7 used throughout the study or was it used to 8 determine whether or not the patients enrolled in 9 the study were suffering from agitated depression? 10 A It was used throughout 11 the study. 12 Q Do you know if that scale 13 or that questionnaire has been validated? 14 A I do not believe it has 15 been validated. 16 Q Why not? 17 A Because, to the best of 18 my knowledge, there had not been any questionnaire 19 available for use in that specialized of a study 20 and to incorporate the research diagnostic 21 criteria would have required a separate validation 22 criteria to use those in a validated way, and it 23 was felt that we should just go forward with the 24 study. 175 1 Q What is the name of this 2 questionnaire? 3 A The Agitation Rating 4 Scale. 5 Q Who at Lilly put this 6 together? 7 A I was the lead person. 8 Q Anybody else? 9 A If I recall correctly, I 10 engaged in consultation Doctor Beasley for a 11 component of that, as well as the statistician. 12 Q Who was? 13 A I don't recall the 14 statistician on that project. 15 Q Was that person listed as 16 an author on the paper? 17 A I'm trying to recall if 18 the statistician who was the lead statistician 19 left the company and then was replaced by a 20 statistician when it became time to publish the 21 paper; I don't recall who the statistician was on 22 the paper. 23 Q Who was the lead 24 statistician that left the company? 176 1 A I believe the lead 2 statistician on this project -- and I can't be 3 sure because there are many statisticians and many 4 projects -- was Doctor Dornseif. 5 Q And Doctor Dornseif has 6 left Lilly, correct? 7 A That's correct. 8 Q Do you recall Doctor 9 Dornseif having some input in the study at any 10 point in time? 11 A The statistician for the 12 project would have had input into this project. 13 Q But I'm asking 14 specifically about Doctor Dornseif. Do you recall 15 him having input in the project at any time before 16 he left? 17 A To the best of my 18 recollection, he was the lead statistician. 19 Q What is the 20 statistician's rolled in putting together a scale 21 like the Agitation Rating Scale? 22 A Frequently their role is 23 to question the validity of instruments used, and 24 then to reflect upon, perhaps write an analysis 177 1 plan for the measure which is being used. 2 Q How would Doctor Dornseif 3 question or somebody like Doctor Dornseif question 4 the validity of the Agitation Rating Scale when it 5 was never validated? 6 A They would ask me if 7 there wasn't some measure that we could use in the 8 study that would measure what we're looking to 9 measure. 10 Q Other than the scale that 11 you were putting together, and you said no? 12 A That's correct. 13 Q And given that, did the 14 statistician still feel comfortable in using the 15 Agitation Rating Scale in that study? 16 A Yes. 17 Q Why? 18 A I can't speak for him or 19 her, depending on who the lead statistician was, 20 but when there is nothing, then oftentimes such a 21 study will be the initial effort to develop such a 22 questionnaire and statisticians, to the best of my 23 knowledge, oftentimes will not have difficulties 24 with that process. 178 1 Q How much of an effort was 2 made to see if there was an Agitation Rating Scale 3 already being used? 4 A Considerable. 5 Q Give me an example of 6 what was done. 7 A As I recall, I reviewed 8 the literature, and I called and spoke with 9 several individuals relative to whether they knew 10 of such an instrument. 11 Q Who? 12 A I can't be precise. 13 People I might have called would have been Doctor 14 Picaro possibly, Doctor Michael Stanley 15 possibly -- 16 Q Doctor Feighner? 17 A No. 18 Q Why not? 19 A Because the focus of his 20 work was not, in the best of my knowledge, 21 agitation, but rather more generic depression, and 22 I felt that someone who might have some 23 information about potential questionnaires would 24 be individuals who had some specialized interest 179 1 within depression. 2 Q Doctor Feighner was a 3 part of the St. Louis group that developed the 4 criteria, was he not? 5 A That's correct. 6 Q Why didn't you call him 7 and see if he was aware of anybody else who had 8 developed a scale or if that group itself had 9 developed a scale for agitation? 10 A In part because I felt, 11 number one, that I was contacting or networking 12 with those people who would be more knowledgeable 13 of anything new and validated that would be a 14 potential measure in the study. Secondly, it 15 became obvious that since there was none, this was 16 the best that was available. 17 Q Why didn't you use Doctor 18 Feighner as a clinical investigator on the study? 19 A Well, in the course of 20 preparing protocols for study, I began to 21 internally think through investigator lists of 22 people and Doctor Feighner did not cross my mind. 23 I can't say why, I don't know. 24 MR. SMITH: Who did cross 180 1 your mind? 2 MR. MYERS: Wait a 3 minute. Before you answer that, Doctor -- 4 THE WITNESS: The two 5 investigators -- 6 MR. MYERS: Before you 7 answer that, that's not a serious question, is 8 it? 9 MS. ZETTLER: Sure it is. 10 MR. MYERS: Are you going 11 to withdraw that? 12 MR. SMITH: Certainly. 13 MR. MYERS: If for you to 14 answer that question you are going to have to 15 disclose a number of fluoxetine clinical 16 investigators, then I'm going to instruct you not 17 to answer that for the same reason that I voiced 18 this morning that that issue was covered by 19 several court orders. 20 Q (BY MS. ZETTLER) Who did 21 you consult with outside of Lilly in putting 22 together the Agitation Rating Scale? 23 A Outside of Lilly? 24 Q Uh-huh, yes. 181 1 MR. MYERS: Did you say 2 in putting together or looking for a scale? 3 MS. ZETTLER: Putting 4 together the scale. 5 A I may have spoke with the 6 two gentlemen I just mentioned, Doctors Stanley 7 and Carcaro, although again I can't be sure of 8 that. I might have spoken with a Doctor Rush or 9 Doctor Dunner, Doctor Greist, Doctor Tollefson. 10 Q Before or after he was a 11 Lilly employee? 12 A That would have been 13 before. 14 Q When did Doctor Tollefson 15 start working for Lilly? 16 A As best I recollect, it 17 was June of '91. 18 Q Okay. Anybody else 19 besides Doctor Stanley, Doctor Carcaro, Doctor 20 Dunner, Doctor Rush, Doctor Greist and Doctor 21 Tollefson that you may have consulted with in 22 putting together the agitation scale? 23 A There may have been 24 others, but I would not recall who they would be, 182 1 and I'm not sure I even spoke to some of those 2 people that I just mentioned. 3 Q Where was Doctor 4 Tollefson located before he became an employee at 5 Lilly? 6 A St. Paul. 7 Q How about Doctor Greist, 8 where is he located? 9 A Currently? 10 Q Yes. 11 A Madison. 12 MR. SMITH: Where? 13 THE WITNESS: Madison, 14 Wisconsin. 15 Q (BY MS. ZETTLER) How 16 about Doctor Rush? 17 A Dallas, Texas. 18 Q Doctor Dunner is in 19 Seattle, right? 20 A That's correct. 21 Q How about Doctor Carcaro, 22 where is he located? 23 A Currently, I believe he's 24 in Philadelphia. 183 1 Q How about Doctor Stanley? 2 A Deceased. 3 Q When did he die? 4 A Pardon? 5 Q When did he pass away? 6 A A year, year and a half 7 ago. 8 Q How old was he? 9 A Early forties. 10 Q Were Doctor Greist and 11 Doctor Tollefson the clinical investigators on the 12 agitation study? 13 MR. MYERS: Don't answer 14 that. 15 MS. ZETTLER: Well, he 16 said he consulted with the clinical investigators 17 in putting together the scale, Larry. 18 MR. MYERS: We're not 19 going to play games, so don't you play games. 20 He'll answer your questions about the trial, he's 21 not going to tell you who the investigators are, 22 so ask him some more questions about the trial or 23 something else. 24 Q (BY MS. ZETTLER) Are the 184 1 clinical investigators on this trial going to be 2 listed as authors on the paper if it's published? 3 A Yes. 4 MR. SMITH: Who are 5 they? 6 MR. MYERS: He's not 7 going to tell you that now. 8 MS. ZETTLER: Certify 9 those questions. 10 (QUESTIONS CERTIFIED.) 11 MS. ZETTLER: First of 12 all, Larry, there is no order in Fentress that 13 prohibits him from telling us who the clinical 14 investigators are and you know it. 15 MR. MYERS: There is an 16 order that addresses their disclosure of the 17 identity of the clinical investigators, there is 18 an order. 19 MS. ZETTLER: Where, 20 which order? 21 MR. MYERS: I can't give 22 you the date; it was sometime in the summer or 23 fall of last year. 24 MS. ZETTLER: There is 185 1 absolutely no order that address that and you know 2 it. It's your interpretation of Eckert's original 3 order where you tried to bootstrap the report of 4 third-party reporters of adverse events into 5 constituting clinical investigators. 6 MR. MYERS: No, in fact 7 I'm specifically speaking of an order that Judge 8 Potter entered on the subject of remasking of 9 nonpivotal clinical trials and the order from the 10 Magistrate in the Southern District of Indiana on 11 the remasking of clinical trials. 12 MS. ZETTLER: That order 13 that Judge Potter entered does not cover whether 14 or not Lilly employees during depositions can 15 disclose the names of investigators. 16 MR. MYERS: It would be 17 best if we continue to agree that we disagree and 18 go on because he's not going to go into that. 19 Q (BY MS. ZETTLER) Did 20 Doctor Tollefson complete his work on the 21 agitation study before or after he became an 22 employee of Lilly? 23 MR. MYERS: Don't answer 24 that question. 186 1 MS. ZETTLER: Certify it. 2 (QUESTION CERTIFIED.) 3 MR. MYERS: Same basis. 4 Q (BY MS. ZETTLER) Are you 5 familiar with a Doctor Jay Kohn? 6 A I know of him. 7 Q Did you know he passed 8 away recently? 9 A I did not. 10 Q Had Doctor Kohn been 11 doing any work for Lilly in the past six months or 12 so, to your knowledge, on fluoxetine? 13 A I'm not aware that he's 14 participated in any studies currently, but I would 15 not know the full scope of current studies. 16 Q What other scales were 17 used in the agitation study besides the scale 18 developed by Lilly? 19 MR. MYERS: Any scales on 20 it other than -- 21 MS. ZETTLER: The 22 agitation scale developed by Lilly. 23 MR. MYERS: Okay. 24 A As I recall, the Hamilton 187 1 Depression Rating Scale, the Adult Suicide 2 Ideation Questionnaire, and we used the -- as I 3 recall, we used the SF-36. 4 Q Is there a difference 5 between anxiety and agitation in depressed 6 patients? 7 A Are you asking from a 8 general clinical sense? 9 Q I'm asking you as a 10 psychiatrist. 11 MR. MYERS: I'm sorry, 12 you did say occurring in depression? 13 MS. ZETTLER: Uh-huh. 14 A In my estimation, there 15 are some similarities and some differences. 16 Q What are the 17 similarities? 18 A The sense within of 19 feeling anxious, nervous -- I'm trying to find the 20 right word to capture that inner sense, but it's 21 hard to find a word when one's vocabulary has been 22 so focused on anxious and often connotes 23 something. I assume in that question you are 24 looking at the broad definition of anxiety? 188 1 Q Sure. 2 A And I assume that you are 3 not speaking of specific anxiety disorders? 4 Q Right. Let me try and 5 simplify a little bit. If a physician were to 6 report that somebody was suffering the adverse 7 event of anxiety, what would that mean to you? 8 A Without additional 9 information, I'm not sure what it would mean. 10 Q Isn't it true, Doctor, 11 that it is sometimes difficult to differentiate 12 between anxiety and agitation? 13 A I think it depends upon 14 how one defines each of those. 15 Q So would you agree that 16 the determination of whether somebody is suffering 17 from anxiety as opposed to agitation is a somewhat 18 subjective determination? 19 A Somewhat subjective. 20 Q How about nervous, would 21 you kind of group nervousness in that same 22 subjective determination? 23 A Without additional 24 information, I would say that there's a subjective 189 1 component. 2 Q In fact, you could have 3 one patient who is suffering what one doctor may 4 call anxiety and another doctor may call it 5 nervousness and another doctor again may call it 6 agitation, correct? 7 A Agitation in the eyes of 8 many would connote a motor component, pacing, hand 9 wringing, that sort of thing, which would not -- 10 which would be a feature that would lead someone 11 to think more of agitation rather than anxiety in 12 that situation. 13 Q Somebody who was nervous 14 could pace, couldn't they? 15 A They could. 16 Q Somebody who was nervous 17 could wring their hands, correct? 18 A They could. 19 Q The scale that Lilly 20 developed regarding agitation, did that have a 21 physical component to it? 22 A It did. 23 Q Is it a self-rating scale 24 or was that a clinician administered scale? 