1 1 NO. 90-CI-06033 JEFFERSON CIRCUIT COURT DIVISION ONE 2 3 4 JOYCE FENTRESS, et al PLAINTIFFS 5 6 VS TRANSCRIPT_OF_THE_PROCEEDINGS __________ __ ___ ___________ 7 8 9 SHEA COMMUNICATIONS, et al DEFENDANTS 10 11 * * * 12 13 14 FRIDAY, NOVEMBER 11, 1994 15 VOLUME XXXIV 16 17 * * * 18 19 20 21 _____________________________________________________________ REPORTER: JULIA K. McBRIDE 22 Coulter, Shay, McBride & Rice 1221 Starks Building 23 455 South Fourth Avenue Louisville, Kentucky 40202 24 (502) 582-1627 FAX: (502) 587-6299 25 2 1 2 I_N_D_E_X _ _ _ _ _ 3 Hearing In Chambers...................................... 4 4 * * * 5 WITNESS: JOE_WERNICKE,_M.D.,_Ph.D. _______ ___ _________ _____ _____ 6 By Mr. McGoldrick........................................ 29 7 * * * 8 Hearing in Chambers......................................140 9 Reporter's Certificate...................................168 10 11 * * * 12 13 14 15 16 17 18 19 20 21 22 23 24 25 3 1 2 A_P_P_E_A_R_A_N_C_E_S _ _ _ _ _ _ _ _ _ _ _ 3 FOR THE PLAINTIFFS: 4 PAUL L. SMITH 5 Suite 745 Campbell Center II 6 8150 North Central Expressway Dallas, Texas 75206 7 NANCY ZETTLER 8 1405 West Norwell Lane Schaumburg, Illinois 60193 9 IRVIN D. FOLEY 10 Rubin, Hays & Foley 300 North, First Trust Centre 11 Louisville, Kentucky 40202 12 FOR THE DEFENDANT: 13 EDWARD H. STOPHER Boehl, Stopher & Graves 14 2300 Providian Center Louisville, Kentucky 40202 15 JOE C. FREEMAN, JR. 16 LAWRENCE J. MYERS Freeman & Hawkins 17 4000 One Peachtree Center 303 Peachtree Street, N.E. 18 Atlanta, Georgia 30308 19 JOHN L. McGOLDRICK JOHN F. BRENNER 20 McCarter & English Four Gateway Center 21 100 Mulberry Street Newark, New Jersey 07102 22 23 * * * 24 25 4 1 The Transcript of the Proceedings, taken before 2 The Honorable John Potter in the Multipurpose Courtroom, Old 3 Jail Office Building, Louisville, Kentucky, commencing on 4 Friday, November 11, 1994, at approximately 8:00 A.M., said 5 proceedings occurred as follows: 6 7 * * * 8 9 (HEARING IN CHAMBERS) 10 JUDGE POTTER: Did you-all get something last 11 night on how this thing was calculated? 12 MS. ZETTLER: We got last night some appendices 13 for Protocol 27. 14 MR. MYERS: I'm not going to insist on the HCDD 15 and HCCP slides. The only one that we're ready to produce on 16 this morning and will produce on is the concomitant- 17 medication-use slides on HCAG. 18 JUDGE POTTER: (Reviews documents) Okay. As I 19 understand it, the only expert opinion dealing with -- other 20 than those dealing with what Doctor Wernicke felt or held -- I 21 mean, what I'm saying is, if he had some kind of opinion in 22 1983 to '87 -- when were you there, sir? 23 DOCTOR WERNICKE: '84 to '89. 24 JUDGE POTTER: During that period of time, the 25 only opinion he intends to give other than things he can 5 1 honestly say "at that time I believed thus and so" involves 2 Study No. 27, which is a compilation of some sort; is that 3 right? 4 MR. McGOLDRICK: Judge, I haven't looked through 5 the entire outline with that in mind. As I sit here, I think 6 that's true. 7 JUDGE POTTER: Doctor Wernicke, what is this? 8 DOCTOR WERNICKE: This is a graph representing 9 the percent of patients in study HCAG who took various 10 categories of concomitant medications anxiolytics, sedatives 11 and antipsychotics, during the double-blind controlled phase 12 of this study. 13 JUDGE POTTER: And if I'm reading it right, 14 26 percent of the fluoxetine people took a sedative, 24 15 percent took -- the placebo people took it, and practically 24 16 percent of the -- I take it that's the active comparitor took 17 it? 18 DOCTOR WERNICKE: That's correct. That's 19 essentially correct. 20 JUDGE POTTER: I may be off a percent. Where 21 did that information come from? 22 DOCTOR WERNICKE: From the clinical trial 23 database. 24 JUDGE POTTER: Who generated that thing? 25 DOCTOR WERNICKE: A statistician at Lilly. 6 1 JUDGE POTTER: And he generated it within the 2 last couple of weeks? 3 DOCTOR WERNICKE: Yes. 4 JUDGE POTTER: So you have no idea where it came 5 from; you just know what it's supposed to represent? 6 DOCTOR WERNICKE: I do know where it came from. 7 JUDGE POTTER: Because he told you where it came 8 from? 9 DOCTOR WERNICKE: Well, I did that analysis 10 independently, also, but I'm not a statistician. 11 JUDGE POTTER: Tell me how you did it. 12 DOCTOR WERNICKE: The database they sent me on 13 disks -- on computer disks, and it has flags for the patients 14 whether they took these medications, basically, yes/no, 15 yes/no in a little computer table. So I then sorted and 16 extracted for these various concomitant medications and 17 calculated the percentages and did the statistical analysis, 18 and that was then confirmed by a professional statistician. 19 JUDGE POTTER: Well, I mean, we talk statistics, 20 but except for N=240, N=227, N=239, statistics aren't involved 21 in this; right? 22 DOCTOR WERNICKE: Except for on the bottom it 23 says no statistical difference, but that's basically correct. 24 MR. MYERS: Those Ns are simply the number of 25 patients in the treatments. That's just how many, an 7 1 aggregate number. 2 JUDGE POTTER: Where are the 239 fluoxetine 3 patients? 4 DOCTOR WERNICKE: They're listed on those 5 attachments which were part of the NDA, was part of the final 6 full study report for this study. 7 MR. MYERS: Judge, just so it's clear, what the 8 Court is looking at are the concomitant medication tables for 9 Protocol 27 broken down by the 6 investigators, Investigators 10 1 through 6, showing 3 different depictions. And you can -- 11 I'll examine the Doctor or you can examine him. One is by 12 drug and the number of patients on the drug. The second group 13 in each stack is the drug and the patients who -- relative 14 patients who are on that drug, and the third slide is by -- 15 third group of drugs is by patient, by visit, and the onset 16 date of the use of the individual drugs. 17 JUDGE POTTER: Do that for me again, Mr. Myers. 18 MR. MYERS: Yes, sir. 19 Doctor Wernicke, looking at a document bearing 20 the number, PZ 4402, would you tell the Court what that 21 package of documents consists of, sir? 22 DOCTOR WERNICKE: Yes, this is a listing, this 23 is for Doctor Finer, one of the investigators in study HCAG, a 24 listing of the concomitant medications. 25 JUDGE POTTER: That whole pack is one 8 1 investigator's? 2 MS. ZETTLER: Judge, could we put him under oath 3 if we're going to do this? 4 5 JOACHIM WERNICKE, M.D., Ph.D., after first being 6 duly sworn, was examined and testified as follows: 7 8 JUDGE POTTER: Okay. Go ahead. 9 DOCTOR WERNICKE: This is for Doctor Finer, 10 Investigator One in study HCAG, that first lists all the 11 concomitant medications taken, and it's divided by study drug 12 group. The first page is fluoxetine and it indicates the 13 number of patients and the percent of this investigator's 14 patients who took each of these concomitant medications. 15 That's the first list, and it goes on for a number of pages. 16 MR. MYERS: Doctor Wernicke, can you tell 17 whether the first list is broken down by fluoxetine, 18 imipramine and placebo? 19 JUDGE POTTER: First couple of pages is 20 fluoxetine, then I assume we're going to get -- 21 DOCTOR WERNICKE: Imipramine. First few pages 22 are fluoxetine, imipramine and placebo, but there are six 23 pages in the initial listing. Then it goes on again by 24 investigator, only Doctor Finer again starting with fluoxetine 25 listing each concomitant medication and identifying the 9 1 patient who took it, and also has the age and sex of that 2 patient and a reference in the NDA where that case-report form 3 may be found; that's the column marked Reference. 4 MR. MYERS: And, Judge, just for the record, 5 since this was -- Protocol 27 was a remasked trial for which 6 the remasked case-report forms were furnished. 7 JUDGE POTTER: And so we're going to have had 8 four pages for fluoxetine, four pages for -- 9 DOCTOR WERNICKE: Well, this will be longer 10 because it lists each patient. It's a few more, six -- 11 JUDGE POTTER: We're going to have three sets? 12 DOCTOR WERNICKE: Yes. Fluoxetine, imipramine 13 and placebo. 14 MR. MYERS: Tell the Judge what the third group 15 of documents is. 16 JUDGE POTTER: This got left out. Put it where 17 it belongs. 18 DOCTOR WERNICKE: Then it goes to another level 19 where it lists all the drugs together. The third list is not 20 split out by treatment drug; it's fluoxetine, imipramine and 21 placebo all together, listed by investigator, now listing 22 every patient. 23 JUDGE POTTER: You said listed by investigator. 24 All this has to be the same investigator? 25 DOCTOR WERNICKE: There are similar lists for 10 1 the other investigators; this is all just Doctor Finer. It 2 lists by patient so one can look up and see for any particular 3 patient what concomitant drug they were taking, what their 4 treatment drug was and what visit they were at, by visit by 5 patient. That's all. 6 JUDGE POTTER: And if I'm assuming correctly, 7 there were six investigators? 8 MR. MYERS: Yes, sir. 9 JUDGE POTTER: Study 27? 10 DOCTOR WERNICKE: Yes, sir. 11 JUDGE POTTER: Mr. Smith, do you have any 12 questions for him about what this thing is? 13 MR. SMITH: Well, in connection with this 14 listing of investigators, Doctor Wernicke, you and I never 15 discussed this at your deposition, did we? 16 DOCTOR WERNICKE: I would not agree with that. 17 There were questions about what concomitant medications were 18 taken. And I don't remember my exact words, but I believe I 19 testified that to my knowledge the analysis we had done 20 indicated that the use of concomitant medications was about 21 equal in the treatment groups. 22 MR. SMITH: You never made reference, if we did 23 discuss that, to these documents, did you? 24 DOCTOR WERNICKE: Those were not presented to 25 me; that's correct. 11 1 MR. SMITH: You didn't even have these at that 2 time, did you, sir? 3 DOCTOR WERNICKE: That's correct. 4 MR. SMITH: These documents you haven't seen 5 until when, sir? 6 DOCTOR WERNICKE: I looked at those yesterday, 7 those actual paper documents. 8 MR. SMITH: Yesterday is the first day you've 9 seen them? 10 DOCTOR WERNICKE: Right. But I used the data to 11 generate these graphs. 12 MR. SMITH: Now, this graph that you have here, 13 when did you first see this graph? 14 DOCTOR WERNICKE: Oh, about a week ago. 15 MR. SMITH: Okay. And we didn't discuss 16 anything about this graph -- this graph obviously wasn't 17 discussed at your deposition, either, was it? 18 DOCTOR WERNICKE: We discussed the information 19 on that graph; we did not discuss that physical graph. 20 MR. SMITH: We discussed generally the issue of 21 concomitant medications in the Prozac clinical trials 22 generally, but we never discussed the issue of concomitant 23 medications in Protocol 27, did we, sir? 24 DOCTOR WERNICKE: I would disagree about that, 25 because the only study that I talked about that we looked at 12 1 concomitant medications was in Study 27. Now, that may not 2 have been obvious in the answer, but it should be implicit, 3 and that's the only one where we had a comparitor and placebo 4 and fluoxetine in the same study that was part of the NDA that 5 we had available at that time. 6 MR. SMITH: This was an independent analysis 7 sent to you by the statistician; is that right? 8 DOCTOR WERNICKE: It confirmed the analysis that 9 I had performed. 10 MR. SMITH: What we're looking at is an 11 independent analysis sent to you by the statistician at Lilly; 12 is that correct? 13 DOCTOR WERNICKE: That is correct. 14 MR. SMITH: Ms. Snyder? 15 MS. ZETTLER: Sailer. 16 DOCTOR WERNICKE: Mary Sailer did that. 17 MR. SMITH: And your statistical analysis was 18 made based on some computer printout? 19 DOCTOR WERNICKE: No. They sent me the computer 20 data sets. 21 MR. SMITH: And that's not what this is, is it? 22 JUDGE POTTER: It's supposed to be. 23 DOCTOR WERNICKE: That is the information 24 printed out on paper. 25 MR. SMITH: You looked at it just in electronic 13 1 form for the first time a couple weeks ago? 2 DOCTOR WERNICKE: That's correct. 3 MR. SMITH: When we took your deposition you 4 hadn't looked at any of that, had you? 5 DOCTOR WERNICKE: Only back when I did the 6 analysis when I was working at Lilly. I did not have those 7 pieces of paper, but I asked for that same type of analysis. 8 MR. SMITH: All right. 9 MR. MYERS: Judge, may I make just a couple 10 things for the purposes of the record? 11 JUDGE POTTER: Uh-huh. 12 MR. MYERS: The deposition of Doctor Wernicke 13 taken on August 25 and 26, 1994, understanding that these were 14 the third and fourth days of his deposition in this litigation 15 taken by Mr. Smith in Texas, beginning at Page 182, Line 24, 16 questions by Mr. Smith. 17 "Question: Were individuals given concomitant 18 benzodiazepines during the Prozac clinical trials? 19 "Answer: It was allowed. It was systematically 20 done -- it was not systematically done, but it was something 21 investigators were allowed to do under the protocol. 22 "Question: That's not what my question was. 23 Listen to my question, Doctor Wernicke. Were benzodiazepines, 24 Valiums, for instance, tranquilizers, given to patients in the 25 Prozac clinical trials? 14 1 "Answer: To some patients. 2 "Question: All right. 3 "Answer: If it's more than one, the answer is 4 yes. 5 "Question: You don't know how many patients 6 were given benzodiazepines, Doctor Wernicke? 7 "Answer: I don't know the exact number, but I 8 do remember a comparison we did to look at the benzodiazepine 9 use between the different drugs, including the sedating 10 tricyclics and placebo and, in fact, the use of 11 benzodiazepines was not different than all of those groups. 12 "Question: It's your testimony here that 13 benzodiazepines were given at the same rate to patients within 14 the fluoxetine group as they were to patients on placebo and 15 comparitors? 16 "Answer: In the comparison that I remember, 17 there was no statistical difference between the use in those 18 three groups. I'm not talking about the absolute number; I'm 19 talking about the statistical comparison to look at the use of 20 these drugs in the analysis that I was involved in. 21 "Question: Did you make such an analysis? 22 "Answer: Yes. I remember being involved in 23 that. 24 "Question: Why did you make such an analysis? 25 "Answer: To look at this issue of is the drug 15 1 activating, is it sedating, how sedating is it, should 2 benzodiazepines be used. So we asked the question, in fact, 3 let's see what people are doing. And this was at relatively 4 free-use. Investigators were allowed to use these drugs at 5 their discretion. So we asked the question, "We have thoughts 6 like this, that maybe these people should have a sedating drug 7 or maybe they need it, because this is not a sedating drug." 8 And that completes at Page 185, Line 3. 9 Also, for purposes of the record, the Plaintiffs 10 in this case filed with the Court a document entitled Group A 11 and B Plan of Supplemental Responses to Defendant Eli Lilly 12 and Company's First Request for Production of Documents, and 13 that was served on the 6th day of September, 1994. Included 14 in that document was what I'll call a bibliography of medical 15 articles that the Plaintiffs have. In the listing for 16 6 June 1991 is a listing from the Journal of Clinical 17 Psychopharmacology, Volume 11, No. 3, Pages 166 through 174. 18 The title of the article is "High Dose Fluoxetine Efficacy and 19 Activating Side Effects in Agitated and Retarded Depression." 20 On September the 20th of this year, I presented 21 myself at Mr. Irv Foley's office for a review of the 22 Plaintiffs' trial exhibits. There is a like index of these 23 articles that has all these articles in it, including this 24 article which I have marked as Defendant's Exhibit 407, which 25 is an article about the study of fluoxetine versus imipramine 16 1 versus placebo. And in that article -- if I can borrow Ms. 2 Zettler's copy for just a minute. 3 JUDGE POTTER: Is this Protocol 27, this 4 published part of it? 5 MR. MYERS: It is one of the articles published 6 on Protocol 27. At page -- I think it's 169, there is a table 7 showing the concomitant use of medications and the relative 8 rate of the concomitant medications. Doctor Wernicke and 9 Ms. Sailer happened to be authors on that article. It was 10 published after Doctor Wernicke left Lilly. This is one of 11 the Plaintiffs' trial exhibits that I was shown in Mr. Irv 12 Foley's office on September 20th of this year, and it's listed 13 in the Plaintiffs' supplemental interrogatory answers. 14 The fact of the matter is that the data on the 15 concomitant medication tables for Protocol 27, which the Court 16 has reviewed this morning and which I have marked as exhibits 17 and would probably put in the record, is depicted on the 18 concomitant-medication-use chart which is under investigation 19 this morning. It is simply a graphic depiction of that data 20 which appears in that chart; thus, the article the Court is 21 reviewing, Doctor Wernicke's prior testimony, and this table 22 simply go to the point that there's no difference among the 23 treatment groups. It's not an expert opinion; it's simply a 24 count and a tally of the patients in there, and they applied a 25 statistical analysis to that count and there was no 17 1 difference. The claim of any surprise or unfair prejudice 2 with respect to Protocol 27, which we have heard about to some 3 extent in this trial from all three of the Plaintiffs' expert 4 witnesses and from some Lilly witnesses concerning the use of 5 concomitant medications and the difference or the relative 6 incidence of the use of those medications has been well known 7 to all the parties before this trial started, and all this 8 chart does in fairly simple fashion is depict the percentage 9 of patients using those drugs. 10 JUDGE POTTER: How come if we got an article, if 11 he did it in 1991 -- it says -- 12 MS. ZETTLER: It was published in '91, Judge. 13 JUDGE POTTER: If he did this in 1984 or 14 whenever, why is he down in Texas with his home computer 15 redoing it all last week? 16 MR. MYERS: During the Plaintiffs' case in chief 17 through both Doctor Breggin and Doctor Lord, there were 18 representations made in their testimony as to what the rate of 19 concomitant medication usage was without any specific 20 citations. Doctor Lord specifically said it was 10- to 21 30-percent rate of the use of concomitant medications in these 22 patients and that it was substantially more in the fluoxetine 23 patients, and that was testimony elicited at trial without any 24 specific reference. And it thus became necessary, in order to 25 get the facts straight, to provide a graphic depiction. 18 1 Additionally, Doctor Wernicke was the medical 2 monitor at Eli Lilly and Company for fluoxetine during the 3 period of time that he was employed there. While this study 4 had been filed with the FDA as part of the original New Drug 5 Application, it was under submission to the Food and Drug 6 Administration during that period of time which he was 7 responsible for the drug. And as he testified in his 8 deposition, he is aware of the relative rate of concomitant 9 medication usage in the Prozac clinical trials and 10 specifically in this trial, and I suspect if I or the Court 11 were to ask him does this graphic depiction comport with your 12 understanding of the relative use of concomitant medications, 13 his answer would be in the affirmative that, yes, it does. 14 JUDGE POTTER: Anything else anybody wants to 15 say? 16 MR. SMITH: I think for completion Nancy has 17 something. 18 MS. ZETTLER: What was not read in is Paul asked 19 him specifically, "Was this a clinical trial that was done? 20 "Answer: No. We looked at all the clinical 21 trial data. We gathered all the information, and we actually 22 looked at the drug use that was reported in the clinical 23 trials," multiple. 24 MR. SMITH: Plural. 25 MS. ZETTLER: "So it's your testimony here that 19 1 you-all examined each clinical trial and you looked back at 2 each depression clinical trial and you recorded how many 3 patients and what patients got tranquilizers; is that right? 4 "Answer: We looked at the comparitor trials. 5 There were some that didn't involve comparitors so there was 6 nothing to compare to, so those were probably not included in 7 the analysis. 8 "So when you say comparitor trials, do you mean 9 you looked at all trials where we use placebo or we used a 10 drug like imipramine or some other antidepressant as the 11 comparitor drug? 12 "When you say all trials, I'm not sure that 13 every single trial was used. We looked at what our database 14 was and what we were using for comparisons, which was mainly 15 the fluoxetine/imipramine/placebo study. 16 "Well, didn't your database include all your 17 clinical trials, Doctor Wernicke? 18 "Answer: Well, it didn't include some of the 19 European clinical trials; those were handled separately 20 because they were not in the same database. 21 "What database were they on? 22 "Answer: Something they kept in Europe; I was 23 not closely involved in that, but the U.S. trials we had a 24 large database. And when I say not all of the trials, there 25 may have been very early ones that for some reason or another 20 1 may not have been included. But the way we tried to answer 2 these questions, this, like many others that have nothing to 3 do with any of this, is we had a large block of data that we 4 understood the data, we knew where it came from, and we felt 5 comfortable it was all correct. 6 "Question: Liked it? 7 "It was usable data. 8 "Question: Okay. 9 "Answer: And we used that in the form of the 10 analysis -- 11 "Question: Uh-huh. 12 "Answer: -- as to answer these questions. And 13 to be consistent, we tried to always stay with the same 14 database unless there was some particular question we had to 15 go somewhere else. 16 "See, I need to know what was in that database 17 in connection with -- you say, well, we examined our clinical 18 trial and we looked at this issue and found that there wasn't 19 any problem, but I want to go back with you and I want to make 20 sure that you define for me what you're talking about. 21 "Answer: Okay. 22 "Question: Are you saying you revisited all 23 your depression clinical trials? 24 "Answer: I wouldn't say revisited. There was 25 ongoing analysis on a number of different issues. 21 1 "Question: Here the issue is, were 2 benzodiazepines, tranquilizers, used in the clinical trials 3 and, if so, to what extent were they used; what patients got 4 tranquilizers; when did they get them; and why did they get 5 them? Are those reasonable questions? 6 "Answer: Those are reasonable questions. 7 "Question: All right. So what did you do? Did 8 you look at all the United States clinical trials? 9 "Answer: We looked at the ones -- the major 10 ones, certainly, where there was a comparitor." 11 I mean, he never gave us a straight answer, 12 Judge. 13 MR. SMITH: One other thing I'd like to say, 14 Your Honor, is this material here was not provided to us. We 15 have not seen this material. 16 JUDGE POTTER: How can that be, Mr. Smith? 17 MR. MYERS: That is not true, Mr. Smith. This 18 is a remasked clinical trial. 19 JUDGE POTTER: We've got a Confidential 20 Protective Order MDL, the PZ number, which you seem to be so 21 enamored of. 22 MR. SMITH: When I want to authenticate, it 23 comes in handy. 24 JUDGE POTTER: But when you want to say you 25 haven't seen it, it gets awkward, doesn't it? 22 1 MR. SMITH: This is, as Mr. Myers says, 2 Exhibit C to the final report. 3 MR. MYERS: It is, Mr. Smith. 4 MR. SMITH: Let me complete my argument, please, 5 Counsel. 6 MR. MYERS: Okay, sir. 7 MR. SMITH: We had an agreement in our Texas 8 litigation and in our MDL litigation that Lilly would furnish 9 to us the final reports on all the clinical trials but would 10 not furnish us the appendices, and so, therefore, this has not 11 been furnished to us. It's got PZ numbers on it. I'm sure 12 they stamped it confidential last night when they ran it off, 13 but we have not seen this data. 14 JUDGE POTTER: Mr. Smith, I'm assuming that once 15 you put the stamp on it, this thing is buried in a pile of 16 documents up in Indianapolis somewhere in the federal 17 courthouse. 18 MS. ZETTLER: They have preprinted paper that 19 they use as copy paper. They have given us numerous pieces of 20 paper with nothing else on it. Ms. LuAnna McFarland, she said 21 they have preprinted paper with the stamp on it. It's not 22 something that's individually done. 23 MR. MYERS: I want the record to be absolutely 24 clear, in January of 1983 in one of Mr. Paul Smith's Texas 25 cases, we sent to him 58 final reports of various clinical 23 1 trials without appendices. He's correct on that one subject. 2 However, in the multidistrict litigation by order of that 3 court in -- I believe it's November the 18th of 1992 or 1993, 4 we remasked the number of pivotal clinical trials, including 5 Protocol 27, which this is. That agreement provided for the 6 provision of and did in fact include the transmission of the 7 final study reports, all appendices and all case-report forms 8 in an unmasked fashion to the Plaintiff. 9 Mr. Smith correctly cites the agreement we had 10 in the Texas case, and he is absolutely wrong and I'm sure 11 simply mistaken that they were not provided with these 12 appendices as part of the multidistrict remasking project. 13 And if I need to, Judge, I will go back to Mr. Stopher's 14 office and bring the reremasked Protocol 27 over here in 20 or 15 30 boxes. 