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 MONDAY, OCTOBER 17, 1994 15 VOLUME XVI 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 4 Hearing in Chambers...................................... 4 5 * * * 6 WITNESS: DOCTOR_W._LEIGH_THOMPSON - Continued _______ ______ __ _____ ________ 7 Examination by Mr. Smith................................. 15 Examination by Mr. Freeman............................... 80 8 Further Examination by Mr. Smith.........................160 9 * * * 10 WITNESS: DOCTOR_PETER_BREGGIN _______ ______ _____ _______ 11 Examination by Mr. Smith.................................190 12 * * * 13 Reporter's Certificate...................................240 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 4 FOR THE PLAINTIFFS: 5 PAUL L. SMITH Suite 745 6 Campbell Center II 8150 North Central Expressway 7 Dallas, Texas 75206 8 NANCY ZETTLER 1405 West Norwell Lane 9 Schaumburg, Illinois 60193 10 IRVIN D. FOLEY Rubin, Hays & Foley 11 300 South, First Trust Centre Louisville, Kentucky 40202 12 13 FOR THE DEFENDANT: 14 EDWARD H. STOPHER Boehl, Stopher & Graves 15 2300 Providian Center Louisville, Kentucky 40202 16 JOE C. FREEMAN, JR. 17 LAWRENCE J. MYERS Freeman & Hawkins 18 4000 One Peachtree Center 303 Peachtree Street, N.E. 19 Atlanta, Georgia 30308 20 * * * 21 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 Monday, October 17, 1994, at approximately 8:00 A.M., said 5 proceedings occurred as follows: 6 7 * * * 8 9 (THE FOLLOWING PROCEEDINGS OCCURRED IN ROOM 147) 10 JUDGE POTTER: Have you-all been able to reach 11 any kind of agreement about live witnesses versus depositions? 12 MR. SMITH: We haven't talked, Your Honor. 13 MR. FREEMAN: What I would be prepared to do, 14 Judge, is to commit to bringing, during our case, with the 15 understanding that there's not any kind of waiver, Wernicke, 16 Tollefson, and then today we will check with Wheadon's 17 employer and see if we can get him, and I should know that by 18 Tuesday or Wednesday how difficult it is. 19 JUDGE POTTER: Let's get the names straight so 20 I -- Wernicke. 21 MR. FREEMAN: Spell it for him, Larry. 22 MR. MYERS: W-E-R-N-I-C-K-E. 23 JUDGE POTTER: And the others? 24 MR. FREEMAN: Tollefson, T-O-L-L-E-F-S-O-N. 25 MR. MYERS: -E-F-S-O-N. 5 1 JUDGE POTTER: And there was another one. 2 MR. MYERS: We can bring Ray Fuller, as well. 3 MR. FREEMAN: Wheadon. 4 JUDGE POTTER: Wheadon. 5 MR. MYERS: W-H-E-A-D-O-N. 6 JUDGE POTTER: And the fellow you're going to 7 check on? 8 MR. FREEMAN: That's Wheadon. 9 JUDGE POTTER: So it's just Tollefson, Wernicke, 10 and you're going to check on Wheadon. 11 MS. ZETTLER: And you're not going to bring any 12 of these other people like Weinstein, Heileginstein or 13 Beasley? 14 JUDGE POTTER: Let's see the newest revised list 15 of witnesses. 16 MR. MYERS: I've got it here, Judge. 17 JUDGE POTTER: Let me just look at it, if I can. 18 MR. SMITH: Of course, you're going to bring 19 Leigh Thompson back. 20 JUDGE POTTER: Well, he's here today. Is this 21 kind of your last list, Ms. Zettler, or at least close to your 22 last list? 23 MS. ZETTLER: It's close to it. We've got a few 24 others on here. 25 JUDGE POTTER: Breggin is your man, Brown is 6 1 your man, Coleman is here, Heiligenstein is a Lilly employee. 2 MS. ZETTLER: And so is Beasley, the first guy 3 on the list. 4 JUDGE POTTER: Heiligenstein is a Lilly 5 employee? 6 MS. ZETTLER: Right. 7 JUDGE POTTER: Lord is your person. 8 MS. ZETTLER: Schulze-Solce is a Lilly employee, 9 also. 10 JUDGE POTTER: Wernicke is a Lilly employee. 11 MS. ZETTLER: Talbott is a Lilly employee. 12 JUDGE POTTER: And you told me who Zerbe is. 13 MS. ZETTLER: He's an ex-Lilly employee. 14 JUDGE POTTER: Tollefson isn't on your list. 15 MS. ZETTLER: No. I'm just trying to keep what 16 we've got. 17 JUDGE POTTER: But you think he's somebody 18 you're going to want? 19 MS. ZETTLER: Yes, sir. 20 JUDGE POTTER: You-all are -- Mr. Freeman, are 21 you-all going to call Mr. Beasley? 22 MR. FREEMAN: Not planning to. 23 JUDGE POTTER: How about Heiligenstein? 24 MR. FREEMAN: Not planning to. If so, it would 25 be by deposition, but it would be very brief on either one of 7 1 them. 2 JUDGE POTTER: How about Schulze-Solce? 3 MR. MYERS: No, sir. He's in Japan. 4 JUDGE POTTER: How about Talbott? 5 MR. FREEMAN: Not planning to. 6 JUDGE POTTER: How about Zerbe? 7 MR. FREEMAN: Not planning to. 8 JUDGE POTTER: So the people you were planning 9 to call were Wernicke, Tollefson and Wheadon? 10 MR. FREEMAN: And Ray Fuller. 11 JUDGE POTTER: Right. We passed Fuller. All 12 right. This is your thing, is they will let you have those 13 witnesses live as cross-examination during their part of the 14 case. 15 MR. FREEMAN: In other words, we'll put them up 16 for the direct and then they can cross them. 17 JUDGE POTTER: And they won't make a motion for 18 directed verdict at the end of your case, provided anything 19 that flows from that -- and, personally, I don't think 20 anything flows from that -- is not waived. 21 MR. SMITH: That's not going to reduce much of 22 the testimony in this case. 23 JUDGE POTTER: It's going to reduce it by three 24 witnesses, because you're going to go through their entire 25 deposition and we're going to go through their entire 8 1 testimony again under cross-examination. 2 MR. SMITH: But it forces us to read four 3 depositions of -- three of the four are directly employed by 4 Lilly, one is certainly under their control. 5 JUDGE POTTER: Well, I don't know that I have 6 the power to make them bring here -- 7 MR. SMITH: Oh, I understand. 8 JUDGE POTTER: I'm convinced I have the power to 9 say if you want him you've got to bring him. And just so 10 we're not playing games, Beasley, Heiligenstein, the rest of 11 this crowd, unless the sky falls, they're not going to be 12 called live. 13 MR. SMITH: What about Dunner? Do we have him 14 listed? 15 MR. FREEMAN: We're not bringing Doctor Dunner. 16 MS. ZETTLER: Doctor Perelman. Mel Perelman. 17 MR. SMITH: We probably won't read much from 18 him. 19 MS. ZETTLER: Jamie Street. 20 MR. SMITH: He's no longer their employee, is 21 he? 22 MR. FREEMAN: Jamie's a woman. She's a 23 neurologist. 24 MS. ZETTLER: You put her on your expert list. 25 MR. FREEMAN: I'm not planning on calling her. 9 1 MS. ZETTLER: Earlene Ashbrook? 2 MR. MYERS: No. 3 MS. ZETTLER: Richard Wood? 4 MR. FREEMAN: No. 5 MS. ZETTLER: James Kotsanos? 6 MR. MYERS: No. 7 MS. ZETTLER: A lot of these, Judge, will be 8 smaller. 9 JUDGE POTTER: Listen, I'm all for smaller 10 parts. 11 MS. ZETTLER: Allan Weinstein? 12 MR. SMITH: We could try to cut that down pretty 13 good. 14 MS. ZETTLER: Yeah. I think that was it from 15 our original list. 16 MR. SMITH: One, two, three, four, five, six, 17 seven, eight, nine. Well, we've cut it down from twelve to 18 nine. 19 JUDGE POTTER: And just from listening to 20 you-all talk, isn't Wernicke a fairly substantial one, or not? 21 MR. MYERS: His videotape deposition is two days 22 long. 23 MR. SMITH: I was going to try to, if we could 24 possibly do it, cut it down some, but if you're going to bring 25 him... 10 1 JUDGE POTTER: So is that the understanding, 2 that they will not make a motion for a directed verdict at the 3 end of your case, provided that no appellate rights are waived 4 -- although I can't conceive that there are any. I mean, Mr. 5 Stopher may be able to think one up, but I really don't see 6 any appellate rights being waived -- and that you will not 7 read these people's depositions; you will put your stuff in 8 through cross-examination? 9 MR. FREEMAN: Now, when do you-all anticipate, 10 roughly, being through so that I'll have some idea of when to 11 tell particularly people that are not my employees, like 12 Wheadon and Wernicke, when we're going to need them? Are we 13 talking about another two weeks or another week or what? 14 JUDGE POTTER: I was just guessing, next week is 15 hump week. We're shooting for eight. That would be the 16 fourth week out of seven. I was kind of viewing maybe you-all 17 finishing up your case next week somewhere. I'm not putting 18 the limit on you, but -- 19 MR. SMITH: I would certainly like to. 20 JUDGE POTTER: -- looking ahead, that's what I 21 see. Pushing these three people to their part of the case 22 would make that reasonable. And, Mr. Smith, if you're 23 concerned, at the end of the case -- at the end of your case, 24 I'll give the admonition again that I gave in the beginning, 25 or part of what I gave in the beginning, that nobody owns a 11 1 witness and that it comes in -- you-all probably weren't 2 listening, but in the very beginning I say something about 3 just because one person calls them or the other person calls 4 them doesn't mean that it can't be good for both sides, if you 5 want me to put up something like that. 6 Now, the other flip side of it -- and, 7 Mr. Freeman, I take it this is -- you don't want to do this, 8 but if there's any person you want to prevent them from 9 reading a deposition, all you've got to say is, "Judge, we'll 10 have them here," and I will prevent them from reading the 11 deposition. Is there anybody that's in that category? 12 MR. FREEMAN: Not that I know of. And we're 13 going to try to get a hold of Wernicke and Wheadon today. 14 JUDGE POTTER: Okay. There was a double name 15 that we talked about. 16 MS. ZETTLER: That was Weinstein, Judge. 17 JUDGE POTTER: And whatever potential error, 18 you're alerted to it? 19 MS. ZETTLER: Right. 20 JUDGE POTTER: Okay. 21 MR. SMITH: Do we need to revise our 22 designations of any of these depositions, Nancy? I don't want 23 to get caught without any witnesses, because I know we were 24 planning on Wernicke probably taking a day. Can we get some 25 kind of flexibility on that? 12 1 MR. MYERS: We've objected to his deposition if 2 it's -- not to the entire deposition, but we did our review 3 based on you using two days of testimony. If you're going to 4 revise, I guess we need to take another look. 5 MR. SMITH: I'm talking about since we're not 6 going to read Wernicke, Tollefson or Wheadon, that may take up 7 some time that we've already allotted. 8 JUDGE POTTER: Is Mr. Breggin still on tap after 9 you finish Doctor Thompson? 10 MS. ZETTLER: Yes. 11 JUDGE POTTER: So I have a feeling that's going 12 to get us through most of tomorrow, if not all of tomorrow; is 13 that fair to say? 14 MR. SMITH: Yeah. 15 JUDGE POTTER: So you need to, Ms. Zettler, sit 16 down with Mr. Myers and make whatever changes you've got here 17 so he's not working on something and you're not working on 18 something that's not going to happen. 19 MS. ZETTLER: Okay. We've got some outstanding 20 designations like Schulze-Solce and Greist that -- 21 MR. MYERS: Those will be filed today and that 22 brings us current on everything. 23 JUDGE POTTER: And the plan for today is 24 finishing up Mr. Thompson, because Mr. Smith will take an hour 25 and a half, somewhere close to that; Mr. Myers (sic) will take 13 1 two hours and, if there's any redirect, Mr. Smith, we're 2 talking 10, 15 minutes, something like that to finish it up. 3 MS. ZETTLER: We have a couple objections to -- 4 MR. SMITH: If you're going to read -- if you're 5 going to bring Greist, Granacher and Schwab, does that mean we 6 can't bring -- read any of their depositions in our case? 7 JUDGE POTTER: Wait. You're talking about 8 people I don't even know about. 9 MR. SMITH: This is their experts, and we have 10 taken their experts' depositions and had planned on reading 11 part of their depositions in our case. 12 JUDGE POTTER: I had thought about maybe making, 13 you know, this apply to all witnesses, but I decided it would 14 really be unfair with experts. So we're talking about these 15 people that are really fact witnesses in kind of a crude 16 sense. You know what I mean? They're talking about -- 17 they're giving some opinions but presumably these people were 18 there at the creation; right? I mean, they did things and 19 tested things and sent things off. This would not apply to 20 their Beasley, Lord and Brown, their comparable people, the 21 pure expert kind of people. 22 MR. STOPHER: Judge, we object to reading any 23 portion of a deposition of somebody that's going to be here. 24 They're entitled to cross-examine our experts with a prior 25 inconsistent statement, if that exists, from the depositions, 14 1 but these people are all going to be here, and we object to 2 just reading some section of a deposition before they even get 3 here. 4 JUDGE POTTER: We'll just have to take that up. 5 Okay? Because I really -- I've also thought about that, that 6 we're talking about the pure experts. It's their show and, 7 Mr. Smith, it was part of the reason that I made him do two 8 hours on Thompson because this is your show. 9 MS. ZETTLER: Doctor Greist isn't a pure expert. 10 He was also a clinical investigator. 11 JUDGE POTTER: All I can say is I can see some 12 argument for Mr. Stopher's position is that these are their 13 experts, they've hired them. It's part of their dog and pony 14 show, and it's unfair to let you go in and kind of present a 15 discombobulated view of their position by picking and cutting. 16 And I guess what you need to do is designate; I'll listen to 17 them and I'll listen to you. It's not an argument that I'm 18 adverse to, it's just something I have to see it in reality. 19 MR. SMITH: Okay. 20 MS. ZETTLER: Could we have a couple more 21 minutes, because we've got some objections to the documents 22 they plan on using with Doctor Thompson? 23 JUDGE POTTER: Okay. Let's do that, then. 24 MS. ZETTLER: Let's see. I'll try to do this in 25 some semblance of order. First, Judge, they have a number of 15 1 documents that go into Citizens Commission on Human Rights, 2 including the FDA Talk Paper. 3 MR. MYERS: We're not going to use those today. 4 MR. FREEMAN: We'll use the talk paper. 5 MR. MYERS: We're not going to use letters on 6 the public citizens position or the CCHR petition or the talk 7 paper on the CCHR position today. 8 MR. SMITH: Are you just giving us weekend work 9 to do? 10 JUDGE POTTER: He's wearing belts and 11 suspenders. If that's all you got to go over, you got off 12 light. Oh, this is just what you object to? 13 MS. ZETTLER: Yeah, basically. We've never seen 14 this document before. I have no idea what it was. They've 15 never produced it to us. 16 MR. MYERS: Is that the BGA approval letter? 17 We're not going to put that in. 18 MS. ZETTLER: Well, maybe you could look at this 19 and tell us, and we could short-circuit this. 20 MR. MYERS: We wanted to be inclusive as opposed 21 to underinclusive. 22 JUDGE POTTER: If all you-all got is eight 23 inches, you got off light; only an inch and a half is 24 objectionable. 25 MS. ZETTLER: Do you plan on using the materials 16 1 submitted to the PDAC? 2 MR. MYERS: Yes. 3 MS. ZETTLER: Besides the fact that it's hearsay 4 in its entirety, there are sections that we feel are 5 irrelevant. This is the written materials that they submitted 6 to the committee members for the 1991 advisory committee 7 meeting. 8 JUDGE POTTER: This is the ad hoc review thing 9 that produced a talk paper? 10 MS. ZETTLER: Right. Now, I've gone through 11 this and, basically, not word for word but skimmed it very 12 thoroughly, but I want their representation that there's 13 nothing on scientology in there that they're going to refer 14 to. 15 MR. MYERS: I certainly didn't read it with that 16 in mind. 17 MS. ZETTLER: I think it needs to be gone 18 through thoroughly, and anything on scientology needs to be 19 taken out. I mean, there is a court order on this, and I 20 didn't want them to bury something. 21 JUDGE POTTER: I think the court order was that 22 nobody was going to ask Doctor Breggin about scientology. And 23 I went through his -- part of his deposition this weekend and, 24 you know, it's a collateral issue and he denies it, and that's 25 the end of it. And I don't think you can ask him because he's 17 1 going to deny it. 2 MS. ZETTLER: There's two other sections in 3 here, one is a rather lengthy section on the impact of taking 4 the drug off the market as opposed to putting a warning on 5 here claiming that there's going to be lack of treatment, 6 people are going to discontinue their drugs, putting people in 7 danger, that kind of stuff. I think it's wholly irrelevant, 8 it's unsupported, and we're not asking that the drug be taken 9 off the market anyway. 10 MR. MYERS: Our position is that's a Lilly 11 document. It was submitted to the FDA advisory committee for 12 their consideration. It's what we relied on, it's what the 13 FDA relied on, not unlike, I think, the Court's rulings on a 14 lot of this BGA stuff that's come in. It's the complete 15 filing we made. 16 JUDGE POTTER: That's all going to come in one 17 way or the other because their whole benefit ratio thing and 18 their labeling, that's the kind of argument that's going to 19 come in. I mean, you got stuff in that said we'll cut half 20 our profit if we go to ten milligrams. 21 MS. ZETTLER: But the risk/benefit ratio does 22 not include what the impact on psychiatry in general is. 23 First of all, it's not proven; it's purely propaganda. Second 24 of all, when you're talking about a risk/benefit ratio you're 25 talking about the efficacy of the drug as opposed to the side 18 1 effects, not whether or not somebody is not going to take a 2 drug because they may be a little hesitant to take it. 3 MR. MYERS: Our position is the risk/benefit 4 takes into account a lot of other things. 5 JUDGE POTTER: You-all have been pretty 6 free-wheeling about what comes in from submissions, and since 7 one of their big defenses is that government has looked at 8 this thing again and again and come up positive, I think 9 almost everything the government saw is going to be relevant, 10 unless it, you know, has some specific prejudicial effect. 11 MS. ZETTLER: Okay. 12 JUDGE POTTER: Mr. Freeman, why do they call 13 these things talk papers? Why don't they put out something 14 that has a lot more official title to it, the Bible or 15 something? 16 MS. ZETTLER: Basically, Judge, because it's not 17 official. 18 JUDGE POTTER: Other agencies at least call it a 19 white paper or a report or something that has a semblance of 20 officiality to it. A talk paper, I mean, is that some buzz 21 word within the industry or something? 22 MS. ZETTLER: It's a cute user-friendly 23 government type thing to use. We object to using this other 24 talk paper. It's reporting on the results of the PDAC. 25 MR. FREEMAN: It quotes from the people and 19 1 about what they found. 2 JUDGE POTTER: This is their end report, isn't 3 it? 4 MR. FREEMAN: Yes. 5 MS. ZETTLER: What that is, Judge, is it's their 6 talk paper. It's the kind of thing they put out within the 7 industry mostly. They have an official finding. 8 JUDGE POTTER: But this was prepared by the FDA. 9 This is not like the verbatims that went to the board; this is 10 their, like, press release or something? 