190 1 A It's a clinician 2 administered scale. I take that back, it's a 3 scale that's scored by the physician based upon 4 information both by query and by observation that 5 he or she obtains in the course of the assessment. 6 Q Kind of like the Hamilton 7 Depression Rating Scale? 8 A In some ways, although I 9 think that the Agitation Rating Scale, although 10 briefer, requires fairly keen observational 11 skills. 12 Q Who trained the 13 administrators of the scale? 14 A Who -- 15 Q Who trained the people 16 administering the scale in the study to administer 17 the scale? 18 A Investigators? 19 Q Right. 20 A Those were reviewed and 21 used in the start-up meetings that was held with 22 both sides. 23 Q So is it your 24 understanding that the investigators, the two 191 1 investigators that ran the studies were the ones 2 who actually administered the scale to every 3 single patient? 4 A I can't recall. In many 5 situations there are skilled research personnel 6 who are part of that process as well. 7 Q Since that study has been 8 conducted, has anybody else, to your knowledge, 9 created an agitation scale? 10 A I'm not aware of one. 11 Q How does somebody go 12 about validating a scale without a previous scale 13 existing? 14 A You're asking me to 15 venture into an arena that I'm not really very 16 expert. As best I understand, one would take that 17 scale and target a population and see if that 18 scale indeed measures what it is intended to 19 measure and that it is relatively specific for 20 that condition for what is intended -- 21 Q I'm sorry, I didn't mean 22 to cut you off. 23 A Or for what it is 24 intended to measure. 192 1 Q Is it your testimony that 2 the agitation study that we've been talking about 3 was really a study to validate the Agitation 4 Rating Scale? 5 A No. 6 Q Isn't it true that a 7 study could have been performed to try to validate 8 that scale prior to performing this agitation 9 study we've been talking about? 10 A I think one could have 11 embarked upon that study. 12 Q You could have done a 13 pilot study, for instance, correct? 14 A Again, I'm not an expert 15 at how one goes about validating a measure, so I 16 can't really comment exactly on how we would have 17 structured that. 18 Q Why didn't you do a study 19 to validate the scale or try to validate the scale 20 before you used it in the agitation study? 21 A I don't recall the 22 specific reason. 23 Q Do you recall a decision 24 being made not to try to validate it before it was 193 1 used in the agitation study? 2 A I don't recall there 3 being a specific meeting to discuss that, 4 something more formal. What I recall is that a 5 consensus developed as to how best to study the 6 patients who at baseline had depression with 7 agitation. 8 Q Would you have preferred 9 to see the scale validated before it was used in 10 the study? 11 A I think in this situation 12 most likely it depended upon the timing. I think 13 oftentimes it is preferable to have a validated 14 scale. 15 Q What was it about the 16 timing of this study that affects your opinion? 17 A As best I recall, part of 18 the thinking as to doing this study was to 19 reassure physicians that fluoxetine could be used 20 in a population of depressed and agitated 21 individuals and that the compound would be 22 efficacious. 23 Q Have the results of that 24 study been published anywhere yet? 194 1 A No, ma'am. 2 Q Have the results of that 3 study been transmitted to prescribing physicians 4 in any way, like through a Dear Doctor letter or 5 something? 6 A Not that I'm aware of. 7 Q Is it your understanding 8 that there is a perception within the medical or 9 psychiatric community at this time that there is a 10 problem with prescribing fluoxetine to agitated 11 depressed people? 12 A I think within the 13 psychiatric community there is no significant 14 concern. Within the larger prescribing 15 community -- and I'm speaking anecdotally and I 16 haven't spoken with a primary care physician for 17 quite some time -- that there might be some 18 caution, but I think my sense is that the concerns 19 are not universal nor are they overriding. 20 Q So what is the haste in 21 getting this study done and published? 22 MR. MYERS: Wait a 23 minute, before he answers, let me object to the 24 form. I don't think he's used the term haste, so 195 1 you've mischaracterized what he said before. 2 MS. ZETTLER: He's 3 testified that the reason they didn't try to 4 validate the scale first was because there was a 5 need to reassure physicians that there wasn't a 6 problem with prescribing this drug for people who 7 were suffering from agitated depression, and now 8 he says that there is, as far as he knows, no 9 perception. 10 MR. MYERS: I think he 11 did say the first thing you said, but he didn't 12 say haste. That was my objection to the form of 13 the question. 14 Q (BY MS. ZETTLER) Then 15 why couldn't you have taken the time, Doctor, to 16 validate the agitation scale before you performed 17 the study? 18 A I don't recall all the 19 thinking that went into that, but to the best of 20 my recollection, it was felt that we should embark 21 upon the study to address what was a concern for 22 some physicians, and that to have sought to 23 validate the scale -- again, I'm not an expert, 24 I'm not sure what the time frame would be for a 196 1 full validation. The question that one may 2 have -- that I would have is did the study itself 3 validate the questionnaire. 4 Q Did you feel the study 5 validated the questionnaire? 6 A I don't know, I can't 7 answer that. 8 Q Do you know of anybody 9 who was of the opinion at Lilly or outside of 10 Lilly that the study did validate the 11 questionnaire? 12 A I don't know that either. 13 Q In your opinion, is it 14 good science to structure a study based on a scale 15 that hasn't been validated? 16 A I would suspect that 17 that's how many scales come about are through an 18 initial use of a proposed scale that then is 19 looked at post hoc for its reliability and 20 validity and perhaps in future studies, so I don't 21 think it's necessarily bad science where there is 22 no scale that exists. 23 Q Answer my question: Is 24 it good science to run a clinical trial to measure 197 1 agitation or the effect of a drug on agitated 2 depressed people structuring the study on a scale 3 that has not been validated? 4 MR. MYERS: I object to 5 the form, he's answered that question. 6 MS. ZETTLER: I don't 7 believe he has, it wasn't responsive. 8 MR. MYERS: Answer it 9 again, Doctor. 10 A I don't know. I think I 11 would let my colleagues sit in judgment on that. 12 Q Who? 13 A My colleagues, 14 individuals who are involved in clinical 15 psychopharmacology research. 16 Q Outside of Lilly? 17 A Yes. 18 Q When is the last time you 19 talked to a primary care physician related to 20 fluoxetine? 21 A Eight months ago. 22 Q Would you, as a 23 psychiatrist, feel comfortable in recommending to 24 primary care physicians who are not trained in 198 1 psychiatry that they can treat agitated depressed 2 patients with fluoxetine? 3 MR. MYERS: Before he 4 answers, let me object to the form to the extent 5 your question assumes that primary care physicians 6 are not trained in psychiatry. 7 MS. ZETTLER: I said 8 primary care physicians not trained in psychiatry, 9 Larry. 10 MR. MYERS: That's what 11 I'm saying and I object to the form because you're 12 assuming that primary care physicians are not or 13 that those that are not have no training -- 14 MS. ZETTLER: Those that 15 are not. 16 MR. MYERS: All right. 17 MS. ZETTLER: Are you 18 withdrawing your objection? 19 MR. MYERS: I understand 20 what Ms. Zettler said and I'm not withdrawing my 21 objection. Do you understand the question? 22 THE WITNESS: I would 23 like for you to repeat it. 24 Q (BY MS. ZETTLER) Do you, 199 1 as a psychiatrist, feel comfortable in 2 recommending to primary care physicians who are 3 not trained in psychiatry to prescribe fluoxetine 4 in treating agitated depressed people? 5 A I'm not sure that the 6 premise that primary care physicians are not 7 trained in psychiatry is a fair assumption, given 8 the experience that every physician has across 9 multiple disciplines. I would feel comfortable 10 with a primary care physician who has completed 11 medical school and has been in the practice of 12 medicine prescribing fluoxetine for the agitated 13 patient. 14 Q Do you feel that they are 15 as qualified to treat agitated depressed people as 16 somebody like yourself who is a psychiatrist, in 17 general? 18 MR. MYERS: Wait a 19 minute, before he answers, let me object to the 20 form. I don't know that it's a proper question to 21 ask one physician whether some undefined physician 22 or group of physicians is any more or less 23 qualified than he or she. 24 Q Doctor, would you feel 200 1 comfortable in doing a heart transplant? 2 A No. 3 Q Obviously you've been 4 trained in the cardiovascular system as a 5 physician, though, correct? 6 A That's correct. 7 Q Okay, and so would you 8 feel comfortable in somebody who is a primary care 9 physician and who has had as much training in 10 psychiatry presumably as you've had in cardiology 11 treating somebody who is severely depressed and 12 suicidal, or would you prefer that that person 13 refer them to a psychiatrist? 14 MR. MYERS: Same 15 objection as to form, and that is a different 16 question, but go ahead and answer, if you can. 17 A Yes, I would feel 18 comfortable. 19 Q You'd feel comfortable 20 with somebody who is a primary care physician who 21 does not have your specialized training in 22 psychiatry treating somebody who is severely 23 depressed and suicidal? 24 A Oh, severely depressed 201 1 and suicidal. It's a very difficult question to 2 answer because oftentimes more information is 3 available. It's quite possible -- for instance, I 4 would say yes if that physician, as a primary care 5 physician, as is very likely, has seen any of a 6 number of individuals who presented with 7 depression with and without suicidality. The bulk 8 of those patients are treated and treated well by 9 primary care physicians. 10 Q People who are suicidal? 11 A Yes. 12 Q Then why do we need 13 psychiatrists? 14 A That could take days. 15 MR. SMITH: No, in 16 connection with treatment of severe depression. 17 A I think psychiatrists 18 serve as a referral source for those patients that 19 a primary care physician does not feel that he or 20 she can comfortably treat, so that's a decision 21 quite often that a primary care physician makes. 22 In addition, a psychiatrist, of course, has more 23 direct referrals that do not come through a 24 primary care physician referral, so that relative 202 1 to the primary care physician, I think it's a 2 process of selection of patients that he or she 3 judges to require something more than what he or 4 she can offer. 5 Q Which would be, 6 typically? 7 A Could be psychotherapy, 8 it could be that they detect a level of ideation 9 that they may feel warrants evaluation for 10 hospitalization, and those individuals would -- 11 those primary care physicians would understand 12 that, for the most part, a patient to be 13 hospitalized would be under the care of a 14 psychiatrist, not always, but most of the time, so 15 that they would facilitate that process, the 16 evaluation and possible hospitalization. 17 Q Do you know of any state 18 in this country that prohibits a primary care 19 physician from hospitalizing a patient who may be 20 harmful to themselves or others? 21 A Allows a non -- 22 Q A nonpsychiatrist, a 23 primary care physician or other nonpsychiatrist, 24 prohibits them from hospitalizing a patient that 203 1 they feel may be an immediate danger to themselves 2 or others. 3 MR. MYERS: Before he 4 answers, let me ask, you used some language, are 5 you talking about like in a committal proceeding? 6 MS. ZETTLER: Right. 7 MR. HARRIS: I'm going to 8 object to the form of the question as asked from 9 this witness because I don't believe that he is 10 qualified to answer on the basis of what legal 11 criteria that must be met in the State of Texas 12 for admission. As such, he's not qualified, 13 there's been no proper predicate or anything, that 14 requires him to speculate. 15 Q (BY MS. ZETTLER) Did you 16 understand the question? 17 A I understand and I don't 18 know the answer to that question. 19 Q Can a primary care 20 physician in this state have somebody committed to 21 prevent them from harming themselves or others if 22 they feel that they fit the criteria? 23 A I don't know. 24 Q In your private practice 204 1 experience, have primary care or other physicians 2 who are nonpsychiatrist or nonpsychiatric-based 3 physicians referred patients to you that they felt 4 needed to be hospitalized? 