16 MR. SMITH: Was this in this form submitted with 17 that? 18 MR. MYERS: Yes, sir. Yes, sir. 19 MR. SMITH: Okay. 20 JUDGE POTTER: Okay. I'm assuming that -- 21 you-all really have reams of white paper that just say 22 confidential? 23 MR. MYERS: When we did this remask; yes, sir. 24 It was approximately 100,000 pages and when we produced them 25 that's how we produced them to get them run off. 24 1 JUDGE POTTER: I'm going to change my mind from 2 yesterday. I was going to let this thing in; now that I know 3 what it is... I mean, I thought this gentleman was going to 4 be able to point to something here or something there, but 5 this is a total reworking of information. I mean, it's 6 something that he didn't do while he was there. I mean, if he 7 wants -- he's an author on this article, it, I assume, deals 8 with 27 when he was there. If he wants to rely on that and 9 say we did this study and here it is published and here's what 10 it says, that he'll have to do. 11 But, I mean, this is exactly the kind of thing 12 that I think we discussed and people were concerned about, 13 that there would be a total -- I mean, this is very powerful 14 stuff. I'm sorry to keep it from a jury. But I don't know 15 how it would come out if they had been given the same diskette 16 and their witnesses had been allowed to manipulate it or 17 massage it, whichever is proper. But at this point I'm going 18 to sustain the objection to introducing testimony about the 19 statistical analysis he did to this data within the last month 20 or two. 21 MR. MYERS: For purposes of the record, Judge, 22 then I would offer a copy of the chart which we've marked as 23 Exhibit 225, the article which is marked as Exhibit 407, and 24 the data which has been marked Exhibits 401 through 406, for 25 purposes of the record. 25 1 JUDGE POTTER: And you can give up this copy of 2 407? 3 MR. MYERS: I have exhibit-marked copies. Those 4 are Ms. Zettler's. 5 MR. MYERS: Here's Exhibit 250. Exhibits 401 6 through 406 and Exhibit 407, which is the article which I 7 think the Court put back in there. 8 JUDGE POTTER: Well, the article can come in. 9 You can't complain about the article, right, Mr. Smith? 10 That's something that's published, you had, and it's written 11 about what he did while he was there. Complain with 12 anticipated success, I guess I should say. 13 I mean, there's a lot of stuff -- I'm sure that 14 article is a surprise to you, you know. But there's so much 15 stuff it can get lost. You took him over what he did when he 16 was there. If he didn't mention the article, I guess maybe he 17 forgot about it or didn't know they attached his name on it 18 when they published it. 19 Are we going to have this problem with the rest 20 of the Lilly witnesses? Because we need to think about how to 21 do it, or maybe we'll just take them up a witness at a time. 22 Mr. McGoldrick, Mr. Freeman said that he couldn't leave the 23 trial to prepare these people so you had done it. So, you 24 know, have we got redone, revamped material that's been 25 generated within the last month or so for these other 26 1 witnesses? 2 MR. McGOLDRICK: Judge, we may have some other 3 problems. I have prepared these witnesses, and what I don't 4 know with clarity is what has been done before and what had 5 not been done before. What I can do is very quickly this 6 weekend we can try to make sure we know what, if anything, 7 there is of any similar or analogous nature and bring it to 8 the Court's and Mr. Smith's attention. 9 MR. MYERS: I know of one thing just offhand, 10 and it's nothing new. It's Doctor Tollefson's slides from the 11 advisory committee meeting which were produced in hard copy 12 form for Doctor Beasley's deposition. I would expect that 13 Doctor Tollefson would utilize those slides during his 14 testimony. That's just something that comes to mind, Judge. 15 MR. McGOLDRICK: There are some pieces of 16 demonstrative evidence; I'm trying to run through them in my 17 mind as I sit here. And, of course, frankly, when we get 18 ready for trial we're continually trying to find ways to bring 19 the message home to the jury of what the truth is, and when we 20 do, we can bring them to the attention of the other side as 21 soon as we have them, within the Court's rules. 22 But I'm not trying to evade Your Honor's 23 question. I don't know. I think there may be some things of 24 this sort, and I'm not sure exactly what the line is on 25 putting things on one side or the other side. 27 1 JUDGE POTTER: Well, you've got your main 2 experts and they took their depositions and, you know, that's 3 going to kind of be a free-for-all. But these people were 4 designated as might give expert stuff related to their work at 5 Lilly and what they did. So we had a discussion at one point. 6 My memory is really they're basically fact witnesses; they're 7 telling what they did and what they thought and why they did 8 it, so they really may be fact witnesses and aren't even 9 necessary as experts. But there was some concern on the part 10 of the Plaintiffs that -- and this is a very qualified person, 11 he can probably testify about most of what's going on in this 12 trial -- that they would be kind of dressed up and wander out 13 of what they did while they were at Lilly. 14 And I can't remember exactly, but the idea was 15 that if they got outside of that area, it would be important 16 for you-all to let them know way ahead of time what they were 17 going to do, and I think it was that we'd have hearings like 18 this, was this outside of what had been disclosed to them and 19 what they did at Lilly. And, you know, when you'd taken his 20 deposition, I don't know if it had just been a month before, 21 but if on cross-examination you had said, "Doctor Wernicke, 22 did you take 27, did you manipulate it, did you do this, are 23 these your results," you know, I'd have a different problem. 24 I don't know what I'd do because of the lateness of it, but 25 right now it's an easy call for me. 28 1 MR. McGOLDRICK: Well, perhaps we should address 2 them as they come up, Your Honor. I guess my only comment 3 would be -- and I was, of course, not at the hearing that Your 4 Honor speaks of -- is that in situations like this, the 5 persons who work for a company like this are often, by their 6 nature, highly expert and what they do is expert stuff, and 7 that's what we would come in typically and ask them about in 8 any trial as employees of the company. 9 MR. SMITH: That's why we wanted a designation 10 on what they were testifying to. 11 JUDGE POTTER: Well, we'll just get through them 12 one at a time. 13 (THE FOLLOWING PROCEEDINGS OCCURRED 14 IN OPEN COURT) 15 SHERIFF CECIL: All rise. The Honorable Judge 16 John Potter is now presiding. All jurors are present. Court 17 is now in session. 18 JUDGE POTTER: Please be seated. Mr. Higgs, 19 have you had any trouble observing the admonition about not 20 getting information about the case? 21 JUROR HIGGS: Absolutely not. 22 JUDGE POTTER: Thank you. Anybody else have any 23 difficulty? 24 Doctor, I'll remind you you're still under oath. 25 Mr. McGoldrick. 29 1 MR. McGOLDRICK: Thank you, Your Honor. 2 3 EXAMINATION ___________ 4 5 BY_MR._McGOLDRICK: __ ___ __________ 6 Q. Doctor Wernicke, at the end of yesterday, we had 7 I think just talked about your CV, your resume, and let me 8 turn then, if I may, to just another subject sort of related, 9 and that is, can you describe to the jury the other medicines 10 that you worked on or with at Eli Lilly and Company? 11 A. Yes. One of the main ones was pergolide. The 12 trade name for it is Permax; it's a drug for Parkinson's 13 disease. I was involved in following or monitoring, as we 14 called it, a number of marketed drugs, like Aventyl and 15 Brevital and some of the more mature drugs. I was quite 16 involved with what we call the project teams and drugs that 17 were in the earlier stages of development where there were 18 representatives from all the various areas of research. 19 Q. All right. Could you please tell us a little 20 bit about some of these other medicines. Pergolide, what is 21 it, what does it do, what does it treat? 22 A. It's what we call a dopamine agonist. It's for 23 treatment of serious Parkinson's disease. It's one of the 24 medicines that are used for that condition. 25 Q. And Parkinson's disease is what? 30 1 A. It's a very severe degenerative disease, usually 2 affects older people but it can occur in younger people. And 3 there are some cases, like Muhammad Ali, that have what we 4 call traumatic Parkinson's disease. But most of it occurs in 5 older people and it's not really known what the cause is, and 6 it's very debilitating in that people have trouble moving. 7 What we usually think of as Parkinson's is a pill-rolling 8 tremor. A characteristic tremor where people sit and they 9 sort of roll their fingers. But that's not really their main 10 problem. Their problem is moving or initiating movement, and 11 so these people, it's -- in a very late form, they get 12 infections, they get pneumonia because they just can't move 13 very well, so it is a very debilitating disorder and it 14 usually gets worse with time. 15 Q. And the pergolide treats the symptoms or what 16 does it do? 17 A. Yes. It treats the symptoms and basically 18 restores some degree of function, with some people virtually 19 completely, some much less, but the attempt is to give them 20 back some of their function so they can move and aren't so 21 debilitated. 22 Q. Now, you spoke of a medicine called Aventyl? 23 A. Yes. 24 Q. What is that, sir? 25 A. That is a tricyclic antidepressant that Lilly 31 1 developed a number of years ago that's marketed. 2 Q. And you had some monitoring responsibilities for 3 that while you were at the company? 4 A. Yes. All drugs manufactured by the company are 5 monitored in terms of spontaneous adverse-event reports in the 6 literature, basically gathering all information that comes in 7 and that's then processed and reported, as appropriate. 8 Q. And is that true really of all prescription 9 medicines in the United States, that after they're marketed 10 they're followed? 11 A. Yes. That's part of the requirement. 12 Q. And without going into any great length, how are 13 they followed? 14 A. There's usually -- well, I can't speak to how 15 it's done at other companies, but at Lilly and certainly when 16 I was there there's typically a physician assigned as their 17 main monitor for that drug and they have some level of support 18 staff. As any spontaneous reports come in, meaning that if a 19 physician or a pharmacist or a patient calls and says I've 20 taken this drug and I've had this problem or I have this 21 question, that's put into an adverse-event tracking system. 22 In addition, we systematically monitor the 23 literature, the scientific literature primarily, looking for 24 any reports about these medications, and that's done through a 25 literature search service where they pick up key words that 32 1 those systems are in place, and it's very straightforward. 2 And they would then send us the articles and we would review 3 them to see if there was any information, material, say, from 4 newspaper, media, that would also go into the system somehow. 5 Q. So it's basically following information about 6 the medicine after it's been marketed? 7 A. That's correct. 8 Q. All right. Now, Doctor Wernicke, let's turn to 9 some of your work and the work of the company in connection 10 with Prozac, fluoxetine. You weren't here when Doctor Fuller 11 was here yesterday or the day before. He's told us something 12 about that process, but I'd like you to take it a little bit 13 further for us. After a medicine is -- or a compound that may 14 be useful is developed and it's thought that it may be useful, 15 how -- I want you to tell us and take us through it step by 16 step, how you get from that point to the point where the 17 medicine is approved and usable by physicians regularly to 18 treat patients. So let's start at the beginning. After the, 19 say, the synthesis and the first testing, what happens? 20 A. Well, there are a number of very systematic 21 steps that a compound has to go through. After the initial 22 synthesis and any idea that it might be of any value usually 23 on a chemical basis, animal tests are conducted or continued, 24 usually there have been some done before, to further try to 25 establish if this compound has any use. There are usually 33 1 what we call a number of diseases where that's tested. 2 There's a beginning of an understanding of how this drug is 3 handled in the living system, in what we call the metabolism, 4 how it's absorbed, excreted, what compounds it's made into. 5 And in parallel with that, toxicology studies 6 are started, and those are done specifically to look at the 7 safety. They are very systematic tests, there are many of 8 them, some of them last a long time to look at the safety of 9 the drug just in terms of side effects, but also their 10 potential to cause cancer and birth defects. They're very 11 systematic, rigid studies that are put into place. 12 Q. When you say systematic, what do you mean by 13 that, sir? 14 A. Well, that there's a very distinct protocol that 15 these drugs -- these studies follow, the number of animals or 16 test subjects are determined. At some -- quite a lot of 17 toxicology-type studies are also done in nonanimals, like in 18 tissue culture and whenever possible that they try to use 19 bacteria or tissue culture or cells. And they have a battery 20 of tests that the drug has to go through and specifially 21 things like for carcinogenicity to see if a drug causes 22 cancer. They do bacterial tests, they do DNA. 23 Q. Bacterial tests and what was the next one? 24 A. DNA change test. They look at cells in culture 25 and determine whether this drug changes the DNA of those cells 34 1 as an indicator that this might cause cancer. And then when 2 it passes all of those screens, it then goes further into more 3 systematic tests or in organisms and animals themselves to 4 confirm or sometimes find out that it does cause cancer or 5 confirm that it doesn't. 6 Q. Perhaps we could look at that chart of drug 7 development that we've looked at before. The jury has seen 8 this before, Doctor Wernicke. We are talking -- this is kind 9 of a stylized thing of drug development. I guess at this 10 point my question is this kind of work you're talking about 11 where you test for carcinogenicity, whether medicine causes 12 cancer or might for -- there's a term called teratogenicity 13 which we've heard? 14 A. Birth defects. 15 Q. And that's to see if the medicine could cause 16 birth defects. And other kinds of testing? What other kinds 17 of testing does it have? 18 A. Looking for side effects of the drugs, potential 19 side effects. And there are continuing studies on potential 20 efficacy or effectiveness to determine whether in fact this 21 drug may have -- or this compound may have potential use. 22 Q. All right. And these studies are all before 23 it's ever given to a human being? 24 A. Right. In that red box up there. 25 Q. In this red box here? 35 1 A. Yes. 2 Q. And are those tests that you run, at that stage, 3 tests which are run, some of them, on any medicine that might 4 be thought of for possible use? 5 A. On all medicine for possible use. They all have 6 to pass these screens to be considered further. 7 Q. They're called screens? And this means, what, 8 you screen out medicines that for some reason are too 9 dangerous or whatever? 10 A. Yes. If you put a compound into this system and 11 it turns out it causes cancer in mice or some other thing that 12 would not be considered tolerable or that can't be in a 13 medicine for humans, causes birth defects, for instance, then 14 that drug is eliminated at that point. So it's to detect 15 those kinds of things and other side effects. 16 Q. In drug development in general, are some 17 medicines medicines that don't make it to the final NDA 18 approval? 19 A. Yes. In fact, the vast majority don't. If you 20 look at -- and I think that's shown at the very bottom line. 21 For every 10,000 molecules that are started with, less than 1 22 makes it to final approval. So it's a very rigid system to 23 eliminate drugs before they ever get into humans, and that's 24 in fact where most of them are eliminated. 25 Q. When you say 10,000 molecules, you mean for 36 1 every 10,000 possible medicines? Is that what you mean by 2 molecules? 3 A. Yes. That's correct. 4 Q. And only one makes it to the end. All right. 5 Now, we've heard in this red phase about toxicology, that's 6 listed here. Is that what you've been telling us about? 7 A. In part. There are other types of study, what 8 we call pharmacology that start to look at how the drug is 9 broken down, how it's taken into the body, excreted from the 10 body, all in animals or tissue culture now. 11 Q. And, again, without -- I'm sure you could give a 12 long lecture on this, but just in short version, how do you go 13 about figuring out how the drug is broken down in the body and 14 that sort of thing? 15 A. Usually what's done is, is the compound is made 16 radioactive chemically. For instance, I don't want to bore 17 people with the details. Some of the carbons may be replaced 18 by radioactive carbons and so then one can trace the paths or 19 the life of a molecule in a system, be it tissue culture or 20 sometimes a serum, sometimes animals and be -- by then taking 21 blood or urine, whatever tissue is appropriate, and then 22 looking for those label carbons where they are identifying the 23 molecules that they're in. 24 Q. Okay. So if you took -- I'll put this down for 25 a minute. If you took a medicine -- a potential medicine that 37 1 you called a molecule and you put one of these radioactive 2 carbons as part of this big molecule, then you could see how 3 that molecule changed? If it changed from that molecule to 4 carbon dioxide or something, you could then see that same 5 carbon with the radioactivity; is that what you're saying? 6 A. Yes. That's called a tracer. 7 Q. I'm sorry? 8 A. A tracer. 9 Q. A tracer? 10 A. And that's how you follow the life and fate of a 11 molecule through the system and you can identify what all the 12 little steps are in between. And I think carbon dioxide, 13 that's ultimately right, that's ultimately what molecules -- 14 in that way, but they go through many little steps. And the 15 reason you want to do this is because in some cases those 16 intermediate compounds can be toxic or they can have their own 17 effect that may be the same or different than the apparent 18 compound. So it's important to really understand the fate of 19 the molecule as it goes through the system. 20 Q. All right. Well, let me just try to do that one 21 more way. Let's see if I can get this easel out. 22 JUROR FELKER: Excuse me. Would you mind 23 putting on the lapel mike? And, Mr. Wernicke, would you speak 24 up? You have competition with this air-conditioning and we're 25 losing the last part of your words. 38 1 DOCTOR WERNICKE: I'll get on the mike. Remind 2 me if I slip onto that. 3 MR. McGOLDRICK: This one is the microphone. 4 This one is of some significance, but for the jury the brown 5 one is important. And I'd better learn how to use this, which 6 I have not used. Maybe Mr. Smith can help me. Should I have 7 asked for that? 8 All right. Now, does that seem to help a 9 little. Is that better when I'm out here? 10 VARIOUS JURORS: Yes. That's better. 11 MR. McGOLDRICK: Okay. I'm sorry. All right. 12 Good heavens. 13 Doctor Wernicke, I'm going to ask you -- I'm 14 going to put some things up here and ask you some questions. 15 And maybe I won't get this right, so you tell me if I don't. 16 But if we have a molecule that starts out as a potential 17 medicine and you want to see -- it may end up being carbon 18 dioxide and water at the end. Would that be common that 19 organic things like the medicines we're talking about might 20 end up to be that sort of thing? 21 A. Yes. 22 Q. And carbon dioxide we breathe out when we 23 exhale? 24 A. Yes. 25 Q. And water we, of course, excrete? 39 1 A. Yes, sir. 2 Q. Now, so this may be a huge molecule and it ends 3 up being these things at the end. Is it true that it breaks 4 down into different products at different times, like this one 5 may break down into this and this? 6 A. That's right. 7 Q. And then maybe this thing will break down 8 into -- I'm trying to make a representative of chemicals here. 9 It looks like a bunch of Hs or goal posts or something, but 10 that might break down itself into other things? 11 A. Absolutely, that's the way it is. 12 Q. And this one might, too? 13 A. Yes. 14 Q. And this one might go through many stages? 15 A. Yes. 16 Q. Just give us an idea, how many kinds of stages 17 might it go through. 18 A. Some compounds might go through 15, 20 or more 19 stages. Typically, I'd say about 10 for fairly small 20 molecules. 21 Q. So without my taking the time to draw it, you 22 could have these things going through this many -- ten or more 23 stages and each one of them might break it up into different 24 kinds of things, and I guess it gets to be a big tree kind of 25 thing? 40 1 A. Yes. And it's not even that simple because at 2 any one of those intermediate steps, those smaller compounds 3 may react to something else to form new things, so it doesn't 4 go into a one-way downward spiral; it can go into a lot of 5 different other things. 6 Q. So one of the things you do is you check for -- 7 this would be called a metabolite of this and you check for 8 that and for these various metabolites? 9 A. Yes. 10 Q. And part of that -- is that part of pharmacology 11 testing? 12 A. Yes. 13 Q. And one of the ways you do that is you take -- 14 do we have a different color pen -- thank you, Robin. 15 So this molecule up here may have hundreds or 16 even more of atoms in it? 17 A. Yes. That's correct. 18 Q. And what you might do is you might mark -- I've 19 marked with my green pen, but the way a scientist might do it 20 is they might mark it by making that little atom radioactive. 21 A. That one or several so that you can follow 22 different pathways. 23 Q. But just taking the one for simplicity, it might 24 end up in this one or it might end up in this one? 25 A. Yes. 41 1 Q. So if it ended up here and you looked in and 2 found this compound in your system you're testing, you would 3 know that this came from this? 4 A. Yes. 5 Q. And then this broke down and could go into any 6 one of these three things? 7 A. Yes. That's correct. 8 Q. And let's say it went in here; and if you found 9 this one in your system you'd know that it came from here? 10 A. That's right. 11 Q. Is that what radioactive labeling is? 12 A. That's right. That's what it's used for. 13 Q. And how do you count little -- how do you 14 measure little atoms like that? Do you have machinery that 15 does that? 16 A. Yes. There are a number of ways. The 17 radioactive ones with a Geiger counter, basically, it's much 18 more complicated than that, but it's put into a machine that 19 senses the radioactivity. I can go through how that's done, 20 but I'm not sure that's so important. Other molecules, there 21 are a number of other techniques that are very sophisticated 22 to identify all of those molecules. There's something called 23 mass spectrometry that will tell you exactly the number of 24 atoms and how they are arranged; there's chromatography, it's 25 a very detailed sophisticated analytical system that's used. 42 1 Q. I guess that's what I wanted to try and get us a 2 sense of; it's not just this radioactive labeling but you do a 3 whole lot of different techniques? 4 A. Yes, sir. 5 Q. What's the specialty of the kind of people who 6 do that kind of work? 7 A. They're chemists, they're pharmacologists. 8 There are a lot of people involved. Typically, the 9 pharmacologists may design the studies, but then the samples 10 may be submitted to chemistry labs that actually identify the 11 chemical compounds. Before I forget, I think it's important 12 to also understand it's not just the compounds; it's where 13 they're handled in the body and the rate, how fast they're 14 handled. That all becomes very important in understanding the 15 drug and its fate and how it works. What we call 16 pharmacokinetics, that looks at the rate of speed of all of 17 this happening is another whole element of this. 18 Q. Pharmacokinetics? 19 A. Yes. 20 Q. And is that the specialty that looks at rate of 21 speed? 22 A. Yes. And the amount that's absorbed. When a 23 drug is given, not all of it is absorbed, so one has to know 24 how much is absorbed, where it goes, how fast it gets there. 25 So there are a lot of different specialties that deal with 43 1 nuances of this whole process. 2 Q. Are there people, scientists who devote their 3 lives to things like how medicines are metabolized? 4 A. Absolutely. 5 Q. People whose entire professional life is devoted 6 to pharmacokinetics? 7 A. Yes. 8 Q. And is that all within the general realm of 9 pharmacology? 10 A. Yes. 11 Q. And these kinds of tests, among others, are what 12 go on in the period that we're calling pharmacology? 13 A. Yes. That's correct. 14 Q. All right. And that's, or much of it, 15 preclinical? 16 A. Yes. 17 Q. Again, before we give it to a human being? 18 A. That's right. 19 Q. So during that period -- how often -- how long 20 can that kind of thing take? 21 A. Several years. 