11 MR. SMITH: That's the best characterization. 12 JUDGE POTTER: Okay. I think they're entitled 13 to get it in. I mean, there is a white paper or a ten-page 14 bound book or something somewhere? 15 MS. ZETTLER: Yes. But the problem with this, 16 Judge, their official finding is that there was no credible 17 evidence to support a label change. This says there was no 18 evidence. The official finding is that there was no credible 19 evidence. 20 JUDGE POTTER: I think you can each get in your 21 side of it. That's it. 22 (HEARING IN CHAMBERS CONCLUDED AT 8:20 A.M.; 23 THE FOLLOWING PROCEEDINGS OCCURRED IN OPEN 24 COURT AT 9:35 A.M.) 25 * * * 20 1 20 2 SHERIFF CECIL: The jury is now entering. All 3 rise. The Honorable Judge John Potter is now presiding. 4 Court is now in session. 5 JUDGE POTTER: Please be seated. As a general 6 question, did anybody have any difficulty over the weekend 7 observing the admonition about not talking or communicating 8 with anybody or letting anybody communicate with you about 9 this case? 10 How about you, Mr. Miller, did you have any 11 problem? 12 JUROR MILLER: Not at all. 13 JUDGE POTTER: Doctor Thompson, I'll remind you 14 you're still under oath. 15 Mr. Smith. 16 Q. Doctor Thompson, you have in front of you 17 Plaintiffs' Exhibit 92, that is the July 18, 1990 memo that 18 you wrote in connection with your conversation with Doctor 19 Paul Leber of the FDA. 20 A. Yes, sir. Good morning. 21 Q. On Page 1 you indicate that Doctor Leber had 22 suggested several methods of analyzing the issue of 23 suicidality; correct? 24 A. Yes, sir. 25 Q. And the first item was a case-control 21 1 retrospective study before Teischer seeing frequency of 2 patients developing the Teischer syndrome; correct? 3 A. Yes, sir. A case-control study is where you 4 find cases of something; for example, you might be looking at 5 breast cancer. So you find patients who have breast cancer 6 and you try to find in the same population patients who don't 7 have breast cancer, and then you look back to see if you can 8 find something that separates those patients. Did they have 9 relatives with breast cancer, did they smoke, did they eat 10 fatty foods and so forth. That's a case-controlled study. 11 Q. And that was not done? 12 A. That was not done. 13 Q. Number Two listed there is a cohort study in 14 connection with Doctor Teischer's phenomenon. 15 A. Yes, sir. 16 Q. And that was not done? 17 A. Well, as I testified on Friday, a cohort study 18 that looked at suicidality and violence was in fact done, but 19 a cohort study designed specifically to look for the Teischer 20 phenomenon was not done because we couldn't find investigators 21 who had seen any of the same kind of patients, so we never 22 figured out how to do that study. 23 Q. All right. So that was not done? 24 A. Yes, sir. That was not done. 25 Q. Then Item Three is that Doctor Leber had 22 1 suggested that best would be a larger blind prospective study 2 designed with the help of Teischer to detect his phenomenon; 3 correct? 4 A. Yes, sir. 5 Q. And his phenomenon was the situation, as he 6 described generally in his paper, where patients were 7 developing an intense suicidal preoccupation; is that right? 8 A. That's right. They had akathisia, which means 9 that they were very restless, and they had thoughts of suicide 10 that made them very, very unhappy. These were not just 11 thoughts, but they were very disturbed by these thoughts, and 12 I think there were six patients total that he described that 13 had this phenomenon. 14 Q. And that was not done, either, was it? 15 A. Well, as I testified on Friday, we did dozens of 16 blind prospective studies in depression where we looked at 17 suicidality with scales like the Madras scale and the Hamilton 18 scale but, again, because we could not find a good definition 19 of the Teischer phenomenon, we had no instrument in those 20 studies to specifically distinguish people that had the 21 Teischer phenomenon; however, in those huge studies we never 22 found a patient that would fit that definition. 23 Q. All right. Now, up to that time, Lilly had done 24 controlled clinical trials in connection with Prozac studying 25 depressed individuals; is that correct? 23 1 A. Yes, sir. 2 Q. And in those trials, Lilly had employed various 3 scales to measure the patient's depression; correct? 4 A. Yes, sir. 5 Q. One of them -- we have a scale, I believe, 6 already in evidence -- is the Hamilton Depression Scale? 7 A. Yes, sir. 8 Q. Now, that scale by virtue of its title is called 9 the Hamilton Depression Scale, is it not? 10 A. Yes, sir. Doctor Hamilton invented it. 11 Q. And it was to measure fluctuations or movements 12 or categorize depression as an entity, is it not? 13 A. You're correct, but it characterizes more than 14 just overall depression because Questions Eight is used to 15 classify patients as agitated and Nine as sedated. So there 16 are subscales that you commonly could put depressed people in 17 different categories of depression. 18 Q. But the Hamilton Depression Scale is measuring 19 depression, not agitation -- it's designed to measure 20 depression directly, is it not? 21 A. Well, the scale overall is made up of 21 22 questions: One of those measures agitation; one measures 23 sedation; and one measures suicidality; and the others measure 24 other things. 25 Q. To get to the total depressive features of a 24 1 patient's illness; correct? 2 A. Yes, sir. 3 Q. In other words, the Hamilton Depression Scale is 4 not designed specifically to examine suicidality, for 5 instance? 6 A. Well, there are nine general categories of 7 symptoms that you use in making the diagnosis of depression 8 and, for example, one of those is agitation. Now, not 9 everybody with depression has agitation, but to the extent 10 that that question is part of the scale, if you do have 11 agitation, then those points count towards your total score of 12 depression. 13 Q. I understand that. I understand that. But as 14 far as the Hamilton Depression Scale being a scale to rate 15 specifically agitation, it does not, does it, Doctor? 16 A. Well, I think it's about the best one we have 17 and it's certainly the most widely used for agitation, for 18 sedation and for suicide and for some of the other elements 19 that are in the scale. 20 Q. But it's a scale for depression; it's not a 21 scale for agitation, is it? 22 A. Well, sir, there's another scale that's commonly 23 used for anxiety, but for agitation as a part of depression, 24 that's the most widely used instrument to measure agitation. 25 Q. Did Lilly ever employ a specific agitation scale 25 1 to study depressed patients and measure specifically, 2 exclusively, their agitation, DoctorThompson? 3 A. No, sir. We used that question on the Hamilton 4 scale and we used a similar question on the Madras scale, but 5 we didn't use a third scale for agitation. But we did use the 6 anxiety scale that was described by Covi. 7 Q. The anxiety scale is a Covi anxiety scale? 8 A. Yes, sir. 9 Q. How many questions is that, sir? 10 A. I don't remember. Is it five or six? I mean, 11 it's a relatively small questionnaire. 12 Q. It's not 17 or 21 like the Hamilton Depression 13 Scale, is it? 14 A. No. But we also use the clinical global 15 impression of the patient and the symptom checklist developed 16 at Hopkins. I think that's a 56-question scale of what the 17 patient fills out about how they feel and what's happening to 18 them. 19 Q. Well, again, there was no specific agitation 20 scale employed in the Prozac depression clinical trials to 21 measure agitation as a separate scale, was there? 22 A. Well, Mr. Smith, you and I just disagree, 23 because it is commonly used that that -- the specific question 24 in the Hamilton scale is used to classify people as to whether 25 or not they have agitation. The questions asked about 26 1 agitation or sedation are pretty comprehensive. The jury has 2 the scale; you can read them for yourselves. The same thing 3 about suicide; it asks: Are you thinking about suicide, are 4 you thinking a lot, have you committed a suicidal act. It's 5 fairly comprehensive, and that's what is widely used around 6 the world to measure those features of depression. 7 Q. Is the Hamilton Depression Scale the most 8 comprehensive scale that can be employed to measure 9 suicidality, Doctor Thompson? 10 A. It's the one that's the most widely accepted. 11 You can certainly make up more questions that address 12 suicidality. 13 Q. While we're getting that exhibit, why would 14 Doctor Leber and the FDA be suggesting a larger blind 15 prospective study if you had already done that? 16 A. Because we hadn't found any patients that had 17 the Teischer phenomenon, even though we had studied -- I think 18 the FDA said we had 8,000 people on Prozac in the control 19 trials before the drug was approved, and that was the largest 20 data base they had ever seen, we still hadn't found anybody 21 with the Teischer phenomenon. So maybe if we studied 20,000 22 people we would have been able to find a couple of those 23 patients. 24 Q. (Hands document to Doctor Thompson). 25 A. Thank you. 27 1 Q. Can you identify Exhibit 98? 2 A. Yes, sir. It seems to be a memo, the top page, 3 from Doctor Max Talbott to the FDA IND on Prozac that 4 identifies a Protocol No. 203, which he describes as a draft 5 protocol for a rechallenge study in patients who developed 6 suicidal ideation while under treatment, I assume under 7 treatment for depression. 8 Q. And is the document behind it a copy of the 9 draft protocol? 10 A. Yes, sir; it appears to be. 11 MR. SMITH: We'd offer Exhibit 98, Your Honor. 12 MR. FREEMAN: No objection. 13 JUDGE POTTER: Be admitted. 14 SHERIFF CECIL: (Hands exhibit to jurors). 15 Q. We'll discuss the rechallenge protocol itself in 16 detail in a little while, Doctor Thompson, but for purposes of 17 my questions, would you now look back at Appendix D, which is 18 on Page PZ1339 1086, I believe it is. 19 A. Yes, sir. 20 Q. Up in the upper right-hand corner, it has 21 Page 46706 Bates stamped. 22 A. Yes, sir. 23 Q. Do you see that, sir? 24 A. Yes, sir; I do. 25 Q. And that item there is apparently identified as 28 1 a scale for suicidal ideation, is it not? 2 A. Yes, sir. 3 Q. And it was going to be administered to the 4 patients who were going to be participating in the rechallenge 5 protocol? 6 A. That's correct, sir. 7 Q. This scale for suicidal ideation, Doctor 8 Thompson, has 21 questions on it, doesn't it? 9 A. That's correct. 10 Q. If you look back at the Hamilton Depression 11 Scale, which has been marked into evidence as Item 123 -- 12 Plaintiffs' Exhibit 123, it only has one question, Question 13 Three, in connection with suicide, doesn't it? 14 A. That's correct. 15 Q. This scale for suicidal ideation that was going 16 to be used in the rechallenge protocol has more questions? 17 A. Yes, sir. 18 Q. It is more sensitive? 19 A. That has never been established. 20 Q. Equally sensitive? 21 A. Well, it's never been validated so we don't know 22 how it performs versus the Hamilton Depression Scale. 23 Q. You were going to use it in connection with the 24 rechallenge protocol, weren't you? 25 A. Absolutely. We were going to validate it as 29 1 part of doing that study. 2 Q. It had been in existence for quite some time, 3 hadn't it, Doctor Thompson? 4 A. Doctor Beck had suggested it back -- in 1979 he 5 copyrighted it. 6 Q. Yes. If you look back on the last page of the 7 entire exhibit, it says, "Acknowledgment to the author, Aaron 8 T. Beck, M.D., Professor of Psychiatry, University of 9 Pennsylvania, Copyright 1979. 10 A. Yes, sir. 11 Q. This document then had been in existence, this 12 scale had been in existence for how many years? 13 A. Up until this letter, 12 years. 14 Q. Twelve years. It had -- this exhibit had -- 15 this scale had been in existence from almost the beginning of 16 the depression clinical trials, had it not? 17 A. About that time; yes, sir. 18 Q. Aaron T. Beck, M.D., is an acknowledged world 19 leader on the issue of suicidality, is he not? 20 A. Yes, sir. 21 Q. These are not questions that he developed off 22 the top of his head, are they, sir? 23 A. I have no idea of how Doctor Beck developed it. 24 Q. Do you think that Doctor Beck sat down and wrote 25 these 21 questions on the back of an envelope as he was riding 30 1 to work one day? 2 A. Mr. Smith, I have no idea how Doctor Beck 3 developed the scale. 4 Q. Have you seen -- have you reviewed this 5 questionnaire before? 6 A. No, sir. You showed it to me for the first time 7 just now. 8 Q. Have you ever, as the chief scientific officer 9 of Eli Lilly since this question of suicidality arose, taken 10 some time to stop and look at this scale to see if it might be 11 helpful in administering to patients in the clinical trial to 12 measure their suicidal ideation? 13 A. I was in a whole host of a number of meetings in 14 which it was discussed, but I don't think I've seen it written 15 out this way before. 16 Q. Would you agree that this is a more sensitive 17 measurement of suicidal ideation, Doctor Thompson? 18 A. Well, Mr. Smith, I agree it has 21 questions, 19 but it has never -- sensitivity is a very specific word. To 20 my knowledge, it's never been validated so that its 21 sensitivity has been compared with another validated 22 instrument like the Hamilton Depression Scale, so I can't 23 answer your question. I don't think it has had sensitivity 24 measured. 25 Q. This document is dated March 29th, 1991, is it 31 1 not, Doctor Thompson? 2 A. Yes, sir. 3 Q. Up to March 29th, 1991, did Eli Lilly and 4 Company use Doctor Beck's scale in any of its clinical trials? 5 A. I don't think so. 6 Q. Since March 29th, 1991, has Lilly used Doctor 7 Beck's scale in any of its depression clinical trials? 8 A. I don't think so. I might be wrong, but I don't 9 think so. 10 Q. As of March 29th, 1991, has Lilly employed any 11 specific scale to measure violence and aggressive behavior in 12 participants in the depression clinical trials? 13 A. Well, we've used two different methods, one is 14 these Hamilton Depression and Madras scales in all the studies 15 of depression, one or the other was used. And the second 16 thing, of course, is that every patient in a controlled trial 17 on every visit with the investigator has a complete 18 description of every adverse event, and that's a highly 19 standardized, very well-taught and rigorously enforced way of 20 collecting observations on the patients, and every word that 21 the investigator says about the patient is studied in great 22 detail. So, yes, that's an extremely sensitive way of 23 collecting data about violence or aggressive behavior or hair 24 falling out or diarrhea, and those were studied very 25 intensively. 32 1 Q. But as part of a scale specifically employed to 2 specifically look at the issue of whether or not patients were 3 becoming violent or aggressive on the depression Prozac 4 clinical trials, there was never any scale specifically 5 employed for that purpose, was there? 6 A. I've never heard of -- well, the answer is no, 7 Mr. Smith, but I've never heard of such a validated scale. 8 Q. Did you ever think about trying to determine a 9 scale? 10 A. Yes, sir. Absolutely. 11 Q. All right. And was a scale ever done? 12 A. No, because the incidence of the events are so 13 small that it's better -- it's more sensitive to collect the 14 words of the investigator and then go back and ask the 15 investigator. If they say, "This person seemed mad," we would 16 then call up the investigator and say, "Tell me what mad 17 means," I mean, "Tell me more about the patient." And if they 18 had any hint of aggression or hostility, then we would use 19 that classification term, the COSTART terms we talked about 20 last week, and amplify the description from the investigator. 21 That was the most sensitive way we knew to look at the issue. 22 Q. It was simply going to be picked up as an 23 adverse event as opposed to being rated on a systematic basis 24 by use of a systematic scale? 25 A. But the FDA says we as Lilly have the most 33 1 sensitive and elegant system of collecting adverse events. 2 That's the most sensitive thing there is, sir. 3 Q. So that's what you did, looked at adverse 4 events? 5 A. Yes, sir. Remember, we had 20 full-time people 6 looking at adverse events at one time from one of my memos? 7 That's the best way you can do it. 8 Q. (Hands document to Witness). 9 A. Thank you. 10 Q. Can you identify Exhibit 96, Doctor Thompson? 11 A. Yes, sir. This is an E-mail message on the 12 Lilly E-mail system that I generated on February the 13th, 13 1991, at 10:32 in the morning. The very top couple of lines 14 and the very bottom couple of lines are, again, a note that 15 someone has forwarded it to someone else, but I can't tell who 16 that was. But the middle of it is what I generated from the 17 date February 13th down to the Thompson, Leigh, RVAX. 18 MR. SMITH: Offer Exhibit 96, Your Honor. 19 MR. FREEMAN: No objection. 20 JUDGE POTTER: Be admitted. 21 SHERIFF CECIL: (Hands document to jurors). 22 Q. Exhibit 96 is authored by you approximately six 23 months after Exhibit 92, is it not? 24 A. Yes, sir. 25 Q. And you start off by saying, "To let you know 34 1 where we are on depression, let me give you a brief note. 2 Primarily for the FDA, but also to nail down that Prozac 3 reduces the risk of suicidality, we will probably do two 4 studies, Number One is a challenge study, blinded 5 prospective." Correct? 6 A. Yes, sir. 7 Q. That was not done, was it? 8 A. No, sir. We worked real hard but we never found 9 a way to do it. 10 Q. "Item Two is a prospective study using new 11 instruments to measure suicidality..." And, then, I'm sorry, 12 but it looks like the first line of your next page is cut off. 13 A. I think it's okay in mine. I think that's just 14 a random line up there, because I think it reads, "...to 15 measure suicidality in depressed folks randomly given Prozac 16 versus placebo or active comparitor." 17 Q. And is the next line? 18 A. "This would be global and would not be big 19 enough to contrast rates of actual suicide but possibly acts." 20 Q. All right. Again, you say "a prospective study 21 using new instruments to measure suicidality." That was not 22 done, was it, Doctor? 23 A. New studies were. New instrument to measure 24 suicidality different that Hamilton depression or Madras; no, 25 that was not done. 35 1 Q. Now, when you say new instruments to measure 2 suicidality, are you talking about other scales in addition to 3 this Beck suicidal ideation scale that had been in existence 4 since 1979, at least? 5 A. No. I meant that we would probably use that and 6 we were working on trying to develop others, as well. 7 Q. But that was not done, the Beck scale was not 8 done? 9 A. The new scales were not incorporated in those 10 studies; that's correct. 11 Q. Was the FDA putting pressure on Lilly to do some 12 new studies in connection with this issue? 