5 A I have had referrals from 6 primary care physicians for evaluation for 7 hospitalization. 8 Q Before or after they were 9 hospitalized? 10 A Before. 11 Q Have you ever been in a 12 situation where you have been called in as a 13 member or a consultant on a medical staff such as 14 a hospital or medical center where -- like for 15 instance at Loyola, where a primary care or other 16 nonpsychiatric physician has committed a patient 17 because of psychiatric reasons? 18 A That goes back a long 19 way, I can't recall that. 20 Q Okay. As a psychiatrist, 21 do you feel comfortable in a primary care 22 physician's ability to make a determination on the 23 level of suicidal ideation a person is suffering? 24 A Yes. 205 1 Q Do you feel comfortable 2 in that respect with the primary care physician 3 making a determination as to whether or not 4 somebody presents an immediate danger to 5 themselves or others, from a psychiatric 6 standpoint? 7 A Yes. 8 Q Doctor, are you aware 9 that the majority of physicians who are 10 prescribing Prozac today are nonpsychiatric-based 11 physicians? 12 A I am aware of that. 13 Q Do you know what 14 percentage of the people who are prescribing 15 Prozac today are in fact psychiatric-based 16 physicians? 17 MR. MYERS: Are? 18 MS. ZETTLER: Are. 19 A I don't know offhand. 20 Q Have you heard that up to 21 seventy percent of the people who are prescribing 22 Prozac to date are nonpsychiatric-based 23 physicians? 24 A I've heard numbers in 206 1 that range, yes. 2 Q Do you agree with those 3 numbers? 4 A Yes. 5 Q What is subsyndromal 6 syndrome? 7 A My understanding of 8 subsyndromal depressive disorder is that it is a 9 disorder which does not meet criteria for either a 10 major depressive episode or for a dysthymic 11 disorder which occurs with a lesser degree -- 12 MR. MYERS: Dysthymic 13 disorder? 14 A I'm sorry, does not meet 15 criteria for major depression or dysthymia, it 16 occurs with a lesser degree of severity and of 17 variable duration. 18 Q Give me an example of a 19 patient who is suffering from subsyndromal 20 depressive disorder. 21 MR. MYERS: Like an 22 example presenting symptoms? 23 MS. ZETTLER: Right. 24 A I suspect that that 207 1 individual might complain of some degree of 2 depressed mood of variable intensity and/or some 3 perhaps decrease in energy or loss of pleasure in 4 some activities, but would be for the most part 5 free of any of what we call vegetative symptoms, 6 the GI complaints, the anxiety -- that's not 7 vegetation -- GI complaints, in some you have 8 weight changes, may experience minimal if any 9 anxiety, so, you know, I guess what I'm saying is 10 it's a very -- it's a milder type of depression. 11 Q Is this a recognized 12 disorder? 13 A Depends upon who you talk 14 to. 15 Q In your opinion, is it a 16 recognized disorder? 17 A In my opinion there is a 18 disorder that exists that is different than 19 dysthymia and/or major depression that meets those 20 features; as far as I know, it has been discussed 21 in Europe as well the United States; and that 22 there will perhaps be some inclusion in the 23 next -- in the DSM-IV relative to that particular 24 disorder. Does it exist, in my estimation, yes. 208 1 Q Is that in your 2 estimation as a psychiatrist or as an employee of 3 Eli Lilly and Company? 4 A My estimation as a 5 psychiatrist who has practiced. 6 Q Do you believe this is a 7 chemical imbalance, the result of a chemical 8 imbalance? 9 A In many instances, it 10 might very well be. 11 Q Do you believe it needs 12 to be treated with a psychopharmacological drug? 13 A I think we need more 14 information. 15 Q Has Lilly done any 16 studies on fluoxetine and subsyndromal depressive 17 disorder? 18 A I believe we have one, 19 possibly several studies underway. 20 Q One and possibly several? 21 A Uh-huh. 22 Q A whole new area of 23 possible revenue, huh? 24 MR. MYERS: Don't answer 209 1 that. 2 Q Who first came up with 3 the idea of subsyndromal depressive disorder? 4 A I don't know. 5 Q Who has been pushing it 6 to the DSM committee? 7 MR. MYERS: I object to 8 the form assuming someone has been, quote, 9 unquote, pushing it to anybody. 10 A There has been an 11 emerging literature that has addressed both 12 subsyndromal disorder and something that I suspect 13 is akin and perhaps one and the same, and that is 14 brief reactive depressive disorder. I believe the 15 person in the forefront of that particular 16 disorder -- there are several, but in Europe 17 Doctor Jewell Angst comes to mind, and in the 18 United States I think there have been a number of 19 senior investigators and psychopharmacologists 20 throughout the country who feel that -- and 21 perhaps have written. I'm not conversant with the 22 literature relative to this disorder. 23 Q Do you remember, has 24 Lilly worked with Doctor Angst? 210 1 A I don't know. 2 Q Have you ever talked with 3 Doctor Angst? 4 A I believe, as I recall, I 5 met him at a symposium. 6 Q What symposium? 7 A It was either the 8 Congress Internationale Neuropsychopharmacology or 9 it was a symposium in Vienna. 10 Q When would the Congress 11 Internationale have been? 12 A I don't recall which one 13 it would have been, possibly the one held in Nice. 14 Q When? 15 A As best I recollect, 16 1992. 17 Q Have you been a clinical 18 monitor on any subsyndromal depressive disorder 19 studies done through Lilly on fluoxetine? 20 A Not formally. 21 Q How about informally? 22 A Yes, in a sense. I have 23 responsibility for a study currently that is a 24 study in a naturalistic setting. 211 1 MR. SMITH: Naturalistic? 2 THE WITNESS: It's a 3 primary care setting. 4 A And patients are eligible 5 for entry into the study if they are assessed as 6 being depressed by the physician. And when that 7 study is completed, there will be an opportunity 8 to look at those individuals who may have milder 9 forms of depression, in which subsyndromal can be 10 one unique subset. 11 Q When you say that the 12 patient is evaluated as being depressed, you mean 13 suffering from major depressive disorder? 14 A No, the patient is 15 assessed by the physician as being depressed much 16 as he or she would make that assessment in their 17 practice. And then it would be a patient that the 18 investigator would feel would be appropriate for 19 treatment with medication, that he or she would 20 treat with medication, and that patient then is 21 invited to participate in a double blind study. 22 Q Where is that study as 23 far as completion is concerned? 24 A We hope to enroll the 212 1 last patient in June, and there is a two-year 2 follow-up. 3 Q So there are people who 4 have been treated, have been given fluoxetine on 5 this study? 6 A Yes. 7 Q When did the study start? 8 A Approximately twenty, 9 twenty-two months ago. 10 Q How many sites are 11 involved? 12 A One. 13 MR. SMITH: Where? 14 MR. MYERS: You can tell 15 him where. 16 THE WITNESS: Seattle. 17 Q (BY MS. ZETTLER) And 18 these are primary care physicians who are 19 administering the drug, not psychiatrists? 20 A That's correct. 21 Q And you have primary 22 responsibility for this study? 23 A I'm the in-house clinical 24 monitor. 213 1 Q What other studies on 2 subsyndromal syndrome have been conducted by Lilly 3 on fluoxetine that you are aware of? 4 A I'm not aware of others. 5 Did I mention there was one formal study ongoing, 6 did I speak to this one? 7 Q I don't think so. 8 A There is another study 9 which I believe has started which I'm not a 10 clinical monitor. 11 Q Who is the clinical 12 monitor on that? 13 A I believe Doctor Atul 14 Pande is. 15 Q Is that a man or woman? 16 A That's a man. 17 Q Is he here in 18 Indianapolis? 19 A Yes, ma'am. 20 Q Is that primary care 21 physician administering fluoxetine in that study 22 also? 23 A I don't believe so. I 24 don't know for sure. 214 1 Q To your knowledge, is 2 subsyndromal syndrome an indication that Lilly is 3 going to have to make a formal application to the 4 FDA on? 5 A I don't know. 6 Q The agitation study that 7 we were talking about earlier, is that an IND or 8 an NDA study? 9 A An NDA study. 10 Q Was that protocol 11 submitted to the FDA, to your knowledge? 12 A To my knowledge, it has 13 been, yes. 14 Q Did they question the use 15 of the agitation scale? 16 A They did not, to my 17 knowledge. 18 Q You said that in the 19 agitation study, the Adult Suicide Ideation 20 Questionnaire was used, correct? 21 A That's correct. 22 Q Why didn't you use Doctor 23 Miller's Suicidal Ideation Scale? 24 A I do not believe that 215 1 Doctor Miller's scale was available at the time we 2 were to start the study or it was not suitable for 3 the study, I cannot recall the specifics. 4 Q Doctor Miller had more 5 than one scale that he developed, did he not? 6 A I don't know. 7 Q Is it your understanding 8 that Doctor Miller developed a suicidality scale 9 specifically for Eli Lilly? 10 A I understood that there 11 was some work being done on that. 12 Q Do you know whether or 13 not Doctor Miller had an existing scale on 14 suicidality before he developed the one for Lilly? 15 A I recollect that he may 16 have, but I'm not sure. 17 Q Did you participate in 18 any way in the study that was conducted by Lilly 19 to validate Doctor Miller's scale? 20 A I did not. 21 Q Do you know if that study 22 has been completed? 23 A I don't know. 24 Q Do you know if Doctor 216 1 Miller's scale is being used in any current 2 fluoxetine depression studies conducted by Lilly? 3 A I don't know. 4 Q Do you know if his scale 5 has ever been used by Lilly in any of its 6 fluoxetine studies? 7 A I don't know that either. 8 Q Was the Adult Suicidal 9 Ideations Questionnaire a questionnaire that was 10 developed by Lilly? 11 A It was not. 12 Q Who developed it? 13 A Doctor William Reynolds. 14 Q Where is Doctor Reynolds 15 located? 16 A I believe he's at the 17 University of British Columbia. 18 Q Why did you feel it was 19 necessary to use the Adult Suicidal Ideations 20 Questionnaire on the agitation study instead of 21 relying on the Hamilton Depression Question 3? 22 A As I recall, there was a 23 request from the FDA to include something in 24 addition to an Item 3 analysis in future studies. 217 1 In reviewing the available questionnaires, it was 2 my assessment that the ASIQ, the Adult Suicide 3 Ideation Questionnaire, would be an appropriate 4 instrument to use in this particular study. 5 Q The FDA request that 6 you're talking about where they asked that 7 something more than the HAMD-3 be used with 8 regards to suicidality, was that a request made 9 specifically of Lilly or was that a request made 10 across the board with regards to antidepressant 11 drug testing? 12 A I don't know. 13 Q Do you know when that 14 request was made? 15 A I don't recall. 16 Q Was it before or after 17 January of 1990? 18 A I don't recall. 19 Q Was it before or after 20 your analysis of violent aggression in the 21 databases? 22 A I can't recall. 23 Q Was it before or after 24 Doctor Beasley's meta-analysis article was 218 1 published? 2 A I don't recall. 3 Q Is there something that 4 would refresh your recollection as to that date? 5 MR. MYERS: As to when 6 they asked? 7 MS. ZETTLER: Right. 8 A I believe that request 9 came at a meeting with the FDA, and I'm not sure 10 which meeting that was; I don't remember the time 11 frame. 12 Q A meeting between Lilly 13 employees and the FDA? 14 A Yes. 15 Q Do you know if that 16 meeting was held before or after the 1991 Advisory 17 Committee meeting? 18 A To the best of my 19 recollection, it was before. 20 Q Was the fact that the FDA 21 requested at a meeting between Lilly employees and 22 the FDA that a suicidality scale or some other 23 measure of suicidal ideation be used in future 24 Lilly studies besides the Hamilton Depression 3 219 1 discussed at the Advisory Committee meeting in 2 1991? 3 A I don't recall. 4 Q Was Doctor Miller 5 retained by Lilly to develop a suicidal ideation 6 scale for Lilly in response to that request, to 7 your knowledge? 8 A I have no substantial 9 knowledge of what that relationship was, whether 10 he was retained or how that was developed. 11 Q Do you know whether or 12 not he is working on validating that study in 13 response to the request by the FDA? 14 A I don't know. 15 Q Who would know that? 16 A I would suspect Doctor 17 Beasley. 18 Q Were you at the meeting 19 where the FDA requested that a scale be used as 20 opposed to the HAMD-3? 21 A Yes. 22 Q How did that come up? 23 A As best I recall, there 24 was a wish to supplement the Item 3 analysis in 220 1 such a way that one could perhaps study a bit 2 further suicidal ideations over the course of the 3 study. 