22 Q. And -- strike that. 23 We have then toxicology, which we've heard about 24 some before; and pharmacology, including this drug metabolism 25 and pharmacokinetics, and of course you're looking for safety 44 1 features in this prehuman phase, animal testing. Is there 2 any -- animal testing for efficacy. Is there anything else? 3 A. I believe that essentially covers it. 4 Q. All right. Now, when you talk about animal 5 testing for efficacy, in the case of a medicine that causes 6 mental illness that animals don't have, what does -- is that 7 meaningful in those kinds of drugs or is that just in the 8 other kind of drug? 9 A. No. That's meaningful, too. It's a little bit 10 harder. If one, say, wanted to test a drug for cancer and one 11 had an animal with these types of cancers, it would be rather 12 straightforward. On looking at psychoactive drugs to be used 13 for mentally-ill patients, it is harder, but there are animal 14 models that predict the effect of drugs in humans. They're 15 not direct, but there have been very firm predictors 16 established over the years by scientists. 17 Q. In some cases? 18 A. Yes. 19 Q. Now -- all right. Now, we have the toxicology 20 studies and in the toxicology studies, very briefly because we 21 have heard about them, what happens? 22 A. Well, it's a battery of tests that are conducted 23 basically to see if the drug is safe, if it looks -- if 24 there's any evidence it might cause cancer, birth defects, and 25 also to look at the potential side effects of the drug, for 45 1 instance, weight loss, if that's an issue. It's basically to 2 see what happens, what may happen in humans. 3 A. All right. 4 Q. And do you sometimes give toxic doses in that 5 phase? 6 A. Well, yes, that is important to remember that 7 the doses given to animals in toxicology studies are typically 8 much, much, much higher than is given to humans. And, in 9 fact, as bad as it sounds, one of the types of studies done is 10 to see how much does it take to kill animals. It's what's 11 called LD-50 or lethal dose to kill half the animals. And 12 it's not a very pleasant thing, but it's important to know how 13 toxic just on a fundamental level this drug is. 14 Q. Does the FDA require you to do that? 15 A. Yes. 16 Q. The FDA thinks it's important enough that you do 17 that before you give it to humans, they make you do it even as 18 unpleasant as it is? 19 A. Absolutely. You can't develop a drug unless you 20 know some of those basic parameters. 21 Q. All right. Now, let's turn to the next phase. 22 After all of this testing is done, which you say can take 23 years, you then can get to the point where you can first test 24 it in the healthy human being; is that right, sir? 25 A. Yes. 46 1 Q. And that's what's indicated on this chart by 2 this line and moving into the yellow phases; is that right, 3 sir? 4 A. Yes. 5 Q. Now, this says IND filing is the marking point 6 there. What is the IND and an IND filing? 7 A. By law, a drug cannot be given to a human unless 8 it's approved by the FDA. Well, you can't -- you have to be 9 able to get the data to submit to the FDA for approval, so the 10 IND filing is what's called an Investigational New Drug. IND 11 stands for Investigational New Drug. 12 JUDGE POTTER: I'll tell you, if you can get to 13 the break without standing absolutely at the podium, we'll 14 solve the problem then. You'll just have to stay away from 15 the podium. 16 MR. McGOLDRICK: I can do that. 17 JUDGE POTTER: We don't need a statistical 18 analysis, but something seems to happen when you get to that 19 area. 20 JUROR HIGGS: Could he keep the remote on and 21 turn off the podium mike or would that get it, or can you? 22 JUDGE POTTER: Well, you can try that. 23 MR. McGOLDRICK: I'm happy to try the 24 suggestion -- any suggestion. 25 JUDGE POTTER: That's going to cut everything 47 1 off. 2 MR. McGOLDRICK: I'll take my watch off. 3 JUDGE POTTER: Mr. Tyler, can I get you to step 4 around and disconnect the power mike on the podium? It's just 5 too early to take the morning break. 6 MR. TYLER: The problem is not the podium mike, 7 the problem is the wireless picking up other transmissions. 8 (OFF THE RECORD) 9 JUDGE POTTER: I hate to do this to you, but 10 we'll go ahead and take a recess this morning and it will be a 11 little long till lunchtime. As I told you-all before, do not 12 permit anybody to talk to you about this case. Do not discuss 13 it among yourselves and do not form or express opinions about 14 it. We'll take a 15-minute recess. 15 (RECESS) 16 SHERIFF CECIL: The jury is now entering. All 17 jurors are present. Court is back in session. 18 JUDGE POTTER: Okay. Please be seated. 19 Doctor, I'll remind you you're still under oath. 20 Mr. McGoldrick. 21 MR. McGOLDRICK: Thank you, Your Honor. Let's 22 hope this works. I'm going to try, if it's all right, to work 23 without this. If there's any problem, through the Court, if 24 the jurors would let me know, I will put it back on because it 25 may not work, I recognize. 48 1 Now, Doctor Wernicke, I'm not exactly sure where 2 we were. 3 A. I think we were just talking about the IND and 4 what it is and what the purpose of it is. 5 Q. Right. So we're at this point on the chart at 6 this time at the IND filing, and I'm not sure how -- some of 7 these smaller numbers here might not have been quite as 8 visible and the words, so maybe periodically I'll bring it 9 over here, but at this point we're at the IND filing stage. 10 Now, Doctor, tell us again, what is the IND 11 filing? 12 A. Well, the purpose -- I'll explain what it is, 13 but let me again explain the purpose of it. IND means 14 Investigational New Drug, and it's to ask the FDA for 15 permission to study that drug in humans. Remember, it's 16 against the law to give people unapproved medications, so it's 17 called an exemption from that law, and it's a a very formal 18 process. And what goes into the submission is everything 19 that's known about the drug, everything from the chemical 20 structure to the toxicology studies, pharmacology studies, 21 basically a whole package of information and the proposed 22 protocol for how the first human studies are to be done, and 23 that material is all put together and sent to the FDA. 24 Q. All right. So is this a fairly big submission? 25 A. Typically it will be about ten volumes -- ten 49 1 two-inch binders. 2 Q. And does the FDA then get back to you -- I'm 3 talking about the typical case now. Does the FDA get back to 4 you either to say okay we approve the IND or we have a 5 question or something of that sort? 6 A. Yes. 7 Q. Is that how it typically works? 8 A. That's how you -- you may not start until you 9 have approval of that IND. 10 Q. Now, let's talk about the first human work. 11 That's what's called Phase 1? 12 A. Yes. 13 Q. And would you explain generally the purpose of 14 Phase 1 and what one does in Phase 1? 15 A. The purpose of Phase 1 -- there are two purposes 16 -- is to establish the initial safety profile in humans. 17 There's been a large amount of other safety data collected, 18 but this is the first time it's put in humans. So it's done 19 under very tightly-controlled conditions, very carefully 20 studied with very low doses and they slowly go up and observe 21 those people very thoroughly. It's done in what we call 22 normal volunteers, not patients. These are healthy, young 23 people without active disease that could complicate the issue, 24 so that's done. And at the same time a lot of blood and other 25 samples are taken from them to start studying these same 50 1 pharmacological properties in humans, the absorption, 2 metabolism, excretion and so forth. So it's a very tightly- 3 controlled systematic progression now into human beings, but 4 not in patients. 5 Q. And can we say -- again you used the word 6 systematic -- this is a set of rules in the way you do these 7 things that's been worked out for medicines over time? 8 A. Yes. And those studies also have to be approved 9 besides by the FDA by what we call an institutional review 10 board. Every time any drugs or actually device is put into a 11 human, before it's approved by the FDA, has to be done under a 12 protocol and that protocol has to be approved by what we call 13 an institutional review board, which is an independent body 14 that approves that study. 15 Q. Maybe we'll come back to the institutional 16 review boards in a minute, but at this point we now are going 17 to use the medicine with healthy volunteers before we do 18 anything else, and there is a protocol set up for that? 19 A. Yes. 20 Q. As a general matter, what's a protocol? 21 A. Well, you can think of it as the road map or the 22 cookbook for the study. It tells you what to do, when to do 23 it, how many patients, what you're going to measure, when 24 you're going to measure it, how you're going to analyze the 25 data. The best way to think of it is as the cookbook. 51 1 Q. And the rules are set at this time. Do -- 2 strike that. 3 Where are these patients tested? In the case of 4 Prozac, where were they tested? 5 A. In what we called the Lilly clinic, which is two 6 floors of Wishard Hospital at Indiana University. Volunteers 7 come in and they actually stay at that facility. They're 8 essentially inpatients or residents for depending -- days or 9 months depending on the studies. They have nurses and doctors 10 and it looks just very much like a hospital ward, but people 11 usually just walk around because they're healthy people. 12 Q. If they're healthy people, why do you keep them 13 in the hospital? 14 A. So you can watch them very closely in case 15 something happens to them. Remember, this is the first time 16 these drugs are put into humans, and although there's a lot of 17 data from animal studies there's nothing like the real thing 18 and actually watching it in people, so they're monitored 19 around the clock. 20 Q. And about how long would they be in the 21 hospital? 22 A. Depends on the study. It's typically from a 23 week to three months. I think the longest studies that I've 24 heard about are three months long. 25 Q. And during that period what do you do? You give 52 1 them the medicine and you run all kinds of tests on them? 2 A. Yes. 3 Q. And the tests are trying to get at what? 4 A. Well, the safety and the pharmacology of the 5 drug. They do a lot of heart monitoring, EKGs, take a lot of 6 blood samples, look at the blood chemistries, and those blood 7 samples are also used to study the metabolism of the drug. 8 Q. So the same kinds of things, not just this study 9 of the type I put up here, but these metabolic studies, 10 pharmacology studies are now done in the healthy volunteers? 11 A. Yes. 12 Q. They had previously been done in animals or even 13 nonanimal methods? 14 A. Yes. 15 Q. Now, Doctor, about how long does the Phase 1 16 period take? 17 A. That may take several years, depending on how 18 complex the drug is. 19 Q. In the case of Prozac, do you recall 20 approximately how long it took? 21 A. Several years. I don't know the exact time. I 22 think it indicates on there several years. 23 Q. I'm not sure this one is -- this is sort of a 24 generic drug development. We may come back. 25 A. Yeah. 53 1 Q. Is there anything else the jury should 2 understand to understand Phase 1, or is that basically what 3 happened? 4 A. Well, just that it's a very methodical, 5 systematic approach to the study of drugs and a great deal of 6 attention is paid to the safety of the subjects. 7 Q. What -- what were the results of the Phase 1 8 studies with Prozac, as you understand it? 9 A. Well, as I understand them, that it showed that 10 there were really no safety issues; that it was well tolerated 11 and some of their metabolic pathways had been worked out or 12 were being worked out at that time. 13 Q. Now, at some point do you move into what's 14 called Phase 2 trials? 15 A. Yes. At the end of Phase 1 all the data is 16 gathered together and it's reviewed and a decision is made, is 17 this drug safe, does it cause toxic metabolites, is it even 18 absorbed in humans. Those are the kind of things that have to 19 be found out, too. Just because you can give it to animals 20 doesn't mean it's absorbed into the body. So once all that's 21 established in Phase 1, a decision is then made whether or not 22 to proceed into actual patients, and that then starts Phase 2. 23 Q. All right. And how does that go about? Is the 24 FDA involved in that at all? 25 A. Only in that the protocols for Phase 2 are 54 1 submitted and have to be approved by the FDA. 2 Q. All right. So now you have a series of rules, 3 protocols for the testing that you're going to do in Phase 2? 4 A. Yes. 5 Q. And those protocols are sent to the FDA, as 6 well? 7 A. Yes. 8 Q. All right. Now, at this point are we testing 9 people who actually have depression or any other kind of 10 condition that you're testing for? 11 A. Yes. 12 Q. And what are the first trials like? What are 13 they typically like? 14 A. Well, we think of them as pilot studies. They 15 usually in a smaller group of patients, 10 to 30, typically, 16 that depends on the disorder and the drug, and that is the 17 drugs are then tested in those patients to determine if 18 there's any evidence of effectiveness and to again build on 19 the safety database. Everything that's ever done goes into 20 the safety accumulation of information. 21 Q. And this resides in computers, in part? 22 A. In general, yes. 23 Q. You may have just said this but how long does 24 the Phase 2 study take? 25 A. An individual study may take several months. 55 1 The whole process may take several years, depending on the 2 drug and the disorder. Typically over several years, a year 3 or more. 4 Q. Is there sometimes overlap between these two -- 5 or various phases? 6 A. Yes. Typically there is. 7 Q. And where might you see overlap? 8 A. Well, for instance, when the toxicology studies 9 were started in the red phase, there are some very long-term 10 studies, usually two-year toxicology studies, that may still 11 be ongoing. Now, the initial ones have to have a good result, 12 but the long-term ones have to be ongoing. 13 Q. And that's part of the FDA procedures that you 14 have certain studies that have to be completed before Phase 1 15 but other toxicology studies continue? 16 A. Yes. 17 Q. All right. 18 A. There are studies that started in Phase 1, 19 typically, the pharmacology, metabolism studies, those usually 20 will go on. The chemical testing to identify the molecules 21 and intermediates usually will go on. Those take quite a long 22 time to sort all of these complex reactions out, so those are 23 ongoing. 24 Q. So this kind of work and others like it go -- 25 they start in this -- actually start in the animal period? 56 1 A. Yes. 2 Q. Then they also continue in Phase 1 and they may 3 continue on as time goes by? 4 A. That's right. And usually do. 5 Q. All right. And then Phase 2 studies, they 6 have -- there's overlapping of them or not? 7 A. Usually, unless there's a new indication 8 considered, Phase 2 generally stops. Those are the pilot 9 studies. And then there's a decision made whether to go on 10 then to Phase 3, but typically those are not carried on 11 because the information has been determined. 12 Q. All right. And you mentioned there a word 13 indication. In normal use of the rest of us, what does an 14 indication mean? 15 A. That is the purpose for which the drug is 16 intended. For instance, if one, say, decided this drug had -- 17 molecule had potential to treat a certain kind of infection, 18 for instance, ear infection in children, then the indication 19 is ear infections in children, if that's what the sponsor or 20 the company decides to develop this drug for. So it's for the 21 disease. Indication is equivalent to disease process. In the 22 case of fluoxetine it would be depression or major depressive 23 disorder as the indication. 24 Q. So just to get the terminology straight, 25 depression would be said to be an indication for Prozac; is 57 1 that the way you'd say it? 2 A. The treatment of depression is the indication. 3 Q. Okay. And sometimes you look at medicines for 4 more than one use, more than one indication; is that right? 5 A. Yes. 6 Q. And indeed is it true of Prozac that it's been 7 looked at for more than one indication? 8 A. Yes. 9 Q. Some of the other indications it's been looked 10 at for are what? 11 A. A number of indications. A disorder called 12 obsessive-compulsive disorder where people can become totally 13 debilitated by the need to do certain things, like hand 14 washing, checking to see if their door's locked. And some 15 people have this in such a serious form that they can't work, 16 they can't take care of their house. That's one. Bulimia, a 17 serious eating disorder, where people, usually younger women, 18 self induce vomiting or take laxative and actually become very 19 debilitated. It's been looked at in smoking cessation as a 20 potential use, in obesity, and possibly in alcoholism use. 21 Q. In some of these uses that it's been looked at 22 for, it's been approved, has it? 23 A. Yes. 24 Q. But besides depression are there any other uses 25 it's been approved for thus far? 58 1 A. In the United States for obsessive-compulsive 2 disorder. In some other countries also now for bulimia. 3 Q. And in some of the other uses you've looked at 4 it for, it hasn't been approved and that's that? 5 A. That's right. 6 Q. Just one minute more on this use it's been 7 approved for in the United States, obsessive-compulsive 8 disorder. I mean, I check my lock on my door; that doesn't 9 mean I'm obsessive-compulsive, does it? 10 A. I don't think so, not because of that. Just 11 doing it once would not qualify you as being 12 obsessive-compulsive. 13 Q. It really can be a serious condition? 14 A. It can be, and I've seen patients like this. I 15 had a patient when I was in the psychiatry rotation. This 16 woman put doilies on her table and she actually had to measure 17 them, she had to put tape down, she had to go back. She would 18 go out and she would have to rush back home time after time to 19 measure those doilies on her table. It got to be where she 20 couldn't do anything else. 21 I know of another woman that had hand-washing 22 compulsion that was so bad that actually her hands got raw. 23 She had to quit her job and finally got divorced, all because 24 of this obsessive-compulsive disorder. It is serious. 25 Q. It's the kind of thing we sometimes hear of in 59 1 everyday life, obsessive-compulsive, but for some people this 2 is a very serious thing? 3 A. Absolutely. 4 Q. And Prozac is approved for treatment of that? 5 A. Yes. 6 Q. Now, let's turn back to this drug-developing 7 process. At the end of -- let me take us back a step. At the 8 IND filing, was it believed at that point that there was 9 reason to believe that it would be safe and effective? 10 A. On the basis of the animal studies. 11 Q. That's right. That's all I'm talking about at 12 that point. 13 A. Yes. 14 Q. Now, at the end of Phase 1 when we've done 15 healthy volunteers, what did it look like? 16 A. It was safe in humans. 17 Q. You weren't testing it for efficacy because they 18 didn't have the disease? 19 A. That's correct. There was no more known about 20 efficacy unless other animal studies had been done in 21 parallel. 22 Q. Because nothing in that phase with the humans 23 would address that question? 24 A. That's right. 25 Q. Now, what about the next phase, Phase 2? At the 60 1 end of Phase 2, did you know any more about safety and 2 efficacy, and what was the view at that point? 3 A. Well, it continued to be safe. The efficacy 4 studies indicated at least in some studies that there was -- 5 that it probably was effective as a treatment of major 6 depressive disorder. 7 Q. What is an open-label study? 8 A. That is where the patient, the investigator and 9 the sponsor know what the patient is taking. There is no 10 attempt to hide or mask the identity of the drug. 11 Q. There's no blinding? 12 A. Correct. 13 Q. And why do you do open-label studies? 14 A. There are really several reasons. Initially, 15 efficacy is measured in fairly objective ways. There's no 16 attempt to hide it from the patient necessarily. The main 17 reason later on is to provide the drug as a compassionate use 18 on a compassionate-use basis for patients who have really no 19 other alternatives. There may not be a study to qualify or 20 there may not be one in their area, so there's no reason to 21 not let them know what they're taking. So the open label just 22 basically means they're getting the drug as if it were 23 approved, but it's still under a protocol. 24 Q. But when we turn to the development of Prozac, 25 would you be apt to use any open-label studies and would you 61 1 use them in the beginning of Phase 2, in Phase 3? Where would 2 they be apt to be if you did them? 3 A. They would be more likely to be in Phase 1 in 4 the normal volunteers because they would be getting the drug 5 and they would know that. In Phase 2, you would start to see 6 some attempts at blinding. Typically, it might be single 7 blinded, it might be open label and it varies with the drug 8 and indication. And then again you see them in Phase 3 until 9 the drug is approved in that compassionate-use protocol and 10 extension -- I'm sorry -- and extension of blinded studies, 11 those are typically fairly short, but then patients have the 12 opportunity to continue treatment and that's done on an 13 open-label basis. 14 Q. All right. Now, let's just go through -- Your 15 Honor, with your permission, I'm up here without the mike. Am 16 I being audible now? Okay. Thanks. 17 VARIOUS JURORS: Yes. 18 Q. I want to just go through some of these terms 19 because we've heard them in this trial a lot, and let's see if 20 we can make sure we get them straight. We have an open-label 21 study you've just talked about. Is it fair to say that means 22 unblinded, everybody knows that the person is getting the 23 medicine or not getting the medicine? 24 A. Yes. 25 Q. We'll called that unblinded. Now, what is a 62 1 single-blind study? 2 A. That's a study in which the patient does not 3 know what drug they're getting specifically. Now, they 4 know -- I think that needs to be clarified. That's typically 5 a placebo or comparitor-controlled study. Patients know that 6 they're in a study where they may or may not get any of these 7 drugs. They may get placebo, they may get fluoxetine or 8 whatever the drug, but at any moment they don't know which of 9 those they're taking but they do know that they're voluntarily 10 participating in a study of these drugs. 11 Q. So maybe it's better if we just said open label 12 means uncontrolled; is that right or wrong? 13 A. Well, it is controlled in the sense that it's 14 done under a protocol, data is collected. In a strict sense, 15 if you limit controlled to comparitor, yes, it's uncontrolled, 16 but that is not to imply that it's just sort of done -- the 17 drug is just sort of given out in handfuls and people go away. 18 Q. So maybe I'm going to start over here because I 19 think I probably didn't do that right. Let's start by looking 20 first at -- we have controlled studies and uncontrolled 21 studies; right? 22 A. Yes. 23 Q. Now, all of these studies are in the layman's 24 sense, the way I might use it, controlled in that there are 25 rules and careful watching of them? 63 1 A. Yes. 2 Q. But as the scientists use the term controlled 3 study, what do they mean? 4 A. That there's some comparison or there's the 5 opportunity to make a valid comparison between the drug and 6 something else. 7 Q. All right. So in an open-label study do you 8 typically have controlled or comparitor? 9 A. Usually not. There are some circumstances where 10 that can be done, but usually not. 11 Q. All right. So I'll put down again open label, 12 and that means, one, not blinded. And what do you think is 13 right to say, Doctor, that it's -- 14 A. No comparitor. 15 Q. No comparitor? And a comparitor is just 16 something you're comparing it with? 17 A. Yes. 18 Q. And sometimes no comparitor is referred to as 19 uncontrolled? 20 A. Yes. 21 Q. But that's not the same meaning in everyday 22 life? 23 A. That's correct. 24 Q. All right. Then we have the blinded studies. 25 Are they -- do they typically have control? 64 1 A. Typically they do. There are blinded studies 2 where there is no separate control group, where the patient 3 acts as their own control, but that tends to be less so. 4 Q. Okay. So typically if it's blinded, it's 5 controlled, and that means there's a comparitor? 6 A. Yes. There is not much reason to blind it if 7 there's not a comparitor. There are exceptions, but for the 8 most part that's true. 9 Q. Okay. Now, under blinded we have single blind. 10 Tell us again what that is. Excuse my back again. 11 A. That is where the patient does not know the 12 specific identify of the drug they're taking at that time. 13 Q. Okay. Patient doesn't know. Now, we say the 14 patient doesn't know. I'm a patient. I'm taking medicine. I 15 know that I'm taking it, don't I? 16 A. Yes. But you don't know whether that pill 17 you're taking has active drug or placebo or some comparison 18 drug in it. They all look the same. 19 Q. They do all look the same? 20 A. They all look the same. 21 Q. If I took the pill I couldn't tell which was a 22 sugar pill and which was the Prozac? 23 A. Exactly. 24 Q. All right. Now, so that's single blind. And 25 what's double blind? 65 1 A. That's a study in which the patient and the 2 investigator or the people administering the drug don't know 3 the specific identity of that drug at that time. 4 Q. All right. So the patient doesn't know and the 5 doctor? 6 A. Yes. 7 Q. Now, I asked the question the other day is there 8 such a thing -- is there such a thing as triple blind? 9 A. Yes. 10 Q. And what is that, Doctor? 