13 A. Before the advisory committee meeting in -- 14 wasn't it September of 1991? I'm not sure of the year. But 15 before the advisory committee meeting that specifically looked 16 at suicidality and aggression and violence, the FDA was very 17 eager that we get all the data that we could. But as we 18 looked at more and more data, both from studies that had been 19 completed and from new studies that were ongoing, the FDA 20 became less and less interested in starting any new special 21 study. And when we talked with them about special scales that 22 you've emphasized, they became less and less interested in us 23 using those because they felt that the Hamilton scale and the 24 adverse event system was not only entirely sufficient but was 25 as sensitive as we could have on a validated instrument to 36 1 address this question. 2 Q. Who from the FDA told you that, Doctor Thompson? 3 A. Doctor Paul Leber and Doctor Tom Laughren. 4 Q. Okay. (Hands document to Witness). 5 A. Yes, sir. 6 Q. Can you identify Exhibit 90, Doctor Thompson? 7 A. I don't think I've seen this before, but it 8 looks like it's a memo to Doctor Talbott from Ms. Irene 9 Brandt, who is a Lilly employee in the Washington office of 10 Lilly, and it's dated October 23rd, 1986, and has the initials 11 SAB, who I presume is somebody who typed it. I don't know who 12 that is. 13 Q. At the time, Doctor Max Talbott, Doctor M. W. 14 Talbott, was the director -- 15 A. Of regulatory affairs; yes, sir. 16 Q. -- of regulatory affairs. He was the individual 17 responsible for interfacing with the government and the FDA? 18 A. Yes, sir. 19 Q. For Lilly? For Lilly? 20 A. Yes, sir. 21 Q. And Ms. Brandt was a Lilly employee in 22 Washington? 23 A. Yes, sir. 24 MR. SMITH: Offer Exhibit 90. 25 MR. FREEMAN: No objection. 37 1 JUDGE POTTER: Be admitted. 2 SHERIFF CECIL: (Hands document to jurors). 3 Q. Exhibit 90 is dated before Prozac was approved 4 in the United States, was it not? 5 A. Yes, sir. 6 Q. And, in fact, a year and several months before 7 it was approved; correct? 8 A. Yes, sir. 9 Q. Mr. Tony DeCiccio, who is mentioned there, was 10 the FDA safety officer; is that right? 11 A. Yes, sir. 12 Q. And he was looking at the Prozac NDA for the FDA 13 in connection with the safety aspects presented by Prozac? 14 A. Actually, he is an assistant to the division, 15 but he is not one of the scientists who would review the data. 16 Doctor Kapit, mentioned below, the FDA medical reviewer, he 17 was the physician assigned to the safety aspects of Prozac; 18 they had a separate physician looking at the efficacy aspects, 19 and then it was all looked at by Doctors Laughren and Leber. 20 Q. Look with me, Doctor Thompson, what is said -- 21 apparently Ms. Brandt and Mr. DeCiccio were having a 22 conversation; is that right? 23 A. Yes, sir. 24 Q. Look with me down under the Discussion section 25 there. 38 1 A. Yes. 2 Q. It says, "Tony DeCiccio stated that Doctor 3 Laughren said the firm has a friend in Doctor Temple, who 4 wants an action letter by the end of the year." Correct? 5 A. Yes, sir. That was delightful news to us. 6 Q. The firm there is Lilly; is that correct? 7 A. Yes, sir. And an action letter is either a 8 refusal to approve the drug or an approvable letter. 9 Q. Did you know that at that time, prior to 10 approval of Prozac that Doctor Temple was a friend of Lilly's? 11 A. Well, it depends on how you use the word 12 "friend." Doctor Temple is one of the toughest reviewers at 13 the FDA and is notorious for how stringent he is at review, 14 but what was delightful about this was that the FDA is 15 supposed to give an action letter six months after you file an 16 NDA, and we filed this NDA in September of 1983. So now it's 17 been three years later and we hear that we're going to get an 18 action letter by the end of the year. We didn't know whether 19 it was going to be approval or disapproval, but at least an 20 action is going to come out of the FDA. Of course, it's three 21 years rather than six months, but at least we're going to get 22 something. 23 Q. But the point is that Mr. DeCiccio told 24 Ms. Brandt that Doctor Laughren said that the firm has a 25 friend in Doctor Temple; correct? 39 1 A. Because Doctor Temple was going to get an action 2 letter out by the end of the year. 3 Q. Doctor Temple is Doctor Leber's boss, is he not? 4 A. Yes, sir. 5 Q. (Hands document to Witness). 6 A. Thank you. 7 Q. Can you identify Exhibit 91? 8 A. This appears to be -- and, again, I'm not sure 9 I've seen this before, but it appears to be a memo to the Food 10 and Drug Administration filed to -- this is filed to the New 11 Drug Application, rather than the IND, on Prozac from Doctor 12 Max Talbott, dated March 26, 1990. 13 MR. SMITH: We'd offer Exhibit 91, Your Honor. 14 MR. FREEMAN: No objection. 15 JUDGE POTTER: Be admitted. 16 SHERIFF CECIL: (Hands document to jurors). 17 Q. In this letter it appears that in the second 18 paragraph Doctor Talbott is saying as a follow-up to the 19 conversations, "We herewith formally request a meeting with 20 division representatives and other appropriate FDA scientists 21 to present our safety experience from the first 24 months of 22 Prozac spontaneous reporting." Correct? 23 A. Yes, sir. 24 Q. My question to you is, that letter appears to 25 have been sent on March 26th, 1990, and signed by Doctor 40 1 Talbott. It says -- typed in there in the lower right-hand 2 corner of the page, it says, "At the request of Lilly, 3 Mr. A. W. DeCiccio was able to pull and destroy all copies of 4 this submission except Doctor T. P. Laughren's desk copy." Do 5 you see that? 6 A. Yes, sir. 7 Q. Do you know if that was indeed done, that Mr. 8 DeCiccio was requested by Lilly to destroy documents that had 9 been submitted to the FDA? 10 A. I'm sorry. I don't have any personal knowledge 11 of it, and I agree with you that's exactly what's typed there. 12 Q. Do you know of any other instances where Lilly 13 had asked employees of the FDA to destroy materials that had 14 been sent by Lilly to the FDA? 15 A. It happens occasionally when there's more data 16 that comes in and we want to update it, but I can't remember 17 any specific examples. 18 Q. Do you know of any data at all that was 19 destroyed after it had been submitted by Lilly to the FDA? 20 A. Well, no data would be destroyed. This doesn't 21 say that there was any data destroyed; it says that, in fact, 22 there were analyses. You see, the data goes in under -- the 23 original data all go in under very formal controls. 24 Q. But this would be one of the summaries that had 25 been sent, probably? 41 1 A. Some summary that we prepared and, I don't know, 2 we'd either maybe not included everything they wanted to get 3 in or we had a new way of doing the analyses or something. 4 Q. It doesn't say that there, though, does it, 5 Doctor Thompson? 6 A. No. I'm guessing because I don't remember the 7 incident. 8 Q. This was just a few months after the publicity 9 started to become known with respect to the issue of Prozac 10 and suicide, violent-aggressive behavior? 11 A. Yes, sir. 12 Q. That was February 1990? 13 A. Well, that was the Teischer report. There was 14 publicity, of course, about this tragic incident earlier than 15 that. 16 Q. (Hands document to Witness). 17 A. Thank you. 18 Q. Can you identify Exhibit 93, Doctor Thompson? 19 A. Yes, sir. This is a Lilly E-mail memo that I 20 generated on the research vax at just after noon on 21 September 12, 1990, and it has been forwarded by Max Talbott 22 to -- it looks like it's forwarded to me as well as to Doctors 23 Masica, Perelman, Weinstein and Zerbe, who were among the 24 people I addressed. 25 MR. SMITH: All right. Offer Exhibit 93, Your 42 1 Honor. 2 MR. FREEMAN: No objection. 3 JUDGE POTTER: Be admitted. 4 SHERIFF CECIL: (Hands document to jurors). 5 Q. At the 12:01 notation, you start off by saying, 6 "Urgent. Doctor Leber, with Doctor Laughren on the 7 speakerphone, called at 11:40 A.M., and Dan Masica and John 8 Heiligenstein joined me on the speakerphone. Leber said that 9 he was to have a meeting with Bob Temple in the next couple of 10 days to bring him up to speed on suicidality." Correct? 11 A. Yes, sir. 12 Q. Down there in the next paragraph you say, "I 13 think this means that he is being pushed by Temple, and from 14 Peck's comments yesterday, at least Peck is concerned to 15 change the label." Correct? 16 A. Yes, sir. 17 Q. Now, Doctor Peck is who? 18 A. Doctor Temple's boss. At this time he was 19 responsible for the entire Center for Drugs at the Food and 20 Drug Administration. 21 Q. All right. The last paragraph of the first page 22 says, "I am now very concerned that Temple, et al, may force a 23 label change even before we get there on 25 Sep or, next 24 worst, have this a fait d'accompli when we arrive." Correct? 25 A. Yes, sir. 43 1 Q. Then you say, "This report must move swiftly 2 through approval and to Doctor Leber's hands, dash, he is our 3 defender." Correct? 4 A. Yes, sir. 5 Q. How long had Doctor Leber been your defender, 6 Doctor Thompson? 7 A. Well, on the issue of suicidality and violence, 8 I would say after he started looking at all the data the FDA 9 had and all the data that Lilly had. And, see, this memo asks 10 for a specific kind of statistical analysis, the odds ratio 11 analysis, to add to the meta analysis that we had already sent 12 that you said was the famous meta analysis. And at the time 13 he saw the meta analysis, I would say that he was quite 14 reassured and was our defender. 15 Q. (Hands document to Witness). 16 A. Thank you. 17 Q. Can you identify Exhibit 94, Doctor Thompson? 18 A. Again, I don't think I've seen this before, but 19 it comes from -- this looks like an internal E-mail message at 20 Lilly from Bill Grosse, who is director of -- something -- 21 quality control or quality reassurance, to John Fose, who was 22 responsible for the chemistry kinds of testing of drugs in 23 relation with the FDA on January 16th, 1991, and it's been 24 forwarded by John Lechleiter to a whole bunch of people, and 25 at this time -- including my boss, Mel Perelman. John at that 44 1 time I think was an executive director responsible for the 2 chemistry of making the Prozac capsules and testing them for 3 stability and so forth. 4 Q. This memo has to do with Prozac, doesn't it? 5 A. Yes, sir. It's a preapproval inspection for 6 Prozac liquid. 7 MR. SMITH: Offer Exhibit 94, Your Honor. 8 MR. FREEMAN: No objection. 9 JUDGE POTTER: Be admitted. 10 SHERIFF CECIL: (Hands document to jurors). 11 Q. Again, this is another one of the Lilly 12 interoffice E-mails that actually the bottom of the page or 13 the bottom, I guess, two-thirds of the page would go first and 14 then the top of the page would go second; is that right? 15 A. Yes, sir. The next day. 16 Q. All right. It looks like there is going to be 17 some review of Prozac liquid; is that right? 18 A. Well, what's happening here is that the FDA 19 comes out, as they often do, and audits and inspects pieces of 20 Lilly. In this case, they come out and actually look at the 21 production line where this particular product, the liquid 22 Prozac, is manufactured and look at all the data associated 23 with it. So it's talking about that inspection. 24 Q. All right. At the top of the page, the Comments 25 section, who was that written by? 45 1 A. I think John Lechleiter, who I mentioned I think 2 was the executive director who was responsible for -- inside 3 we call it fill finish. It's taking the bulk Prozac chemical 4 and making it into and actual product. But you have to add 5 all the inert ingredients, put it in bottles, label it, test 6 it for stability and so forth. He was responsible for that. 7 Someone else actually made the bulk chemical Prozac 8 separately. 9 Q. He said there under Comments, "Looks like 10 internal connections now in place within FDA. Know of no 11 reason why there should be any remaining issues on M/C side." 12 Correct? 13 A. Yes, sir. M/C means manufacturing and control. 14 Again, it's internal slang. What that statement means, if you 15 read the memo, is that the FDA couldn't locate the documents 16 within the compliance area to determine their status. Later 17 he called back and indicated that the results of his 18 inspection -- that he was unable to locate the results of his 19 inspection within the compliance area. 20 If I could just explain that, there are really 21 two pieces of the FDA: There's a field piece that does the 22 inspections wherever the locality is, and there's the central 23 piece in Rockville. Their communications aren't quite as good 24 as ours and there's often, often, that they can't find various 25 submissions and pieces of paper. So what this is saying is 46 1 that's a problem for us. 2 Q. Does the Comments section there say, indeed, 3 "Looks like internal connections now in place within FDA; know 4 of no reason why there should be any remaining issues on 5 manufacturing and control side," Doctor Thompson? 6 A. Yes, sir; that's what it says. The field in 7 Rockville have gotten their act together. 8 Q. Were the postmarketing event numbers or the 9 clinical trial numbers in connection with numbers of 10 individuals taking Prozac big? 11 A. Yes, sir. There were many people -- this drug 12 was widely used not long after it was marketed and it also had 13 a lot of adverse events. 14 Q. Were the numbers on suicide big? 15 A. Yes, sir. 16 Q. (Hands document to Witness). 17 A. Thank you. 18 Q. Can you identify Exhibit 81, Doctor Thompson? 19 A. Yes, sir. This is not E-mail; this is actual 20 pieces of paper that I typed on the computer. 21 Q. To Doctor Robert Zerbe? 22 A. Yes, sir. 23 Q. Who was at that time -- 24 A. I think he was vice-president at that time, and 25 I think at this time he was responsible for all of the medical 47 1 group at Lilly in the United States. 2 MR. SMITH: All right. Offer Exhibit 81, Your 3 Honor. 4 MR. FREEMAN: No objection. 5 JUDGE POTTER: Be admitted. 6 SHERIFF CECIL: (Hands document to jurors). 7 Q. It looks like you're going to do a speech on 8 Prozac in Washington, D.C.? 9 A. Yes, sir. And I can't -- I'm trying to remember 10 what the specific Washington symposium was, but I can't 11 remember it. I'm sorry. 12 Q. And you were asking Doctor Thompson to give you 13 some assistance in adverse events on Prozac and data in 14 connection with Prozac? 15 A. Yes. I was asking Doctor Zerbe to help me. 16 Q. I'm sorry. Doctor Zerbe. Did I say Doctor 17 Thompson? 18 A. We know who we are. 19 Q. All right. If you look at the next-to-last 20 paragraph on Page 2, you say, "Then the question is what to do 21 with the big numbers on suicidality. If the report numbers 22 are shown next to those for nausea, they seem small. Should I 23 get into the total count at all, (I'm afraid someone will ask 24 for sure), or should I leave this to David to introduce." 25 A. Yes, sir. 48 1 Q. Correct? 2 A. That's David Wheadon. 3 Q. All right. Were the adverse events in 4 connection with Prozac in October of 1990, highest in 5 connection with nausea? 6 A. I think so. What this says is that there are 7 more with nausea than with suicidality but, you know, it 8 changed over time. Probably nausea was the highest. 9 Q. In fact, it says -- you say, "If the report 10 numbers are shown next to those for nausea they seem small." 11 Right? 12 A. Yes, sir. 13 Q. After you referred to them as big earlier? 14 A. Well, there are a lot of reports of suicidality, 15 but there are even more reports of nausea, so it depends on 16 what you're going to show; are you going to show that there 17 are lots of reports on one or that they're even less than with 18 nausea. 19 Q. Was there any massaging of the numbers in 20 connection with those big numbers on suicidality to make them 21 big or small, Doctor Thompson? 22 A. Well, no, the numbers themselves speak for 23 themselves. The question is the statistical analyses of them, 24 are there significantly less or more or can you find some way 25 of relating it to age or dose or duration of therapy or 49 1 anything else about the patients. 2 Q. Was there any massaging? 3 A. Oh, yes, sir. We analyzed to look for 4 indicators of who would get suicidality almost every day as 5 new data came in. 6 Q. Do you remember as a point of information what 7 the numbers were at that time? 8 A. I'm sorry. I couldn't possibly even guess at 9 it. They were big, hundreds, but I couldn't even make a 10 guess, because, again, this all changed day to day, remember. 11 Q. All right. Were you aware, Doctor Thompson, of 12 933 reports of suicidal ideation as of July 1993? 13 A. Sounds like a reasonable number. You've quoted 14 several here from the FDA, as well as for us. That seems 15 compatible. 16 MR. SMITH: Your Honor, at this time, maybe 17 since my time with Doctor Thompson is limited, I have Exhibits 18 124 through 150, which are the SRS computer data printouts as 19 of July 1993 in connection with this. I'm wondering if I 20 could offer these in bulk. 21 MR. FREEMAN: Your Honor, we have a matter to 22 take up with the Court about these. 23 (BENCH DISCUSSION) 24 MR. FREEMAN: Judge, we had indicated earlier in 25 several of the pretrial conferences these are summaries of 50 1 hearsay data that have been compiled by some unknown person. 2 In other words, they are summaries of reports that have come 3 in by doctors, by newspapers, by television and so forth. 4 It's hearsay based upon hearsay based upon hearsay. It's just 5 summaries of those 1639 reports is what I believe them to be. 6 We object in that they're irrelevant, would mislead the jury 7 and would unduly prejudice the case. 8 JUDGE POTTER: I've previously ruled on this and 9 your objection is overruled. 10 Mr. Freeman, is there any problem with 124 11 through 150 being what they say they are? 12 I tell you what, Mr. Smith, why don't you let 13 them look through them and then go on. 14 (BENCH DISCUSSION CONCLUDED) 15 MR. SMITH: I can move onto another area, but we 16 would offer those at this time. 17 JUDGE POTTER: If they're what you said they 18 were, they'll be admitted. 19 MR. SMITH: And there are some stickers on there 20 that obviously we'll take off before introducing them into 21 evidence. 22 MR. FREEMAN: Okay. 23 Q. While they're doing that, Doctor Thompson, let's 24 talk about rechallenge for a minute. 25 A. Yes, sir. 51 1 Q. Explain to the jury the principle of rechallenge 2 in connection with examining the issue of whether or not a 3 particular reaction is caused by use of a drug. 4 A. Thank you. Causality is very difficult or 5 impossible to assess in an individual patient, and the way you 6 try to look at causality is to look at groups of patients. 7 Let me give you an example. Suppose you were given a 8 prescription for an antibiotic and you had a cold, and you 9 were taking the antibiotic and you got a bad rash. Now, you 10 might say, "Well, gee, the rash is caused by the antibiotic." 