4 Q Did they ask Lilly to 5 perform a specific study to investigate the 6 incidence of increase of suicidal ideation or the 7 emergence of suicidal ideation on patients being 8 given fluoxetine for depression? 9 A Could you repeat that 10 again, please? 11 Q Sure. During that 12 meeting or at any other time did the FDA request 13 that Lilly perform a specific study whose 14 objective it was to study the relationship between 15 the use of fluoxetine and suicidal ideation? 16 A I'm uncertain as to what 17 the final outcome of that meeting was. As best I 18 recall, a request was made for us to incorporate 19 for a period of time a questionnaire relative to 20 suicidal ideation in our future Plan D depression 21 protocols or Phase 4 depression protocols. 22 Q And the scale that was 23 incorporated was the Adult Suicidal Ideation 24 Questionnaire? 221 1 A Yes, ma'am. 2 Q How many studies was that 3 incorporated into, as far as you know? 4 A As far as I know, two. 5 Q The agitation study, 6 correct? 7 A That's correct. 8 Q What other study? 9 A There is a study 10 currently ongoing that it is being used in. 11 Q What study? 12 MR. MYERS: Wait a 13 minute, is it a fluoxetine study? 14 THE WITNESS: Fluoxetine 15 is in the study, but it's not a Phase 4 study. 16 MR. MYERS: Okay. 17 Q (BY MS. ZETTLER) Okay, 18 what study is this? 19 A It's the study with one 20 of our new antidepressants in which fluoxetine is 21 a comparator. 22 Q It's an efficacy study on 23 a new antidepressant? 24 A Yes, ma'am. 222 1 Q Is there a tricyclic arm 2 on that study? 3 A No. 4 MR. SMITH: Is there a 5 placebo arm? 6 THE WITNESS: Yes, sir. 7 MR. SMITH: So it's a new 8 drug, fluoxetine and placebo, three arms? 9 THE WITNESS: Four arms. 10 There are two arms of the new compound. 11 MR. SMITH: Two new 12 compounds? 13 THE WITNESS: I'm sorry, 14 two arms of the same compound that is new, so two 15 arms of the new compound, different doses, 16 fluoxetine and a placebo. 17 Q (BY MS. ZETTLER) Any 18 other studies that you know of where fluoxetine is 19 involved and the Adult Suicidal Ideation 20 Questionnaire is being used, being conducted by 21 Lilly? 22 A None that I recall. 23 Q How long did the FDA ask 24 that the questionnaire be included in fluoxetine 223 1 studies, Plan D studies? 2 A I don't remember that a 3 specific time frame was given. I vaguely recall 4 one other study that I should mention where I 5 think it was included, but I can't be sure. 6 Q Okay. 7 A And that was a 8 comparative study with desipramine in a population 9 of depressed women with breast cancer. 10 Q Okay. 11 A I believe we incorporated 12 it in that one, I can't be sure. 13 Q How many studies 14 comparing fluoxetine to desipramine in depressed 15 patients have been conducted by Lilly that you are 16 aware of? 17 A I'm sure of two. 18 Q Okay. A breast cancer 19 study, correct? 20 A Which didn't finish. 21 Q Okay, and two others? 22 A One other one. 23 Q What is the other one? 24 A The other one is a study 224 1 in which various biological markers were used 2 to -- it's called the biological marker study, to 3 look at prediction of response based upon the 4 presence or absence of these markers at baseline. 5 Q What biological markers 6 were used? 7 A I don't recall them all, 8 but as I recall they did a dexamethasone 9 depression test, they may have done some uptake 10 inhibition studies. I can't be real sure without 11 reviewing the protocol. There were some -- three 12 or four markers, I think, that were being looked 13 at. 14 Q Was cerebral spinal fluid 15 taken during that study? 16 A Not that I recall. 17 Q Was it basically blood? 18 A As I recall. 19 Q Inpatients or 20 outpatients? 21 A I'm not sure. It may 22 have been both, but I'm not sure of that. 23 Q How many sites? 24 A As I recall, three. 225 1 Q When was that study 2 conducted? 3 A When? 4 Q Uh-huh. 5 A I suspect that it started 6 in 1986 or maybe '85, and then continued over a 7 long period of time because of the difficulty in 8 recruiting patients for biological marker studies. 9 Q Have the results of that 10 study been published? 11 A Not that I'm aware of. 12 Q Does Lilly intend to 13 publish results of that study? 14 A I don't know what the 15 plans are at this point. As I understand it, the 16 materials are in the hands of the lead 17 investigators and they have been working on a 18 manuscript or they have worked on one. 19 Q Has a final report been 20 submitted to the FDA on that study? 21 A I don't know. 22 Q Do you know when the last 23 patient was enrolled in that study? 24 A I don't know. 226 1 Q Are you aware of any 2 studies conducted by Lilly to investigate 3 specifically the relationship between the use of 4 fluoxetine and suicidal ideation? 5 A What do you mean by 6 specifically? 7 Q Where the objective of 8 the study was to determine if there was a 9 correlation between the use of fluoxetine and 10 suicidal ideation either occurring or increasing. 11 A I'm not aware myself of 12 that as a primary objective, but one of our 13 objectives in including the ASIQ in our studies 14 was to look at that over the course of time. 15 MR. SMITH: You mean in 16 the agitation study? 17 THE WITNESS: In the 18 agitation study, and also, as I recall, we've 19 included it in that four-arm study that I just 20 mentioned, and I believe in the breast cancer 21 study. 22 Q How about studies 23 conducted by Lilly where the primary objective of 24 the study was to study the incidence of violent 227 1 aggressive behavior, either the emergence or the 2 intensification of violent aggressive behavior in 3 patients using fluoxetine? 4 A I'm sorry, could you 5 repeat that again? 6 Q Are you aware of any 7 studies conducted by Lilly or being conducted by 8 Lilly or being planned by Lilly where the primary 9 objective of the study is to study the incidence 10 or the correlation of the emergence of or the 11 increase of violent aggressive behavior in people 12 using fluoxetine? 13 A I'm not aware that we 14 have funded any such study as part of our Plan D 15 plans. 16 Q Okay, are you aware of 17 any such study that's ever been conducted or 18 funded in any way by Lilly? 19 A There have been several 20 studies in which investigators were looking at 21 patients who at baseline had problems with 22 impulsive aggression where we provided perhaps 23 drug and placebo in some instances and perhaps in 24 other instances drug and placebo and a small 228 1 amount of funding or research associates who were 2 at those various sites. 3 Q What studies are those? 4 A The one that comes to 5 mind, and there are others but I don't want to 6 mention names if I don't know that they're the 7 right people -- 8 MR. MYERS: Before you 9 answer, let me tell you, Doctor, don't disclose 10 the identity of any clinical investigators. You 11 can tell them about the study, but don't disclose 12 the identity of any investigators. 13 A Okay. As I recall, there 14 is a study in adolescents who have significant 15 difficulties with impulsivity that could result in 16 self or other injurious behaviors. 17 Q Is that ongoing? 18 A I believe that it is. I 19 also recall another study in which individuals 20 with posttraumatic stress disorder who had 21 significant problems with their impulsivity and 22 aggression were being studied. 23 Q Is that study still 24 ongoing? 229 1 A That may be in the 2 literature at this point in time. 3 Q Is that the Vietnam 4 veterans' study? 5 A As I recall, there may 6 have been several of those, and I don't know which 7 of those we might have -- I can't recall which we 8 might have provided funding and support for. 9 These were not fully funded studies, nor were 10 they, of course, IND or NDA studies. 11 Q Any other studies that 12 you might recall? 13 A There may be others. The 14 only other one that I have some recollection for 15 is a study in patients with, as I recall, severe 16 personality disorders, possibly borderline 17 personality disorder and problems with compulsive 18 aggression. 19 Q That's a Lilly funded 20 study? 21 A I don't recall what was 22 provided, if anything. 23 Q These studies, are they 24 studies to look at the relationship of fluoxetine 230 1 and the treatment of patients and the emergence or 2 intensification of such problems like the 3 impulsivity in children, or are these studies 4 geared to look at the effectiveness or the 5 efficacy of fluoxetine in treating these different 6 problems? 7 A It's the latter. 8 Q So, in other words, these 9 adolescents were given fluoxetine to study its 10 efficacy in treating impulsivity, correct? 11 A Impulsive aggression. 12 Q And the posttraumatic 13 stress disorder, it was an efficacy study 14 regarding fluoxetine in treating posttraumatic 15 stress disorder? 16 A It was looking at 17 individuals who had high baseline impulsive and 18 aggressive behaviors who would be most at risk for 19 exhibiting those behaviors, so patients could in 20 fact have gotten worse or gotten better. One 21 doesn't know what the relationship of either of 22 those would be for the drug study. 23 Q Are any of these studies 24 published, to your knowledge? 231 1 A I believe there are 2 perhaps at this point in time several studies 3 relative to the severe personality disorders in 4 the literature. There, I believe, may be one or 5 two studies relative to the Vietnam or 6 posttraumatic stress disorder population. I'm not 7 sure about the adolescent studies I mentioned 8 earlier. 9 Q What studies have been 10 published regarding posttraumatic stress disorder 11 or the severe personality disorder that have been 12 funded by Lilly in whole or in part? 13 A I really don't know. I 14 might add that none of them have been wholly 15 funded by Lilly. 16 Q Why not? 17 A These were not fully- 18 funded studies because these are studies that are 19 not what we call Phase 4 studies. They are 20 studies that scientist investigators bring to us 21 where they feel there is some potential efficacy 22 for the compound, and more as a courtesy, if we 23 feel that the study looks scientifically correct, 24 if their methodology is worked out, upon reviewing 232 1 it here, we may or may not decide to provide them 2 with drug and placebo, drug and placebo or some 3 limited amount of dollars, but typically the 4 funding for these studies would not nearly recoup 5 what it costs for them to do the studies. 6 Q So none of these studies 7 would have been initiated by Lilly? 8 A None of the ones that I 9 mentioned have been initiated by Lilly, to my 10 knowledge. 11 Q Do you know of any 12 studies initiated by Lilly where the primary 13 objective has been to study the incidence of 14 emergence or increase of violent aggressive 15 behavior in people taking fluoxetine? 16 A I'm not aware. 17 Q Are you aware of a 18 instance where Lilly considered conducting such a 19 study and decided not to? 20 A I'm not aware. 21 Q Did you ask that Lilly 22 conduct such a study? 23 A No, I did not. 24 Q Why not? 233 1 A Let me ask for a 2 clarification. Are you asking that relative to 3 the population of depressed patients or the 4 general population? 5 Q Any capacity whatsoever? 6 A Well, I think, number 7 one, it would be an -- in the general capacity, it 8 would require, as I understand it, a new IND, so 9 it would be a new indication. Secondly, it's very 10 hard to get one's hands around to some extent 11 impulsive aggression. Thirdly, it would not 12 appear that this is a problem with fluoxetine. 13 Q Based on your analysis of 14 the database that we talked about earlier? 15 A Based upon the analysis 16 and my experience as a child and adult 17 psychiatrist. 18 Q Who has only prescribed 19 fluoxetine one time in his entire career? 20 A That's correct. 21 Q How about a rechallenge 22 study of people who allegedly became violent 23 aggressive or hostile towards others while taking 24 fluoxetine? 234 1 MR. MYERS: What about 2 it? 3 Q Why not conduct one like 4 that? 5 A I can't answer it except 6 for the same reasons I just gave you, that it does 7 not appear to be a problem. 8 Q You found people that had 9 become hostile or injurious, had become injurious 10 towards others in the clinical trials, did you 11 not? 12 A It was very interesting 13 to look at those specific events because, as I 14 mentioned earlier, they were relatively benign, 15 and it was a very small number relative to the 16 total population studied. So it would -- 17 regardless of any kind of causal relationship, it 18 would be a very unusual event. 19 Q How about agitation? 20 It's been reported that people have become 21 agitated while using fluoxetine, correct? 22 A We have done a study in 23 agitation. 24 Q I'm talking about a 235 1 rechallenge study. 2 MR. MYERS: What is the 3 question, have people reported becoming agitated, 4 is that the question that's pending? 