11 A. That's where -- it's double-blind study but in 12 addition, the sponsor, in this case the drug company or Lilly, 13 where the people working with the study on a day-to-day basis 14 do not know what that patient is taking at that time. 15 Q. Somebody must know sometime or you can't figure 16 out what's going on, so in a triple blind who does know? 17 A. Usually the statistician, and that's kept in a 18 list that's sealed until the study is over. The people in 19 manufacturing or where they make up these patient kits, they 20 of course have to know, but they're not involved in 21 communicating with the investigator, so they don't really have 22 an opportunity to, even by accident, share that information. 23 Q. All right. Now, you said the patient, the 24 doctor and the sponsor don't know in the triple blind. In the 25 case of fluoxetine the sponsor is Eli Lilly? 66 1 A. Yes. 2 Q. But there are sometimes sponsors who are not -- 3 when you do these kind of triple-blind studies might not be a 4 pharmaceutical company, it could be other kinds of 5 institutions? 6 A. That's correct. There are NIH studies done by 7 the government, and certainly our company in any medical 8 devices, we did a triple-blind study. 9 Q All right. Now, we go through all these 10 things. It's complicated and I guess a little expensive to do 11 some of these blinding techniques? 12 A. Yes. 13 Q. What is the purpose? First, let's take them one 14 at a time, what is the purpose of using a comparitor? 15 A. Well, scientifically, by definition, you have to 16 say in comparison to what. You can't just say is the drug 17 effective. Compared to what? You might say, well, let's just 18 give it to people and see if they get better. Well, it's like 19 a cold. People usually get better from a cold and other 20 infections and people with depression may get better on their 21 own. That's true with a lot of illness. Even with cancer 22 some people improve, typically not in that situation, but you 23 always have to say in reference or compared to what. 24 Q. And so you can't just look at somebody taking 25 the medicine and getting better and say the medicine is the 67 1 reason? 2 A. That is absolutely correct, because there are 3 many other factors that could lead to them getting better or 4 worse or them having side effects. People could develop side 5 effects from other illnesses or some other medicine they're 6 taking, but that could be ascribed falsely to the medication 7 that's being tested, so it's for both the safety and 8 effectiveness point of view. 9 Q. So you're saying not only with safety, but if 10 you took a medicine and something adverse happened, you 11 couldn't say that the medicine caused it unless you had done 12 some comparison? 13 A. That's right. You just wouldn't know. 14 Q. Now, so that's why you do comparitors or 15 controlled studies? 16 A. Yes. 17 Q. And why do you do single blinding? 18 A. That -- 19 Q. I mean, what's the purpose of blinding at all? 20 A. So that the patient doesn't know. Now, why 21 would you want to do that is the question. 22 Q. That's really what I want to know. 23 A. Well, in all of medicine, and in some disorders 24 much more than others, there's what we call a placebo effect, 25 and that is that people get better in some situations, they 68 1 may get worse, but typically they get better for no reasons 2 related to the therapy. And usually that's thought to be on a 3 psychological basis, but that's known for many things, 4 including depression, in epilepsy. It's well known that if 5 you bring patients into the hospital to study them they may 6 stop having seizures. And this placebo effect, just because 7 of the care patients are getting, the frequent visits or the 8 disease just changing on its own, is why you need to have a 9 blinded study, and the patients can't really know whether 10 they're getting that medication. 11 Q. Is it true, Doctor, that this placebo effect 12 occurs broadly with lots of different kinds of medicines? 13 A. Yes. 14 Q. It's not just even medicines? 15 A. Not even medicines. It can happen with surgery, 16 the device I'm working with or sometimes just bringing people 17 into the hospital. 18 Q. Can it happen with diet? 19 A. Yes. 20 Q. If I think chicken soup makes me feel better, 21 maybe it will make me feel better just because I think it; is 22 that right? 23 A. That's correct. 24 Q. So we want to compare -- we want the patient not 25 to know what the patient's getting so we can filter out that 69 1 effect; is that what single blinding is about? 2 A. That's right. 3 Q. Now, double-blinding. Here we've got the 4 patient, now the doctor, too. Why is it important for the 5 doctor not to know? 6 A. Well, virtually all investigators, doctors that 7 study their therapy will not tell the patient, "Well, I think 8 you're going to get better because you're getting active 9 drug," and another one, "I don't think you'll get well because 10 you're getting placebo," but they can give subconscious clues 11 to the patient. 12 Q. Like what? 13 A. Let's take the example of depression. In taking 14 the depression scale, the Hamilton, it's not always clear, for 15 instance, whether it's a two or a three. If the investigator 16 knows whether the drug is active or not, that might even 17 subconsciously sway their decision. They may treat patients 18 somewhat differently and even in their body language they may 19 say, "Well, you're getting better, aren't you," versus saying 20 "Well, you don't really feel any better, do you." It's those 21 kind of sometimes very subtle messages that can influence what 22 appears to be the outcome of the study but, in fact, has 23 nothing to do with the drug effect. It's called bias. That's 24 the word that's used in the study. 25 Q. It's called bias. It doesn't mean that the 70 1 doctor or the patient is intentionally trying to fool the 2 study, so to speak? 3 A. That's right. 4 Q. Or does it? 5 A. That's correct. 6 Q. But there are all these little ways that the 7 messages could be communicated? 8 A. Yes. 9 Q. Unintentionally? 10 A. Unintentionally often. 11 Q. Now, you mentioned in your answer something we 12 heard -- maybe hear a little more about, called the Hamilton 13 Depression Scale? 14 A. Yes. 15 Q. Very briefly, because others will talk about it, 16 what is the Hamilton Depression Scale? 17 A. Well, it's a measure of the degree of 18 depression. There are several versions of it, but typically 19 there's an 18- and a 21-question version that's applied and it 20 goes -- it's a systematic way of assessing the degree of 21 depression in a fairly objective way rather than just saying, 22 "Well, do you feel depressed or not." It goes through 23 different items. 24 Q. So the depressed patient may answer the 25 questions on the Hamilton Depression Scale and that's a way to 71 1 try to get a rating of how depressed they are? 2 A. Yes. Exactly. 3 Q. Who administers those questions? 4 A. A psychiatrist. 5 Q. And who puts the answers down on the rating 6 scale? 7 A. The psychiatrist, the interviewer. 8 Q. So a psychiatrist or interviewer asks the 9 depressed patient these various questions to measure how 10 depressed they are and then what does the psychiatrist write 11 down? 12 A. There are usually a number of choices. You 13 think -- for most questions, it's four, and they'll circle the 14 most appropriate category. 15 Q. So it might be One, Two, Three, Four? 16 A. Yes. 17 Q. Would that relate to what, a symptom or what? 18 A. It relates to signs or symptoms of depression. 19 There are categories like "How do you feel overall, how is 20 your mood," and within that it might ask, "Have you been 21 crying uncontrollably." It asks about thought processes, can 22 you think clearly or how unclearly can you think; sleep 23 disorder; it asks about ideas about suicide with the patient, 24 whether they had ever thought about it, whether they have a 25 plan to do it. All of those are addressed step by step and 72 1 then the scores are added up. 2 Q. And there's a number placed on those by the 3 psychiatrist or the interviewer? 4 A. Yes. 5 Q. Now, so I guess what you're saying -- strike 6 that. 7 You were referring to that earlier in connection 8 with the double-blinding, the psychiatrist writes down a 9 number, one, two, three, four on the Hamilton scale. And are 10 you saying that psychiatrists could be affected in writing 11 down that number if the psychiatrist knew what the patient was 12 getting? 13 A. Subconsciously they could. They are people, 14 too. 15 Q. It's less important perhaps with the physician 16 than it is with the patient that they don't know? 17 A. I would say so, but it still is important. 18 Q. All right. Now, tell us about the third of 19 these blinding techniques. What is that, triple blinding? 20 A. That's when the people in the office, in this 21 case Lilly, that are working with the study don't know what 22 that individual or patient is getting at that time. 23 Q. And what is the purpose of that? 24 A. It's a further attempt to keep the study as 25 scientific and objective as possible. The example would be if 73 1 an investigator calls up not knowing what the study drug is 2 and says, "Well, Mr. Jones came in and he has a headache 3 today." And just take as an example we knew that in quite a 4 few patients this study drug caused headache. If the clinical 5 research associate or the research physician knew that the 6 patient was on the active drug, they may let it slip or even 7 in their tone of voice say, yes, we would expect that, or 8 don't worry about that, whereas, if they knew the patient was 9 on placebo, they may say, well, that's odd. I wouldn't have 10 expected that. So that's sort of an example to limit any 11 opportunity to put erroneous information into the system. 12 What we're trying to establish is what is the effect of the 13 drug and nothing else. 14 Q. If you could put it in a sentence or two, in all 15 of science, not just at Lilly but generally in good science, 16 what is the purpose for all of these things that are gone 17 through at some length and time? 18 A. To determine the effectiveness and safety 19 profile of that compound and to not have that interfered with 20 by false information. 21 Q. You said earlier, I think yesterday afternoon, 22 something about science driving the process at Lilly. Is that 23 related to this? 24 A. Well, I think this absolutely illustrates that; 25 that every attempt is made to keep these studies as objective 74 1 and as clean and as meaningful as possible, and I think great 2 lengths are gone to to assure that. 3 Q. Now, let's go back to the drug development chart 4 for a minute. We have had in your testimony thus far a 5 description of the Phase 2 trials. Are some of those blinded? 6 A. Yes. They may be. Usually single blinded or 7 perhaps double blinded. It's a combination at that point. 8 Q. Okay. And at the end of the Phase 2 period, 9 what was your understanding about where things stood as to 10 whether the medicine looked like it might be efficacious, 11 might not or was worth a further look? 12 A. Well, the Phase 2 studies indicated that there 13 was probably efficacy, as I understood it, and I'm not that 14 familiar with those studies, that some of the studies it was 15 questionable that they didn't seem to differentiate from 16 placebo. So there was a mix. There was some that was 17 positive and some neutral. 18 Q. Was it a -- given the mix, was the decision 19 made -- sometimes a decision made in Phase 2 to just stop? 20 A. Oh, absolutely. 21 Q. That happens commonly, uncommonly? 22 A. I would say in between. I wouldn't say half the 23 time, but there are a significant number of times the initial 24 efficacy tests just don't show a drug to be effective and then 25 it's stopped. 75 1 Q. With these mixed results but some of them did 2 show efficacy, was there a decision to go forward into 3 Phase 3? 4 A. Yes. 5 Q. How can you distinguish Phase 3 from Phase 2 for 6 us? 7 A. Phase 3 is really the major effort to now gather 8 highly controlled, very scientific data on a large number of 9 patients to ultimately submit to the FDA for approval. 10 Typically those studies are multicenter, meaning they're done 11 at many institutions at the same time using the same or 12 similar protocols. Many, many more patients, usually a number 13 of studies are done and those are typically triple blinded. 14 Q. Is it -- we don't have this shown graphically, 15 Doctor, but is it true that the amount of study, the number of 16 patients expands from relatively small in Phase 1 to larger in 17 Phase 2 to much larger in Phase 3? 18 A. Much larger. 19 Q. Can you give us a sense of order of magnitude, 20 not necessarily in numbers but in words? 21 A. Easily 10 times or more patients. Typically at 22 the end of Phase 2, we might have 50 to 100 patients. By the 23 end of Phase 3 there are thousands of patients, many, many 24 more. Many, many more studies. 25 Q. Now, there comes a point when those phases end 76 1 up with a submission of something called an NDA. We've heard 2 a lot about that. What's an NDA? 3 A. NDA stands for New Drug Application. And what 4 that is is all the data that's been collected on the 5 effectiveness and safety of the drug is compiled, analyzed, 6 summaries are written which then have attached to them actual 7 patient-by-patient tabulations, and all of that is submitted 8 to the FDA and a request is made that this drug be approved 9 for that indication for which it's been studied. 10 Q. And that -- at the point of that submission in 11 the case of Prozac, what was the evidence with respect to 12 safety and efficacy, whether it worked to help depression or 13 not? 14 A. It was shown to be safe and effective in those 15 studies. In the majority or on balance, safety and 16 effectiveness was felt to be demonstrated. But that, of 17 course, has to be determined by the FDA. But our opinion was 18 that, yes, it is safe and effective. 19 Q. Now, when a medicine, any medicine, not just 20 Prozac but any medicine is said to be safe does that mean it 21 has no side effects? 22 A. No, it doesn't mean that, and personally I think 23 there should be a better word to describe that. All 24 therapies, all medicines have side effects. What it really 25 means is that on balance, compared to the risks of the 77 1 disease, it is relatively safe. One should really think about 2 this as a risk/benefit ratio. 3 Q. A risk/benefit. That is, the benefit of the 4 medicine balanced against any adverse effects that it may 5 have? 6 A. Yes. 7 Q. Now, when you submitted the Prozac NDA, did 8 the -- did the Phase 3 studies stop or did they continue or 9 what's the situation? 10 A. No. They continued, both in depression more 11 studies were done and were ongoing. Typically by this time 12 more comparitors as opposed to placebo is used. Studies of 13 other indications were ongoing and later new ones even 14 started. 15 Q. And is the FDA kept aware of the work that's 16 done after the submission of the NDA? 17 A. Yes. There are formal periodic reports that are 18 done. All studies that are completed or for some other reason 19 stopped have to be written up and submitted to the FDA, and at 20 any time the FDA can ask for any information they want and 21 that is supplied. 22 Q. Is there -- is there in fact with medicines and 23 with Prozac in particular, communication where the FDA will 24 make inquiries about things it's interested in knowing beyond 25 the reporting? 78 1 A. Oh, yes. If something comes to their interest 2 or attention, they'll call up and ask us to tell them about it 3 or do an analysis or just send them raw data. 4 Q. How does that work? I mean, did you experience 5 that personally? 6 A. Yes. 7 Q. Is that one of the things you do today, in your 8 work today? 9 A. Yes. Quite a bit. 10 Q. There came a time when the FDA approved the New 11 Drug Application. When was that? 12 A. In 1987, December. 13 Q. And then at that point the medicine was approved 14 and you still -- do you still have studies ongoing after 15 approval? 16 A. Well, they do. I'm not at Lilly anymore, but, 17 yes, studies are ongoing. And when I was there through the 18 time of approval, there were a lot of studies ongoing. 19 Q. When did you leave, Doctor? 20 A. In 1990. 21 Q. And why did you leave? 22 A. To join this medical device company, Cyberonics, 23 that I'm with now. 24 Q. All right. I wonder if in illustrating this 25 interchange with -- between Lilly and the FDA and the reports 79 1 that have to be filed, we might bring that chart out and see 2 if that's helpful. 3 MR. SMITH: Can we have an opportunity to see 4 the chart? 5 MR. McGOLDRICK: I'm sorry. I believe we showed 6 it to you before. 7 MR. SMITH: (Reviews document). 8 MS. ZETTLER: (Reviews document). 9 Q. You've seen this before, Doctor Wernicke? 10 A. Yes, I have. 11 Q. I'm going to try to set it up so it works here. 12 Q. It's possible at times you may have to come down 13 and take a look at this, if so, please be sure you -- if 14 possible, I guess, stay on that side for the Reporter and keep 15 your voice up especially because your voice does tend to go 16 down. 17 Now, first of all, what is this set of two 18 boards? 19 A. This is a time line for the development of -- 20 that illustrates the development of Prozac, but it actually 21 starts way before the development with the discovery of 22 serotonin and goes up to the current time. 23 Q. Does this chart contain everything that happened 24 with respect to Prozac? 25 A. Well, certainly the highlights. It illustrates 80 1 all of the important milestones. 2 Q. Of reporting to the FDA on the top? 3 A. Yes. 4 Q. And studies on the bottom? 5 A. Yes. 6 Q. But there's a lot of information that isn't 7 here? 8 A. Well, yes; many, many details, of course. 9 Q. Right. But this gives an overview? 10 A. Yes. 11 Q. All right. 12 If Your Honor please, I'd like to offer the 13 document. I have a smaller form which could be handed to the 14 jury because it's a little hard to read, and ask that it be 15 published. 16 JUDGE POTTER: Exhibit number? 17 MR. BRENNEN: 246, your Honor. 18 MR. SMITH: Your Honor? 19 (BENCH DISCUSSION) 20 JUDGE POTTER: Mr. Smith. 21 MR. SMITH: This is another exhibit that was not 22 disclosed to us in the pretrial process. We just saw it 23 yesterday for the first time, and we'd object to it by virtue 24 of the fact it was not disclosed to us pursuant to the rulings 25 of the Court. 81 1 JUDGE POTTER: What's all these strikes down 2 here at the bottom? 3 MR. McGOLDRICK: They are clinical studies just 4 to show when they occurred on the time line. That's all. 5 It's really just a series of dates. 6 MR. SMITH: When I was shown the document 7 yesterday, I thought it was going to be used for demonstrative 8 purposes only. I didn't know it was going to be offered as an 9 exhibit. 10 MR. MYERS: Those are periodic adverse drug 11 experience reports. They're just large binders of 1639s that 12 they sent in periodically. They're periodic reports. 13 MR. McGOLDRICK: Basically the top report's 14 reporting a few things and the bottom part is studies. I 15 think it is a demonstrative exhibit, but it seems to me it's 16 hard to read some of the small stuff, even for the big boards, 17 and that's why I think it would help for the jury to have 18 them. 19 JUDGE POTTER: Is there anything on this thing, 20 Mr. Smith, that's misdescribed or in any way in dispute? 21 MR. SMITH: Again -- 22 JUDGE POTTER: Maybe this stuff I can make them 23 cut off. 24 MR. SMITH: Yeah. In all candor, Your Honor, I 25 really don't think there is any dispute about the time line, 82 1 but obviously the bottom is -- 2 MR. McGOLDRICK: It's just a demonstrative 3 showing of when the studies occurred. 4 MR. SMITH: It's not identified as to what 5 studies, you know, who the investigators were. 6 MR. McGOLDRICK: We could make it more 7 complicated, but it would just be vastly complicated for the 8 jury. 9 JUDGE POTTER: If you want this to come in as a 10 prepared exhibit with him able to testify from it, you need to 11 take off the bottom stuff, because none of that has been 12 identified, none of it has been given to Mr. Smith, he has no 13 way of verifying what any of that stuff is. So we'll take a 14 five-minute recess and either cut off the top or put your 15 charts up. 16 MR. McGOLDRICK: All right, Your Honor. Two 17 points, one, I can use the boards as a demonstrative exhibit 18 but can't offer the bottom part of the chart in evidence, I 19 hear Your Honor saying? 20 MR. SMITH: He can use the boards as a 21 demonstrative exhibit, but the boards have that on it. 22 JUDGE POTTER: While we take this recess just 23 cover a piece of white paper on the board over here, but if 24 you want to draw over the top of that you can. But all of 25 this looks very official, very precise and very timed and it's 83 1 not. 2 MR. McGOLDRICK: I think this Witness can say 3 that that's representative of the times of the studies. 4 JUDGE POTTER: What I'm saying is -- 5 MR. McGOLDRICK: You want to take a recess. 6 JUDGE POTTER: Yes. 7 (BENCH DISCUSSION CONCLUDED) 8 JUDGE POTTER: Ladies and gentlemen, we're going 9 to take a ten-minute recess. As I've mentioned to you-all 10 before, do not permit anybody to talk to you about this case. 11 Do not discuss it among yourselves and do not express any 12 opinions about it. We'll take a ten-minute recess. 13 (RECESS) 14 SHERIFF CECIL: The jury is now entering. All 15 jurors are present. 16 JUDGE POTTER: Please be seated. 17 Doctor, I'll remind you you're still under oath. 18 Mr. McGoldrick. 19 MR. McGOLDRICK: Thank you, Your Honor. 20 Doctor Wernicke, before the break we were 21 starting to address this time line and we have it here in 22 cutoff fashion in front of the jury now. And I'm going to 23 ask, Your Honor, if I can have admitted and published to the 24 jury individual copies of this one so they'll be able to see 25 it. 84 1 JUDGE POTTER: What's the exhibit number? 2 MR. BRENNER: 245, Your Honor. 3 MR. McGOLDRICK: 245. 4 JUDGE POTTER: 245 will be admitted. 5 SHERIFF CECIL: (Hands document to jurors). 6 Q. All right. This exhibit is a two-page document 7 just like these two boards, should be put next to each other. 8 I can't do it very easily with a staple but, in any event, 9 Doctor Wernicke, I wonder if you could come down front for a 10 minute and just point out a few things on this time line to 11 the jury. I think for ease of the Reporter I think that side 12 would be better. We've spent a lot of time with these boards, 13 but what is it? 14 A. This shows the time line of the development of 15 Prozac, but it really goes back further to the very beginning, 16 to the discovery of serotonin. This really represents 40 17 years, but let me point out that there's a large gap in here. 18 So if we were to really make this all on one line the 19 discovery of serotonin would be out in the hall somewhere, so 20 this is broken. But then this is an uninterrupted, continuous 21 line of time representing about 20 years over which 22 fluoxetine, or Prozac, was developed. 23 Q. Just let me stop you there, Doctor Wernicke, 24 from here, 1972, to say 1992, just to have an ease of 25 reference of 20 years takes that much space, and from 1972 85 1 back to '53 I guess it was discovered in the brain would be 2 another out here if we made the boards that big? 3 A. Right. Another 20 years in that direction. 4 Q. What does this little line represent? 5 A. That just shows it's not continuous, that 6 there's a break, that after this point you see every year, and 7 all the other 20 years are represented in just this little 8 section, but that would be way over there. 9 Q. And again this does not show every event that 10 happened, just some of the events? 11 A. Right. Some of the major milestones. 12 Q. Can you show the jury -- we'll do this real 13 quickly -- where is the synthesis of fluoxetine? 14 A. Back here in 1972. 15 Q. And when is the IND filed? 16 A. In 1976. That's this first red marking. 17 Q. And if we look at this chart again -- too many 18 charts here -- all of the earlier work occurs before this 19 time; is that right, sir? 20 A. Yes. That's correct. 21 Q. All right. And then we go forward. When is the 22 NDA filed? 23 A. At this point in 1983. 24 Q. And what would that correspond to on this chart? 25 A. NDA submission right there. 86 1 Q. And when does the FDA approve as safe and 2 effective? 3 A. In 1987. That's right here. 4 Q. All right. And where does that correspond to on 5 this chart? 6 A. Right here at NDA approval. 7 Q. Now, I don't know that you necessarily need to 8 go through all of these things on the top, but let's just 9 start with a few of them. This red thing here I think you 10 just testified to, is what? 11 A. That's the NDA filing. 12 Q. NDA? 13 A. I'm sorry. IND filing. 14 Q. All right. And then tell us a little bit about 15 these red annual reports that are all along the top of the 16 chart, what are they? 17 A. Well, they are a number of types of what we call 18 periodic reports that are submitted to the FDA and those are 19 required by law. There's a minimum number and, in addition, 20 the sponsor can file at any time they feel appropriate if they 21 have information they think the FDA needs to know before the 22 next scheduled report or the FDA can at any time ask for a 23 report. And initially, and that's indicated here, they're 24 filed periodically, usually annual report to what we call the 25 IND, and that's what all of these lines represent. Then as 87 1 more and more data are accumulated and as their review of the 2 NDA starts and continues, these reports become much more 3 frequent because there's a lot more back-and-forth activity. 4 There's a lot more data. Analyses become much more complex 5 and involved. 