11 It turns out, however, that in many cases the rash is caused 12 by the virus that's causing the cold and not the antibiotic at 13 all. Well, one way for an allergic reaction that you might 14 think that you could find out whether you're allergic or not 15 is to take the same antibiotic again and see if you get 16 another allergic reaction. If you took penicillin and you got 17 a rash, then you wait for a couple months and you take 18 penicillin again, if you get another rash that looks just the 19 same, most scientists would say that's pretty good evidence 20 that you're allergic to penicillin and you ought to watch out. 21 The problem is that my study that was in the New 22 England Journal showed that very few people who have a real 23 penicillin-related serious reaction will have one when you 24 give them penicillin again. So challenges are not perfect, 25 but, again, it's pretty good evidence in causality that if you 52 1 give a drug and you get one kind of reaction, stop the drug, 2 give it a second time and at the same time after you give the 3 drug you get the same kind of reaction, it's not 100-percent 4 proof positive, but it's pretty good. 5 Q. It's other valid scientific evidence in 6 determining causality in connection with whether or not the 7 drug causes a particular reaction, isn't it, Doctor Thompson? 8 A. Yes, sir. Especially with allergic reactions 9 because there you've got antibodies you can actually measure. 10 Q. But it was suggested earlier on, was it not, 11 that Lilly do a rechallenge study in connection with the 12 issues of Prozac and suicidality and violent-aggressive 13 behavior? 14 A. Exactly. If we could find patients who had 15 taken Prozac and had emergence of a lot of suicidal thinking 16 or an act or an attempted suicide, then if we could treat 17 those patients again when they were in the same state and give 18 them Prozac or give them a comparitor, and if the people 19 treated with comparitors did not have any suicidality and the 20 people treated with Prozac did have suicidality, that would be 21 powerful evidence that the Prozac was related to the 22 suicidality. 23 Q. And that had not been done in the Lilly clinical 24 trials up to the time it was suggested by the FDA, had it? 25 A. It was not done and there are a whole number of 53 1 reasons why, but it was not done. 2 Q. And it has not been done to date, has it? 3 A. That's right. And there are a whole number of 4 reasons why it hasn't been done to date. 5 Q. In fact, if we look back at Exhibit 98, which I 6 think is already in evidence, you or Lilly submitted to the 7 FDA a proposed protocol for a rechallenge study in patients 8 who had become suicidal in association with Prozac treatment; 9 correct? 10 A. Absolutely. 11 Q. And the FDA was concerned about the possibility 12 of doing that? 13 A. Yes, sir. And the first few pages describe in 14 great detail what this challenge study would do and not do and 15 some of the problems in doing it. 16 Q. The study would, in essence, have to be in 17 hospitalized patients, would it not? 18 A. That was one of the key difficulties, that -- 19 and it's important to understand that putting a patient with 20 depression in a hospital changes the patient; that in and of 21 itself is a form of therapy, no matter what else you do. So 22 in a challenge, again, what you try to do is completely 23 duplicate the first event. So you've got an outpatient, you 24 give them Prozac, suicidality develops. What you want to do 25 is have exactly the same situation when you do the challenge. 54 1 Well, there are two problems: As time goes on, the patient 2 may not be in the same depressed state, and the second thing 3 is if you then put them in the hospital, they may in fact be 4 quite different than they were when they were treated as an 5 outpatient. 6 Q. Well, the primary problem is that if a patient 7 has been suicidal on Prozac in an outpatient study, you 8 don't -- you want to be able to protect that patient if you're 9 going to give him Prozac a second time so you're going to need 10 to hospitalize that patient; correct? 11 A. Or give him a comparitor. If this is a patient 12 who is under therapy with anything gets worse with a 13 life-threatening event, you don't want that to happen when 14 they're an outpatient. 15 Q. And there was a lot of discussions between Lilly 16 and the experts and Lilly and the FDA as to whether or not 17 this particular type of study could be done, was there not? 18 A. Well, yes, sir. We designed this protocol, 19 which was a valid protocol, but then we could never find 20 investigators to do it, was the problem. 21 Q. Is it your testimony here that the problem with 22 doing the rechallenge study was not in designing the study but 23 getting an investigator to do it? 24 A. Yes, sir. That's exactly correct. 25 Q. (Hands document to Witness). 55 1 A. Thank you. 2 Q. Can you identify Exhibit 101, Doctor Thompson. 3 It's actually two letters, is it not? 4 A. Yes, sir. The cover letter appears to be a 5 letter by Catherine Mesner, who is a full-time Lilly employee, 6 who is an administrator that helps with trials, to Doctor 7 David Dunner, who is an expert psychiatrist at the University 8 of Washington. And the second two pages are a letter from 9 Doctor Dunner to Doctor Beasley, who we know to be one of the 10 Lilly psychiatrists. 11 Q. Doctor Dunner is a well-known psychiatrist in 12 the Washington state area, is he not? 13 A. Yes, sir. Very well known. 14 Q. In fact, he's known throughout the country, 15 isn't he? 16 A. Throughout the world. 17 Q. In fact, he is on the Lilly psychiatric advisory 18 board, is he not? 19 A. Well, he was at one time. 20 Q. Well, has he been removed or do you know if he's 21 not still on? 22 A. I don't know if the board still exists, but he 23 certainly was at one time. He's an extremely well-qualified 24 psychiatrist. 25 Q. And he, in fact, did Lilly clinical trials -- 56 1 A. Yes, sir. 2 Q. -- on Prozac, didn't he? 3 A. Yes, sir. 4 Q. And, in fact, he did part of Protocol No. 27, 5 didn't he, which was a pivotal Lilly trial; that was the 6 comparison Prozac versus imipramine versus placebo? 7 A. I don't remember all the investigators, but I'm 8 sure you're correct if that's what you assert. 9 MR. SMITH: All right. Offer Exhibit 101, Your 10 Honor. 11 MR. FREEMAN: No objection. 12 JUDGE POTTER: Be admitted. 13 SHERIFF CECIL: (Hands document to jurors). 14 Q. All right. The first page of Exhibit 101 is Ms. 15 Mesner's transmittal letter to Doctor Dunner transmitting the 16 rechallenge protocol, is it not? 17 A. Yes, sir. 18 Q. And that's the protocol we've just been speaking 19 of that's probably already into evidence as Exhibit 98; right? 20 A. Yes, sir. I think that's correct. 21 Q. All right. And then the second two pages are 22 Doctor Dunner's impressions concerning that protocol, are they 23 not? 24 A. Yes, sir. It is exactly the same protocol. It 25 carries our Code Number B1Y-MC-HCFQ, so that is exactly the 57 1 same protocol. 2 Q. Now, Doctor Dunner apparently is a great 3 psychiatrist and a very smart individual, but he -- whoever -- 4 I guess it was Doctor Beasley needed to itemize his thoughts 5 because Doctor Dunner doesn't use paragraphs as frequently as 6 maybe some others; correct? 7 A. Well, we have eight numbers that are written in 8 by somebody on this letter. 9 Q. All right. He begins by saying, "Dear Charles, 10 thank you for the opportunity to review the B1Y-MC-HCFQ 11 fluoxetine/desipramine/placebo alternative treatment study. A 12 few comments and questions." Correct? 13 A. Yes, sir. 14 Q. Item Number Three there says thirdly -- it's in 15 the middle of that same paragraph. Item Three says, "Thirdly, 16 as I mentioned on the phone, would it be useful to audiotape 17 the suicide ratings? At least this would provide a way of 18 keeping everybody a little more honest." Do you see that? 19 A. Yes, sir. 20 Q. Had there been a problem in connection with the 21 veracity of the suicidal ratings in the Prozac clinical trials 22 in depression? 23 A. No, not specifically. In fact, we have five 24 different layers of audit of all of our clinical trial data, 25 so it would be almost impossible for dishonesty to occur 58 1 without it being detected. I think what he means by "honest" 2 is there's a difference among different psychiatrists in how 3 they evaluate the same patient. So we train our psychiatrists 4 of actually showing them videotapes of interviews with 5 patients and showing them what other psychiatrists have 6 evaluated those patients as having. Psychiatry, 7 unfortunately, is not quite as an exact science as some other 8 areas of medicine, so I think Doctor Dunner's word in terms of 9 honesty relate to interinvestigator reliability rather than 10 any sense of true dishonesty. 11 Q. He says, "If you audiotape the suicide ratings, 12 it would provide a way of keeping everybody a little more 13 honest," does it not? 14 A. Yes, sir; that's exactly what it says. But I 15 think, again, that you should not interpret the word "honest" 16 as that there's any falsification or changing or 17 misrepresentation of data, rather than just the difference 18 between investigators. That's the way I interpret what he 19 said. 20 Q. Well, Doctor Thompson, did you speak with Doctor 21 Dunner about his comments here? 22 A. No, sir. 23 Q. If you'll turn -- it appears that he has 24 reviewed this protocol in some detail, and if you turn to the 25 top of the last page of his letter, it says, "I think the 59 1 study is doable." 2 A. Yes, sir. 3 Q. But it was your testimony earlier that you 4 couldn't get any investigator to do it? 5 A. We couldn't get enough investigators who would 6 predict that they would enroll enough patients that we would 7 get any meaningful data; that's correct. 8 Q. But he says it is doable. 9 A. He says it's doable, but read his next sentence. 10 Q. "I'm not sure if the patient flow would be very 11 high for any particular center. The criteria who have not 12 made recent suicidal attempt are fairly stringent." Correct? 13 A. Yes, sir. 14 Q. But he precedes all that with saying, "I think 15 the study is doable," doesn't he? 16 A. Yes, sir. 17 Q. He's just going to say it may be hard, it may 18 take awhile, but it's doable? 19 A. Yes, sir. 20 Q. But it wasn't done, was it, Doctor Thompson? 21 A. No, sir. 22 Q. He also says in that next sentence, "As an 23 additional point, why are patients who have been on an 24 investigational study recently, excluded? Certainly, patients 25 who became suicidal while participating in an investigational 60 1 study and have terminated from that study might need to be 2 treated and might be excellent candidates for this particular 3 study. Any thoughts about that?" 4 A. Yes, sir. That's what he says. 5 Q. Did you discuss this issue with him? 6 A. No. I didn't discuss, I don't think, this 7 protocol with Doctor Dunner at all. 8 Q. Did you discuss Doctor Dunner's letter with 9 Doctor Charles Beasley, the psychiatrist at Lilly who was 10 responsible for this? 11 A. Yes, sir. Doctor Dunner's and comments from all 12 the other people we were trying to get to be investigators. 13 Q. Well, did you ask Doctor Beasley about this 14 question of honesty in connection with these suicide ratings? 15 A. I don't remember that, but I honestly would not 16 have reacted as you did to the use of that word, so I doubt 17 that I would have asked him about it. We have, over time, 18 tried to both audiotape and videotape interviews with 19 patients, and there are very major problems in terms of 20 confidentiality. And most of our investigators that we've 21 described this to, feel that the presence of either an 22 audiotape or a videotape would actually change the milieu or 23 the content of the discussion between the psychiatrist and the 24 patient. So it sounds like it's something that's easy to do; 25 in fact, it is not easy to do. 61 1 Q. Doctor Dunner concludes by saying, "Again, we 2 will be happy to participate," doesn't he? 3 A. Yes, sir. 4 Q. "I forward your protocol to both blank and blank 5 and have asked them to send their comments to you 6 independently. Sorry we cannot attend your meeting. Best 7 personal regards." 8 A. Yes, sir. 9 Q. In Exhibit 92, do you have that before you? 10 A. If you can give me just a second, if you would. 11 Q. Sure. 12 A. Can you describe it to me, so I can find it 13 easier? 14 Q. Yeah. It's what we casually referred to in 15 discovery and maybe to you as the Leber memo. 16 A. Okay. I've got it. 17 Q. All right. The next-to-the-last paragraph says, 18 "Paul is taking a position in talking with outside folks today 19 that Lilly and FDA are working together on the suicide issue 20 and following closely the postmarketing events, but that there 21 are no denominators, and the best that can be done is to put a 22 cap on the number of events." Correct? 23 A. Yes, sir. 24 Q. And I believe you testified Friday you didn't 25 know if that word "cap" was Doctor Leber's word or your word; 62 1 correct? 2 A. That's right. It could either be one or the 3 other or both of us. 4 Q. (Hands document to Witness) Can you identify 5 Exhibit 111, Doctor Thompson? 6 A. Yes, sir. Again, this has a number of pieces, 7 and so we probably ought to go through it and show who did 8 each one. The first page that begins with this is -- 9 Q. Well, if you can just identify it and then -- 10 we're running a little short on time, maybe it would be most 11 helpful if you gave a description of it once the jury had it 12 in their hands so we won't have to repeat it. 13 A. I'm sorry. I think these are actually two 14 different memos or maybe even three, or two, at least, from 15 Claude Bouchy. 16 MR. SMITH: Offer Exhibit 111, Your Honor. 17 MR. FREEMAN: No objection. 18 JUDGE POTTER: Be admitted. 19 SHERIFF CECIL: (Hands exhibit to jurors). 20 Q. While that's being passed out, do I understand 21 it from your previous testimony, Doctor Thompson, that 90 22 percent of the postmarketing spontaneous reports that are sent 23 to the FDA are sent by Lilly -- Eli Lilly and Company? 24 A. Well, by drug companies in general. The 90 25 percent I was quoting is the FDA maintains that about 90 63 1 percent of the reports they receive come from drug companies. 2 I don't know about the Lilly ones because we don't ever look 3 at the FDA records of Lilly reports. 4 Q. All right. But does that sound unreasonable to 5 you in connection with Lilly? 6 A. No. I think that's probably in the ballpark, at 7 least. 8 Q. Okay. Now why don't you -- since the jury has 9 it in front of them, why don't you explain Exhibit 111. It 10 looks to me like the first message is on the first page. 11 A. Yes, sir. I think that's a message from Claude 12 Bouchy, who I think at this time was the general director of 13 the German affiliate, to me and Doctor Weinstein and Zerbe. 14 And then the second page and the top of the third page is 15 actually a memo from me, which is forwarding the middle of the 16 third page, which is another memo from Claude Bouchy to me, 17 and the first one is on the 13th of November and the rest is 18 on the 14th of November. 19 Q. Okay. Let's go to --Mr. Bouchy is the manager 20 of your German affiliate at this time? 21 A. He's the head of the German affiliate, whatever 22 his title is. 23 Q. He's not a doctor? 24 A. No, sir; I don't think so. 25 Q. He's a manager. But he is dictating this with 64 1 -- in connection with discussions with Hans Weber, is he not? 2 A. Yes, sir. 3 Q. And we've had Hans Weber's deposition played by 4 video here in this case. He is a medical doctor, is he not? 5 A. Yes, sir. 6 Q. All right. The message goes to you and at that 7 time you were a group vice-president in charge of medical? 8 A. I've forgotten whether I was group or executive 9 vice-president, but medical was one of the pieces of research 10 that I was responsible for. 11 Q. Doctor Allan Weinstein was specifically in 12 charge of international medical, was he not? 13 A. Yes, sir. But as I mentioned to you before , 14 people like Doctor Weber did not report to Doctor Weinstein. 15 Q. And Doctor Zerbe we've identified? 16 A. Yes, sir. 17 Q. Gerhard Mayr is? 18 A. Gerhard Mayr would have been Mr. Bouchy's boss. 19 He was responsible for all of the European affiliates of 20 Lilly. 21 Q. Is he a doctor? 22 A. No, sir. 23 Q. Okay. And Sidney Taurel is who? 24 A. I think he was Gerhard Mayr's boss at the time. 25 He was responsible for all of international of Lilly. So 65 1 everything outside of the United States reported to Mr. 2 Taurel. 3 Q. Mr. Taurel was indeed a Lilly corporate officer, 4 was he not? 5 A. Yes, sir. 6 Q. As were you and Doctor Weinstein? 7 A. And Mr. Mayr, at least. 8 Q. But Sidney Taurel was a senior Lilly officer, 9 was he not? 10 A. Yes, sir. He was senior to Gerhard Mayr, who 11 was senior to Claude Bouchy. 12 Q. Was Mr. Terrell on the board of directors of 13 Eli Lilly at that time? 14 A. He went on the board right around this time, but 15 I don't remember whether this was just before or just after he 16 was made a member of the board. 17 Q. So he was at least, if not then, shortly 18 thereafter, an actual sitting member of the board of 19 directors? 20 A. Sometime around this time. 21 Q. The subject of the memo was Adverse Drug Event 22 Reporting Suicide Fluoxetine; correct? 23 A. Yes, sir. 24 Q. And these are the same adverse events that are 25 mentioned by Doctor Leber in connection with Exhibit 92, are 66 1 they not, on Page 2, putting a cap on adverse events; correct? 2 A. Well, some of them. As you know, there were 3 thousands of adverse-event reports. 4 Q. This has to do with two and -- this has to do 5 with suicidal ideation and attempted suicide, does it not? 6 A. Yes, sir. 7 Q. Let's read it. It says, "Hans Weber and I have 8 problems with the directions our safety people are getting 9 from the corporate group, drug epidemiology unit, and 10 requesting that we change the identification of events as they 11 are reported by the physicians." Correct? 12 A. Yes, sir. 13 Q. Now, apparently, these physicians that are 14 reporting these events are who, clinical trial investigators 15 or physicians who are treating patients who are depressed? 16 A. I think the drug was approved and marketed in 17 Germany before this time and, therefore, it's more likely that 18 these were spontaneous reports from German physicians using 19 the drug, but just from the code number I can't tell you for 20 sure. 21 Q. Then underneath that statement, he says they're 22 having problems with the directions that our safety people are 23 getting from the corporate group, drug epidemiology unit; 24 would that be in Indianapolis? 25 A. Yes, sir. The drug epidemiology unit are a 67 1 group of clinical pharmacists and nurse specialists who are 2 primarily charged with following up on adverse events all 3 around the world, works as we've talked about before with the 4 physicians in Indianapolis primarily, one of the things they 5 do is to assign the FDA COSTART terms. 