5 MS. ZETTLER: Yes. 6 MR. MYERS: While on 7 fluoxetine. 8 A I really can't answer all 9 of those questions as to why some of those studies 10 weren't considered because I'm not always the 11 decision-maker. I can tell you that from my 12 perspective it would not appear necessary. 13 Q Why, with regards to 14 agitation? 15 A Because it does not 16 appear that agitation represents a significant 17 problem in terms of aggressivity towards self or 18 others. 19 Q How many doctors who are 20 prescribing fluoxetine today, to your knowledge, 21 also prescribe a concomitant sedative or tricyclic 22 antidepressant to act as a sedative with 23 fluoxetine? 24 A I have no idea. 236 1 Q How about a rechallenge 2 study on people who allegedly became suicidal 3 while taking fluoxetine? 4 MR. MYERS: What is the 5 question? 6 Q Do you think that such a 7 study would be scientifically helpful? 8 A I believe that such a 9 study was considered, but I was not a player in 10 that study, so I don't know what the outcome of 11 that particular process was. 12 Q I'm asking you, do you 13 think it would be helpful to conduct such a study 14 to determine whether or not people on fluoxetine 15 become suicidal or their suicidality is 16 intensified? 17 A Not knowing all of the 18 specifics and the difficulty that it would require 19 to assemble such a group of individuals and how to 20 design such a study, I can't -- I can't really 21 answer that. 22 Q Are you aware that there 23 are reports in the literature where physicians 24 have rechallenged patients who have become 237 1 suicidal on fluoxetine and have found that they 2 have become suicidal again when fluoxetine is 3 readministered? 4 A I'm aware of that. 5 Q Do you feel it was 6 difficult for them to conduct such a study? 7 A I understand that that's 8 an open label study and that occurred in the 9 context of significant media coverage, and so I 10 think that it's very hard to choose a part in an 11 open label study of what is real and what is not. 12 Q So you're saying it's a 13 figment of these physicians' imaginations that 14 their patients became suicidal once they were 15 placed back on fluoxetine because of the media? 16 MR. MYERS: I object to 17 the form of the question. Those are certainly 18 your words and not his. 19 MS. ZETTLER: He can 20 disagree with me if I'm misquoting him. 21 MR. MYERS: She wants to 22 know if you thinks it's a figment of these 23 people's imaginations. 24 MS. ZETTLER: He 238 1 understood the question and doesn't need -- 2 THE WITNESS: Could you 3 repeat the question again? 4 MS. ZETTLER: Read it 5 back. 6 (QUESTION READ ALOUD.) 7 A I think what I'm saying 8 is it's very difficult when one uses a compound 9 like fluoxetine in open label fashion in the 10 environment in which the media coverage was 11 occurring to know for sure what the relationship 12 would be relative to the compound. So, no, it is 13 not necessarily a figment of their imagination, I 14 think that more information is needed, and I think 15 that in addition one has to be very cautious in 16 interpreting data from open label studies in 17 general. 18 MR. SMITH: Did you say 19 you think more information is needed in connection 20 with the issue with respect to whether or not 21 fluoxetine causes suicidal ideation? 22 THE WITNESS: Yes. 23 MS. ZETTLER: Let's take 24 a break. 239 1 (SHORT BREAK TAKEN.) 2 Q (BY MS. ZETTLER) Doctor, 3 has anybody recommended the use of fluoxetine in 4 treating subsyndromal depressive disorder? 5 A Anyone meaning whom? 6 Q Well, anybody who has 7 published a paper, Eli Lilly, anybody. 8 A I'm not aware that that 9 has been recommended. I am aware that people have 10 an interest in that and that we were approached by 11 a group of individuals to perhaps look at that. 12 Q Is the marketing 13 department paying for the subsyndromal syndrome 14 studies that you are aware of? 15 A For the one, yes. 16 Q Which one? 17 A Well, for the formal 18 study, the Phase 4 study, yes. For the 19 naturalistic study, yes, but it's a different kind 20 of study. It's not a true subsyndromal, it's just 21 depression. 22 Q When you say 23 naturalistic, what do you mean; primary care 24 physicians as opposed to psychiatrists? 240 1 A Yes, in a sense, but also 2 when patients present in the setting where the 3 study is occurring, the physician assesses 4 depression, as I mentioned earlier, and then the 5 patient, if agreeable, is blindly randomized to 6 one of three treatment arms, and after that it's 7 up to the physician to do whatever he or she 8 wants, as they would usually do in their practice. 9 Q So you mean what their 10 natural course of treatment would be as opposed to 11 a structured course of treatment according to a 12 protocol? 13 A That's correct. 14 Q How about the agitation 15 study, did the marketing department pay for that? 16 A That was funded through 17 our Phase 4 budget, which comes from Prozac 18 support, which is -- 19 Q Marketing? 20 A Marketing, yes. 21 Q Have you ever heard of 22 Barbara Geller? 23 A I have. 24 Q Who is Barbara Geller? 241 1 A Barbara Geller is a child 2 psychiatrist. 3 Q Where is she located? 4 A The last I heard she was 5 in St. Louis. 6 Q To your knowledge, has 7 Barbara Geller worked with Lilly on fluoxetine? 8 A Are you asking did we 9 fund a study with Doctor Geller? 10 Q Or did she consult in any 11 way with Lilly on fluoxetine and the use with 12 adolescents or anything? 13 A No, in terms of a formal 14 arrangement. 15 Q Have you ever spoken with 16 Doctor Geller? 17 A I have. 18 Q On what occasions have 19 you spoken with Doctor Geller? 20 A I spoke with Doctor 21 Geller at a point in time -- several points in 22 time when the company was considering embarking 23 upon a study in children and/or adolescents to see 24 what her availability might be, but prior to that 242 1 time I had also spoken with her relative to some 2 comments that I believe Doctor Teicher may have 3 made. 4 Q What comments were those? 5 A As I recall, in a journal 6 he alluded to a study that Doctor Geller had done 7 with fluoxetine and in which she reported some 8 events occurring. 9 Q What events? 10 A I believe they were 11 events of suicidality. 12 Q On patients that she had 13 given fluoxetine? 14 A That's correct, I'm 15 sorry. 16 Q Why did you talk to 17 Doctor Geller about comments made by Doctor 18 Teicher? 19 A Because those events had 20 not been reported to us, I'm a child psychiatrist, 21 I wanted to get more information. 22 Q What did Doctor Geller 23 tell you about Doctor Teicher's comments? 24 A She told me that if she 243 1 would have known that Doctor Teicher was going to 2 make those comments, she would have wrung his 3 bloody neck, as best I can remember. 4 Q Why did she say that? 5 A Because she said that she 6 indeed had not done a study with fluoxetine and 7 her data was misrepresented. 8 Q Had she seen the article? 9 A I don't recall if at that 10 point in time she had seen the article. 11 Q So she was relying on 12 your representation of what was in the article? 13 A As I recall, after I made 14 that call I faxed her a copy of what had been 15 published. 16 Q Did she make that comment 17 about wringing his bloody neck with regards to 18 Doctor Teicher before or after you sent her the 19 article? 20 A I believe it was before, 21 although I cannot be sure. 22 Q Was Doctor Teicher 23 incorrect when he discussed some of her patients 24 becoming suicidal while on fluoxetine? 244 1 A According to her account, 2 he was incorrect. 3 Q He was incorrect. Isn't 4 it true that in fact Doctor Geller reported that 5 at least one of her patients had to be 6 discontinued from fluoxetine because of their 7 suicidal ideation? 8 A I don't recall the 9 specifics of her communication in response to 10 that, but I remember that she had patients or a 11 patient, as best I recollect, that that may have 12 been the case. 13 Q Had been discontinued 14 from fluoxetine because they had been suicidal? 15 A Because the patient had 16 been suicidal without any notation as to 17 causality. 18 Q But they were 19 discontinued from fluoxetine? 20 A Yes. 21 Q Were they on any other 22 medications, as far as you know? 23 A I can't recall. 24 Q Do you know if the 245 1 suicidality disappeared once fluoxetine was 2 discontinued? 3 A I don't recall. 4 Q How about Judith 5 Rappaport, have you ever heard of her? 6 A Yes, I know Judith 7 Rappaport. 8 Q Who is Judith Rappaport? 9 A Judith Rappaport is a 10 child psychopharmacologist. 11 Q Where is she located? 12 A She is with the National 13 Institute of Mental Health. 14 Q Has she ever consulted 15 with Lilly with regards to fluoxetine? 16 A I'm trying to remember. 17 Relative to my experience with her, I do not 18 believe that I engaged her in a formal consultant 19 role. That's not to say that others may not have 20 engaged her, I just don't recall and I wouldn't 21 know the specifics of that. 22 Q How do you know Judith 23 Rappaport? 24 A Judith Rappaport is one 246 1 of the leading child psychopharmacology 2 researchers in the United States. 3 Q Has she ever conducted a 4 clinical trial on fluoxetine? 5 A Yes. 6 Q When? 7 A I'm not sure when. 8 Q Was it a Lilly-funded 9 clinical trial? 10 A The ones I'm aware of 11 were not. 12 Q More than one? 13 A Yes. 14 Q How many? 15 A I'm aware of two. 16 Q What were those studies 17 about? 18 A I'm aware that she looked 19 at fluoxetines in a group of children or 20 adolescents with attention deficit hyperactivity 21 disorder, and I'm aware that she did a study in 22 dogs. 23 Q Dogs? 24 A Yes, with an obsessive 247 1 compulsive disorder, I think it's called the Abril 2 Lick Syndrome or something where dogs lick their 3 paws until their fur comes off. She may have also 4 been a participant in a study, this is a third 5 study, and I'm not sure of this, in OCD in 6 children and adolescents. 7 Q Were those studies done 8 through the National Institute of Mental Health? 9 A To the best of my 10 knowledge, yes. 11 Q Are you aware of any 12 other studies that the National Institute of 13 Mental Health has participated in on fluoxetine? 14 MR. MYERS: When you say 15 participated, do you mean that they have known 16 whether or not Lilly has done any funding? 17 MS. ZETTLER: Right. 18 A I'm aware that there was 19 a study by an NIMH researcher who is interested in 20 pain management, specifically looking at 21 fluoxetine in some chronic pain condition. 22 Q Who was that? 23 A I don't recall the 24 name -- I think I just did, I believe it was 248 1 Doctor Max Mitchell or Doctor Mitchell Max, one of 2 the two. 3 Q Any others? 4 A Let me think here a 5 second. I vaguely recall that there was a study 6 done by some other researchers at the Institute 7 looking at some biological markers. 8 Q Using fluoxetine? 9 A I believe. 10 Q You believe that that's 11 the case? 12 A I believe -- yes, I 13 believe that fluoxetine was one or the only drug, 14 I'm very vague on that study. 15 Q Any depression studies 16 that you are aware of that the NIMH conducted 17 using fluoxetine? 18 A I'm not aware of any 19 specific study where depression was looked at by 20 NIMH researchers. 21 Q Any of these studies that 22 you've listed for us, like Doctor Rappaport's 23 study or the pain study or the biological marker 24 study, that was funded in whole or in part by 249 1 Lilly? 2 A I'm not aware that we 3 funded any of those studies. 4 Q When you first started 5 working with Lilly in September of 1986 -- is that 6 correct? 7 A It was late August, early 8 September, as I best recollect. 9 Q In 1986, though? 10 A That's correct. 11 Q How is it that you came 12 to Lilly? 13 A At the time my ex-wife 14 and I were looking to return to the Midwest, we 15 were both from the State of Illinois, and I 16 thought it was an opportunity to look at some 17 other career possibilities. 18 Q Did you approach Lilly or 19 did they approach you? 20 A I approached an executive 21 recruiter. 22 Q Did you know anybody who 23 had worked at Lilly at that time? 24 A No, I did not. 250 1 Q Had you ever been 2 approached by Lilly or anybody from Lilly to 3 conduct a clinical trial on any of their products? 4 A I had not been. 5 Q What position did you 6 start at with Lilly? 7 A I believe my title was 8 Assistant Clinical Research Physician. 9 Q Who was your superior at 10 that time? 11 A I reported directly to a 12 Doctor Michael Draper. 13 Q When did you first start 14 having responsibilities with regard to fluoxetine? 15 A Immediately. 16 Q Was that your sole 17 responsibility? 18 A It was not. 19 Q Okay. How much of your 20 time was spent on fluoxetine when you first 21 started at Lilly? 22 A A guesstimate would be 23 about seventy-five percent of my time. 24 Q Is Michael Draper still 251 1 with the company? 