6 After the drug is approved, the process 7 continues, but in addition to that, there are what we call 8 periodic safety reports that summarize all the data that comes 9 in to the sponsor that is then summarized and put together and 10 transmitted to the FDA. So that's what this PADR, Periodic 11 Adverse Drug Reaction Reports means. And those are filed on a 12 routine basis and as needed, as requested or as the company 13 feels is appropriate. So that activity goes on for a long, 14 long time, even after the drug is approved, actually forever. 15 Drugs that were approved many, many years ago still have 16 periodic reports. That never stops as long the drug is on the 17 market. 18 Q. Doctor, I think there's one thing in here that 19 you might just mention that. This is called safety update. 20 What's that? 21 A. All right. That -- well, let me go back to the 22 NDA. The NDA was the first major submission of data by 200 23 volumes of material submitted to the FDA. That was thoroughly 24 reviewed and analyzed by the FDA themselves. They then had 25 what they call an advisory committee meeting of outside 88 1 experts to advise them of the findings or their view of what 2 the FDA has found and what we have submitted. 3 Q. Let me stop you there. You have an advisory 4 committee when? Is there more than one advisory committee? 5 A. Right. This was -- if I can find it on here. 6 Q. It may not be listed on the chart, I'm not sure. 7 A. So that would have been about '85, FDA advisory 8 committee meeting, 10-10-85. That's a formal standard process 9 where the FDA conducts their review based on the material 10 submitted and they then present their findings to an outside 11 panel of experts and typically the sponsor may or may not 12 present their view. If it's different from the FDA's, if 13 there's anything in addition, then the panel recommends to the 14 FDA whether or not this drug should be approved or if 15 additional studies need to be done or what their view of it 16 is. And that meeting was held and the panel and the FDA 17 advisory committee unanimously recommended to the FDA that 18 they approve this drug. At that same advisory committee 19 meeting, which I attended, the FDA said well that's all good 20 and well and what we have is fine but we know many, many 21 studies have gone on and, in fact, before the NDA and as the 22 NDA is filed many, many more studies continue and thousands 23 more -- many more patients are treated. It was obvious to 24 everybody, including us, that there was much, much more data 25 that the FDA had not had the opportunity to see because they 89 1 were reacting to the original NDA. 2 Q. The NDA is filed in '83? 3 A. Right. 4 Q. And this meeting is in -- 5 A. '85. 6 Q. -- '85, in here, and all the clinical studies 7 that had been submitted by the time of the NDA was what the 8 NDA was reacting to at this meeting? 9 A. Yes. That's what they had reviewed at that 10 time. 11 Q. And then there was more that was ongoing during 12 this time? 13 A. Yes. During those two years there were many, 14 many studies ongoing so much, much more data was being 15 accumulated. That's a constant process. So there was much 16 more for the FDA to consider. So what they said, which was 17 quite appropriate, is that, yes, we've reviewed all the data, 18 everything looks fine, but we know there's a whole lot more, 19 so we would like to do a very, very thorough comprehensive 20 safety analysis of this drug. 21 MR. SMITH: We're going to object to what the 22 FDA said and this Witness's characterization of the FDA's 23 position in this matter. 24 A. Well, I'm only relating what they -- 25 JUDGE POTTER: Let me see you-all here a second. 90 1 (BENCH DISCUSSION) 2 JUDGE POTTER: Mr. Smith, I was -- this was so 3 routine I really wasn't listening very carefully. What was he 4 saying that you found objectionable? 5 MR. SMITH: He said the FDA said we want you to 6 do this and we want you to do this to make a very, very, very 7 careful analysis. 8 MR. McGOLDRICK: Well, I don't think it's 9 necessary to ridicule his accent, Your Honor. 10 MR. SMITH: Well, I don't think he should 11 interrupt me when I make an objection on this. 12 JUDGE POTTER: We picked on his Texas accent so 13 fair is fair. 14 MR. SMITH: Obviously it's related as hearsay, 15 Your Honor. 16 JUDGE POTTER: I'm going to overrule the 17 objection as long as he just keeps it somewhat general and 18 objective. They asked for us to respond to this, we responded 19 to it. They approved it, they didn't approve it. If he 20 starts getting down into real detailed stuff, I will sustain 21 an objection. 22 (BENCH DISCUSSION CONCLUDED) 23 Q. All right, Doctor. You may continue. You say 24 at this meeting there was a lot of new data that the FDA said 25 that it wanted to review, as well? 91 1 A. Yes. As I mentioned that we had many more 2 patients by this time, many studies ongoing, and they said we 3 agree with the findings so far but we would like now to see a 4 very, very comprehensive safety analysis. And we talked with 5 the FDA about what that should be, how it was to be done, what 6 types of analyses, what types of issues they wanted to look at 7 in particular, but also for us to do what I characterize as an 8 everything-by-everything analysis, to look at everything that 9 might somehow pertain to the safety of this drug. And we did 10 that. There was quite a piece of work. We submitted that; 11 there was another 200 volumes of material that was as large as 12 the original submission. 13 Q. And that was before the medicine was approved? 14 A. Yes. And after that, there were a few more -- 15 they had a few more questions, very detailed, very 16 sophisticated questions that we then answered and then the 17 drug was approved. 18 Q. All right. And then these reports continue on, 19 as you've described? 20 A. Yes. 21 Q. Let me call your attention in here there was 22 another FDA advisory committee meeting? 23 A. Yes. 24 Q. Was that the one in which the panel addressed 25 the questions of suicidality and violence and found no 92 1 credible evidence? 2 A. To my knowledge, that's what happened. 3 Q. You had left the company by then? 4 A. Yes. And I was not at that meeting. 5 Q. Why don't you just show the jury quickly on the 6 map the time line when you came and when you went on to 7 Cyberonics? 8 A. I joined the company in 1984 and left in 1989, 9 at the very end of 1989, the transition to 1990. Right here. 10 Q. All right. Thank you, Doctor. Well, let me 11 just ask you one other question. If we were to put on this 12 chart information with respect to when the clinical studies 13 occurred, roughly where would it be? 14 A. Everything from IND first human all the way 15 to -- well, it stops in '94, but all the way to there. 16 Q. And clinical studies occur for various 17 indications? 18 A. Yes. 19 Q. Depression? 20 A. One of them, yes. 21 Q. Others? 22 A. Yes. 23 Q. What others? 24 A. Obesity, smoking cessation, obsessive-compulsive 25 disorder, bulimia. There were some specialized depression 93 1 studies in patients with cancer, things more of a refinement. 2 Those are the major ones that I'm aware of. 3 Q. Okay. All right, doctor. Thank you very much. 4 You may resume the stand. Who -- you talked about protocols. 5 Well, let's talk about these -- strike that. 6 Let's talk about clinical studies. A clinical 7 study is what? 8 A. Well, it's an investigation of that compound in 9 humans to determine either efficacy and always safety. 10 Q. All right. And a protocol is a set of rules, a 11 road map for how a study is conducted? 12 A. Yes. That's correct. 13 Q. Can there be more than one protocol for a given 14 study? 15 A. Yes. 16 Q. Explain that. 17 A. Well, sometimes if there are different 18 investigators involved they may have a different protocol 19 because often they may have a special expertise or a special 20 interest so the study is slightly modified, but the core of 21 information is the same. There may be, for instance, in a 22 long-term efficacy study there may be some very specific 23 pharmacokinetic study that's done, so that would be another 24 protocol in addition to the ongoing study. So a study can 25 involve several protocols or it may just be one major 94 1 protocol. 2 Q. Now, does a study or a protocol take place only 3 at one physical place with one doctor? 4 A. No. No. Many of them, especially the Phase 3 5 studies, typically are what we call multicenter and may be 6 done at many institutions and sometimes at different countries 7 all at the same time, but they all follow the same road map. 8 Q. All right. So if you have a study and one 9 protocol within a study, that can be multicentered? 10 A. Yes. 11 Q. Give the jury an example of a multicentered 12 study and where in the country it might be conducted or more 13 than the country. 14 A. Well, there are many examples in the Prozac 15 development, but one of what we call the pivotal studies was a 16 three-arm study comparing fluoxetine to imipramine, a standard 17 tricyclic antidepressant, and placebo, and that was done at 18 seven centers. Typically, we always try to have a good 19 geographical distribution, some in Chicago and northeast, New 20 York, typically some on the west coast, the southwest, so 21 there's a real attempt, actually a conscious effort made to 22 get a good geographical distribution, and that really works 23 out very well. 24 Q. So if we hear of one study or one protocol if 25 it's multicentered, it may mean that it's going on in southern 95 1 California and Indiana, Kentucky, and in the northeast or 2 Georgia or wherever? 3 A. Yes. 4 Q. Are there any agencies, public agencies or 5 people other than Lilly who look at a protocol to see if it's 6 a good idea? 7 A. Well, two, the FDA, of course. And they have to 8 see every protocol before we can start it and study it. Then 9 each institution, by institution, that may be a hospital, a 10 university or a doctor's office, has to have what we call an 11 institutional review board. That's a legal requirement; 12 there's no negotiating on whether or not one can have that. 13 That has to be in place. And that is an independent body of 14 people that are not involved in the study, not involved with 15 the company and not involved with the FDA, that review the 16 protocol and verify that this is appropriate to do in humans 17 and approve it, if they approve it, not all protocols are 18 always approved, but they have to approve it before the study 19 can start at that institution. 20 Q. Does the FDA sometimes make suggestions about 21 protocols? 22 A. Oh, yes. 23 Q. Changes they'd like to see made? 24 A. Yes. 25 Q. Things they'd like to see you do differently? 96 1 A. Yes. Quite often. 2 Q. Pardon? 3 A. Quite often. 4 Q. Quite often? Now, the institutional review 5 board, if I had a -- if I was a doctor at a hospital and I was 6 going to be part of a study and I was going to help run part 7 of it there, I would have to go to that hospital and get 8 approval from this institutional review board? 9 A. Yes. 10 Q. What kinds of people typically compose an 11 institutional review board? 12 A. It's actually fairly formally determined and 13 there are guidelines. It typically is some medical 14 professionals, some doctors, but it has to also contain some 15 nonmedical people. There may be laypeople from the community, 16 sometimes they are lawyers or ethicists, but it has to be a 17 mix of people that are professionals and nonmedical 18 professionals. 19 Q. You said ethicists. What's an ethicist? 20 A. Well, they're a group of people that consider 21 and study and think and write about what is the appropriate 22 thing to do in medicine. Right now it just comes to mind that 23 this whole issue of assisted suicide and euthanasia that 24 that's really a big ethical issue for this society, and these 25 people are involved in that. But they also look at individual 97 1 studies and ask the question is this appropriate to do in 2 people, and render an opinion on that. 3 Q. Doctor, watch your mike, make sure you're 4 talking into it. Maybe I'll just at this point put these 5 down. 6 A. I could use this. 7 Q. I think you're all right. Is he all right with 8 you, or would you like him to use the mike? 9 JUDGE POTTER: Ladies and gentlemen of the jury, 10 can you-all hear him all right? Use the mike. 11 DOCTOR WERNICKE: Well, let me know if it 12 doesn't work so good. 13 JUROR FITCH: That's fine. That's fine. 14 Q. All right. Now, on these -- these institutional 15 review boards he reviewed -- 16 JUDGE POTTER: I think, Doctor, we'd better go 17 back to the brown one. 18 A. I'll try. Just yell if I fade off. 19 Q. Remember that the mike that counts is -- 20 A. I know, but I can only get it so close. 21 Q. I understand. Do your best. 22 All right. The institutional review board then 23 reviews each protocol that's being done at that site of where 24 that board is? 25 A. Yes. 98 1 Q. And they have to approve it? 2 A. Yes. 3 Q. You were talking about the ethics of protocols 4 and these studies and the role of the institutional review 5 board there. Let me ask you a question in that connection. 6 We've discussed in this case, I think the jury will have heard 7 testimony, with respect to some of the protocols for Prozac 8 that excluded patients at serious risk for suicide. Are you 9 aware of that exclusion, sir? 10 A. Yes. 11 Q. Describe for the jury first what's the 12 difference between a suicidal patient and a patient or patient 13 with suicidality and a patient at serious risk for suicide? 14 A. Well, suicide is a very major serious component 15 of depression. It's generally agreed in the medical 16 literature that over a lifetime about 15 percent of patients 17 with major depressive disorders commit suicide, so that is a 18 serious consideration. Now, in the process of depression, 19 patients have some degree of what we call suicidality. It may 20 be nothing at that moment, but typically there is at least a 21 thought, well, I just wish I weren't here or I wish I were 22 dead, I wish I had never been born. Everything then -- then 23 that goes up by grades: I really want to kill myself and I 24 have a plan to kill myself and, in fact, I have a gun or a 25 bottle or a rope or I'm standing at the window and I'm about 99 1 to jump. And that latter part is what we call imminent risk 2 of suicide. There are a lot of degrees leading up to that, 3 but the psychiatrist in his professional opinion does not feel 4 that this patient is going to leave this office and go and 5 kill himself. So one can have a large component of 6 suicidality without being an immediate risk. 7 But there are patients -- and this is the 8 judgment of the psychiatrist -- that if they don't do 9 something right here and now it's very likely that they are 10 going to go out and kill themselves right now, and that's 11 imminent risk. 12 Q. Now, when a patient is at that kind of risk for 13 suicide, is it appropriate or ethical to have them in one of 14 these studies? 15 A. No, not in the earlier studies. 16 Q. Why not? 17 A. Well, several reasons. Remember, by definition, 18 until the drug is approved by the FDA you cannot say it is 19 effective. Now, a large body of data may be accumulated and 20 the medical community and the sponsor and even FDA may be 21 convinced it's effective, but until they say yes, this drug is 22 approved, it is by definition not effective. So it is not 23 appropriate to treat patients with a drug unless special 24 precautions are taken. 25 There are several other reasons. One is in a 100 1 placebo-controlled study you know very well that you're giving 2 patients an inactive compound and it would not be appropriate 3 or ethical to expose people that are at serious suicidal risk 4 to something you know is not effective. 5 Q. You mean, if you're giving them a sugar pill 6 it's not going to help their depression, and if a person is at 7 really that kind of risk you wouldn't give them a sugar pill? 8 A. Right. That would not be considered appropriate 9 or ethical. 10 Q. You would want to give them some treatment to 11 help save their lives? 12 A. Yes. Unless special precautions were taken to 13 prevent the patient from committing suicide. 14 Q. What kind of precautions? 15 A. Usually hospitalization, and there's a formal 16 process that they put into place called suicide prevention or 17 suicide watch to make sure people are very closely monitored 18 and watched. 19 Q. Now, in that connection, if people are less 20 suicidal than that, whatever the line is, is it appropriate 21 for them to be in a study of this sort? 22 A. Yes. 23 Q. Why? 24 A. Well, because that -- the investigator feels and 25 the investigator has to make that case-by-case determination. 101 1 Q. This is the doctor on the scene? 2 A. Yes. I'm sorry. I refer to them as 3 investigators because that's what I do, but they're always the 4 doctors or psychiatrists, they have to make the determination 5 whether that patient is likely to commit suicide in the near 6 future before a drug can have an effect. And if they make the 7 determination that that is not very likely, and of course this 8 is only an educated guess, then it is appropriate to enroll 9 the patient in that study. 10 Q. And you measure for patients who are in the 11 studies their degree of suicidality? 12 A. Yes. That's part of it. 13 Q. And is one of the standard measures of that what 14 you were telling us earlier, what's that? 15 A. The Hamilton Depression Scale. 16 Q. So people could have suicidality scores on 17 Hamilton Depression that were significant and still be in the 18 studies? 19 A. Yes. 20 Q. It's only when the psychiatrists believe there 21 is a serious risk of suicide that they be excluded? 22 A. That's correct. 23 Q. Now, Doctor Wernicke, have studies been done and 24 conducted by physicians, investigators for Lilly which did not 25 specifically exclude patients at serious risk for suicide? 102 1 A. Yes. 2 Q. Now, again, how could you do those studies 3 ethically? 4 A. Well, there are two ways. Some of the studies 5 were done with the opportunity -- where there was the 6 opportunity to hospitalize patients, and in some that was 7 actually I believe required that initially they be 8 hospitalized, so certainly they had the opportunity. Later 9 studies were done with an active comparitor when it had been 10 determined that fluoxetine was effective, so in that sense 11 patients were getting effective therapy. There was no placebo 12 arm. 13 Q. So, in other words, in those studies where 14 you're going to test people who are that suicidal, you have to 15 be very careful to make sure they're getting treatment. So 16 one thing you do is maybe you have them in a hospitalization 17 setting where you can watch them? 18 A. Yes. 19 Q. And then the other is what, you do or don't use 20 placebo? 21 A. You don't use placebo. They all have active 22 treatment of one sort or another. 23 Q. When you say active treatment, what do you mean 24 by that? 25 A. Another approved or approved antidepressant. 103 1 Something like imipramine or amitriptyline or some other 2 known -- therapy that's known to work. 3 Q. Okay. Now, you say that Lilly did do some of 4 those studies. Please describe those studies for us. 5 A. Well, as I remember, there were fourteen or 6 sixteen of those studies. I'm not exactly sure. Two were in 7 the United States and those two allowed for inpatient 8 hospitalization and they were active comparitor studies, as 9 were the ones in Europe. 10 Q. Okay. And do you have a sense of the numbers of 11 patients in that kind of category, the serious risk for 12 suicide who were looked at in a controlled way? 13 A. Yes. Overall there were about 750 patients in 14 those studies, approximately half of them were receiving 15 fluoxetine. 16 Q. All right. Now, Doctor, what is -- we've heard 17 in this trial, I think the jury has heard discussion of 18 something called randomization. Please tell us what 19 randomization is. 20 A. Randomization is one of the key elements of a 21 good study. One does not have proper randomization, the study 22 would be not really appropriate and one could not draw valid 23 conclusions. And what randomization does, as the word 24 implies, it assigns patients to the different treatment groups 25 without the patient's either knowledge or without considering 104 1 their characteristics. In other words, the intent of a 2 controlled study is to have the two or three or as many 3 treatment groups as there are be as equal to each other as 4 they can be. And the only way to achieve that is to 5 essentially blindly take people and put them in different 6 groups. 7 If one says, well, I'm going to put all the men 8 in this group or all the women in that group or all the very 9 sick patients in one group and the others in the other, one 10 cannot draw any valid conclusions about the drug because the 11 two groups are not the same. One has to compare two equal 12 groups, and the only way to achieve that is to randomize the 13 people that come into the study in a totally unbiased way. 14 Q. So if I -- if you were running a study, you were 15 a clinical investigator, a physician, and I was one of the 16 people who was going to be in your study and I met the 17 road map/cookbook requirements for the kind of person to be 18 studied, and I came in and others came into the office, how 19 would it be decided whether I got the placebo or a comparitor 20 drug or Prozac? 21 A. That would already have been determined. 22 Q. How could it already have been determined? I 23 just walked in. 24 A. Let's say you were the 50th patient to walk in, 25 to enter into the study. I would assign you the number 50 and 105 1 then you would get a patient kit -- let's say you were signing 2 informed consent and agreed to participate in the study. You 3 would get Patient Kit No. 50. Now, I would have no idea what 4 50 is, what drug, whether it's fluoxetine or comparitor or 5 placebo. That was determined before the study ever started. 6 There's a randomization code that's generated by a computer 7 that determines on a random cycle which treatment goes into 8 which number. In other words, One and Two might be 9 fluoxetine; Three, Four, Five might be placebo and then maybe 10 there's an imipramine or other comparitor, and that's done on 11 a totally random basis generated by a computer. But that's 12 how the randomization schedule is determined, and that's a 13 very tightly guarded secret until the study is over. 14 Q. So if I'm No. 32, it's been selected by some 15 computer somewhere whether No. 32 gets Prozac, gets a sugar 16 pill or gets a comparitor drug? 17 A. Right. Before the study is ever started, that's 18 determined. 19 Q. All right. And No. 34 would get whatever the 20 computer said and nobody knows that at the time if it's a 21 blinded study? 22 A. Well, somebody knows that, there is a list, and 23 of course the people that made up the study kits would know 24 what's in what kit. They would have to in order to make that 25 up, but they have no contact with the study, the patients, the 106 1 investigator or even with the people in the office running the 2 study. 3 Q. Somebody needs to know who gets what or else you 4 can't make the comparisons? 5 A. Well, yes. And at the end of the study it's all 6 unblinded, of course, and people are sorted into their 7 treatment groups. 8 Q. All right. Well, let me just add this to this 9 part of the chart. Green happens to be handy. Is this 10 another -- the randomization feature, is that like the 11 blinding? 12 A. It's part of it. The blinding is really to -- 13 well, they go hand in hand. One complements the other. They 14 all are elements of a very tightly-controlled scientific 15 study. 16 Q. And the purpose of all of those elements is? 17 A. Is to conduct a valid, ethical study where one 18 can draw real meaningful conclusions. 19 Q. Now, Doctor, I believe it is true that there has 20 been some suggestion here that patients in this trial, that 21 patients were not properly randomized in Lilly's clinical 22 trials for Prozac. Is that true? 23 A. I don't believe that that's true. I don't 24 believe that's possible. 25 Q. Why not? 107 1 A. Because the mechanism is so rigid and so 2 foolproof and has been tested so many times that I just don't 3 see how that could be possible. It's just not even 4 conceivable that that could be. 5 Q. And overseeing this process was part of your job 6 at Lilly when you were there? 7 A. Yes. 8 Q. Now, Doctor, what about these clinical 9 investigators, these physicians we're talking about who 10 actually conduct the clinical studies, talk to the patients, 11 get the Hamilton Depression score answers? How are they 12 selected? 13 A. A lot of them have conducted prior studies so 14 there is experience, but -- 15 Q. I'm sorry. Prior studies? 16 A. Prior studies, either with Lilly or with other 17 companies, so we know from their publications and their 18 experience what their capabilities are. But there's actually 19 a fairly formal process in addition to that that's gone 20 through where a research -- on behalf of them a research 21 representative of the company goes and interviews and inspects 22 the study site. They look at the investigator's credentials, 23 their specialty. These investigators have to be specialists 24 in the area. They look at their experience in conducting 25 studies and in the area of medicine that they participate in, 108 1 and then they actually inspect the facility to see if they 2 have a place, for instance, to keep their study binders, the 3 case-report forms, if they have a place to lock up the study 4 drug. And a large part of it is do they have the personnel to 5 adequately and properly conduct the study. So it's a fairly 6 formal checklist that they fill out and then submit back to 7 us. 8 Q. Do you have people from Lilly who actually go 9 out and interview these people or look at them? 10 A. Yes. 11 Q. What kinds of people do that from Lilly? 