6 Q. All right. And Mr. Bouchy and Doctor Weber 7 mention two specific reports, do they not? 8 A. Yes, sir. 9 Q. This first report, and I'm not going to give all 10 those numbers, but it says on this one, "Our safety staff is 11 requested to change the event term suicide attempt, paren, as 12 reported by the physician, close paren, to overdose." On the 13 second one, it says on this one, "It is requested that we 14 change from suicidal ideation to depression." Correct? 15 A. Yes, sir. This was in relation to assigning the 16 FDA COSTART classification terms. 17 Q. Okay. I understand that. On this one, a doctor 18 had reported the adverse event of suicide attempt and Lilly 19 corporation, the drug epidemiology unit, was requesting that 20 that event term be used as overdose instead of suicide 21 attempt. Correct? 22 A. No, it's not correct, because what the German 23 physician actually said is almost for 100-percent sure not a 24 COSTART term, since that's a classification term that the FDA 25 uses. So what -- 68 1 Q. Okay. Is it your testimony, Doctor -- 2 MR. FREEMAN: Let him finish his answer. 3 Q. Was suicide attempt not a COSTART term? 4 JUDGE POTTER: Mr. Smith, let him finish and 5 then you can clarify. 6 A. Let me finish the first piece and then answer 7 your second question that you just asked me. Is that fair? 8 Q. (Nods head affirmatively). 9 A. There are two parts. Actually, there are many 10 parts of each adverse event report. One is the actual 11 language used by the reporter, so whatever the actual words 12 were used by the physician in Germany who initiated this 13 report are indelibly made part of the record and never changed 14 by anybody. Now, as a voluntary action to improve our 15 sensitivity in analyzing the reports, we try to assign the FDA 16 COSTART terms. At this time, the rule was that Indianapolis, 17 the drug epidemiology unit could not change the term assigned 18 by an affiliate like Germany. And you recall that you showed 19 me on Friday, I think it was -- it might have been Thursday -- 20 that the FDA had changed two terms in COSTART; one was suicide 21 attempt and the other one was something related to hostility 22 or intentional injury. Before they added suicide attempt, FDA 23 had been classifying all the suicide attempts under overdose 24 or depression. And remember I talked about the fact that it 25 was very confusing because even if the suicide attempt was by 69 1 hanging or shooting yourself in the head, the FDA was 2 classifying those under overdose? We were trying to do what 3 the FDA was doing and follow their rules. So Germany, in this 4 case, had put the -- this event in a bucket which was not the 5 bucket the FDA told us to use, so we tried to move it to the 6 right bucket. 7 Q. Were you finished? 8 A. Yes, sir. 9 Q. Suicide attempt, are you saying wasn't a COSTART 10 term in November 1990? 11 A. You gave me as an exhibit either Thursday or 12 Friday the FDA dates when they added the term, and I can't 13 remember them off the top of my head. 14 Q. Well, for purposes of Exhibit 111 is it your 15 testimony here, Doctor Thompson, that suicide attempt wasn't a 16 COSTART term in November 1990? 17 A. To the best of my recollection, that was not the 18 way the FDA was classifying the events at that time, and 19 that's why the request was to change the bucket that this 20 event got classified in to the same bucket that we thought the 21 FDA would put it in. 22 MR. SMITH: Let me -- may I approach the 23 Witness, Your Honor? 24 JUDGE POTTER: Sure. 25 Q. Have a seat. I'll stay right here. This is the 70 1 COSTART dictionary, Thesaurus of Adverse Reaction Terms, 2 Third Edition; correct, from the Food and Drug Administration 3 in Rockville, Maryland; right? 4 A. Yes, sir. 5 Q. This is September 1989, a year and two months 6 before that, is it not? 7 A. Yes, sir. 8 Q. It shows on Page 58 suicide attempt, does it 9 not, as a COSTART term? 10 A. Is the left-hand column the COSTART -- yes. 11 That's correct. Well, this is their thesaurus that maps one 12 term versus another, so let me check which column is the 13 COSTART terms. Can I do that? 14 Q. Sure. 15 A. This is the glossary of included terms. The 16 right column is the COSTART term, the left column is the term 17 reported. 18 Q. Right. 19 A. There are about 1400 COSTART terms over here. 20 Those are the COSTART terms. What this glossary does, 21 starting right here, is say if a term comes in like strawberry 22 mark, please carry it to -- 23 Q. Doctor Thompson, look at both sides of the 24 column, sir. 25 A. Okay. They've got suicidal tendency maps to 71 1 suicide attempt. 2 Q. Look at suicide attempt on the left-hand side. 3 A. Okay. Suicide attempt maps to suicide attempt. 4 Q. It's on both sides, isn't it? 5 A. Yes, sir; it is. 6 Q. So suicide attempt was a term in November 1990 7 that could be used to classify an adverse event? 8 A. Yes, sir. I must have been wrong in what I 9 said. They changed it, I guess, earlier. 10 Q. And what's wrong is it's wrong here in 11 Exhibit 111, too, isn't it? 12 A. I guess we were trying to continue the same 13 mapping that we had been mapping in concert with the FDA 14 before. But, again -- 15 Q. You had had this for a year, hadn't you? 16 A. The FDA, if you remember from my deposition, 17 purposely told me to be very careful in changing the way we 18 mapped adverse events, sir. 19 Q. It looks to me like FDA told you in July of 1990 20 to purposely put a cap on the number of adverse events, if we 21 look at Exhibit 92, Doctor Thompson. 22 A. Sir, you're really misrepresenting this 23 completely. If you look at the front page of the memo where I 24 use the word "cap," you will notice at the end of Number Two, 25 cohort study, Doctor Leber talks about the difficulty in 72 1 coming out with an incidence rate, and he says, "Also, it 2 should set an upper limit on the incidence of the emergence of 3 suicidal ideation." That is exactly what's meant by a cap by 4 both Doctor Leber and me. 5 Q. Have you gone back and asked Doctor Leber what 6 he meant when he said cap? 7 A. No. Because he's used that term with me 8 repeatedly, and that's what he's meant every time, and that's 9 what I meant when I read it. 10 Q. He's told you that's what he meant when he says 11 cap? 12 A. Yes, sir. We communicate all the time in 13 scientific terminology and that's what that means, sir. 14 Q. I'm sorry. Okay. Let's go back to 111. 15 A. I want to make very clear again, because you're 16 suggesting that this was some attempt to change the report. 17 Remember, every word that comes to us from an outside source 18 goes to the FDA unchanged, and the FDA does their own 19 classification. So they use their own COSTART terms any way 20 they want to. 21 Q. Can we go back to Exhibit 111? Are you on that? 22 A. That's what I was talking about. 23 Q. All right. Let's look at -- now we know that 24 suicide attempt was a COSTART term and that there wasn't any 25 need in November 1990 to change it to overdose, don't we? 73 1 A. Was it an elect term, because we do not change 2 the COSTART dictionary that we use internally as quickly as 3 the FDA changes theirs because they told us not to. 4 Q. Well, you use the term COSTART on Page 2 of your 5 memo. 6 A. On Page 2 of the three pages? 7 Q. Yes, sir. 8 A. Well, that would be the first page of my memo, 9 wouldn't it? (Reviews document) Okay. But, again, Lilly was 10 trying to do the same thing that FDA did, but there's a real 11 problem when you add or subtract terms or change the buckets 12 they go in, but the problem is that if all of the suicides 13 went into the overdose bucket, at least that's one bucket and 14 you can go look there and find all the reports that will talk 15 about hanging and shooting and thinking and so forth. Once 16 you start putting them in different buckets, then you've got 17 to go look carefully in all the buckets to find them. 18 Q. Let's look in Lilly's own bucket, the elect term 19 dictionary? 20 A. Yes, sir. 21 Q. And let's look at where suicide attempt maps in 22 Lilly's elect term bucket. 23 A. And this is on January 1990? 24 Q. Right. 25 A. Suicide attempt maps to suicide attempt. 74 1 Q. So why change it to overdose? 2 A. I have no idea. 3 MR. FREEMAN: Your Honor, time is about run. 4 JUDGE POTTER: Mr. Smith, when you finish this 5 series of questions we'll take a recess. 6 A. I can make a guess that maybe this wasn't a 7 suicide attempt, maybe it was just an overdose, but I don't 8 actually remember that event. 9 Q. It says suicide attempt was reported by the 10 physician, doesn't it? 11 A. No, I don't think so. 12 Q. It says suicide attempt ran as reported by the 13 physician? 14 A. It said the event term. Why don't we look at 15 the individual report and see what it says. I don't remember 16 it. 17 Q. Well, you go on and on about it on Page 2 of 18 this exhibit, so let's try to get through Page 1. Okay? 19 A. Yes, sir. 20 Q. On the second report there was the request that 21 suicidal ideation be changed to depression; correct? 22 A. That we change it from suicidal ideation to 23 depression. 24 Q. All right. Then Mr. Bouchy says the following, 25 on Page 1, right there at the middle of the page he says: 75 1 "Hans has medical problems with these directions, and I have 2 great concerns about it. I do not think I could explain to 3 the BGA, to a judge, to a reporter, or even to my family why 4 we would do this, especially on the issue of -- sensitive 5 issue of suicide and suicidal -- suicide ideation, at least 6 not with the explanations that have been given to our staff so 7 far. I am quoting, when an overdose is taken in a suicide 8 attempt, our research physicians prefer to list the event term 9 overdose even if when tracking suicides we always look at all 10 overdose and suicide attempt reports," end quote. Correct? 11 A. Yes, sir. That's what he's saying that in fact 12 we look at all the reports and, as you know, we actually don't 13 even look just in the buckets; we go back and search for key 14 words in what the physician said. So we look for S-U-I, we 15 look for H-A-N-G, we look for G-U-N, we look for Dead. We 16 look for all the pieces of words that might be used in 17 describing a suicide and read the original reports. 18 Q. Why divide suicide attempt, Doctor Thompson, 19 into a different event term when you've got suicide attempt in 20 both your COSTART and your elect? Why change it from suicide 21 attempt to overdose? 22 A. We're trying to stick with the FDA, and look at 23 what is quoted. When an overdose -- when an overdose is taken 24 in a suicide attempt, our research physicians prefer to list 25 the event term overdose. Now, as we talked about last week, 76 1 overdose could also be the patient just took two pills instead 2 of one or a patient that was never supposed to take the drug 3 took it. And as I said last week, most of the things you'll 4 find in the overdose bucket will in fact be suicide attempts. 5 But that's where they say go look for a suicide that is 6 attempted by an overdose of drug. That leaves the suicide 7 attempt bucket for people who tried to hang themselves or use 8 carbon monoxide or other attempts. 9 Q. And you deny, Doctor Thompson, that this 10 changing of buckets, that this changing from suicide attempt 11 to overdose is in any way an attempt to put a cap on the 12 number of adverse events reported? 13 A. Those are completely different. The cap refers 14 to trying to statistically estimate what's the highest 15 incident rate for something that you could predict to be 16 occurring. This, remember, doesn't change any word in the 17 original report. We and the FDA and the German government 18 have a report that has every single original word in it. Now, 19 from the FDA, the FDA is going to assign their own COSTART 20 term and they don't care what term we use. 21 Q. Mr. Bouchy says Hans has medical problems with 22 this, doesn't he? 23 A. Yes, sir. 24 Q. And Hans is your medical doctor? 25 A. Yes, sir. 77 1 Q. And he has problems with it, that is, Mr. 2 Bouchy? 3 A. That's right. Because they don't use COSTART in 4 Germany at all; they have a different group of terms. The 5 BGA, I believe, uses the World Health Organization terms that 6 are completely different than the COSTART terms. 7 Q. But he's asking you how to use these terms in 8 English, isn't he, and these terms in connection with 9 reporting adverse events through the FDA; isn't he? 10 A. Yes, sir. Because when we send this report off 11 of our computer back to Germany, in addition to all the 12 original words that came in from the German physician, we type 13 a list of the buckets that we have classified this in on 14 there. And we don't pick up the bucket that the FDA puts it 15 in, and that's why we don't use the SRS system that you 16 described, because if we put it in the suicide bucket they may 17 choose to put it in the overdose bucket or if we put it in the 18 overdose bucket, the FDA may put it in the suicide bucket. 19 We're just trying to have consistent rules so that our doctors 20 know which bucket to go to to find which kind of suicide 21 attempt. 22 Q. Why don't you use your own elect dictionary? It 23 says suicide attempt matches to suicide attempt. 24 A. What they were trying to do there is to put the 25 overdose suicide attempts into overdose and the other attempts 78 1 at suicide like gunshot, hanging and so forth under suicide 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 78 1 attempt, so they could know which bucket to go to for the two. 2 That's all they're doing. The event terms speak for 3 themselves, and every word used by the person who's talking to 4 us goes into these reports, every single word. They're not 5 changed at all. 6 MR. SMITH: Your Honor, I have -- do you want to 7 take a break? 8 JUDGE POTTER: Okay. The 123 through 150 is in, 9 Mr. Smith. 10 Ladies and gentlemen, we'll take the morning 11 recess. As I've mentioned to you-all before, do not permit 12 anybody to talk to you about this case. Do not discuss it 13 among yourselves and do not form or express opinions about it. 14 We'll take a 15-minute recess. 15 (RECESS; BENCH DISCUSSION) 16 JUDGE POTTER: Mr. Smith, since this question 17 came up on your watch, I'll allow you to ask one or two more 18 questions, if you want to; if not, I'll pass it to Mr. 19 Freeman. I don't know if there is an answer. That's a 20 written question from the juror, one of the questions that was 21 given to my sheriff over lunch (sic). Is that the kind of 22 thing he can say yes or no on fairly quickly. 23 MR. SMITH: I don't think he can say yes or no 24 on anything very quickly. 25 JUDGE POTTER: My sheriff just gave it to me. I 79 1 told them they didn't have to put their name on it if they 2 didn't want to. 3 Doctor Thompson, can you step over here very 4 quickly? 5 MR. FREEMAN: Since he's had his time, I'd like 6 to ask it. 7 JUDGE POTTER: Do you know what those questions 8 mean. 9 DOCTOR THOMPSON: The questions are very 10 logical. 11 JUDGE POTTER: Are they things you can answer 12 yes or no? 13 DOCTOR THOMPSON: I can come close to this 14 number. I don't know the number for 100-percent sure. 15 JUDGE POTTER: I'll just do it at the beginning. 16 (BENCH DISCUSSION CONCLUDED) 17 MR. SMITH: Your Honor, before the jury comes 18 in, we probably need to make copies of these events. Can 19 we -- can we do that at noon? 20 JUDGE POTTER: (Nods head affirmatively). 21 SHERIFF CECIL: The jury is now entering. All 22 rise. 23 JUDGE POTTER: Before you do that, Mr. Smith, 24 let's talk about it. 25 MR. SMITH: All right. 80 1 SHERIFF CECIL: All jurors are present. Court 2 is back in session. 3 JUDGE POTTER: Please be seated. 4 Doctor Thompson, I'm remind you you're still 5 under oath. During the break, one of the jurors gave a 6 question to my sheriff. I'll just go ahead and ask it for 7 you. If it's a question you can answer, please do so; if not, 8 say you don't understand it. How many protocols were indices 9 of bipolar disorders studied? 10 DOCTOR THOMPSON: About a half dozen, at least. 11 JUDGE POTTER: And what was the results of these 12 studies? 13 DOCTOR THOMPSON: That the efficacy and safety 14 of Prozac in bipolar disorder looked exactly the same as in 15 the patients that had major depressive disorder, per se. 16 JUDGE POTTER: Okay. Mr. Freeman, do you want 17 to do your cross-examination. 18 19 EXAMINATION ___________ 20 21 BY_MR._FREEMAN: __ ___ _______ 22 Q. Doctor Thompson, while we are on that subject, 23 would you tell the Court and jury what the definition is, from 24 a medical point of view, of a bipolar patient, so we'll all 25 know that we're talking about the same thing? 81 1 A. Yes, sir. There are several different kinds of 2 depression, and the one that we've been talking about most is 3 called a major depressive disorder, and these are people that 4 are depressed, or healthy, but they don't have episodes of 5 mania. And if you have both mania and depression, then you're 6 called bipolar. 7 Now, mania we haven't really talked about, I 8 don't think yet, in this trial. It has nothing to do with the 9 word maniac, but a person who has mania is driven in activity, 10 so that you may find them pacing up and down; you may also 11 find that they have thoughts, florid thoughts that go through 12 their mind. The ones that I've treated often are people that 13 are so committed to converting you to a religion that that's 14 all they can talk about. 15 Q. Let's talk about a couple of examples so we can 16 make this meaningful. Would an example of a manic person be a 17 person that's experiencing a manic episode, the type of person 18 that would try to telephone or use the telephone maybe five or 19 six hundred times a day? 20 A. Yes, sir. 21 Q. And repeatedly call different people about maybe 22 the same subject but try to get everybody several times a day? 23 A. Yes, sir. And wake you up at 3:00 with the same 24 question. 25 Q. And would it be the type person that would not 82 1 sleep, for example, that would be up all night doing this 2 telephoning? 3 A. Yes, sir. Exactly. 4 Q. Would it be the type of person that might go out 5 and try to buy 1,000 stuffed frogs? 6 A. Yes, sir. 7 Q. Or 400 candlesticks? 8 A. Yes, sir. 9 Q. Or not have any appreciation for their money? 10 A. That's correct. 11 Q. Generally speaking, the person that would be 12 very conservative in terms of their money habits and in saving 13 and in scrimping and taking care of those kinds of things 14 would not be described as being in a manic episode? 15 MR. SMITH: Objection to leading, Your Honor. 16 JUDGE POTTER: Overruled. It's preliminary. 17 A. You're correct. One of the common 18 manifestations of mania is they go out and buy everything. 19 They'll overextend their credit cards and, as you say, they'll 20 buy not things that make sense but they'll go out and buy 21 hundreds of the same item. 22 Q. (To the Jury) Did that answer your question? 