2 A He is. 3 Q Is he a doctor? 4 A He is. 5 Q What does he do now? 6 A I believe he is a senior 7 research physician. 8 Q Does he still have 9 responsibilities with regard to fluoxetine as far 10 as you know? 11 A Not to my knowledge. 12 Q What were your 13 responsibilities as Assistant Clinical Research 14 Physician? 15 A I had some responsibility 16 for a new compound in development that was in 17 study, for a new compound in development that was 18 not in clinical study with humans, and then some 19 fluoxetine responsibilities. 20 Q What were your fluoxetine 21 responsibilities? 22 A My primary responsibility 23 with fluoxetine, as best as I recollect, were the 24 monitoring of safety from some ongoing trials, as 252 1 well as -- I'm trying to think if I had any 2 planning responsibilities for new trials, I do not 3 recall that I did. 4 Q What phase was the study 5 of fluoxetine in when you had responsibilities of 6 monitoring safety in ongoing trials? 7 A Preregistration. 8 Q Were these pivotal 9 studies that you were monitoring? 10 A They were not. 11 Q Did you have any 12 responsibility whatsoever with regards to the 13 studies that were the basis of the FDA's approval 14 of fluoxetine, the efficacy studies? 15 A No, I did not. 16 Q What studies were ongoing 17 when you first started at Lilly? Generally, were 18 they all depression studies, were they other 19 indications? 20 A I was focused within the 21 indication of depression. 22 Q What types of studies 23 generally were going on then? 24 A Fixed dose studies. 253 1 Q Any others? 2 A The biological marker 3 study may have been underway; I'm not sure at what 4 point I assumed some responsibility for that 5 study. 6 Q Any others? 7 A I don't recall others. 8 Q When you say fixed dose 9 study, what do you mean? 10 A Looking at several fixed 11 doses of fluoxetine and making comparisons between 12 the groups. 13 Q Like twenty milligrams? 14 A (WITNESS MOVES HEAD UP 15 AND DOWN.) 16 Q If somebody is going to 17 treat subsyndromal syndrome with fluoxetine, what 18 dosage would they use? 19 A I don't know. 20 Q Would it be more than 21 twenty milligrams a day? 22 A I don't know. 23 Q How about less than 24 twenty milligrams? 254 1 A I don't know. 2 Q Do you believe that 3 subsyndromal syndrome is caused by a 4 malfunctioning of the serotonin system? 5 A It is my impression that 6 a significant number of individuals with 7 subsyndromal would likely have a neurochemical 8 difficulty such as serotonin -- sort of 9 inefficient serotonin functioning, sort of a 10 global term. 11 Q Based on what? 12 A Pardon? 13 Q What is your opinion 14 based on? 15 A Based to some extent just 16 on the model for major depression and dysthymia, 17 which it may appear to be a continuum. 18 Q So it is based on your 19 belief that major depression and dysthymia are 20 also caused by an inefficiency of the serotonin 21 system? 22 A I don't know that we knew 23 or will ever know all there is to know about 24 various neurochemical pathways and their 255 1 interrelationships with one another. What appears 2 to be very clear is the serotonin pathway is a 3 critical player in the occurrence and treatment of 4 depression. 5 Q You say it appears to be 6 very clear? 7 A I think there's a 8 significant amount of data that suggests that 9 serotonin is essential for mood regulation. 10 Q How do you determine 11 whether or not a person's serotonin system is 12 functioning appropriately? 13 A There is no sure test to 14 ascertain that. 15 Q How do you tell whether 16 or not somebody's serotonin system is inefficient? 17 A There is no test for that 18 that's consistently reliable as well. 19 Q What's an appropriate 20 level of serotonin in somebody's system, normal 21 serotonin level? 22 A I don't know if that's 23 known. 24 Q Would somebody grieving 256 1 the loss of, say, a loved one be categorized or 2 diagnosed as suffering from subsyndromal syndrome? 3 A Not necessarily. 4 Q Could they be? 5 A It's a possibility. 6 Q Could somebody who is 7 unsatisfied with their job be diagnosed as 8 suffering from subsyndromal syndrome? 9 A It's possible. 10 Q Would somebody who just 11 broke up with an boyfriend or a girlfriend or a 12 spouse be diagnosed as suffering from subsyndromal 13 syndrome? 14 A It's possible. 15 Q Can fluoxetine cause 16 somebody to become suicidal? 17 A In my estimation, no. 18 Q Can fluoxetine intensify 19 suicidal ideation that is already existing? 20 A In my estimation, no. 21 Q Based on what? 22 A Based upon my experience 23 as a physician with a broad spectrum of depressed 24 patients and in the context of what I know about 257 1 various psychopharmacological interventions. 2 Q And based on your 3 experience of prescribing fluoxetine in one case? 4 A I do not rely on that one 5 particular case to make decisions about 6 fluoxetine. 7 Q Have you ever prescribed 8 any other specific serotonin reuptake inhibitor to 9 any patient ever? 10 A No. 11 Q Tell me about the Rocky 12 Mountain Poison Control Center study. 13 A What would you like to 14 know? 15 Q Anything that you recall 16 about it. 17 MR. MYERS: This is one 18 of her favorite subjects. 19 A I know that I am the 20 principal in-house monitor for that study. 21 Q Okay. Whose idea was it 22 to conduct this study? 23 A It was another one of the 24 studies that germinated from within medical. 258 1 Q When you say germinated 2 within medical, what do you mean? 3 A Very early on in the 4 development of the compound and with the accrual 5 of experience became aware of the goodness of the 6 compound when taking an overdose. 7 Q When you say the goodness 8 of the compound in taking an overdose, you mean 9 it's not likely to kill you, correct? 10 A More than that. 11 Q Okay, what else? 12 A Only is it not likely or 13 nearly impossible to kill yourself, at least when 14 taken alone, but it also has a profile of events 15 which occurred during the course of our study that 16 were so benign in comparison to other 17 antidepressants that the patients did remarkably 18 well. 19 Q Do you know of any case 20 where somebody has died from an overdose of 21 fluoxetine alone? 22 A To my knowledge, as I 23 recall, there are one or two instances where the 24 reporter ascribed the death to fluoxetine, and I 259 1 do not recall if that was taken alone or whether 2 there might have been other compounds or other 3 substances taken at the same time. 4 Q How many incidents of 5 overdose have been reported to Lilly through the 6 Rocky Mountain Poison Control Center involving 7 fluoxetine? 8 MR. MYERS: Where there's 9 a death or just an overdose? 10 MS. ZETTLER: Right, just 11 an overdose. 12 A The analysis is not yet 13 completed. 14 THE WITNESS: Can I share 15 data? 16 MR. MYERS: Yes, go 17 ahead. 18 A We have carved out a 19 unique group of patients within the study group -- 20 again, this was part of the methodology set up 21 front, was that we would look and focus our 22 efforts on patients who had taken a solo overdose. 23 Q Okay. 24 A From the study population 260 1 of somewhere between six and seven hundred total 2 patients with either a tricyclic or a fluoxetine 3 overdose, sixteen were solo fluoxetine. 4 Q How many combination 5 drugs, fluoxetine and another drug? 6 A I don't know that; I 7 don't have that breakout for that yet. 8 Q Do you plan on getting 9 it? 10 A We will look at that. 11 Q You reported these 12 overdoses on fluoxetine to the FDA, did you not? 13 A Yes. 14 Q How many adverse event 15 reports were filed with the FDA regarding 16 fluoxetine overdoses as a result of this study? 17 A I don't know. 18 Q More than sixteen? 19 A Yes. 20 Q More than a hundred? 21 A I don't know. 22 Q Who would know that? 23 A The research associates 24 with whom I work would have a listing of those, 261 1 but they would not be uniquely split out with the 2 data that's available. 3 Q I just want to know how 4 many people overdosed on fluoxetine, whether or 5 not it was in combination with another drug or on 6 fluoxetine alone, that you became aware of as a 7 result of this study. 8 A I don't know the exact 9 number; I have no idea. 10 Q How many people died that 11 you are aware of who were on fluoxetine that you 12 became aware of as a result of this study? 13 A None. 14 Q Were 1639's filed on each 15 and every overdose that was reported to you as a 16 result of this study? 17 A In preparation for the 18 study, because it's not a formal Phase 4, we, in 19 working with the investigators and the Food and 20 Drug Administration, filed quarterly -- roughly 21 quarterly reports at intervals of all patients who 22 had overdosed in the study, so the reporting 23 mechanism was a bit different. 24 Q My question was were 262 1 1639's filed on each and every one of these 2 overdoses that you became aware of as a result of 3 the Rocky Mountain Poison Control Center study? 4 MR. MYERS: Involving 5 fluoxetine? 6 MS. ZETTLER: Involving 7 fluoxetine. 8 A I'm not aware of -- 9 because the reporting requirements were different, 10 given the study that we did -- a separate 1639 on 11 each patient. 12 Q So the answer is no? 13 A To the best of my 14 knowledge, a report was filed with the FDA that 15 was a log of all such patients, TCA or fluoxetine, 16 that overdosed during the course of the study. 17 Q The answer to my question 18 with regard to whether or not individual 1639's 19 were filed on each of these reports of overdoses 20 is no, correct? 21 A I would think that's 22 correct. 23 Q Thank you. Where were 24 those periodic reports filed listing these 263 1 overdoses? 2 A I don't understand where. 3 Q They were filed with the 4 FDA, right? 5 A That's correct. 6 Q With what part of the 7 FDA, the neuropsychopharmacology division, the 8 epidemiology division, what area? 9 A As best I recall, that 10 was handled through our regulatory group and they 11 were the ones that established the guidelines in 12 conjunction with the FDA. 13 Q What kind of information 14 was included in these periodic reports? 15 A The patient's age, sex, 16 drugs of ingestion, events that occurred with the 17 ingestion, and the outcome. 18 Q Events besides overdose? 19 A Events, as I best recall, 20 that occurred at the time of overdose. 21 Q Would you agree that an 22 overdose is in and of itself an adverse event? 23 A I do not agree that it's 24 a causally related adverse event. I considered it 264 1 an event that occurs during the course of 2 treatment with depression or nontreatment with 3 depression. 4 Q I'm not asking you 5 whether you ascribe some causal relationship, I'm 6 asking you whether or not you agree with me that 7 overdose in and of itself is an adverse event. 8 A No, I consider an 9 overdose quite often to be part and parcel of the 10 illness itself, as part of the suicidal ideation 11 which occurs within the context of the illness. 12 Q If somebody is being 13 treated with fluoxetine and they overdose on the 14 drug, either intentionally or unintentionally, is 15 it reported to the FDA? 16 A Yes. 17 Q Is that an adverse event 18 that's reported to the FDA? 19 A Technically, but you 20 asked me what I thought. 21 Q So you don't think that 22 they should be reported to the FDA, is that what 23 you're saying? 24 MR. MYERS: I'll object 265 1 to the form; that's not what he's saying. 2 Q Do you understand the 3 question, Doctor? 4 A I understand. I think 5 the event should be reported according to the 6 guidelines that the FDA establishes. 7 Q Does the FDA require that 8 you report overdoses as adverse events? 9 A Yes. 10 Q Okay. Now, my original 11 question with regards to this information in the 12 periodic reports, when you say the events are 13 reported, are you saying that the overdose itself 14 is reported as an event? 15 A That's correct. 16 Q Okay, are you also saying 17 that other events that may occur as a result of 18 the overdose, such as coma or things of that 19 nature, are also reported as adverse events? 20 A That's correct. 21 Q Any other information 22 that's reported in these periodic reports that you 23 know of? 24 A Not that I recall. 266 1 Q Are these events given 2 manufacturing control numbers by Lilly? 3 A As I recall, the serious 4 adverse events were, but the nonserious were 5 provided in the line listing as the agreement had 6 been reached. 7 Q What did you consider a 8 serious adverse event out of those events that 9 were reported through information gleaned by the 10 Rocky Mountain Poison Control Center? 11 A As I recall, those events 12 which resulted in death, disability, congenital 13 anomaly, hospitalization, et cetera. 