12 A. There's the regional representatives that 13 usually cover some area of the country, and they will go out, 14 and that's part of their job is to evaluate study sites. 15 Q. Some of these clinical investigators are 16 persons, men or women, who have done clinical studies on other 17 medicines or other things before? 18 A. Yes. 19 Q. But do you give them any training? 20 A. Yes. 21 Q. What kind of training, sir? 22 A. As part of the study there's a formal what we 23 call startup meeting. Well, before that even they receive 24 what they call an investigator's manual, which contains 25 information about the drug, everything from the chemistry to 109 1 whatever clinical studies have been done, so that's the first 2 part of their training, and that's what they use for the basis 3 for their submission to institutional review board. It also 4 contains the protocol. Then if they want to do the study and 5 we accept them as an investigator, they then come to this 6 formal startup meeting, which usually takes a day to a day and 7 a half, where first there's an overview given, the protocol is 8 described again in detail. There are usually sessions of 9 smaller groups where they learn how to fill out the 10 case-report forms and how to submit the laboratory materials 11 and there's sessions on -- in the case of the depression 12 studies, on how to administer the Hamilton Depression Scale. 13 Although these people know that, there's a concept that we 14 call inter-rater reliability. 15 Q. Inter-rater reliability? 16 A. Right. 17 Q. Kind of a tongue twister. What's that mean? 18 A. Well, it's an important concept. Remember, 19 these are multicenter studies typically. They may be done in 20 5, 10, 15 institutions. What one would like to do is have 21 everybody administer the scale in this case, example, the 22 Hamilton Depression Scale in exactly the same way. Well, 23 people being individuals, that's not entirely possible. Just 24 the way people phrase a question or see a patient varies. To 25 minimize that effect and to create as much inter-rater 110 1 reliability, there are training sessions on how to -- not so 2 much how to administer a HAMD but opportunity, and it's where 3 investigators are shown a videotape of a patient and a 4 psychiatrist taking the Hamilton Depression Scale score on 5 that videotape. And at the same time they fill out their own 6 Hamilton scale. At the end of the tape everybody compares 7 their answers and they discuss where there were differences or 8 where there needs to be some agreement on how we're going to 9 rate this. And after that time then there's really much more 10 consensus on how we're all going to measure this the same way. 11 Q. Doctor Wernicke, let me just drop back for a 12 minute -- we're looking at a lot of trees here -- and ask you 13 about a forest. The randomization, the blinding, the 14 controlling, these videotape -- what did you call them? 15 A. Interviews. 16 Q. Inter -- 17 A. Inter-rater reliability. 18 Q. All of these things, at the end of it all, what 19 is the purpose of doing all that stuff? 20 A. The whole purpose of doing this is at the end of 21 the study to be as accurate as humanly and physically possible 22 to conclude whether or not this compound is safe and 23 effective. In other words, everything we've talked about is 24 to minimize the extraneous noise, so we can say yes, this 25 effect is or is not caused by this drug, not where the patient 111 1 lived, not whether they knew whether they were getting active 2 drug or not because the investigator did it a little bit 3 different than another investigator. What you want to come up 4 with is to sort out and minimize or eliminate every other 5 potential impact except the study drug. 6 Q. To get reliable information? 7 A. Yes. 8 Q. Do -- you can't eliminate everything, but you do 9 all of these steps that you talk about to do the best that can 10 be done? 11 A. Yes. 12 Q. Now, once the clinical investigators start doing 13 the studies, are they monitored or checked on? 14 A. Yes. That again is a very formal and ongoing 15 process. There are several types of monitoring. Typically 16 from the sponsor, in this case Lilly, another group of 17 representatives goes out and they check the case-report forms 18 which we use to gather the data against the clinical hospital 19 chart and make sure that that data has been accurately 20 transferred and that all of it is transferred. There is not 21 information in one place and not in the other. And that's a 22 formal process where people again take check lists and they 23 write down every little potential finding. We do that and the 24 FDA does that on their own. They go to investigation sites 25 and they audit the hospital charts against the data sheets 112 1 that are sent into the company. 2 Q. So both Lilly and sometimes the FDA go out and 3 check on these clinical investigators. It's almost like an 4 inspection, isn't it? 5 A. That's exactly what it us. 6 Q. In the air force that would be like the 7 inspector coming around and inspecting? 8 A. I suppose. I haven't been in the air force. 9 Q. Okay. Now, do these -- are these clinical 10 investigators trained to report what's happening? 11 A. Yes. That is part of the protocol and part of 12 the startup. It's usually a separate section that deals with 13 just adverse-event reporting and part of it is going through 14 the case-report forms and actually practicing filling those 15 out. In addition, they are instructed how to report more 16 serious adverse events that are more appropriate to report not 17 just in a routine manner on the case-report forms so there are 18 special instructions on how and when to do that. 19 Q. And let's take us down to the level of a center, 20 as you call it, but it's really a place, a hospital or a 21 doctor's clinic or something where the study is actually going 22 on. I'm a patient. I come in. I've been randomized. I've 23 gotten my patient's kit. Just in a nutshell, what's a 24 patient's kit? 25 A. That's bottles of medicine. Maybe it's just one 113 1 bottle of medicine or a box, but typically the patient kit 2 contains all the study drug for the whole study. And they are 3 dispensed visit by visit. So they go home with a bottle, they 4 don't get the whole kit usually. 5 Q. Not the whole kit the first time? 6 A. All at once; right. 7 Q. And then in this kind of study they would come 8 in, and the time first time they arrived would they -- what 9 would happen? 10 A. They would be screened the first time to see if 11 they even met the admission criteria for the study and didn't 12 have exclusion criteria, so there's a prescreening. Sometimes 13 that may be done on the telephone before they ever come in. 14 Q. I gather that sometimes these things may vary 15 study to study. The protocol, the rules may vary study to 16 study on purpose? 17 A. Absolutely. 18 Q. But in a kind of a typical study with depression 19 and Prozac, the patient comes in, gets -- well, the first week 20 they interview them and find out whether they fit, they have 21 to have -- if depression is part of the protocol, they check 22 and see if they have depression. 23 A. Yes. 24 Q. And they check other things, too? 25 A. Right. 114 1 Q. And that's the first visit. What happens after 2 that? Are they given medicine right then? 3 A. No. Typically, and this may vary from study to 4 study, if they qualify and they have a -- remember, an 5 important part of this is that the patient understands the 6 study and the risks and the potential benefits, and they have 7 to sign, if they want to participate, what we call an informed 8 consent, which is approved by the institutional review board. 9 Q. They would know that they might be getting a 10 sugar pill, they might be getting a previously established 11 effective medicine or they might be getting a new medicine 12 that's being tested? 13 A. Right. And, in addition, part of that informed 14 consent lists all the known risks of all of those components 15 of those drugs. 16 Q. Now, so here's the patient, comes in, first 17 visit, what happens? 18 A. Well, when they've gone through the screening 19 and the initial evaluation and they decide to participate, 20 then they sign the informed consent. And in most of the 21 Prozac trials, there was what we call a placebo lead-in 22 period. 23 Q. Just stop. Let's get that straight. Placebo 24 lead-in period? 25 A. Right. 115 1 Q. What is that? 2 A. That's usually the first week of the study the 3 patients are told, all right, you're in the study, we're now 4 going to give you a study drug, and they don't know what that 5 is, but in fact that first week it's placebo. 6 Q. For everybody? 7 A. Yes, for everybody. 8 Q. Why do you do that? 9 A. Well, because depression is cyclic and, 10 remember, we talked about placebo response. It's not really 11 appropriate to treat patients with an active drug of any kind 12 if they're going to get better on their own. And as we talked 13 about before, every therapy has some risks, and one should not 14 be giving medicine to people who don't need it. So it's to 15 basically allow them a chance to get better on their own, see 16 if they really persistently are depressed. 17 Q. So in some of these protocols you have this 18 placebo lead-in period where everybody in the study is given 19 placebo? 20 A. Yes. 21 Q. All right. Then what happens? 22 A. Then they have an assessment. They come back 23 the next week. 24 Q. They have an assessment. Tell us what that 25 means. 116 1 A. It's a physical examination, review of any 2 adverse events they have, even though the investigator knows 3 that it's a placebo lead-in period and that, of course, is not 4 a triple blinded because that's not in the protocol. They 5 still assess adverse events because many patients have adverse 6 events on placebo or no drug. They again administer the 7 Hamilton Depression Scale to see what the degree of depression 8 is. There are exclusion criteria. If their depression 9 decreases by a certain amount, they are then out of the study. 10 So it's to determine whether they are still eligible. That's 11 a big part of the second visit, to see if they're eligible for 12 the study. 13 Q. All right. What happens after the second visit? 14 A. If they are still eligible then they receive 15 their next bottle of study drug from their individual patient 16 kit, which then will contain whatever they're randomized to. 17 Q. All right. And it depends on the study, which 18 study it is, what you're studying. If it's -- it could be 19 placebo and Prozac, it could be placebo and Prozac and another 20 medicine. It depends on what's being studied. 21 A. Yes. 22 Q. Again, just for clarity of terminology, we've 23 heard -- is there such a thing as single arm? We've heard 24 double arm and triple arm. I can stop for a second, if you'd 25 like. What's a double-arm study, if that's the right term? 117 1 A. Well, a two-arm study is just comparing two 2 groups. Three arm is comparing three groups that might 3 typically be placebo, Prozac and a tricyclic drug. There may 4 be many arms in the study where different doses are compared. 5 It just depends on what the question is that needs to be 6 answered. 7 Q. All right. And so we have these patients. The 8 first week they come in they all get placebo and they're 9 examined and Hamilton Depression and the psychiatrist sees 10 them, and then the second visit they actually would get the 11 medicine or a sugar pill if that's what's being used and they 12 also get evaluated then? 13 A. Yes. 14 Q. And then the third visit -- 15 A. Again, they're evaluated again, there's a 16 physical examination, the psychiatric evaluation, the Hamilton 17 and whatever other scales they use are administered. They ask 18 about adverse events, those are carefully reported, laboratory 19 studies may be done, blood tests. It depends on what the 20 protocol specifies for that visit. 21 Q. All right. Now, you speak of -- we started on 22 this because you spoke of the assessment. Now, at each visit 23 is there an assessment? 24 A. Yes. Typically there is at each visit. 25 Q. It can vary, the kind of assessment or how does 118 1 that work? 2 A. Usually, for instance, in the depression stage 3 the Hamilton Depression Scale would be administered at every 4 visit. Sometimes there are larger, more complex test 5 batteries that are not given at every visit because they're so 6 large. There may be laboratory studies like X-rays or spinal 7 taps or EEGs or what have you that may not be done at every 8 visit, but there are some standard things that are typically 9 done at every visit, like the Hamilton and the recording of 10 the adverse events. 11 Q. And the -- is there a typical about how often 12 the patient is seen? Is it every other day or how often is 13 it? 14 A. For most of the depression studies it was once a 15 week. There were some where it was more often. 16 Q. They'd come back once a week and be assessed? 17 A. Yes. 18 Q. Now, where is all this information that the 19 psychiatrist gets being recorded? 20 A. Well, each patient has a binder or a file. 21 Q. Does the patient carry it? 22 A. No. That's kept at a specified safe site within 23 the study site. Usually there's a cabinet or a locked office 24 where these binders are kept, and they contain what we call 25 case-report forms, and for each visit there's a packet and 119 1 there are many pages to this. They're usually duplicate or 2 triplicate forms where all of this information is recorded. 3 There may be pages for the baseline characteristics, like age 4 and birth date and sex and so forth, what medications patients 5 were taking, what their previous illnesses were, what 6 medications they're taking now, what their illnesses are at 7 this time. Then there are pages that deal with the efficacy 8 criteria, the degree of depression, adverse-event pages, 9 laboratory pages. So there's a packet for each visit. 10 Q. Are any adverse things that happen recorded in 11 those -- 12 A. Yes. 13 Q. -- assessments? 14 A. Yes. On the adverse event pages. 15 Q. Of the case-report form? 16 A. Yes. 17 Q. A case-report form sometimes called a CRF? 18 A. Or clinical-report form. 19 Q. Clinical or case -- which is it? 20 A. Well, people use both. I'm using case-report 21 form, but CRF fortunately covers both. But they're 22 equivalent. 23 Q. Is it important to the study that the CRF, the 24 case-report form, be filled out -- be filled out accurately? 25 A. Absolutely. It's not only important to the 120 1 study, it would be unethical not to do that because you're 2 subjecting patients to an investigational drug, and if you 3 don't collect good data then there is no benefit to that 4 patient or to society or anybody else, so that's key. 5 Q. So everybody does his or her best at least to 6 make sure that you get as reliable information as you can? 7 A. Yes. 8 Q. What happens to the clinical-report forms? 9 A. They are sent to the sponsor, to Lilly in this 10 case, where they are then further processed and integrated, 11 the information is integrated into the database. 12 Q. Who looks at them when they come into Lilly? 13 A. When they first come in, they're logged in. 14 Every piece of paper is logged in. They then initially go to 15 a clinical research associate who is a part of the group 16 working with that drug. They are reviewed for completeness 17 and accuracy and for any potential and serious adverse events 18 that their research physician needs to know about right away. 19 Q. And if one of those happens, does the clinical 20 research associate bring it to the physician? 21 A. Yes. 22 Q. And did you serve in the role of such a 23 physician? 24 A. Yes. 25 Q. What sorts of training and otherwise do the 121 1 folks have who are CRAs or clinical research associates at 2 Lilly? 3 A. Typically they tend to be scientific people. 4 Some came from the laboratories. A lot of them have some 5 medical background, quite a few nurses or pharmacists. I'd 6 say those are the three major groups of people that become 7 clinical research associates. 8 Q. They look at these case-report forms that come 9 in from the doctors at the clinical studies? 10 A. Yes. 11 Q. They check them? 12 A. Yes. 13 Q. What do they check them for? 14 A. To see whether they're complete and accurate. 15 Every box and space is supposed to be filled out. Each page 16 has to be signed. Sometimes the investigators forget to sign 17 them. Sometimes there are places where nothing is filled in. 18 Sometimes there are obvious errors, so they screen them for 19 all of those. 20 Q. Suppose there's an obvious error, somebody 21 writes down that I weigh -- I'm the patient and they write 22 down that I weigh 1,894 pounds. What happens? 23 A. They -- well, it depends on what it is. In that 24 situation and where the actual value is not obvious, it would 25 go back directly to the investigator and say, obviously wrong, 122 1 please correct and initial. 2 Q. But they have to send it back to that doctor to 3 correct that? 4 A. Yes. 5 Q. Why don't they just correct it themselves? 6 A. Well, they can only correct it themselves if 7 they know what the answer is. For instance, if the visit 8 number is left blank and the visits are one week apart and 9 they know the last week was Visit Seven a week ago, they may 10 put that in, but even that has to go back out to the 11 investigator to be initialed. No changes of any kind may be 12 made without the agreement of the investigator, no matter how 13 trivial. 14 Q. So if I even got Weeks One, Two, Three, Four, 15 Twelve, Six, Seven, Eight, the person couldn't change that 16 without getting it signed by the clinical investigator back 17 doing the study? 18 A. That's correct. 19 Q. All right. Well, I have been going at this at 20 some length here, Doctor, which probably more than any of us 21 really wants, but is this kind of detail and care carried on 22 throughout the process? Is it characteristic? 23 A. Absolutely. 24 Q. And what is the purpose, again, for all of that 25 pains that are taken? 123 1 A. To at the end of the day be able to say whether 2 or not this drug is safe and effective without having other 3 extenuating circumstances shroud the issue. It's to have 4 clean, accurate, reliable data on the basis on which that a 5 company, the FDA and then the physicians and patients can make 6 a rational decision. 7 Q. All right. Well, you referred to the end of the 8 day. 9 Your Honor, I am about to turn to another 10 reasonably long segment. Do you want me to continue? 11 JUDGE POTTER: Well, I tell you what. Why don't 12 you finish up your direct examination today. 13 MR. McGOLDRICK: All right. I think that will 14 take quite a long time, but I'm happy to go forward. 15 Now, Doctor, it has been -- there have been 16 some -- tell us next -- you've told us about the case-report 17 forms. What is the form called the 1639? 18 A. That's stands for FD-1639. That's an FDA 19 federal form that's used to gather, record, capture and 20 process what are considered serious adverse events or 21 potentially serious adverse events. That is the purpose of 22 the form. 23 Q. And by whom are 1639s completed? 24 A. Anybody who finds out anything about the drug. 25 Most of them in fact are completed by people in the company 124 1 because people call in, but other health professionals or 2 nonhealth professionals can fill those in and submit them 3 directly to the FDA. 4 Q. So they ultimately go to the FDA? 5 A. Yes. 6 Q. If a CRA, a clinical research associate, found 7 something in a case-report form that might fit that, that 8 person would bring it to whose attention? 9 A. To the research physician in charge. 10 Q. And that physician would make a decision on 11 that? 12 A. Yes. 13 Q. Now, I think there has been suggestion here -- I 14 may be wrong in this -- that the FDA only looks at 1639s in 15 evaluating the safety of a medicine. Is that true? 16 A. Absolutely not. 17 Q. What does the FDA look at from your experience 18 in dealing with them on this drug development? 19 A. They look at the 1639s, they look at the 20 material we submit to them in the NDA, in the safety reports, 21 updates, other study reports. They may look at literature. 22 There's no doubt at all that they look at much, much more than 23 1639s. 24 Q. Have you ever had experiences that demonstrated 25 that to you? 125 1 A. Yes. One that comes to mind is when I was at 2 that advisory committee meeting in 1985, the FDA made a 3 presentation and actually several of them, their statistician, 4 their efficacy and their safety reviewers each made a 5 presentation. And they talked about the data that they had 6 analyzed, and they actually talked about their reanalysis of 7 the data. We supplied them with reports and summaries, but 8 also patient-by-patient and visit-by-visit tabulations of the 9 raw data. And we know that at least for some of it they 10 reenter that into a computer and they're their totally 11 independent analysis. And from questions they've asked, I 12 know that was not on the 1639, I know that was in the material 13 in study reports. 14 Q. All right. Now, how do you get from the 15 information that gets in the case-report forms that comes from 16 the doctor who's seeing the patient to the information -- what 17 happens to it next? 18 A. Well, when it's -- as I explained, when it comes 19 in, it's logged in. It's checked and verified and corrected, 20 if necessary. It then goes to an area called data entry where 21 people have computer screens that basically mirror the 22 case-report form, and they enter that data from the hard copy 23 into the computer. Now, that's done as a double entry. There 24 are two independent people that enter the same information and 25 then check for accuracy to make sure that somebody hasn't made 126 1 an error in entering the information. It then goes into a 2 computerized database. 3 Q. You mean that if one case-report form from one 4 doctor about one patient comes in, you actually have two 5 different people take that case-report form and enter the same 6 data into the computer? 7 A. Yes. 8 Q. And then the computer compares what the two 9 people entered? 10 A. Yes. That's easy to do with the computer to 11 make sure that the two match. 12 Q. If they don't match, what does the computer do? 13 A. It kicks it out and they have to find out who 14 made the error and fix it. 15 Q. Why do you have people doing the same work 16 twice? 17 A. Well, because we want to know that the database 18 we're going to be using, analysis is correct. We want to make 19 sure it's using the data that's reported to us and doesn't 20 have some error in it. Now, I don't know whether that for 21 every piece of data at all times that that's always double 22 entered, but for the major elements, the major studies, that's 23 the case. 24 Q. Sometimes there's variation study to study in 25 all of these things you've been telling us, but these are the 127 1 central characteristics? 2 A. Yes. 3 Q. Now, Doctor Wernicke, let me change gears 4 entirely now and ask you about one specific clinical trial, 5 one which you had some special relationship to. I believe 6 there's been testimony that the jury's heard about a low-dose 7 study or even a Wernicke low-dose study. You're that guy; 8 right? 9 A. Yes, I am. 10 Q. First of all, this was a dosage study; is that 11 right? 12 A. Yes. 13 Q. Why are dosage studies conducted? 14 A. Well, I have to explain that. I should back up 15 a little bit and talk about classically how depression was 16 treated with medications. The drugs that came before that 17 were in standard use have quite a few side effects and 18 patients usually don't tolerate them from the very beginning 19 at the dose that they finally need to be taken at, so they use 20 what we call escalating doses where patients are titrated or 21 brought up rather slowly, so the final dose of the drug is 22 different than what you start with. 23 But to answer this question more specifically, 24 why do you do dosage studies is one wants to know what is the 25 most effective dose. You always want to give people as little 128 1 medicine as they need because, as we talked about before, all 2 medicines have some side effects, so the idea is you give them 3 what they need and no more. So there are a lot of studies 4 that are designed specifically to answer questions what is the 5 appropriate dose. 6 Q. And that's what dosage studies are? 7 A. Yes. 8 Q. All right. And this study -- well, before we 9 turn to your study, had other dose studies been done with 10 Prozac before your low-dose study? 11 A. Yes. 12 Q. Tell us about those. What kinds of studies have 13 been done and what did they show? 14 A. Well, the initial studies I talked about where 15 doses were escalated had shown that the drug is effective and 16 is safe -- they just went to 80 milligrams. It was shown that 17 somewhere between 20 and 80 milligrams efficacy was achieved 18 and that the drug was rather well tolerated. After that then 19 because of the long half-life of fluoxetine, it was decided 20 that, well, maybe you could just start at the same dose and 21 didn't have to titrate up because the drug was so well 22 tolerated even at 80 milligrams, but the question was do you 23 really need 80 milligrams. So what we called the first 24 fixed-dose study was done, and by fixed dose that implies the 25 same dose was given from the first to the last day. There's 129 1 no upward escalation of the dose. 2 Q. So that with many psychiatric medicines 3 previously there had been a -- an increase in dosage over time 4 and that was done on purpose with the patient? 