23 Now, Doctor, so we can go back and cover a 24 little bit of your background so the jury can understand what 25 your education and everything like that is, I'd like for you 83 1 to start with your first college experience and tell the Court 2 and jury where you went and at what age. 3 A. Well, I went to the University of Chicago just 4 after my 15th birthday. 5 Q. And what did you study at the University of 6 Chicago? 7 A. They have -- I was in both a B.A./B.S. program, 8 so it was a general undergraduate curriculum. 9 Q. Following that, did you return home to 10 Charleston, South Carolina? 11 A. Yes, sir. It was a lot cheaper at the College 12 of Charleston, and I went there for two years and went to the 13 University of South Carolina for one year. 14 Q. What degree did you get from the College of 15 Charleston? 16 A. Bachelor of Science Degree with a major in 17 biology. 18 Q. And after that did you continue at that school 19 or go to a different school? 20 A. No, sir. I actually took a year off so my wife 21 could finish -- I was working to put her through her last year 22 of college, and she worked for twelve years to put me through 23 more school until one day she asked me to go to work. It was 24 a terrible experience but... So I went on to other schools. 25 Q. Did you get a Master's Degree in pharmacology? 84 1 A. Yes, sir. I went next to the Medical University 2 of South Carolina, also in our hometown, and after two years 3 they gave me a Master's Degree in pharmacology. Then I did 4 two years of medical school there, and then my fifth year was 5 back in graduate school and, after that, they gave me a Ph.D. 6 in pharmacology. 7 Q. All right. Since Lilly is a pharmaceutical 8 company, tell the Court and jury how your qualifications 9 particularly fit as repects pharmacology first, doing the 10 kinds of work that you have done for Lilly. First tell us, 11 what is pharmacology? 12 A. Pharmacology is a medical specialty that 13 specifically addresses research within the area of drugs and 14 drug effects on animals and on people. Pharmacy is a separate 15 profession that has to do -- everyone knows what a pharmacist 16 is, in terms of carefully helping physicians choose the right 17 medicine for you and so forth. Pharmacology is a medical 18 subject which does the research in terms of how drugs work on 19 animals and people. 20 Q. When you say how drugs work on animals and 21 people, tell me what you're looking at in terms of how drugs 22 work; for example, are you looking to see how they are 23 metabolized? 24 A. Yes, sir. It includes everything from how 25 they're chemically changed in the body, or metabolized, how 85 1 long they stay in the body, what pieces of the body they go 2 to, what -- we now call them receptors, what chemicals in the 3 body they interact with, what changes you can measure in the 4 animals or people that the drugs produce, good effects, side 5 effects and so forth. 6 Q. All right. Sir, you indicated earlier that you 7 had two years of medical school at the Medical School of South 8 Carolina or Charleston? 9 A. Yes, sir. 10 Q. And then after that, you got your Ph.D. in 11 pharmacology? 12 A. Yes, sir. 13 Q. And following that where did you go? 14 A. I went to the Johns Hopkins University, and in 15 the first two years I finished medical school and got my M.D. 16 in 1965, and then I stayed at the Johns Hopkins University 17 specifically at the Oeschler Medical Service at Johns-Hopkins 18 Hospital. 19 Q. Now, wait a minute. You say in what service? 20 A. I'm sorry. The Johns Hopkins Hospital had two 21 parts of the department of internal medicine, and I was on 22 the -- we like to think of ourselves as the more prestigious 23 part, named for Doctor William Oeschler, who was the first 24 professor of medicine at Hopkins. Then I did three years of 25 training in internal medicine there in that service and was 86 1 interrupted by two years at the National Institutes of Health. 2 Q. First of all, tell the Court and jury what the 3 National Institutes of Health is. 4 A. It's a center for research; it's based primarily 5 in Bethesda, Maryland. And when I was there, that was my 6 active duty in the military as a uniformed officer in the 7 public health service and also doing research. In fact, my 8 primary job was building the first intensive care unit at the 9 National Institutes of Health. 10 Q. So is intensive care and critical care about the 11 same thing? 12 A. Yes, sir. In Europe they tend to use the word 13 intensive care; in America we prefer the term critical care. 14 Q. So your principal job while you were working for 15 the National Institutes of Health getting your service out was 16 in building or developing or what for the critical care unit? 17 A. Well, I actually built the first intensive care 18 unit and trained the nurses and physicians and set up the 19 modus operandi and then ran it. At that time there were very 20 few critical care units in the country, so we were really 21 pioneering. 22 Q. And what years were that, please? 23 A. 1967 to 1969. 24 Q. Following that, what did you do? 25 A. Well, I went back and -- the next year was my 87 1 third year as an internal medicine resident at Hopkins, so I 2 completed my training, and Hopkins asked me to stay on the 3 faculty and build an intensive care unit at Johns Hopkins. 4 And I was also on the faculty in pharmacology and a part of 5 the division of clinical pharmacology that specifically does 6 pharmacology research in human beings. 7 Q. We have heard a lot of conversation and 8 questions while we've been here in court about clinical trials 9 and things of that kind. When you talked about clinical 10 pharmacology, tell the Court and jury what you were actually 11 doing in clinical pharmacology while at Johns Hopkins. 12 A. Well, primarily, I was designing and doing 13 clinical trials mostly with experimental drugs in people. I 14 had invented a drug, an artificial blood as part of my Ph.D. 15 dissertation, and I actually completed the clinical trials for 16 that, which eventually led to the drug being approved and it's 17 widely used around the world. And that was part of what I did 18 as a clinical pharmacologist at Hopkins was doing those 19 clinical trials. 20 Q. Did you stay at Hopkins after the critical care 21 unit was completed? 22 A. For a couple of years. I stayed there four 23 years on the faculty, and then my best friend went to be head 24 of medicine at Case Western Reserve University and asked me to 25 go along and build what was then my third intensive care unit 88 1 and also to build a program of clinical pharmacology there 2 because they didn't have a program in clinical pharmacology. 3 Q. Was your friend that went to -- what was the 4 university? 5 A. Case Western Reserve University in Cleveland. 6 Q. Case Western. Was he from Hopkins? 7 A. Yes, sir. 8 Q. And what was his job responsibility at Case 9 Western? 10 A. He was chairman of the department of medicine, 11 professor of medicine. 12 Q. Did you take him up on the invitation to go 13 there? 14 A. Yes, sir. 15 Q. Did you build a critical care unit there? 16 A. Yes, sir. That was my third critical care unit, 17 and I was there as a -- I got promoted eventually to professor 18 of medicine, and I was an associate professor of pharmacology 19 and ran the clinical pharmacology program as well as the 20 critical care program. 21 Q. Now, one thing I'd like you to explain to the 22 jurors is while you were there at Case Western what kind -- 23 did you see patients? 24 A. Oh, yes, sir. 25 Q. Did you see patients in the hospital? 89 1 A. Yes, sir. 2 Q. Did you see patients in the critical care unit? 3 A. Yes, sir. 4 Q. Did you see patients in the critical care unit 5 that in some way had either tried to overdose on a medication 6 or otherwise kill themselves? 7 A. Yes, sir. About a fourth of my patients were 8 patients who had either taken drug overdose -- there were a 9 small number that were accidental poisoning -- or patients who 10 had tried to commit suicide. We put those patients in the 11 medical intensive care unit unless they had a surgical 12 problem, so that if they had shot themselves or had another 13 surgical problem they might go to the surgery department, but, 14 otherwise, they went to the medical intensive care unit that I 15 ran. 16 Q. I see. And did I understand you to say that 17 that was about 30 percent of the people that you saw or 18 patients that you saw in the critical care unit? 19 A. My own patients, it was right at 25 percent. 20 Q. How did your pharmacology background assist you 21 in being of assistance or helping those people who had tried 22 to either overdose on a medication or kill themselves? 23 A. That's very helpful because, especially when 24 these patients take either life-threatening amounts of drugs 25 or if they take multiple drugs that interact with each other, 90 1 it's a very challenging thing in terms of learning exactly how 2 to treat them and knowing who around the world to call for 3 help who might have had similar experiences. 4 Q. How long were you there doing that work? 5 A. I was at Case Western Reserve for seven and a 6 half years. 7 Q. And when you left Case Western Reserve, about 8 what year was it? 9 A. It was April 1st of 1982. 10 Q. And from there did you go to Lilly? 11 A. Yes, sir. 12 Q. All right. I want you to tell me a little bit, 13 please, sir, if you would, about the job opportunities you had 14 in other either medical centers or agencies or otherwise, or 15 had as a matter of being able to consider an opportunity to 16 make a move before you went to -- or at the same time you went 17 to Lilly. 18 A. Well, I didn't want to leave my best friend, 19 Doctor Carpenter, who was also my boss, but he was only a few 20 years older than I was, so that the next step up in the 21 academic ladder would be for me to be a department chairman. 22 And two major universities had offered me jobs as chairman of 23 the departments; the FDA had asked me to come and run the 24 whole Bureau of Drugs, which is all the drug piece of the FDA. 25 And I was looking at those three opportunities and Lilly 91 1 called me up and asked me to come and be the research director 2 at Lilly. And, quite frankly, my wife said she would divorce 3 me if I left academia and when to a drug company. And I only 4 went the first time because I thought I might want to ask 5 Lilly for some money to do some research if I moved to another 6 job, and I thought it would be rude to just tell them I 7 wouldn't even come look at them. And so I flew to 8 Indianapolis and was, frankly, amazed at the quantity and 9 quality of research. 10 So I went back home and told my wife, Marice, 11 that we really had to make this serious. She said, "Well, go 12 get the divorce attorney." But eventually I went back for a 13 second look and Marice became happy with the idea. And 14 finally I even asked my boss, Doctor Carpenter, I said, "Look, 15 I don't want to leave you. I have four job opportunities." I 16 described each one and I said, "Chuck, tell me what to do." 17 And he said, "Well, I want you to stay here, but for your 18 career I understand why you'd probably need to move and I 19 think you ought to go to Lilly." And that was actually the 20 determining reason that I ended up there rather than in one of 21 the other three jobs. 22 Q. And you have been there since April of 1982? 23 A. Yes, sir. 24 Q. Tell me please, sir, anticipating that this 25 question may come up later, what is a doctor that is board 92 1 certified? 2 A. There are -- I think it's 21 now medical 3 specialties that are recognized by a governing group in 4 America called the American Board of Medical Specialties. I 5 actually was working with them to define the field of critical 6 care medicine, which now has a board examination. But to 7 become board certified you have to complete a required 8 training program at an approved location, so Hopkins was 9 approved in internal medicine and I did the three years that 10 are required there. 11 You have to be certified by your professors in 12 that program as being technically competent, knowledgeable, 13 honest, ethical, upright, good citizens, and then you have to 14 take two examinations that are really tough cognitive exams. 15 At the time I took the boards originally, one of those 16 examinations was actually an oral examination where you 17 actually examined patients under the eyes of the examiners; 18 nowadays they're all written exams. And I've taken two -- 19 they're voluntary recertification exams. I'm certified for 20 life in internal medicine, but just to make sure I'm up on the 21 field, I was recertified in '77, and then just last month, I 22 think it was, or the month before, I took another 23 recertification exam. 24 Q. And what area are you board certified in? 25 A. I'm sorry. In the field of internal medicine. 93 1 Q. Now, if a doctor was going to refer me to 2 another physician and I had a neurological or psychiatric 3 problem, what would board certification mean to him in 4 determining whether or not he should send me to Doctor A or 5 Doctor B? 6 A. That's an excellent question and, in fact, when 7 I refer patients I actually get out the book that lists all 8 the board-certified neurologists or the board-certified 9 psychiatrists in an area and look at where they trained and 10 what their faculty ranks are to send my own patients to other 11 people. So being board certified sort of indicates that 12 you've been trained in a good place, that people have said you 13 were honest and honorable and ethical and hard working and all 14 those good things, and then you've taken a rigorous 15 examination on the specific field. 16 Q. And you have done that? 17 A. In internal medicine; yes, sir. I was not able 18 to take the critical care boards because I was writing them, 19 so we were exempted from ever taking them, so I'm not boarded 20 in critical care. 21 Q. Now, in connection with this case, we have been 22 talking at some length and discussing at some length the 23 subject of depression. 24 A. Yes, sir. 25 Q. I would like for you, please, sir, if you would, 94 1 to describe in a general sense -- one of the jurors had a 2 question about the manic depressive -- but in a general sense, 3 if you can divide it into two categories, the two types of 4 depressed patients that one sees and has to decide on a 5 treatment program for that person. 6 A. Well, the more common form of depression is 7 actually I think very well described in the Prozac package 8 insert that I think the jury has. The FDA gave the nine 9 criteria that you use in diagnosing the more usual type of 10 depression. We've said before there's a separate kind, which 11 is not quite as frequent but probably is more hereditary than 12 the usual depression, which is called the bipolar depression, 13 where people either have mania or have mania and depression 14 and they may alternate back and forth between those two 15 states; that's why it's called bipolar. In the depression -- 16 Q. Before we leave that, with the bipolar patient, 17 when you say they go back and forth between the two events, do 18 some psychiatrists and doctors refer to that as the patient 19 cycling? 20 A. Yes, sir. 21 Q. In other words, you may have cycling that will 22 -- say the patient will be profoundly depressed for two years 23 and they will then cycle into a manic phase, or you might have 24 the patient that unfortunately is cycling rapidly, where you 25 go back and forth within a 24-hour period or even shorter 95 1 term? 2 A. Yes, sir. The more rapid cycling is less 3 common, but it certainly is observed. 4 Q. All right, sir. Now, give me then the types 5 that we were talking about of the depressed patients that we 6 see. 7 A. Well, one is the pure depression where the 8 patient has never had a mania event, so they're just 9 depressed, and they may have one episode in their whole 10 lifetime or they may have many episodes, or, in essence, they 11 may really be depressed over many years. And then the other 12 kind is the bipolar, which, again, you can have a single 13 episode of mania and be classified as bipolar or you can have 14 a whole lifetime of oscillating back and forth. 15 Q. All right. Let's talk about the types of 16 depression where the person doesn't have this bipolar 17 component but, rather, is a patient that is depressed. And do 18 they fall into a couple of categories? 19 A. Well, the most common one by far is what's 20 called the major depressive illness, which is what we've 21 mostly been talking about for the last few weeks. Now, there 22 are a couple of other kinds of subtypes, for example, there's 23 psychotic depression, there's drug-induced depression, but 24 those are smaller groups, and I don't think we've talked about 25 them yet in this case. 96 1 Q. All right. Do we consider ever talking about 2 agitation, agitated depression or depression that is retarded 3 or sedated depression? 4 A. Yes, sir. If you look at the nine kinds of 5 symptoms that you would look for to make the diagnosis of 6 depression -- 7 Q. I'm going to try to put this up on the board and 8 then we'll go to the package insert a little bit later, but if 9 you'd come around, Doctor, and discuss with the jurors the 10 importance of these symptoms. 11 A. Yes, sir. Most people require that the patient 12 have at least four of these symptoms, which must include the 13 first one, the depressed mood, or the second one, the markedly 14 diminished interest or pleasure, and there are a couple of 15 other qualifiers before we get into these. One is these must 16 be present virtually every day for two weeks. So if the 17 patient just has a week where they feel all of these symptoms, 18 that would not make them depressed. 19 The second thing is you specifically exclude 20 people in the two months after they have had a very severe 21 emotional event. For example, the horrible tragedy that 22 happened to the plaintiffs, they could have all of these 23 symptoms for two months after the loss of a spouse or a loved 24 one, and that's called bereavement, and you're not allowed to 25 make the diagnosis of depression during that two-month period. 97 1 So the way that you can classify this is, first 2 of all, the people have a depressed mood. They're unhappy. 3 These are people that really are unhappy. And the thing that 4 triggers it to me when I'm talking to a patient is that 5 they've lost the ability to find pleasure in anything. They 6 no longer enjoy their hobbies; they don't enjoy going out to a 7 baseball game; they don't enjoy being with their family; they 8 don't enjoy their children; they don't enjoy their work. Even 9 the things in the past that used to make them happy, they 10 either quit doing or they say they don't really care anymore 11 about them. They've lost the ability to have pleasure. 