14 Q Overdose itself is an 15 outcome that is considered serious by the 16 regulations, FDA regulations, is it not? 17 A It was at some period in 18 time; I'm not sure that it still is. 19 Q Do you know when they 20 changed that, if they did? 21 A I would say within the 22 last two years or so. 23 Q Have you ever seen a FDA 24 SRS printout including these adverse events 267 1 reported as a result of the information that you 2 got from the Rocky Mountain Poison Control Center? 3 A I don't understand SRS. 4 Q Systematic reporting 5 system. 6 A Not that I recall. 7 Q Have you ever seen a 8 printout of adverse events reported to the FDA 9 regarding fluoxetine that had been gathered by the 10 FDA either from Lilly or other sources? 11 A A composite printout? 12 Q Right. 13 A I don't recall that I 14 have. 15 Q How many alert reports 16 were filed as a result of information that you 17 gleaned from the Rocky Mountain Poison Control 18 Center? 19 A I don't recall. 20 Q Were there any? 21 A There were some, as I 22 recall. 23 Q Can you give me a 24 percentage of the total? 268 1 A I can't really. 2 Q Any of these sixteen? 3 A I don't know; I don't 4 recall. 5 Q Did you sign off on any 6 working form 1639's for alert events reported to 7 the FDA as a result of the Rocky Mountain Poison 8 Control Center study? 9 A I don't recall. 10 Q Is there anything that 11 would refresh your recollection? 12 A I suppose I would have to 13 look at specific adverse events that had been 14 reported to the FDA too from that particular 15 study. 16 Q Has that study been 17 completed? 18 A Yes, it has. 19 Q Are the results of that 20 study going to be published? 21 A It is planned that they 22 will be published. 23 Q Are you going to be 24 listed as an author on that publication? 269 1 A I hope to be. 2 Q Since you are the head of 3 the project, you will be, won't you? 4 A Not necessarily. 5 Q Why not? 6 A Because the lead 7 investigative team will be the primary, and I may 8 or may not be included. 9 Q Who is the lead 10 investigative team? 11 MR. MYERS: He's not 12 going to disclose that for the same reason I said 13 before, the previous orders of the multi district 14 and the Fentress court. 15 MR. SMITH: Was that an 16 investigative team out of Lilly or some other 17 entity? 18 THE WITNESS: Another 19 entity. 20 MR. SMITH: Who is that? 21 MR. MYERS: I'm directing 22 him not to answer that. 23 MR. SMITH: What? You're 24 directing him not to give us the names of the lead 270 1 investigative team for the Rocky Mountain Poison 2 Control study that's not related to Lilly? 3 MR. MYERS: Yes. 4 MS. ZETTLER: Certify it. 5 (QUESTION CERTIFIED.) 6 MR. SMITH: I think we're 7 going to have to have our meeting May 6th with 8 Judge Godesh, this has gone far enough. 9 Q (BY MS. ZETTLER) Was 10 Rocky Mountain Poison Control Center paid by Lilly 11 to conduct this study? 12 A It was a study funded by 13 Lilly, yes. 14 Q Was this a single center 15 study? 16 A It was not. 17 Q How many centers were 18 involved? 19 A As I recollect, there 20 were ten sites. 21 Q These are emergency 22 rooms, are they not? 23 A That's correct. 24 Q Is this investigative 271 1 team that you are talking about members of these 2 various emergency rooms? 3 A Yes. 4 Q Was there one coordinator 5 on the study? 6 A There was. 7 Q Who? 8 MR. MYERS: Don't answer 9 that. 10 MS. ZETTLER: Certify it. 11 (QUESTION CERTIFIED.) 12 Q (BY MS. ZETTLER) Was 13 that coordinator located at the Rocky Mountain 14 Poison Control Center? 15 MR. MYERS: You can 16 answer that. 17 A He was. 18 Q Were these university 19 hospital emergency rooms? 20 A Some were and some were 21 not. 22 Q Can you tell me what 23 hospitals? 24 MR. MYERS: You can tell 272 1 her that. 2 A As best I recollect? 3 Q Sure. 4 A Denver General. A 5 hospital in Sacramento, I'm not sure which. There 6 was a site at Portland. A site in Minneapolis at 7 Henepin County. I believe Cook County may have 8 been a site in Chicago. Hershey, Pennsylvania. 9 Jacksonville, Florida. Charlotte, North 10 Carolina. There was one or two more that escapes 11 my memory. 12 Q Any in New York? 13 A There may have been one, 14 I'm not sure, I can't recall whether a New York -- 15 Q Was Doctor David Dunner 16 involved in this at all, this study? 17 A He's not. 18 Q Were these all county- 19 based hospitals or were some of them private 20 hospitals? 21 A I suspect some were 22 freestanding or private hospitals as opposed to 23 county supported hospitals. 24 Q Were these hospitals 273 1 chosen by people at Lilly or by people at Rocky 2 Mountain Poison Control Center? 3 A By the individual at 4 Rocky Mountain Poison Control Center. 5 Q Was there a criteria that 6 was used to pick the hospitals? 7 A There were some criteria. 8 Q What were the criteria? 9 A I'm not familiar with all 10 of those, but several of the criteria would 11 include -- the lead investigators felt they wanted 12 to have clinical toxicologists, the study occur in 13 a setting with clinical toxicologists; where there 14 was a capacity to gather information including 15 plasma levels, where there was a capacity or 16 potential to follow patients over the course of a 17 medical hospitalization. And there are some other 18 criteria as well they dealt with. 19 Q Did you recall any of the 20 other criteria? 21 A Other than a willingness 22 to participate and some enthusiasm that was 23 assessed by the Rocky Mountain group, I don't 24 recall other specific criteria. 274 1 Q Were the hospitals paid 2 for this study? 3 A There was a stipend; I'm 4 not sure to whom that stipend went. 5 Q This was separate and 6 apart from what was paid to the Rocky Mountain 7 Poison Control Center? 8 A No, we gave a budget to 9 Rocky Mountain or they negotiated a budget with us 10 and they were fully responsible then for their 11 relationship with the individual hospitals. We 12 had no relationship with those hospitals in terms 13 of direct payments. 14 Q Is this considered a 15 grant? 16 A That's, I think, the best 17 way to characterize it. 18 Q Was payment of the entire 19 amount of the grant conditioned on a publishable 20 manuscript being written? 21 A No. As best I recollect, 22 the final payment, as in many of our studies, is 23 contingent on a final report from the 24 investigator -- I'm trying to remember this -- 275 1 that could very well serve as a manuscript. In 2 this particular study, I'm not sure as to whether 3 that was contingent upon a manuscript, I suspect 4 it may be. 5 Q Do you know why Lilly 6 conditions final payment of the grant on the 7 production of a final report by the investigators? 8 A I don't know. 9 Q Do you feel that that is 10 appropriate? 11 A Yes. 12 Q Why? 13 A Because when 14 investigators undertake a study on behalf of Lilly 15 or any other company, I think the company should 16 be entitled to some sort of report that 17 synthesizes the findings from the study. 18 Q But Lilly does the 19 statistical analysis of the data, does it not? 20 A Not in all studies. 21 Q In the majority of them 22 though, doesn't it? 23 A In the Phase 4 studies, 24 yes; not in all grant studies. 276 1 Q Is the clinical 2 investigator ever allowed to do his or her own 3 statistical analysis? 4 A To my knowledge, yes. 5 Q In what circumstance? 6 A Quite often -- well, let 7 me backtrack. Are you asking about Phase 4 or 8 grant studies? 9 Q What's the difference? 10 A In the Phase 4 studies, 11 the data comes in-house, it's gleaned, entered, 12 et cetera, here, and in grant studies oftentimes 13 the data stays at the site in terms of the outcome 14 data, so there's a difference in how the data is 15 handled. 16 Q What's the difference 17 between a grant study and a Phase 4 study? 18 A There are several 19 differences. 20 Q Okay. 21 A But in terms of the 22 funding, quite often, in the kind of grants that I 23 have been involved with, there is a budget that we 24 develop with the lead investigator and whomever he 277 1 or she contracts with to take on any component of 2 the study are paid from that particular grant and 3 not by us; whereas a Phase 4 study, we work out a 4 budget with each investigative site. 5 Q How about an efficacy 6 study that's submitted to the FDA in support of 7 approval for marketing, is that a grant study? 8 A No, I don't think it 9 could be a grant study -- well, I can't say that. 10 I don't know, it may be, but I've not had that 11 experience. 12 Q Do you know whether or 13 not the statistical analysis that was done on 14 those studies that were submitted to the FDA in 15 support of approval on fluoxetine were done at 16 Lilly or were done by the investigators 17 independently? 18 A I don't know the 19 specifics of that. 20 Q Is the Rocky Mountain 21 Poison Control Center study a double blind 22 controlled study? 23 A No, it's not. 24 Q Would it be considered an 278 1 open label study? 2 A No, it would not be. 3 Q What type of study is it? 4 A It is a study in which at 5 various investigative sites, at the time a patient 6 presented to an emergency room with reports of an 7 antidepressant overdose, the patients were 8 prospectively entered into the trial, and at that 9 point in time information was gathered relative to 10 a number of components relative to that individual 11 patient. 12 Q Did the patients know 13 they were being entered into the study? 14 A I am not sure whether all 15 patients were aware of that. 16 Q Were consent forms 17 required on that study? 18 A I do not believe that 19 study required informed consent. It was left to 20 the hands of the lead investigators and their 21 individual sites as to what their institutional 22 review board required. 23 Q Did the investigators 24 know that the study was being funded by Lilly? 279 1 A I believe they did. 2 Q And they knew which of 3 the patients that came in were on fluoxetine and 4 which weren't, correct? 5 A Not always. 6 Q Eventually? 7 A Yes. 8 Q Did they know of your 9 decision to look at only those patients who had 10 overdosed solely on fluoxetine while they were 11 gathering information? 12 A That's not a decision. 13 The primary analysis for the study will focus on 14 solo overdoses. Since those are the most -- the 15 ones that are the least amount contaminated by 16 coingestions that could possibly muddle the 17 interpretation of data. 18 Q The study was conducted 19 to look at the effects of fluoxetine overdoses as 20 opposed to the incidents of fluoxetine overdoses 21 in the population, correct? 22 A The study's objective was 23 to compare fluoxetine outcomes, both safety 24 outcome and economic outcome, to tricyclic 280 1 overdoses. 2 Q How much would constitute 3 a fluoxetine solo overdose as opposed to an 4 overdose on fluoxetine with another compound or 5 with another compound individually? 6 A The primary analysis was 7 to focus on safety and economic outcomes in 8 patients with either solo fluoxetine overdoses or 9 solo tricyclic antidepressant overdoses. 10 Q It wasn't to look at the 11 incidence of overdose with regard to fluoxetine in 12 the population? 13 A No, it was not. 14 Q Have you ever heard of 15 the urn study? 16 A Yes, I have. 17 Q What is the urn study? 18 A That is a study in which 19 fluoxetine was compared to placebo, and at some 20 point in time the randomization of additional 21 patients entering the study was dependent upon the 22 outcome of patients who had been through the study 23 at some point in time. 24 Q Okay, you're going to 281 1 have to explain that to me, Doctor, because I have 2 no clue what you're talking about. 3 A Okay. The urn concept, 4 if we're talking about the same thing, and I 5 suspect we are since the study is kind of referred 6 to as the urn design, is a methodology that 7 addresses concerns relative to patients being 8 treated with placebo. In this study, at the start 9 of the study, a patient entering the study had a 10 one in two chance of being randomized to 11 fluoxetine and one in two chance of being 12 randomized to placebo, it was even. That even 13 randomization occurred for the first six patients, 14 so six of the first patients were randomized on 15 pure chance, one out of two. After that, those 16 initial six had been randomized, further 17 randomizations would have been dependent upon a 18 central urn. 19 Let me explain that. The 20 study actually had several components within the 21 study. We were looking at a biological marker, so 22 there were two strata to the study. I would 23 simplify it and keep it to the urn and stratum as 24 one. As patients progressed through the study, a 282 1 patient -- let's say that you have two balls in 2 your urn, one fluoxetine ball and one placebo 3 ball. A patient declares at a point in time when 4 he or she meets a certain efficacy criteria or 5 needs to drop study due to the occurrence of an 6 adverse event. 