5 A. Yes. 6 Q. You'd start a patient at a certain dose and then 7 increase it? 8 A. Yes. 9 Q. And what had these early -- earlier studies on 10 dose shown with Prozac, the 20, 40, 60, 80, whatever it was? 11 A. That efficacy was achieved by the time you got 12 to 80 milligrams after a couple of weeks. Usually the 13 escalation was faster, that that only took a week or a few 14 days. But the average dose in those studies turned out to be 15 about 60, 65 milligrams. So efficacy was shown in an 16 escalating dose and the side-effect profile was established 17 and it was shown that it was safe up to 80 milligrams. 18 Q. So you've given these patients in trials, 19 clinical trials escalating doses, 20, 40, 60, 80 per day, is 20 that... 21 A. Yes. 22 Q. And you found that it was effective at 80. Did 23 you find it was effective below that in those studies? 24 A. Well, you couldn't establish that because 25 patients had already received more. Now, some patients only 130 1 wound up at 60, some at 80, and it was found to be effective 2 in a lot of those patients. But one couldn't really make very 3 firm conclusions about the effective dose because people were 4 titrated through dose; in other words, one didn't stop at 20 5 and some didn't stop at 40 and 60 and 80, they all went up 6 fairly quickly. 7 Q. So having seen that, what did you decide to do 8 and why? 9 A. Well, it was decided and that was done on that 10 first fixed-dose study before I was there. And because it was 11 well tolerated and it wasn't clear that you needed to 12 escalate, it was decided to do the first fixed-dose study 13 where patients were given 20 milligrams, then 40 or 60 14 milligrams or placebo right from the very beginning, and that 15 dose was carried out throughout the study; that's why it's 16 called a fixed-dose study. 17 Q. Okay. So you did a 20 milligrams, 40 milligrams 18 or 60 milligrams? 19 A. Or placebo. 20 Q. Or placebo, yeah. One of those doses. And you 21 followed the patients who -- the group that got zero, the 22 placebo; the group that got 20; the group that got 40; and the 23 group that got 60, and you looked to see what the differences 24 were? 25 A. Yes. 131 1 Q. They were comparitors, a controlled study? 2 A. Yes. 3 Q. And what did you find out from that? 4 A. That in fact the 20 milligrams was effective. 5 The doses were essentially equally effective; that the 6 20-milligram dose had a very favorable side-effect profile 7 very similar to placebo; as one went up in dose there were 8 more side effects reported. 9 Q. So actually you say that at placebo and 20 10 milligrams of Prozac there was a pretty similar side-effect 11 pattern; is that right? 12 A. Yes. That's correct. 13 Q. But you also in comparing 20, 40 and 60, was it? 14 A. Yes. 15 Q. You found that they all seemed to work about the 16 same in treating depression? 17 A. Yes. 18 Q. So what do you conclude from that? 19 A. Well, from that study it suggests that 20 20 milligrams is the appropriate dose to use because the higher 21 doses didn't give one more efficacy and the lower doses had 22 the best adverse-event profile. So that was their conclusion 23 from that study, that 20 milligrams is the appropriate dose. 24 Q. Was -- is a fixed dose a benefit to the doctor 25 or the patient rather than having an escalating dose? 132 1 A. Yes. Quite a bit. A major problem in the 2 treatment of all disorders, but this really becomes more of a 3 problem in psychiatric, what we call compliance and that means 4 that is the patient taking the drug. It's not always willful. 5 Compliance seems to suggest that people don't do it because 6 they don't want to, but people forget. And it's hard for 7 people to remember to take a drug three times a day than just 8 in the morning they put next to their toothbrush or one at 9 night or whatever. So if you can give it once a day -- and 10 totally independent studies have shown this, that the 11 compliance is the best. 12 Q. And a key thing with any medicine, particularly 13 a psychiatric medicine, is that people take their medicine? 14 A. That's absolutely the key for all medicines. 15 Q. So a fixed dose does have some benefits if the 16 medicine allows it? 17 A. Yes. And they don't have to change it. They 18 don't have to remember, well, on Day One and Two I take one 19 pill and Day Three and Four I take two, but that's only if I 20 don't have side effects. And it gets very complicated trying 21 to escalate these doses and people come up with very difficult 22 schemes and it's very hard for patients, especially if they're 23 already having trouble with their thought processes. 24 Q. All right. So that's what that study showed. 25 Then you did another study; is that right? 133 1 A. Yes. 2 Q. Tell us how that came about. 3 A. Well, that's what we called the low fixed-dose 4 study. 5 Q. Low fixed dose. What's that mean and what's the 6 purpose of that? 7 A. Well, there are several reasons for it. One 8 thing, the whole point of this that we hadn't talked about and 9 I'll have to introduce another term and that's a dose 10 response. 11 Q. Dose response. What's that? 12 A. Well, what one likes to do is find out if you 13 give different doses what happens. Do you get more efficacy. 14 And I've already explained that the effectiveness occurred was 15 very flat, so we knew that it didn't really matter what dose 16 you were taking. From a side-effect standpoint, we knew that 17 the dose response showed that there were more side effects at 18 higher doses, which is true with virtually every medication. 19 So what we wanted to gain more information about this dose 20 response curve what one likes to do is have a no-effect dose; 21 in other words, to anchor the bottom of that curve. 22 Q. You want to have a no-effect dose? 23 A. Right. What one really wants -- 24 Q. Why do you want to have a no-effect? 25 A. To help decide what's likely to be the minimally 134 1 effective dose. Usually one can never find out exactly what 2 the minimum effective dose is and usually that varies between 3 people. You would have to have millions and millions of 4 patients to make any real judgment about the one lowest 5 effective dose, but to help sort of define the lower edge of 6 this curve, it's nice to be able to show that, yes, this dose 7 has really no effect, so the true lowest effective dose is 8 somewhat above that. And we attempted to do that in addition 9 to other things. 10 Q. And what was the study designed to test? 11 A. Well, one is to see if we could find a no-effect 12 dose, to see if there were low effective doses and very 13 importantly to again study the 20-milligram dose. And that's 14 important because this, remember, was a very new concept in 15 the treatment of psychiatric disorders that you could use the 16 same dose from the beginning to the end. 17 Q. Fixed dose? 18 A. Fixed dose. And that -- just on a purely 19 scientific standpoint that has to be confirmed. Whenever you 20 make a new finding in anything in science you have to confirm 21 that in another study; that's sort of a basic principle of 22 science. And the more profound and different and new it is, 23 the more important it is to reconfirm that. 24 Q. So that this study that you ran, you found that 25 a fixed dose would work in treating depression for this 135 1 medicine, and you wanted to confirm it just to be sure because 2 this was a new and beneficial thing? 3 A. Yes. 4 Q. So that was one purpose of your study. What is 5 the other purpose? 6 A. To see if we could detect a no-effect dose. 7 Q. All right. And what did you do this study with? 8 A. We wound up studying fluoxetine at 5, 20 and 40 9 milligrams, in addition to placebo. Initially, there had been 10 a 10-milligram dose that was also included in the study 11 design. 12 Q. Why was that 10-milligram dose not studied? 13 A. Well, it was decided that really not much more 14 would be learned, and in retrospect looking at the data, that 15 was a very insightful decision, and it actually makes a lot of 16 sense because we already had found that the 20 milligrams was 17 effective. The only reason to have a lower effective dose is 18 to have a better side-effect profile. 19 Well, the side-effect profile of 20 was 20 virtually indistinguishable from placebo, so one could hardly 21 improve on that. And this dose was effective, so it was 22 thought that, okay, we want to establish a no-effect dose, but 23 the 5 milligrams more likely would do that and the 10 24 milligrams really wouldn't add much more. 25 Q. And you say in retrospect that turned out to be 136 1 wise. Why do you mean that? 2 A. Well, somewhat to our surprise, the 5 milligram 3 was not a no-effect dose. 4 Q. It actually had effect? 5 A. It had effect in some patients. It was not as 6 good overall as the 20-milligram dose, especially on some of 7 the key parameters. So it was truly not a no-effect dose. We 8 never did find a no-effect dose, and it's not really very 9 important anymore, although from a scientific standpoint it 10 would be nice to know. And I suspect that would be in a one- 11 to two-milligram range, and one could never really determine 12 that without millions and millions of patients. 13 Q. Now, you found that 20 milligrams on a fixed 14 dose with a patient worked. You didn't need to go up to 40 15 and 60 and 80 or give a fixed dose of 60. I think you just 16 said you found that 5 worked to help depression. Why didn't 17 you use the 5 milligram instead of the 20 milligram as a fixed 18 dose? 19 A. Well, remember, we only had one study at this 20 time. But then the question is why didn't we do another study 21 with 5 to confirm that. And having done the analysis very 22 carefully and looking at all the different parameters and over 23 time and different scales and subscales, I concluded and other 24 people agreed that the 5 in fact was not as good as the 20; in 25 spite of the fact that it works for a lot of people, it is 137 1 very important to use the dose that's most likely to be 2 effective. 3 Remember, depression is a very serious disease, 4 so suicide is a very real risk. We felt and I -- I'm 5 absolutely convinced this was right. To use anything less 6 than the dose that's most likely to treat the maximum number 7 of patients is wrong. And one might say, well, let's go ahead 8 and try people on five and see if they get better. Well, in 9 that time they might have killed themselves. So I feel 10 strongly that one needs to recommend the dose that's most 11 likely to be effective. 12 MR. STOPHER: Your Honor, may we approach the 13 bench for a minute? 14 (BENCH DISCUSSION) 15 MR. STOPHER: Judge, I don't know about 16 everybody else, but I'm about frozen and, in addition to that, 17 we've now been here for a long time. I don't know how much 18 Mr. McGoldrick has to go, but I'll do my best over the weekend 19 to get him to shorten it down. I'd like to request that we 20 recess for the day. I think the jury is frozen, and them 21 having some difficulty in understanding the testimony because 22 of the conditions... It's nobody's fault, but it is awful 23 darn cold in here today. 24 JUDGE POTTER: Mr. McGoldrick, how much more do 25 you have? 138 1 MR. McGOLDRICK: Between an hour and two hours. 2 JUDGE POTTER: Then how could you possibly have 3 said to me yesterday that you thought you might take up most 4 of today? 5 MR. McGOLDRICK: Because, Your Honor, I believed 6 that I was not going to be putting in as much of the detail in 7 some of these things as I've decided I should do in light of 8 the cross-examination. It's longer than I expected to go, 9 Judge. I thought I would probably finish today in a full day. 10 I will not finish today, and I've got another hour to go to -- 11 my best guess is an hour and a half. 12 JUDGE POTTER: Okay. Is this a decent stopping 13 point or do you want to go on? 14 MR. McGOLDRICK: If I could just finish a few 15 more things. 16 JUDGE POTTER: Okay. 17 (BENCH DISCUSSION CONCLUDED) 18 MR. McGOLDRICK: All right. Doctor Wernicke, 19 you've talked about your fixed-dose study. What in your 20 opinion is the appropriate dose of Prozac? 21 A. Twenty milligrams a day. 22 Q. Briefly, why? 23 A. Because it's the most likely to be effective and 24 the maximum number of patients. There's no evidence that 25 going higher gives you better efficacy. It's very well 139 1 tolerated. 2 Q. Thank you. 3 I think at this point, Your Honor, we could turn 4 to something else. 5 JUDGE POTTER: Ladies and gentlemen, I've 6 changed my mind. Mr. McGoldrick has more testimony than I 7 thought he had, or needs more time on direct than I thought he 8 has. Also, you-all are going to turn into sides of beef; 9 right? Maybe we ought to do it like the airplanes, you know, 10 give you a blanket and a pillow and you can choose and 11 whatnot. We don't have anybody that works for the airlines on 12 the jury, do we? We don't. 13 Okay. I'm going to take the weekend recess, and 14 obviously the same admonition applies to you. Do not permit 15 anybody to communicate with you about this case, and I 16 emphasize that includes somebody that might communicate with 17 you in an entirely inadvertent, friendly manner, just wanting 18 to know what's going on, what you've been doing. Also it 19 would include somebody who would communicate with you as just 20 part of a general thing, and that would be like the newspaper 21 or the television or a magazine article about this drug or 22 anything like that, if you'd stay away from all of that stuff. 23 Also, do not discuss it among yourselves and do not form or 24 express opinions about it. 25 My schedule has changed. I no longer have this 140 1 8:30 commitment every Monday morning. Is it going to mess 2 anybody up if we start at 9:00 on Monday? Okay. We'll go on 3 that schedule now. We did the 9:30 because of the commitment 4 I had, and my schedule has changed. So we'll stand in recess 5 till 9:00 on Monday. 6 (JURORS EXCUSED AT 12:30 P.M.; 7 HEARING IN CHAMBERS AT 12:45 P.M.) 8 JUDGE POTTER: I got the pink sheet over in my 9 office today on the -- Lilly's motion about punitive damages 10 and, as I understand it, there are three documents I need to 11 read: the original motion, the Plaintiffs' response and then 12 a reply. Is that right, Mr. Stopher? 13 MR. STOPHER: That's correct, Your Honor. 14 MR. FREEMAN: The motion for summary judgment. 15 JUDGE POTTER: Well, summary judgment or 16 whatever, the punitive damage thing, there are briefs and it's 17 ready for submission, or it's submitted. 18 MR. FREEMAN: Yes, sir. 19 JUDGE POTTER: What we're here on today is -- 20 there may have been a little bit of miscommunication, but I 21 don't think it's important for what we're here on today. Mr. 22 Smith filed some interrogatories and also filed a motion that 23 I ordered Lilly to respond within ten days. We had a 24 discussion about how that was going to be argued out. It 25 really isn't important. I think Lilly wanted to file a brief 141 1 before I signed the ten days. I thought they weren't 2 objecting to the ten days, they were just going to object to 3 whether they ought to answer. But, anyway, with that 4 misunderstanding, without really any argument I signed it on 5 10-26. 6 They have filed two responses, a response and 7 then a -- no, that's the punitive damages -- and a 8 supplemental memorandum, and it sort of addresses whether they 9 should answer, whether they have to answer, whether they can 10 answer and whether the ten days -- whether it should be forced 11 ten days on them. So let's just take up all the issues. Have 12 I got the documents that I should have looked at? You filed 13 two responses? 14 MR. FREEMAN: Yes, sir. 15 JUDGE POTTER: Okay. I mean, I've read them and 16 come to some tentative conclusions, and let me just kind of 17 tell you where I think I am. Let me ask you one thing. Does 18 somebody have a copy of the order of 9-9-93? It's referred to 19 several times. I've tried to go get my own copy out of where 20 the documents are stored, and there have been a number of 21 people going through them and it just didn't become popular. 22 MS. ZETTLER: I can call Foley's office and have 23 it over here in two minutes, Judge. Do you want me to do 24 that? 25 JUDGE POTTER: Okay. Let me take that time, 142 1 because I am assuming what it says from how it's quoted and 2 the context, but I would really feel more comfortable if I 3 could see it, so let's take another break. I hate to get 4 started and take a break, but I think that's the safer way to 5 do it. 6 (RECESS) 7 JUDGE POTTER: Okay. I have now read what is 8 Docket No. 1234, which is the order that was referred to in 9 the briefs. It was a commissioner's recommendation which then 10 became a court order. As I see it, there are several areas of 11 objection; one is that it's improper to have the punitive 12 damage portion of the trial handled the way it is or by the 13 method it is because of my prior orders or because there are 14 some procedural due process problems about the way it's 15 rushed. 16 I guess I could address it, you know, line by 17 line, but basically it's water over the dam. In reading my 18 prior order -- to give a background, quite frankly when the 19 prior order was entered, I did not have in my four typing 20 pages of cerebral cortex the issue of punitive damages. I did 21 not think about that issue. I thought about it, what, last 22 spring, I guess, in terms of Marine Electric and came to a 23 conclusion that it would be tried with this case. I still do 24 not have the Plaintiffs' punitive damage claim in my mind. 25 When that finally came up, I did the same thing with the 143 1 Plaintiffs' punitive damage claim that I did with the Marine 2 Electric punitive damage claim. And I will be the first one 3 to admit that the Marine Electric punitive damage claim is 4 different because their compensatory damages were more or 5 less, although not liquidated, were -- 6 MR. FREEMAN: Pretty fixed? 7 JUDGE POTTER: -- fixed, I guess maybe even 8 liquidated. The only thing, if I had to shore it up, I notice 9 that when I did enter the order I said the liability and the 10 damages to the Plaintiffs would be tried separately, if it's 11 quoted correctly in here, and all I can say is that's an 12 indication, since punitive damages are really not damages to 13 the Plaintiffs, it's some different kind of damages, just 14 emphasizes that I had not thought about that issue. So I'm 15 going to stay with my prior order on that. 16 The procedural due process as far as time and 17 preparation goes, I just, you know, all I can think of is 18 criminal cases where many more important things are decided 19 much more quickly and with much less discovery than are being 20 decided here. People have had, by the time it gets to 21 punitive damages, if it gets to punitive damages, will have 22 had three months to prepare for it. You know, that's... As 23 far as being unconstitutional because it's coming before 24 compensatory damages, again, that's a decision that's been 25 made. 144 1 I think the cases I read and that were cited to 2 me in Kentucky and even in the Supreme Court simply say that 3 punitive damages have to be based on actual damages, and I 4 don't think there's any question in this case but this is not 5 going to be a nominal damages case. This is not one -- you 6 know, I mean, this is not one where there's, you know, some 7 maybe contract case or that fraud case that was cited to me 8 that there was fraud but the person wasn't hurt. That's not 9 in this case. Also, in this case, you know, there's not going 10 to be any question but that they're extremely substantial 11 damages. 12 So I think to the extent that punitive damages 13 have to in some way be related to compensatory damages, I 14 think the broad-brush proof that would be necessary to make 15 that connection can be put on quickly. You know, you don't 16 have to put on the economist to show that, you know, the 17 person is dead and had a job, you know. And it even got me 18 thinking about does it have to relate to the amount of 19 compensatory damages as opposed to the injury involved. I 20 mean, if you took that argument to its logical conclusion, it 21 would be that if you killed an elderly, unemployed person 22 quickly, punitive damages would be inappropriate because -- or 23 be very minor, simply because there were no lost earnings and 24 because it was quickly; there was no pain and suffering. 25 Whereas, if you, by the same act, kill a young person slowly, 145 1 the punitive damages could be monumental because there's a lot 2 of lost earnings and there's a lot of pain and suffering. 3 So, as I say, it's primarily water over the dam, 4 but, also, the more I think about it I'm not sure that you 5 have to have actually a dollar amount set before you can do 6 punitive damages. 7 The next issue strikes me is whether we should 8 allow discovery. There has been some quotes from proceeding, 9 and it says the Plaintiffs represented that they were ready. 10 I do not find that that representation is such that it would 11 block any discovery. As a matter of fact, this order was 12 entered because it was my -- not anticipation, but I would not 13 have been surprised had Lilly named some witnesses, expert 14 witnesses that they were intending to call if they got to a 15 punitive damage portion of the trial, and it was just a way to 16 bring a little order to it. I had anticipated -- not 17 anticipated but wouldn't have been surprised if Lilly or even 18 the Plaintiffs had named somebody. 19 Then there seems to me a section of cases that 20 say even if this -- or line of argument that says even if 21 you're going to allow it, you shouldn't do it yet. I just 22 don't see how I could wait till after the Plaintiffs, if they 23 do, obtain a verdict. 24 Now I get down to what I think are some 25 objections that maybe have some merit, and I really base them 146 1 on two things, or let me make it three things. One is that 2 this information is confidential or it's an invasion of 3 Lilly's privacy that somehow this shouldn't be brought out; a 4 second one is that it's not available, and the other one is 5 that it's burdensome. And I guess the "not available" as far 6 as document production I totally agree, Lilly doesn't have to 7 produce something that isn't available, but as far as 8 answering an interrogatory, frequently people have to generate 9 information for an interrogatory answer. 10 Before we discuss those, what I want to say, 11 Mr. Smith, and it just came up in one of these cases, 12 something that, you know, I agree with even if it hadn't come 13 up in the cases. For your purposes, I don't think you need 14 very detailed information. I mean, I don't see that you need 15 to have the amount of detail that strict compliance with your 16 interrogatories would dictate, particularly on the documentary 17 issues. 18 As far as the confidential part of it -- and, 19 quite frankly, some of the cases say that net worth is an 20 issue I think here in Kentucky, at least my initial opinion is 21 -- you haven't asked for it -- is that net worth even in 22 punitive damages is not admissible, and I interpret your 23 request to go to how much money they've made off Prozac, which 24 I think under the statute is, or at least at this point is 25 discoverable. 147 1 On the confidentiality, I mean, I would just say 2 that they can produce it and it can be sealed, and at such 3 time as it becomes to the point to where it -- you want to 4 introduce it at trial then we'll take it up whether the 5 confidentiality of it is -- prevents you maybe from using it 6 at trial, conceivably; I haven't thought that one through. 7 The "not available," I think what you'll have to 8 do for me is to have, either by affidavit or in person, 9 someone that is knowledgeable swear that this stuff is not 10 available, because -- keeping in mind that I'm planning to cut 11 it back some, because I just find it hard to believe that 12 there isn't somebody in Lilly -- this is your-all's biggest 13 product, isn't it? 14 MR. FREEMAN: It's a large product; it's not the 15 biggest. 16 JUDGE POTTER: It's a large product. I mean, I 17 think I even read something in the paper the other day that 18 because there was an anticipated raise in Prozac, that people 19 bought a couple of months ahead trying to stock up and so your 20 sales went up last quarter. Maybe I got that garbled, but, I 21 mean, I just can't believe that in a large company like that 22 with an important product that's generating -- 23 MR. SMITH: Billions. 24 JUDGE POTTER: -- millions or billions, or 25 whatever it is, that that thing isn't tracked right down to 148 1 the nth degree. 2 Burdensome, I do think the document requests are 3 probably burdensome. And what I would think at this time, Mr. 4 Smith, what I might do is go through the areas that you've 5 talked about on your -- 6 MR. SMITH: Request for production? 7 JUDGE POTTER: -- your production, and you tell 8 me -- and let me say about the accuracy of the information. I 9 mean, I understand that we're dealing with numbers to where if 10 it's off by five million one way or the other it really 11 doesn't make much difference to you, does it, Mr. Smith? I 12 mean, does it make a difference to you whether they sold 450 13 million dollars of it last year or 455 million dollars of it 14 last year? 15 MR. SMITH: Not seriously. I mean, you know, I 16 would like to have some way to verify to some degree that the 17 information I'm getting is true. 18 JUDGE POTTER: Well, I suspect that probably 19 what you need more than the information you're getting is 20 true, that you understand the information you're getting. 