12 Let me skip over couple, if you would, and come 13 back to it in just a moment. They're very fatigued. And so 14 one of the things you find is that many of these patients will 15 come in to an internist, and they'll complain that "I just 16 don't have the energy to get through the day. I used to be 17 able to work 8 to 10 hours a day and now by noon I'm just 18 really tired." Of course, there are a lot of things that can 19 do that. That's one of the things that makes an internist say 20 have they got a physical problem like hypothyroidism and might 21 they be depressed. 22 Another one I think is important is the feelings 23 of worthlessness or inappropriate guilt. Now, everybody has 24 problems during their lifetime where we don't feel that we've 25 done as well as we might have done. I've never taken a test 98 1 that I didn't think I could have done better on. That's not 2 what this means. These are people who feel that they are 3 really worthless; that the world would be better off without 4 them. Sometimes their guilt is really extreme. They feel 5 they're responsible for the crisis in Iraq; that somehow I 6 have done something so wrong that that's caused the crisis in 7 Iraq, or my daughter's failure in school is somehow due to me 8 personally not being good enough. 9 I want to emphasize to you -- I've lectured for 10 30 years on this topic -- these people have the most pain of 11 any patient I have ever seen. I have taken care of people who 12 had the worst burns, the worst injuries, the worst cancer, who 13 are in absolute agony and who are going to die in the next few 14 days who fight for an another minute of life. And one out of 15 six of these people kill themselves. I personally have had 16 more pain talking to people with depression than talking with 17 any other patients. That's one of the things that tips me off 18 that I may be dealing with a physical problem than with 19 depression. When I feel bad talking to a patient, I say, 20 "Gee, I better think about these nine things on the list." 21 Q. Let me ask you a question right there. You said 22 that one out of six of the people that have the four of these 23 symptoms or five? 24 A. If you have four or five for a period of at 25 least two weeks every day, then you begin to pick up this 99 1 diagnosis. 2 Q. Six out of ten, did you say? 3 A. Nine primary. 4 Q. No, no, wait. Six out of ten persons 5 successfully -- give me those figures you gave me again. 6 A. One out of six people -- 7 Q. One out of six people? 8 A. -- who has had a legitimate diagnosis of major 9 depressive disorder will die by suicide. 10 Q. How many people in that depressive disorder 11 group will attempt suicide? 12 A. It's a very large number. It's about 3.6 13 percent per year of people who've had a depressed illness in a 14 year will have an attempt at suicide. About 70 percent of 15 people are thinking -- we haven't gotten down there yet, but 16 about 70 percent of people are thinking hard about suicide 17 when they have depression, and 1 out of 6 -- and these are 18 often very young people who otherwise, to you and me, we think 19 of these people as being highly successful. 20 Q. Now, while we're down there, there is an item 21 here that talks about significant weight loss or gain. 22 A. Yes, sir. This is specifically when people 23 don't have any reason for this. They're not trying to lose 24 weight, as I should, or they're not trying to gain weight, but 25 they've suddenly gained or lost 10 or 20 pounds. 100 1 Q. And then we have a person that has a sleep 2 disorder with insomnia or hypersomnia? 3 A. Exactly. They even tell you, "I used to sleep 4 eight hours a night, but now I only sleep three or four 5 hours," or they say, "I sleep all the time. I sleep for 14 6 hours a night." 7 Q. And then you have the person that is agitated, 8 what is that, or retarded? 9 A. Or retared, or neither. Remember, you don't 10 have to have -- you don't have to have all of these, but many 11 people with depression have psychomotor agitation, so they 12 tell you they're constantly walking up and down; they just 13 can't sit still, they're piddling with things, playing with 14 paper clips and so forth, or they're retarded where they 15 literally just sit in the corner and they're the ultimate 16 wallflowers, even at work. Even if you call on them, they 17 don't move, they just sit quiet. 18 Q. We've talked about fatigue and loss of energy 19 and the feelings of worthlessness. 20 A. This is important because these people have the 21 inability to concentrate and do their jobs, so one of the ways 22 you pick them up is that they get referred to you by their 23 employers or people that worked with them and say Joe used to 24 be an excellent whatever and, gee, the last couple of months 25 he hasn't been able to do his job. He doesn't file reports, 101 1 we don't know what's wrong with him; has he lost his mind or 2 whatever. 3 Q. Can't concentrate on what's before him? 4 A. Just can't get the job done because they're 5 filled with these feelings of guilt or worthlessness or aren't 6 any good, or you have No. 9, they're thinking of death, but 7 specifically they're thinking of suicide. And this, of 8 course, is a whole spectrum all the way from "I have a 9 fleeting thought" to, "Well, maybe the world would be better 10 off without me so maybe I ought to kill myself with pills," to 11 "Let me go and figure out how to get a cache of pills that has 12 enough that I can kill myself" to saying, "Well, tonight at 13 8:00 when my spouse has gone off will be a time I'll be alone 14 and that's when I'll take the pills and kill myself." There's 15 a whole spectrum of suicidality that acts and then -- 16 Q. Would you go back to the stand. Now, in several 17 points in the testimony, both yours and others to come, 18 reference has been made to 1639s, or drug experience reports? 19 A. Yes, sir. 20 Q. Now, tell the jury first of all what a drug 21 experience report is. 22 A. The drug experience report is required by the 23 Food and Drug Administration, although many regulators in 24 other countries have similar requirements, but that specific 25 name in the form was designed by the Food and Drug 102 1 Administration. And the requirement is that anyone who 2 markets a drug in the United States must report to the Food 3 and Drug Administration anything that happens to anybody after 4 they were supposed to take a drug anytime in their life. Now, 5 I use those words very advisedly because I know that one of 6 our adverse events on Prozac was a patient who got hit by a 7 bus on the way to the pharmacy to have the prescription 8 filled, and that's important because the intent was that the 9 patient would take the drug. So whether they actually took it 10 or not, it doesn't matter. The intent was that that patient 11 take the drug. And a patient who took a drug 20 years ago who 12 had a bad event today, that event should be reported. 13 So these are reports, the bulk of the report 14 besides identifying the patient's age and so forth, the actual 15 words of the person making the report, it could be a 16 physician, a pharmacist, the patient, the patient's spouse, 17 anyone. 18 Q. Let's go back to one area that you just talked 19 about. You talked about the person who is supposed to take 20 the drug but was on the way to the drugstore to get the 21 medication when they were unfortunately hit by a car? 22 A. Bus; yes, sir. 23 Q. By a bus. So this event should be reported 24 under that scenario to the FDA? 25 A. Yes, sir. And it was. 103 1 Q. And I want to ask you, please, sir, if there's 2 not a good reason for that. Is compliance, that is, the 3 patient's dedication to taking their medication, an important 4 element in being able to evaluate these 1629s? 5 A. Yes, sir. The patients often don't take their 6 medicines as prescribed, and, frankly, the best estimate we 7 have across chronic therapy in general -- this is not Prozac, 8 just chronic drugs in general -- is about half of days the 9 patient takes them correctly. Now, that's a startling figure, 10 but many patients never take a drug that's prescribed; many 11 stop; unfortunately, some take too many. So about 50 percent 12 of the time on any given day, a chronic drug is being taken 13 correctly. 14 Q. You understand I meant to say 1639s and not 15 -29s. 16 A. I know that form well. 17 Q. Now, we were talking, sir, about the symptoms of 18 depression. Does Lilly and other pharmaceutical houses and 19 companies have compounds that are designed, for example, to 20 treat bacterial infections? 21 A. Yes, sir. 22 Q. And can the doctor, in determining whether or 23 not to give the patient a particular compound that will treat 24 that infection, know that there are certain symptoms that if 25 you've got a bacterial infection that you will show? 104 1 A. Yes, sir. I mean, pneumonia produces a certain 2 set of symptoms. 3 Q. All right, sir. Is one of them temperature? 4 A. Yes, sir. Fever is one. 5 Q. Is another one anything to do with congestion in 6 your chest? 7 A. Exactly. 8 Q. What are some others that you can think of? 9 A. Well, a person with pneumonia often will have 10 chest pain, shortness of breath, they'll be producing sputum; 11 it has the characteristics of being purulent or yellow pus, 12 but other signs of pneumonia may just be a person feels punk, 13 but when you listen to them with a stethoscope you can hear 14 they have an area of consolidation in the lungs. 15 Q. I want you to listen to this and think with me 16 on this. Would it be unusual for a pharmaceutical company to 17 come out with a new drug that has been approved and offer it 18 to physicians in the treatment of their patients for 19 pneumonia, for example, find that on a new medication such as 20 that, particularly if it's received some publicity both in the 21 public and private press, that there would be a goodly number 22 of reports filed by way of 1639s for congestion of the chest? 23 A. Well, you see a lot of adverse-event reports 24 when you first market a drug, so in the first few years you 25 see a large number of reports of all kinds. It's probably 105 1 less common in looking at pneumonia treatment than a physician 2 would report to you that the patient got pneumonia as an 3 adverse event to the drug. That could occur, but you don't 4 see quite as many of the symptoms of the disease being 5 reported to you as an adverse event. 6 Q. Can you think of another illness that would be 7 maybe better, such as heart disease or some other condition 8 that would generate a report that is a symptom of the disease 9 process that the doctor and the pharmaceutical house are 10 trying to correct or treat? 11 A. Well, another good example is in treating 12 irregular heartbeats, because only recently have we done -- 13 science has done the research to show that some of the drugs 14 that have been used for 30 years in treating irregular 15 heartbeats actually cause irregular heartbeats, and that was 16 quite an astounding finding. So that happens occasionally. 17 But more commonly, aspirin might produce headache, but we know 18 aspirin produces stomach upset and so forth. You wouldn't 19 tend to see too many reports of headache as an adverse event 20 from aspirin, but that could well happen. 21 Q. All right, sir. Now, in connection with the 22 antidepressants and Prozac in particular, would it be 23 surprising for you to see reported to the FDA on 1639s 24 significant weight loss? 25 A. No, sir; not at all. Because, again, if you 106 1 report rigorously, you would report anything unexpected that 2 happened to the patient after they were intended to be given 3 the drug. And our salespeople, for example, we have 1500 4 salespeople in America they're trained to see this. So 5 suppose I was a salesperson and I came into your office as a 6 physician and I said, "You've been using Prozac for a month 7 now, what have you noticed?" And you said, "Well, you know, 8 Mrs. Jones took it and she lost ten pounds." And I would say, 9 "Well, did you expect her to do that," and you'd say no, that 10 would become an adverse-event report. So Mrs. Jones losing 11 ten pounds and everything about that would go to the FDA. 12 Q. Now, I notice that there a number of adverse 13 reports on agitation and things of that nature that have been 14 reported, which is a symptom of depression; is that correct? 15 A. Yes, sir. Depression changes over time, so that 16 the person who looks to you at one day like they're agitated 17 which would give them a high score on Hamilton, either 8 or 9, 18 might the next day or the next week in fact look more like 19 they were retarded. And if you had intended to give them a 20 drug, that kind of new event that you hadn't expected would by 21 definition be an adverse event. 22 Q. So would it be surprising to you to have it 23 reported that there had been a loss of energy? 24 A. I think that would get reported -- if they 25 initially had a loss of energy when you began treating them 107 1 and it got worse, you would probably report that as an adverse 2 event. If they didn't have loss of energy and then that 3 happened to be manifest a week later, you would report that as 4 an adverse event. Ordinarily, if you had loss of energy at 5 the beginning and it got better, you probably wouldn't report 6 that spontaneously as an adverse event. 7 Q. In any event, in the compilations that we have 8 here that Mr. Smith had earlier showed you about suicidal 9 thoughts and about suicide attempts and those kinds of things, 10 is it surprising to you as a physician that these kinds of 11 1639s have been reported and summarized in the documentation 12 that he's given? 13 A. No, sir. The FDA has repeatedly said that we, 14 Lilly, have the best system for collecting and analyzing and 15 reporting adverse events, and the same thing has been said to 16 us by foreign regulators. So we work very, very hard at 17 collecting those data, and we have our sales force trained to 18 report them. So after you market a new drug of any kind, 19 every one we've marketed, you have a huge spurt of 20 adverse-event reports. It takes a lot of work to try to sort 21 them out and figure out what you're getting. 22 Q. And some of those adverse-event reports, if I 23 understand your testimony, have to do with the very symptoms 24 that you're trying to treat? 25 A. Yes, sir. 108 1 Q. All right, sir. Now, Mr. Smith has handed you 2 over the course of your examination documents that have been 3 marked in the case that date back to 1978, '79. Do you recall 4 that? 5 A. I think the cat study went back to 1977. 6 Q. Let's don't forget the cats. Now, what date did 7 that go back to? 8 A. I think that was 1977 when that was published. 9 Q. All right. And then he has given you documents 10 that were created both here and in Germany in 1984 and 1985; 11 is that correct? 12 A. Yes, sir. 13 Q. And he has given you documents that were created 14 by you and others at Lilly in 1989, 1990 and 1991, has he not? 15 A. Yes, sir. 16 Q. All right. 17 MR. SMITH: Your Honor, may we approach the 18 bench? 19 (BENCH DISCUSSION) 20 MR. SMITH: I don't want to make a continuing 21 leading objection, but these are continuing leading questions, 22 and, additionally, the Witness is volunteering hearsay. Could 23 I have a caution to Mr. Freeman not to lead his witness and 24 have a caution to the witness out of the presence of the jury 25 not to volunteer hearsay? 109 1 JUDGE POTTER: I don't know about the 2 volunteering hearsay. Obviously, Mr. Freeman has led the 3 witness, but we're talking about some guy who's a pro. I 4 mean, I guess if you really get down to something more 5 significant, Mr. Freeman, I would sustain his objection about 6 the leading. What do you mean, Mr. Smith, with the... 7 MR. SMITH: "We've been told that we're the best 8 in the industry in reporting adverse events, not only by the 9 FDA but by foreign regulators," and things of that nature. 10 Totally hearsay and self-serving. I know he's spending time 11 and I just don't want to be waylaid by something that is 12 significant. 13 JUDGE POTTER: As to hearsay, you better make 14 your objections. I'm going to be pretty free with letting him 15 lead this fellow. This is a rehearsed routine; he's a 16 professional so... Objection is overruled. 17 (BENCH DISCUSSION CONCLUDED) 18 Q. Doctor Thompson, at the present time, how many 19 countries and their regulatory agencies have approved Prozac 20 for the treatment of depression? 21 A. I know that it's been approved in 75 countries. 22 I think all of them have approved depression because, as you 23 know, others have approved its use for obesity, bulemia, 24 obsessive-compulsive disorder. 25 Q. All right, sir. What I want to ask you now -- 110 1 getting back to the question I had before we went up to see 2 the Judge, what I want to ask you now is that during the time 3 that medications such as Prozac are considered by various and 4 sundry agencies of our government and of foreign governments, 5 are questions raised by these agencies about what the drug 6 does, won't do, will do, may do, might do? 7 A. Almost always. It would be unusual from a major 8 country not to have a whole list of questions raised by the 9 regulatory authority. 10 Q. And in connection with that, did Germany raise 11 certain questions about Fluctin, or Prozac, that was purported 12 to be sold in Germany? 13 A. Yes, sir. The German regulators did. 14 Q. And did Lilly, as it would with any of its other 15 medications, undertake as best it could to answer whatever 16 questions the German government had? 17 A. Yes, sir. 18 Q. Did we report to the FDA in 1985, that the 19 German government had raised some 21 questions about Prozac? 20 A. Yes, sir. We not only reported that, we sent 21 them the whole analysis we had sent the Germans. 22 Q. Give me that again because I didn't get it. 23 A. We not only told them about the 21 questions or 24 whatever the number was, but we also sent them the big package 25 that was the analysis answering those questions that we had 111 1 sent to the German regulatory authority. 2 Q. I want you to look, here, please, sir, while I 3 hand this to the Court, at 177 exhibit number, defense exhibit 4 number. 5 A. Yes, sir. 6 Q. Can you tell the jurors what that is, please, 7 sir. 8 A. This is a submission to the Prozac IND file at 9 the FDA consisting of Pages 13,188 in that file through 10 14,687, and the cover letter shows that this was submitted 11 February 12, 1985. 12 Q. All right, sir. I want you to give me that date 13 again, please. 14 A. February 12 of 1985. 15 Q. All right, sir. I want you, please, sir, to 16 look at the first four pages of the exhibit. 17 A. Yes, sir. That's primarily the cover letter and 18 table of contents. 19 Q. And then have you found the BGA questions that 20 are on Page 13985, or -86, it looks like? 21 A. I have it numbered as -86. It says BGA 22 Questions at the top and that and the following page lists 22 23 questions. 24 Q. All right, sir. So that the jury can see those 25 questions, and I don't want to spend too much time on this, 112 1 but just go back down there briefly and tell the jury what was 2 asked. 