7 Q Okay. 8 A Let us suppose that the 9 first patient to declare themselves is a patient 10 who meets response criteria and that patient has 11 been randomized to placebo, so you have what we 12 call a placebo responder. At that point in time, 13 a ball goes into the earn that's labeled placebo 14 and you now have two placebo balls and one 15 fluoxetine ball, so that any patient randomized on 16 that day has a two in three chance of being 17 randomized to placebo. 18 The study then 19 continues. Let's say that a placebo patient drops 20 due to an adverse event. To the urn is added a 21 fluoxetine ball. In effect, placebo gets 22 penalized, but it gets penalized by adding a 23 fluoxetine. So now you have two and two, you're 24 back to an even randomization. 283 1 Let's say that the next 2 patient declares a success on fluoxetine, meeting 3 certain response criteria, you add a fluoxetine 4 ball; three to two. Fluoxetine adverse events, 5 you have a patient that drops due to an adverse 6 event, placebo goes in, three to three, and it's 7 continually updated as patients declare themselves 8 over the course of a study. 9 MR. SMITH: What is the 10 value of that? 11 THE WITNESS: It's 12 interesting. The value is -- and it's not 13 something that's been tried very often, and -- I 14 was a monitor for this study as well, and the 15 value is it addresses the concern that some 16 individuals may have or institutional review 17 boards may have about exposing patients to 18 placebo, so that if you have an efficacious 19 compound, you can minimize exposure to placebo if 20 the drug is truly efficacious and has a beneficial 21 adverse event profile. 22 MR. SMITH: So the more 23 positive response that you get from the active 24 drug, the more likely it is that that active drug 284 1 is being put back in the urn and the more likely 2 it is that future patients will be assigned to the 3 active drug as opposed to placebo? 4 THE WITNESS: That's 5 correct, or if you had a drug with an unacceptable 6 adverse event profile, placebo might be 7 preferentially chosen. 8 Q (BY MS. ZETTLER) These 9 studies that you were telling us about earlier 10 that were either about to be published or had been 11 published -- I believe you talked about a 12 statistical study? 13 A Uh-huh. 14 Q Is that one of the 15 studies? 16 A The methodology of this 17 particular study has been accepted for publication 18 as well as the lead article from the study using 19 the enrichment strategy. 20 Q Do you know when they're 21 going to be published? 22 A I believe -- well, it's 23 my understanding that the lead clinical article 24 will be published within two months in all 285 1 likelihood. It's my understanding that the 2 methodology article will be published in the fall, 3 and there's a third article that has already been 4 published in which we did a reanalysis of patients 5 based upon the presence or absence of melancholia. 6 Q And that has already been 7 published? 8 A It has. 9 Q Where? 10 A The Journal of Affective 11 Disorders. 12 Q Who were the authors on 13 that? 14 A Myself, Doctor Tollefson 15 and Doctor Faries. 16 Q When was that published? 17 A I believe it was April of 18 1994, March or April. 19 Q So fairly recently? 20 A Just published. 21 Q The last issue? 22 A Yes. 23 Q Are you going to be an 24 author on the other two? 286 1 A Yes. 2 Q And they have both been 3 accepted for publication? 4 A That's correct. 5 Q In what journal or 6 journals? 7 MR. MYERS: You can tell 8 her that. 9 A Accepted, the lead 10 clinical article is in Psychiatry Research. 11 Q Okay. 12 A And the methodology paper 13 has been accepted, as I understand it, in the 14 Journal of the American Statistical Association. 15 Q Who are the other authors 16 on those papers besides yourself? 17 A Well, on the lead 18 clinical article there are many authors, and they 19 reflect individuals who participated in the study. 20 Q Okay. Tell me who some 21 of the ones you can remember are? 22 MR. MYERS: Are those 23 clinical investigators? 24 THE WITNESS: Yes. 287 1 MS. ZETTLER: Larry, 2 they're going to be published in the article. 3 MR. MYERS: Wait until it 4 gets published. Tell her who the Lilly people 5 are. 6 MS. ZETTLER: You're not 7 going to let him tell me who the non-Lilly people 8 are on those articles? 9 MR. MYERS: Until it's 10 published, that's right. 11 MS. ZETTLER: So you're 12 just going to make me wait until it is published? 13 MR. MYERS: You can 14 interpret it however you want to interpret it. 15 Q (BY MS. ZETTLER) So the 16 other authors on the lead clinical articles, 17 besides the Lilly people, are the clinical 18 investigators on the study? 19 MR. MYERS: Yes, you can 20 tell her that, yes or no. 21 A Yes. 22 Q How many of them are 23 there? 24 A I believe there are six, 288 1 plus one who served as a consultant. 2 Q And all of these people 3 are listed on the article as authors? 4 A That's correct. 5 Q Okay, and the article has 6 been submitted to publication, correct? 7 A That's correct. 8 Q And it has been accepted 9 by that publication, correct? 10 A That's correct. 11 Q And it will be printed in 12 an issue of the publication in the near future? 13 A That's what I was told, 14 to the best of my knowledge. 15 MS. ZETTLER: And you are 16 refusing to let him answer who those people are 17 based on what, Larry? 18 MR. MYERS: Based on the 19 prior order of the Court and the fact that the 20 article is not yet published. 21 MS. ZETTLER: So you're 22 saying this is proprietary information? 23 MR. MYERS: Until 24 published. 289 1 MS. ZETTLER: Even though 2 they've submitted it and they are in effect 3 seeking to make this information public? 4 MR. MYERS: Until it is 5 published, right. 6 Q Are you going to follow 7 your counsel's advice and not tell me who those 8 people are? 9 A Yes. 10 MS. ZETTLER: Certify it. 11 (QUESTION CERTIFIED.) 12 Q (BY MS. ZETTLER) Who are 13 the Lilly people listed on the article? 14 A Of course myself, Doctor 15 Tollefson, Doctor Faries, Don Gardner, Doctor 16 Pande. That should take care of it. 17 Q Who is Don Gardner? 18 A Don Gardner is a research 19 associate. 20 Q Who are authors besides 21 yourself on the article on the methodology? 22 A Doctor Tamura and Doctor 23 Faries. 24 Q Who is Doctor Tamura? 290 1 A He is a statistician with 2 Lilly. 3 Q Anybody else? 4 A No, I don't believe so; I 5 think it's just the three of them. 6 Q Is this the design 7 strategy article you were talking about earlier? 8 A Yes, ma'am. 9 MR. SMITH: What is the 10 conclusion of the article? 11 MR. MYERS: Which one? 12 MR. SMITH: The one 13 that's going to be published in two months in, as 14 I understand it, the publication called the 15 Journal of Affective Disorders -- is that it? 16 THE WITNESS: No, the 17 recently published article is in the Journal of 18 Affective Disorders. The article in roughly two 19 months is in Psychiatry Research. 20 MR. SMITH: Okay. 21 THE WITNESS: Which did 22 you want to have the conclusion? 23 MR. SMITH: The one in 24 Psychiatry Research, what's the conclusion of 291 1 that? 2 THE WITNESS: There are 3 several, but I think the most important one is 4 that this particular methodology is of potential 5 utility in clinical trial design. Another is that 6 fluoxetine proved to be more efficacious than a 7 placebo in the total patient group and the 8 patients who had a reduced rapid eye movement 9 latency. 10 MR. SMITH: Did that 11 paper analyze side effects? 12 THE WITNESS: I recall we 13 looked specifically at the Item 3. I can't recall 14 if the paper addressed the adverse events reported 15 in the trial; I don't recall that we did. 16 MR. SMITH: You say it 17 specifically addressed Item 3 of the HAMD 18 depression scale in the paper? 19 THE WITNESS: Yes. 20 MR. SMITH: And Item 3 in 21 the HAMD depression scale is that item with 22 respect to suicidality, is it not? 23 THE WITNESS: That's 24 correct. 292 1 MR. SMITH: Did your 2 paper or did your findings draw any conclusions 3 with respect to that Item 3? 4 THE WITNESS: Yes. 5 MR. SMITH: What were 6 those? 7 MR. SMITH: Fluoxetine 8 was statistically significantly better in reducing 9 ideation as measured by the Item 3 than was 10 placebo in both the group that was enriched, that 11 is with reduced rapid eye movement latency or REM 12 sleep, and in the total patient group as well. 13 MR. SMITH: Were there 14 any other scales used in that study, specifically 15 Adult Suicide Ideation Questionnaire? 16 THE WITNESS: That was 17 not used in that particular study? 18 MR. SMITH: Why? I 19 thought the FDA was requesting that. 20 THE WITNESS: That study 21 was launched prior to that request. 22 Q (BY MS. ZETTLER) Are you 23 familiar with the Puget Sound study? 24 A I'm familiar with Puget 293 1 Sound. Can you give me more specifics? 2 Q No, unfortunately. Wait 3 a second. We deposed Carol Zapapas and she 4 testified that you would have knowledge of the 5 Puget Sound study, that one of the sites that was 6 involved in the study was in Puget Sound. 7 A Okay. 8 Q Does that refresh your 9 recollection? 10 A Oh, it does. I suspect 11 we have more than one study at any given time at 12 some of these sites that may not be related to 13 depression. There is a study ongoing in 14 depression at Puget Sound. 15 Q With fluoxetine? 16 A Yes, ma'am. 17 Q Tell me about that 18 study. 19 A It's a study in which 20 fluoxetine will be compared to tricyclic 21 antidepressants. 22 Q For what? 23 A For depression. 24 Q For efficacy? 294 1 A On multiple outcomes, 2 efficacy, cost, so the economic outcomes, the 3 quality of life. 4 Q Any others? 5 A I don't recall. There 6 may be other analyses. 7 Q How about safety? 8 A Safety, there would be a 9 comparison of safety. 10 Q Was the Adult Suicidal 11 Ideation Questionnaire going to be administered 12 during the study? 13 A No, it's not. 14 Q Why not? 15 A It's not a Phase 4 study, 16 it is a grant study. 17 Q Is it a Lilly-funded 18 study? 19 A It's a Lilly grant to 20 Puget Sound. 21 Q So it doesn't fall under 22 the FDA's request that the Adult Suicidal Ideation 23 Questionnaire be included, is that what you're 24 saying? 295 1 A That would be the case. 2 Q Did the FDA itself make 3 that distinction? 4 A As I recall, they did. 5 Q Based on what? 6 A As I recall, the request 7 was to look at Phase 4 studies, formal Plan D 8 studies. 9 Q I guess I'm still 10 confused on what is the difference between a Plan 11 D study and a grant study then. 12 A There are distinctions 13 made relative to funding, relative to data 14 collection, relative to the reporting of events 15 that occur during trial are some of the -- three 16 that come to mind. 17 Q What are the differences 18 in reporting of events that occur during the 19 trial? 20 A In the grant studies, the 21 events are reported on a regular basis as opposed 22 to constantly reporting those events on a 23 day-to-day basis, and alert reports are reported 24 as alert reports in the usual fashion. 296 1 Q So in the grant studies, 2 the events are reported on a periodic basis as 3 alert reports? 4 A That's correct. 5 Q Sort of like the Rocky 6 Mountain Poison Control Center? 7 A That's my understanding, 8 yes. 9 Q Is it your understanding 10 that an overdose on fluoxetine or any kind of 11 suicide attempt is considered an alert report? 12 A As I recollect, if the 13 event meets the criteria for serious, then of 14 course one must decide expectancy, and then the 15 event is filed in the frame work, and I think 16 there is a distinction as I recall -- and I get a 17 little fuzzy about this -- relative to a serious 18 unexpected versus a serious expected, but I'm not 19 sure about that, I can't recall. 20 Q Are suicide attempts 21 considered expected on fluoxetine? 22 MR. MYERS: Are you using 23 the regulatory use of the word expectancy? 24 MS. ZETTLER: I'm using 297 1 what Lilly considers it, whether or not it's the 2 regulatory or otherwise. 3 A I always have a hard time 4 recalling the specifics, and I believe the -- it 5 may have changed, I'm not sure. I believe, as I 6 recollect, that those are signed off as expected. 7 Q As expected? 8 A Yes, ma'am. 9 Q When did Lilly start 10 doing that? 11 A I don't recall. 12 Q Was it before or after 13 1990? 14 A I believe it was after 15 1990. 16 Q Was it as of when the 17 package insert was changed to include suicidal 18 ideation in the post marketing report section? 19 A I don't know, I don't 20 recall. 21 Q How about violent 22 aggressive behavior, is that considered -- say 23 somebody went and killed somebody while on 24 fluoxetine, is that considered expected? 298 1 A I don't know offhand how 2 they're scoring that. 3 MS. ZETTLER: Let's quit 4 for the day. 5 (DEPOSITION ADJOURNED.) 6 *-*-*-*-* 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 299