21 MR. SMITH: Probably. 22 JUDGE POTTER: That may be what I'm saying. So 23 what I thought we'd do is, he's gotten certain questions, and, 24 I mean, I see them broken down into certain areas, but just go 25 through them, and since you're getting dailies, I can modify 149 1 them or cut them back and then Lilly can go ahead and answer 2 them. It can be sealed, and if even cut back there's 3 something you don't have or you honestly think is unduly 4 burdensome, then bring me the affidavit or something like that 5 that tells me it's not available, because, quite frankly, I 6 just can't imagine that there isn't somebody there that can't 7 tick all these answers off. 8 MR. FREEMAN: Judge, would you hear from me 9 briefly? 10 JUDGE POTTER: Yes, sir. 11 MR. FREEMAN: First of all, I think we have been 12 put in somewhat of an impossible situation by virtue of the 13 developments that have occurred over the course of the case. 14 I would like to point out that the Ganote case was filed in 15 1990, and in that case punitive damages were sought. And we 16 have had hearing after hearing and inspection of documents 17 after inspection of documents at Lilly, and we have had 18 specific rulings made by the Commissioner and generally by the 19 Court that these types of information would not be made 20 available to the Plaintiff. 21 JUDGE POTTER: Uh-huh. 22 MR. FREEMAN: Secondly, I want to make the point 23 that at the hearing, when Mr. Smith answered your question, 24 which -- the terms of which were a little bit unfortunate in 25 that you said you're going to fire every gun you've got during 150 1 the trial on liability, and he said, "Absolutely, Your Honor," 2 we had the impression and the clear understanding that 3 everything Mr. Smith was going to rely upon as relates to the 4 liability portion of the punitive damage trial was the 5 documentation that Lilly had provided it in the various 6 documents that they have gone over in the trial that you're 7 just about to hear and that actually there would be no 8 additional evidence presented on the liability feature as to 9 whether or not Lilly was liable for punitive damages in that 10 aspect of the trial. 11 Now, from a practical point of view it seems to 12 me that that has put us at a serious disadvantage because the 13 Court had indicated that we were thinking about taking a 14 recess for a couple of days. I suggest to the Court that this 15 is going to have serious repercussions from two points of 16 view. First of all, at the conclusion of the present trial, 17 the Court is going to be obliged to let four of the jurors -- 18 I believe it's four -- go as alternates and we're going to be 19 left with twelve. It is going to take I can't tell you how 20 much time to depose these experts, and I can't tell you how 21 much time it's going to take to amass any of the material that 22 they have asked for in connection with that interrogatory and 23 document request. And to come in at the last minute and start 24 identifying Gwen Tilton and additionally Nancy Lord to come 25 back I think has worked to great prejudice of the Defendant. 151 1 Now, I think when we start talking about this 2 kind of information we've got to really consider 3 constitutionally what we're doing. Lilly has due process 4 property rights in this material. In the first instance -- 5 JUDGE POTTER: Wait. Whoa, whoa, whoa. I 6 thought the due process rights we were talking about is taking 7 the money away, not the material. 8 MR. FREEMAN: The money and the material. 9 JUDGE POTTER: All right. Okay. 10 MR. FREEMAN: The material we've got a definite 11 due process right in connection with it because it, as our 12 property, we have a vested interest in it. It would be 13 like -- 14 JUDGE POTTER: You mean, you're talking about 15 the financial information itself, -- 16 MR. FREEMAN: Yes, sir. 17 JUDGE POTTER: -- not the money he hopes to get 18 from you by using that? 19 MR. FREEMAN: That's exactly right. 20 JUDGE POTTER: All right. Go ahead. 21 MR. FREEMAN: And the reason for that, Judge, is 22 that you can understand I think very quickly, if I were able 23 to go into Paul Smith's law office and determine, from any 24 class of cases that he handled, his profitability and be able 25 to then decide, based on his inside information and his use of 152 1 paralegals and other personnel, how I might then go into 2 Dallas and set up an office in competition with him, that that 3 would be valuable information that Paul would have a property 4 damage right in in keeping confidential because it gives away 5 how he operates, and this kind of information is going to that 6 particular situation. 7 Now, we will be happy to provide the Court with 8 an affidavit, but I think you need to understand what we're 9 talking about here. Much of this information does not exist 10 and is impossible for us to create. Let me give you a couple 11 of examples. 12 For example, we don't keep any records on the 13 cost of sales. And you can understand this very easily. I 14 have a representative to go into a doctor's office, and these 15 representatives may be calling upon that physician, who may be 16 a general practitioner, on 15 or 20 different products, from 17 insulin to Ceclor to Prozac to whatever, you know, is on the 18 table that day. We don't have any way of allocating the cost 19 of that representative in going in there and making those 20 calls to any particular product line. 21 Similarly, product profitability. Let me give 22 you an example about this. You've heard in this case the fact 23 that Lilly is presently working on an additional serotonin 24 reuptake inhibitor which also that same compound will inhibit 25 another neurotransmitter. Now, a lot of that work and a lot 153 1 of the work that went into Prozac was done in connection with 2 our research efforts, say, on serotonin, on dopamine, on the 3 Parkinson drug, on any of these CNS products to the extent 4 that I can't take this physician here or this scientist here 5 and say we're going to allocate 800 rat studies and 800 people 6 that worked for him to any particular one of these CNS drugs 7 because it's not broken out that way, it's not maintained that 8 way, and, frankly, it would be impossible for us to keep it 9 that way. 10 So to get at a particular profits profitability 11 is impossible for us in connection with that kind of thing 12 unless it's a broad category. We can say that CNS drugs 13 so-and-so. We can file the 10K in connection with it. But to 14 get any more specific is virtually out of the question and is 15 extremely complex and expensive to do so. 16 Now, I think personally and argue to the Court 17 that to wait till this long since they've had these claims 18 pending to four weeks into the trial since 1990, is terribly 19 unfair to Lilly to now all of a sudden say hurry up, rush up, 20 get this stuff up for us here at the last minute, when I 21 didn't even think they were serious about any punitive damage 22 claims. And I think when we had the hearing in August in your 23 office -- not in your office but in your courtroom, and this 24 issue was raised, frankly, I detected some surprise on Mr. 25 Smith's part that it was even an element in the case. 154 1 We made the point about designating Nancy and 2 this new witness, and we adopt a brief on all of those issues. 3 Now, we say that the Kentucky law is -- and this 4 violates our due process, as well -- is that there must be a 5 dollar relationship between the amount of compensatory damages 6 given any plaintiff to the amount of punitive damages, if any, 7 awarded. And the reason for that is that many of the cases 8 and in most states, there's almost like a formula that is 9 applied; they say in excess of so many dollars is outrageous 10 and shouldn't be considered because of the damages. Some of 11 these people, for example, have very little damage, some of 12 these people have very serious damages, and you can't, I don't 13 believe, arrive at what any particular person should be given 14 until you have determined, that is, the same jury has 15 determined what would compensate a person that got shot in the 16 leg as opposed to a person that got shot through the head or 17 got killed. And the relationship of those to each other I 18 think are extremely important and would result in taking 19 Lilly's property without due process and would put the jury in 20 the impossible position of not being able to have that before 21 them in their calculations of what relationship there should 22 be between the punitive damage aspects and the compensatory 23 aspects. 24 Additionally, there's going to be considerable, 25 it seems to me, additional discovery that needs to be made, 155 1 and I don't know how it's going to be made with us being tied 2 up in court day in and day out in connection with how we're 3 going to get their experts' depositions and what the mechanism 4 is going to be for all of that. 5 Now, a little bit about the order of the trial, 6 just very briefly. As I see the situation, and I know the 7 Court has ruled upon it, we should have had a liability trial; 8 we should have had a compensatory damage trial; and then we 9 should have an additional severance wherein the jury would 10 try -- the same jury that tried the compensatory damages would 11 try the issue as to whether or not there is liability for 12 punitive damages. If there be no liability for punitive 13 damages, obviously we should not be required to give away our 14 confidential information which -- the property rights in which 15 will be lost the minute they are brought out in the courtroom, 16 because the reporters out there will certainly put it in the 17 paper and everybody that is a competitor of ours will know 18 precisely, or have a feel at least, for what we are doing in 19 this particular area of Prozac and CNS drugs. 20 So we say that the disclosure of our 21 confidential trade secrets, that is, this financial 22 information, should be denied by the Court because it is a 23 violation of our due process rights. And trade secrets, for 24 example, in Kentucky have been held to be a property right 25 that could be violated by illegal taking under the Fifth 156 1 Amendment. 2 I've made the point about the public disclosure 3 once we get out into the courtroom even before the issue of 4 liability at all are decided or the list that is on the 5 general liability question and then the liability on punitive 6 damages. 7 Then we have the same argument or similar 8 argument that the Kentucky punitive damage statute and the 9 common law should support the denial of these claims. I think 10 it also is somewhat premature for the Court to rule on this 11 until you've had a hearing on the punitive damage motion for 12 summary judgment, because I frankly feel very strongly that 13 there has been no showing in this case as respects any 14 liability whatever that should be submitted on that issue, and 15 I'd like to have an opportunity later to argue that to the 16 Court at your convenience. 17 JUDGE POTTER: Well, let me say this, that if 18 somebody wants to have an oral argument about the summary 19 judgment, it needs to be done very promptly because I intend 20 to look at it and decide it and -- 21 MR. FREEMAN: Could we do that on Monday, Judge? 22 JUDGE POTTER: That would be fine. Because for 23 better or for worse, if I read something and think about it 24 for a fairly long time, and I come to a tentative conclusion, 25 although as you-all have found out I change my mind a lot, I 157 1 feel the person whom my tentative conclusion against is at a 2 disadvantage. So if you want an oral argument, I think you 3 need to do it promptly because, you know, I'll briefly look at 4 them, then I'll listen to everybody, then I'll think about it. 5 Because I think that's when you want to catch me is when I 6 have read the stuff and I have kind of the ideas in my head 7 but I really haven't thought about it enough to where I'm 8 convincing myself one way or the other it's the right thing to 9 do. 10 MR. FREEMAN: Could we have that maybe Monday 11 afternoon after court? 12 JUDGE POTTER: Sure. That would be a good time. 13 MR. FREEMAN: And to reemphasize, Judge, we do 14 not believe -- and I apologize for this, but I did not receive 15 and Mr. Stopher did not receive a copy of your order. I don't 16 know whether it was not entered on the docket sheet, but we 17 have been looking at the docket sheet and have not found any 18 such order had been passed. 19 JUDGE POTTER: I'm sorry. I thought -- what I'm 20 talking about is an order -- and maybe it got lost in the 21 papers, but there was a -- I mean, that's what their response 22 was, it was an order that said if you intend to call 23 additional witnesses or produce additional documents at the 24 punitive damage phase, file it by such-and-such a day. 25 MS. ZETTLER: Your order, yeah. 158 1 JUDGE POTTER: My order. 2 MS. ZETTLER: Is that the one you're talking 3 about, Joe? Because you guys disclosed additional experts in 4 compliance with the order. 5 JUDGE POTTER: Oh, they did? 6 MS. ZETTLER: Oh, yeah. Absolutely. 7 JUDGE POTTER: Okay. See, I didn't get a copy 8 of their -- so you have additional expert witnesses, too? 9 MR. FREEMAN: Yes, sir. Yes, sir. 10 MS. ZETTLER: They have like six or eight, 11 Judge. 12 JUDGE POTTER: Okay. Well, I wasn't aware of 13 that. That's why I kept saying I anticipated, wouldn't be 14 surprised if Lilly did something, and then I'd assumed you 15 hadn't, so... 16 MR. STOPHER: No. We did. 17 JUDGE POTTER: Okay. All right. 18 MR. FREEMAN: But to shorten the time there 19 would really be -- 20 JUDGE POTTER: Okay. All right. You did get a 21 copy of the order that said let everybody know what they -- 22 what kind of witnesses are yours, how many? I haven't seen 23 that. 24 MS. ZETTLER: One statistician and a bunch of 25 people from various psychiatric entities and former FDA 159 1 employees that are allegedly going to testify as to what a 2 wonderful drug this is and how it's helping millions and 3 millions of people. 4 MR. STOPHER: We'll get you a copy of that. 5 JUDGE POTTER: It's here. 6 MR. STOPHER: Is it? Well, it may not be, I 7 don't know. 8 MR. SMITH: We've got a copy. 9 MS. ZETTLER: We've got an extra copy if you'd 10 like one right now, Judge. 11 JUDGE POTTER: No. You-all have been so good 12 about giving me Xerox copies that I have stopped relying on my 13 file. 14 MS. ZETTLER: You've gotten ours, haven't you? 15 JUDGE POTTER: Yes. That's why we know about 16 Mr. Timmell or whoever. Eli Lilly Disclosure of Expert 17 Witnesses; here it is right here. 18 Okay. You know, I don't -- let me just say 19 this, Mr. Freeman. As to the profit, can't calculate, isn't 20 available, burdensome, after we go through these if you still 21 think that's valid, what I need is either a very complete 22 affidavit from someone in a very significant position who 23 would be able to say, "I'm familiar with the books and records 24 of Lilly and it's my job to manage it." And we're not talking 25 about, you know, a record keeper or a secretary or a lawyer or 160 1 anything. We're talking about somebody that the controller of 2 the company says, "I can't give you an estimate of how much 3 money we're making off Prozac." Because, to be honest with 4 you, I would just find that hard to believe. Now, he may have 5 to say -- 6 MR. FREEMAN: It can't be accurate, is our 7 point. 8 JUDGE POTTER: Well, that's -- I mean... 9 MR. FREEMAN: Let me ask the Court this question 10 and Counsel. In substitution for that, if I could obtain 11 authority -- and I don't have authority to do this at the 12 present time -- would the net worth of the company serve the 13 same purpose? It's certainly a bigger, bigger number. 14 JUDGE POTTER: Well, I mean, we're talking about 15 a tactical or strategic decision that has to be made between 16 the parties. That's not a question I can answer. I think I 17 indicated earlier that my belief would be that if each person 18 insists upon their rights, that's not something that could be 19 introduced into evidence. 20 MR. FREEMAN: Yes. I think you're right about 21 that. 22 JUDGE POTTER: That's not something I can 23 answer. Let me do this and then maybe we can take a break and 24 you-all can talk about how to handle it. 25 MR. SMITH: I can tell you, I think I'm going to 161 1 have to have information on Prozac. This is a Prozac lawsuit. 2 JUDGE POTTER: All right. You don't have to 3 discuss that in front of me. I mean, take Number One, the 4 problem with -- and they aren't even numbered -- yeah, they 5 are. Well, it's an Interrogatory and Request for Production 6 of Documents No. 1. Obviously, "State the gross sales of 7 Prozac for each year from the first date of sale to the 8 present." 9 MR. FREEMAN: That can be done. 10 JUDGE POTTER: All right. And I'm not going to 11 make them produce any documents on that, Mr. Smith. All 12 documents reflecting, I mean, they'll give you that. 13 MS. ZETTLER: Can we reserve the right to ask 14 you for additional information, because, frankly, there's all 15 kinds of numbers that have been reported in the paper and, you 16 know, if all of a sudden the gross sales amounts drop 17 drastically -- 18 JUDGE POTTER: They'll have to give it to you 19 with a description, you know, of what they -- I think in 20 fairness you ought to give them a description of how it's 21 calculated or what it represents. 22 MR. FREEMAN: Let me make this clear for the 23 record. We can't agree to do anything; what I'm saying is 24 that I think that that figure might be available, but we can't 25 agree to do it. 162 1 JUDGE POTTER: All right. All right. 2 MR. SMITH: Okay. I'm going to say that it's 3 ordered to be produced or answered with a description of 4 how -- 5 JUDGE POTTER: What gross sales means or 6 whatever. 7 MR. SMITH: -- how it's compilated. 8 JUDGE POTTER: I'm just going to take Number 9 Two. 10 MS. ZETTLER: Can you tell us what it is, Judge? 11 We don't have our copy. 12 JUDGE POTTER: That's the cost of sales. You 13 will just have to do the best you can with it. I'm going to 14 strike out the documents on that, too. 15 Okay. I'm sure you have Number Three, that's 16 the quantities. I mean, if you've got... 17 MS. ZETTLER: Did you say quantities? 18 JUDGE POTTER: Yeah, it's Number Three. 19 MR. MYERS: Quantities produced and quantities 20 sold is the question. 21 MS. ZETTLER: Okay. 22 JUDGE POTTER: Yeah. And, again, I'm going to 23 strike out the documents. I mean... Okay. I'm going to -- 24 Two and Four can be combined together, but I think you-all 25 need to take your best estimate. If you have to say this does 163 1 not include the costs of development or whatever you have to 2 say, I mean, if you answer Number One and Number Two, 3 supposedly Number Four is the result. I mean, I think you-all 4 have to make some kind of best estimate you can. 5 And Number Five is the same thing; all those are 6 kind of rolled together. 7 MR. SMITH: So they have to answer Five? 8 JUDGE POTTER: Four and Five and Two can all be 9 kind of rolled into one presentation if they want to do it. 10 MS. ZETTLER: They have to give us specific 11 information on responses to each of those? 12 JUDGE POTTER: As best they can, you know. 13 MR. SMITH: No docs on Four or Five, either? 14 JUDGE POTTER: No. 15 MR. SMITH: Okay. 16 JUDGE POTTER: Number Six is rolled back into 17 it, too, and that's just your explanation of how you... 18 And Number Seven shifts gears. What is the 19 point in giving a detailed description of their marketing and 20 distribution system for Prozac, including commission structure 21 of your sales force? We're just going to do interrogatories. 22 Mr. Smith, what is the relevance of that? 23 MR. SMITH: I think it's so our financial 24 accountant can give an accurate prediction of the cost of 25 sales, what the profit is. So our accountant -- they won't be 164 1 saying, "Well, you're not even including certain elements. 2 You're not discounting." 3 JUDGE POTTER: See, this is how naive I am. I 4 mean, do detail men work on a commission or are they paid a 5 salary? 6 MR. MYERS: No. And there were depositions 7 taken of two Louisville sales representatives in this case and 8 some former sales representatives and -- 9 JUDGE POTTER: Is there even a commission 10 structure in your sales -- 11 MR. MYERS: No, there's not. No, sir. 12 JUDGE POTTER: Okay. Well, I tell you what. 13 You can answer that one just easy. Let me see. Okay. What 14 I'm going to make that, give a general description of your 15 marketing distribution system for Prozac. 16 And Number Eight is the same as the ones that 17 are all rolled up together. I mean, all those, if you give 18 one answer it's all the same thing. 19 And what I think Mr. Smith is entitled to is 20 some broad thing that we've sold -- so many prescriptions have 21 been filled or so many pills have been sold, the gross sales. 22 Do you-all sell it, what, directly to pharmacies is where you 23 sell it? 24 MR. MYERS: To pharmaceutical wholesalers. 25 JUDGE POTTER: To wholesalers? And, you know, 165 1 what your advertising budget is or some in-house allocation of 2 how you allocate your costs or however. Come up with some 3 kind of system so there will be a rough estimate of what 4 Prozac produces for Lilly. And if on the "confidential" part 5 or "it can't be done" part, I just can't emphasize strongly 6 enough that I have to hear it under oath from somebody that's 7 really important. 8 MR. FREEMAN: Certainly. 9 JUDGE POTTER: When we were in here the other 10 day and we put Mr. Wernicke under oath, what ran through my 11 mind, what would be a better way to do it is put Mr. Smith and 12 Mr. Myers under oath and forget Mr. Wernicke. And I'm not 13 criticizing you-all, it's just you-all are making arguments, 14 and it's been my experience in a lot of these situations that 15 when you actually get down to the nuts and bolts and talk to 16 the person who's responsible for it, the stuff is there, and 17 it's, if not easily producible there's a substitute that's 18 easily producible. 19 MR. SMITH: Your Honor, I think in this 20 connection if they're going to claim it's burdensome, that we 21 need somebody here in person as opposed to an affidavit. 22 JUDGE POTTER: I think this is important enough, 23 and the time is important enough that I think we need an 24 in-person person; I'm going to ask for that. Yeah. I mean, 25 it was just like with Doctor Wernicke. He sat here and he 166 1 explained in ten minutes what that stuff was, where it came 2 from and everybody understood it. If he had done an affidavit 3 we would have spent two hours arguing over his affidavit. 4 MR. FREEMAN: The difficulty that we are facing 5 here, Judge, is to have somebody that's important and 6 knowledgeable about each of these areas, I don't believe there 7 is any one person; it may be ten people. 8 JUDGE POTTER: You may have to bring more than 9 ten. But what we're dealing with right now is the stuff is 10 produced, you don't even have to file it, just give it to 11 Mr. Smith; he will keep it confidential. So if you have an 12 objection with that confidentiality thing, at this stage you 13 need to produce a person. If it's -- and what we're dealing 14 with is kind of a generalized profit-and-loss or cost 15 structure, and if you think that is burdensome, at this stage 16 you need to have a person. Mr. Smith may see your answer and 17 say it's insufficient and then we'll argue from there. But I 18 need -- we'll get the answers -- what's today, Friday? So a 19 week from Monday, that will give time, since it's been cut 20 back on documents and it's been cut back on the detail. 21 MS. ZETTLER: A week from this coming Monday, 22 Judge? 23 JUDGE POTTER: Yeah. That's ten days from 24 today, or close to that. 25 MR. SMITH: We'll be in our respective homes. 167 1 As long as it's sent to us at our offices, I'll be in my 2 office on that Monday. 3 MS. ZETTLER: We've got faxes at home. 4 JUDGE POTTER: How about this? We'll do it a 5 week from Tuesday. That will give them that Monday before 6 Thanksgiving to get their final thing together, and that will 7 give you the Wednesday before Thanksgiving to look at it 8 before you start Turkey Day. 9 MR. SMITH: All right. If they're going to 10 claim that this is burdensome, should we set a date now for a 11 hearing on that? 12 JUDGE POTTER: Well, we'll all be here the 13 Monday after Thanksgiving and we can deal with it then. 14 MR. SMITH: All right. 15 (PROCEEDINGS TERMINATED THIS DATE AT 2:05 P.M.) 16 * * * 17 18 19 20 21 22 23 24 25 168 1 STATE OF KENTUCKY )( )( Sct. 2 COUNTY OF JEFFERSON )( 3 I, JULIA K. McBRIDE, Notary Public, State of 4 Kentucky at Large, hereby certify that the foregoing 5 Transcript of the Proceedings was taken at the time and place 6 stated in the caption; that the appearances were as set forth 7 in the caption; that prior to giving testimony the witness was 8 first duly sworn; that said testimony was taken down by me in 9 stenographic notes and thereafter reduced under my supervision 10 to the foregoing typewritten pages and that said typewritten 11 transcript is a true, accurate and complete record of my 12 stenographic notes so taken. 13 I further certify that I am not related by blood 14 or marriage to any of the parties hereto and that I have no 15 interest in the outcome of captioned case. 16 My commission as Notary Public expires 17 December 21, 1996. 18 Given under my hand this the__________day of 19 ______________________, 1994, at Louisville, Kentucky. 20 21 22 23 24 _____________________________ 25 NOTARY PUBLIC 169 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25