3 Can you-all see that? 4 MR. MYERS: Your Honor, we have a copy of the 5 questions for the jury. We didn't make the whole submission. 6 MR. FREEMAN: That will be easier, Larry. Let's 7 do that. 8 JUDGE POTTER: Hand them to my sheriff. Okay. 9 First of all, there's no objection to 177 coming in? 10 MR. FREEMAN: We offer 177. 11 MR. SMITH: I think we've already lodged our 12 objection and had a ruling. 13 JUDGE POTTER: Let me get my sheriff and she'll 14 pass the appropriate page out to the jury. 15 Mr. SHERIFF CECIL: (Hands document to jurors). 16 Q. Now, there are 22 questions in number? 17 A. Yes, sir. 18 Q. And the first one had to do with respect to 19 indications? 20 A. Yeah. They specifically want -- the German 21 regulator wanted to know the German classification of 22 depression because medicine, as you know, is a little 23 different in each country and the German psychiatrists 24 classify depression a little differently than American 25 psychiatrists. 113 1 Q. All right, sir. Let's turn to the next page, 2 18, 19, 20, 21 and 22, to shorten this a little bit, and 3 indicate to the jurors what Lilly indicated to the FDA the 4 Germans had questions about as it respects suicides and 5 suicide attempts and so forth? 6 A. Well, this says that -- one of the BGA 7 questions, No. 18, provide an in-depth analysis of suicides 8 and suicide attempts, and then it notes patient by patient, 9 timing, that probably relates to where they are relative to 10 treatment with Prozac or comparative drugs or sugar pills, 11 symptomatology at trial entry. The Germans are very keen on 12 classifying depression into different buckets, and you pointed 13 out agitated versus retarded. In America, we think that 14 doesn't make any difference in treatment, but the German 15 psychiatrists are very keen on that kind of classification. 16 Phase of trial, I guess that means Phase One, Two and Three, 17 and any other clinically relevant comments. 18 Q. All right, sir. What's the next one? 19 A. Well, they want data on patient tolerance/ 20 safety on concomitant medicines, other antidepressants and 21 neuroleptics. 22 Q. How does that, if it does, differ from what the 23 FDA would want on that subject? 24 A. Oh, I don't think that either of those differ 25 very much from the kinds of things we were submitting to the 114 1 FDA. 2 Q. All right, sir. And what is 20, please, sir? 3 A. Twenty is what conclusions can be made in terms 4 of potential development of dependence and tolerance with 5 long-term therapy. That means does the good effects of the 6 drug or the bad effects, for that matter, wear off as you 7 continue to take the drug. And we had done good studies to 8 show that the good effects didn't wear off, but some of the 9 side effects would tend to occur in the first week or two and 10 then go away. 11 Q. All right, sir. Now, 21 and 22 have to do with 12 what? 13 A. Well, 21 has to do with a classification of 14 depression into nonendogenous, and that's a little arcane, and 15 we don't use it much in America. What I've described to you 16 before as depression is an illness that comes from within the 17 patient; in other words, it's endogenous, it's not a reaction 18 to an external event. Remember I distinguished two months 19 after you have bereavement because of a loss of a spouse or 20 whatever. Exogenous depression in America is usually not even 21 called depression. It's when something bad happens to you, 22 you lose all your money, you have a terrible accident or 23 whatever, and you feel really bad for a few weeks. But in 24 America, it's not thought to even really be the disease 25 depression. And, again, this just reflects the facts that, 115 1 particularly in Germany, they just classify patients in 2 slightly different ways than we do. We had never studied 3 anybody with nonendogenous depression. 4 Q. The main thing I wanted you to direct your 5 attention to is the word efficacy in both those last two 6 questions. 7 A. The last one is: Does Prozac, what is its 8 efficacy and safety in bipolar patients. 9 Q. One of the questions earlier asked by one of 10 jurors. 11 A. Well, the bipolar one is. The nonendogenous -- 12 we just had a study -- at that time, people that had exogenous 13 depression -- 14 Q. Following these questions being asked by the 15 German government and forwarding them to the FDA and so forth, 16 were additional studies done in Germany in hospitals? 17 A. Yes, sir. We did a lot of studies there. I 18 frankly was a little surprised when I came to Lilly to find 19 that the state of the art in American drug companies was 20 generally at the time we submitted a New Drug Application all 21 the studies had been done in America. And we found out that 22 that wasn't the best thing because the German regulators, if 23 you recall from earlier testimony, in essence said "Tell us 24 about how this works in Germany." And, in essence, here we 25 had sent a document to them that had American definitions of 116 1 the disease studied by an American company by American 2 psychiatrists in American patients. And as you can imagine, 3 if a German company had sent that kind of package to the FDA, 4 they'd say, "Hey, how about American diagnoses by American 5 psychiatrists on American patients, so... 6 MR. SMITH: Your Honor, we'd object to that as 7 being hearsay and being clearly self-serving on the part of 8 this Witness. 9 JUDGE POTTER: Overruled. 10 Q. So after the questions were raised, you supplied 11 them with this big packet of information that you have there? 12 A. Yes, sir. Both to the BGA and copied it to the 13 FDA. 14 Q. And you had done before it was approved in 15 Germany additional testing both in hospitals and otherwise? 16 A. Oh, yes, sir. We had a lot of German 17 psychiatrists doing tests with German scales on German 18 patients in Germany. 19 Q. And the medication was approved in late 1989 or 20 early 1990; is that correct, sir? 21 A. In Germany? 22 Q. Yes, in Germany. 23 A. Yes, sir. 24 Q. All right. Now, I'd like to talk with you a 25 minute, please, sir, if we could, about what the companies and 117 1 the FDA that conduct animal studies and clinical trials are 2 trying to determine or predict. 3 A. Well, all of that really is done to try to 4 predict what will happen when you market a drug. And Mr. 5 Smith very correctly indicated that when you market a drug 6 it's going to be used in a wide variety of patients; it's 7 going to be used in a number of different settings. So if you 8 look at it as a timeline, I like to define research as the 9 reduction of uncertainty. 10 Before you've given a new drug, any new drug, to 11 the first animal, you literally have very little idea about 12 what it might do good or bad, so you have huge uncertainty. 13 When you market a drug, you better have a lot less 14 uncertainty, so you ought to be pretty good at being able to 15 predict what will happen in the patients. But, quite frankly, 16 we're not as good the day we market it as we are one or two or 17 five years later. As a matter of fact, I lecture a lot about 18 this process, and I tell people that the time you really know 19 about the drug is five years after marketing. There's an 20 article that comes out in the journal about drugs five years 21 later. So at the beginning you don't know much and you pay 22 attention to every animal. 23 This paper, which is 1977 on cats, is very 24 reflective because every animal you give the drug to, you try 25 to learn everything about. And then you get into human 118 1 beings, and when you give the first human a drug -- I've taken 2 drugs as the first human, the ones I've invented -- you don't 3 know if the drug is going to kill them or do something good or 4 what it's going to do, so you're very, very careful about 5 that. And then after you study a few people, a few patients 6 you learn a little more about the drug and you study more and 7 more and you learn more. At one time, obviously, there was 8 only one human being who had taken this drug in 1976. Today 9 we've got 15 million people that have taken the drug, so we 10 know much more. 11 Q. That's what I wanted to talk to you about just a 12 minute. You indicate that what you want to determine from the 13 clinical trials is make a prediction? 14 A. Yes, sir. I said a prediction of what will 15 happen when you market the drug. 16 Q. Now, the clinical trials that were conducted 17 both in the United States and in other parts of the world, 18 have they or not accurately predicted what would happen when 19 the drug got ino treating the depressed person? 20 A. Yes, sir. For the most part they've been very 21 predictive; certainly the efficacy has been exactly what 22 the -- 23 Q. Efficacy means what? 24 A. Good effects. Most side effects are what we 25 expected from the clinical trial. There were a few that 119 1 completely surprised us. Lowering of the serum sodium 2 concentration surprised us, and we don't today know whether 3 that's related to the drug or not. Causing inflammation of 4 the pancreas, that completely surprised us, and we have no 5 idea -- we don't know today whether that's related to the drug 6 or not. 7 Q. Now, Doctor Thompson, how many people have taken 8 Prozac, according to Lilly's estimates? 9 A. Well, in clinical trials, it was 8,000 at the 10 time of approval in the United States, and clinical trials is 11 now up to about 3 times that. In terms of the marketplace in 12 those 75 countries, roughly 15 million people have been 13 treated with Prozac. 14 Q. Can you give us an idea about how many doctors 15 prescribed Prozac last year for the depressed person, that is, 16 wrote prescriptions for depressed persons? 17 A. In the United States, there were about 11 18 million prescriptions written, but I honestly don't know how 19 many doctors that was. There are 630,000 physicians in the 20 United States and I know there are 11 million prescriptions, 21 but I'm not sure how they connect. 22 Q. Some could have written 10 or 15 or 20 and some 23 could have written 1 is the point you're trying to make? 24 A. Or none; yes, sir. 25 Q. Or none. All right. Now, let's talk, please, 120 1 sir, about how the clinical trials were set up and how the 2 checks were made by the FDA. First of all, can I have this 3 chart? Wait just a minute. Would this be of assistance to 4 you in explaining to the jury how this works? 5 A. Yes, sir. 6 Q. All right, sir. Would you come down before 7 them, please, and give us an explanation of what the chart 8 means and how it relates to the clinical trials. 9 A. Actually, before the first piece here, a company 10 like Lilly would have a program in place to work on a specific 11 kind of disease. So we've been working on making 12 antidepressants for some time, and Doctor Molloy had been 13 actually synthesizing new molecules. As I recall, fluoxetine 14 was the seventy-third molecule in a series to try to find a 15 new antidepressant; nowadays, we often will have a thousand or 16 more molecules in a series before we pick one. So all that 17 happened, and then one day Doctor Molloy made the new 18 molecule, fluoxetine, that had never existed before. And 19 there's a lot of works that had to go on in chemistry to be 20 able to precisely measure it and clean it up so that it was 21 pure and to get it ready to give to the first animal. So 22 that's the work that goes on here. 23 And then that new molecule is injected into the 24 first animal, and you look for how the animal changes, the 25 chemistry, where it goes in the animal, what effects you might 121 1 have, and you do a variety of tests, usually first in mice 2 because they're small and they don't take a lot of your new 3 chemical. And then you move up to rats and then you can get 4 into larger animals, trying to look both at how the body 5 handles this chemical to look at whatever you can about a 6 marker of how it will be effective in a disease. 7 You mentioned earlier pneumonia. That's really 8 easy because you can create pneumonia in animals and see how 9 they respond. Depression doesn't have an animal model except 10 the REM sleep, as we've talked about earlier. And then you 11 also look at what bad things can this molecule do because, 12 after all, if I'm going to be the first human to get this new 13 molecule, I'd like the doctors giving it to me to know the 14 most they can about it. So you actually kill animals with a 15 molecule and find out what the bad things are that happen. 16 Q. Are those tests required or not by the Food and 17 Drug Administration? 18 A. Oh, yes, sir. You have to file this document 19 called the Investigation on New Drug Exemption from the new 20 drug laws, and the FDA requires thousands, thousands of pages. 21 The last one that I submitted as an academician before I went 22 to Lilly was only about 12 pages long; the Lilly ones are a 23 stack about this high with enormous amounts of chemistry, all 24 the animal studies, and the plans for what you're going to do 25 in that first human study. 122 1 Q. Go ahead and then tell me when you say "plan" 2 what you mean by plan. You've used protocol and other words; 3 what is the plan? 4 A. As a minimum, at this point when you haven't 5 given it to people, you have to send the exact protocol you're 6 going to use in the first humans, and the FDA has 30 days. 7 And they can call you up on the evening of the 30th day and 8 say, "You can't go on, you can't dose that human, we have a 9 problem we need to talk about." And then after that, you 10 don't have to have preapproval, but you always have to send 11 the protocol in the hands of the FDA before you actually dose 12 the patient on a new study. So we've had several hundred 13 clinical protocols for Prozac, and today if we started a new 14 one, we'd still have to send the FDA protocol in advance. 15 Q. In a brief way, since we are limited in time 16 here today, I want you to tell us what Phase One, Phase Two 17 and Phase Three are, how the plans worked, giving particular 18 attention to talking about open-label studies, double-blind 19 studies and triple-blind studies. 20 A. Yes, sir. Well, the first Phase One is usually 21 done in normal volunteers unless you have a drug that's so 22 toxic that you would only give it to patients like cancer 23 patients. Cancer drugs are so toxic, we don't normally give 24 them to normal volunteers. This phase you're trying to find 25 out if a drug will do anything bad. 123 1 And then Phase 2 you start giving it to 2 patients. Now, in this phase, Lilly tends to blind it all. 3 Let me try to explain what open label means. Open label means 4 the investigator knows what the drug is. You give them a 5 bottle that says placebo and a bottle that says Prozac, they 6 often will not tell the patient, but the investigator will 7 know which is which. If you just want to measure the 8 chemistry of how much will go into the bloodstream, that may 9 be all right, although we tend to do things double blind, and 10 that's where the patient doesn't know what they're getting, 11 but the investigator also doesn't know what the patient is 12 getting. 13 Q. Why is that important, if it is important, from 14 the scientific point of view? 15 A. I think it is, especially if you want to measure 16 subjective things going on in this chemistry. If you gave me 17 an active drug, I might be more likely to tell you, "Well, I 18 felt a little queasy or I had a little problem with sleep." 19 Whereas, if I knew you were giving me a sugar pill, I might 20 not want to tell you that or I might not feel it. So, the 21 more you want to accurately record adverse events, the more 22 important it is to design it so that the patient nor the 23 investigator know. 24 Now, Lilly invented triple blinding, and we did 25 that at the time we went to the fixed-dose studies on Prozac. 124 1 Q. All right, sir. Now, let's get to -- first tell 2 us what triple blinding is. 3 A. Well, there's no legal requirement by anybody in 4 the world that a sponsor like Lilly running a study has to be 5 blinded. Legally, we can know what patient is doing what. 6 Q. Now, you're getting ahead of us. You're passing 7 over us. 8 A. I'm sorry. 9 Q. We have -- in a triple-blinded study, does the 10 doctor know what the patient is getting? 11 A. The investigator doesn't know. 12 Q. Does the patient know? 13 A. The patient doesn't know; that's double 14 blinding. 15 Q. And does Lilly know in the triple situation, 16 until the data is in, what the patient is getting? 17 A. No. In the triple-blind situation, only one 18 computer expert knows where the codes are buried, and until 19 all the data has been -- we call the term locked -- 20 Q. What does that mean "locked"? 21 A. That means that they've all been checked for 22 accuracy and a copy is locked away so it will never be 23 changed. At that point, we then unblind the study so people 24 at Lilly know which patient got which drug. But that's 25 something we invented; other companies are now doing it and 125 1 generally it is called triple blinding. So we introduced that 2 after the NDA was submitted. Remember, the NDA for Prozac 3 contained data on about 2,000 patients, but at the time the 4 drug was approved, the FDA said they had data on more than 5 8,000 people who had taken Prozac, plus others who had taken 6 comparitors and placebo. 7 Q. Now, to put this in a time reference, the NDA, 8 that is the application, the New Drug Application, was made a 9 little over a year after you got there in September of 1983? 10 A. Yes, sir. It's right there. 11 Q. And it had in its clinical trials about 3,000 12 patients -- excuse me, 2,000. 13 A. A little over 2,000. 14 Q. And then at the time before the FDA had approved 15 the drug, periodically did Lilly have to give a safety update 16 on what was happening with the drug in additional clinical 17 trials? 18 A. Yes, sir. And everything we knew about it from 19 anything, publications. There have been more than 4,000 20 scientific publications on this drug; many of them have 21 nothing to do with Lilly, but we're obligated to report 22 everything that we know about it from all sources. So the 23 stuff that we sent in after the NDA was far more voluminous 24 than the NDA itself. In fact, FDA said it was the largest 25 collection of data that they had ever seen at the time of the 126 1 approval of a new drug. 2 Q. At the time of the approval of the new drug, how 3 many patients had actually received the drug for the treatment 4 of depression in clinical trials, approximately? 5 A. Well, the FDA record from the advisory committee 6 said they had analyzed 8,000 people who had been given Prozac. 7 Not every one of those was for depression, Mr. Freeman, and I 8 can't tell you the exact number, probably at least 7,000. 9 But, of course, we also reported on people with depression 10 treated with placebo and with comparitor drugs like 11 tricyclics, so the package was big at that time and it's 12 gotten bigger since. 13 Q. Now, was Prozac being looked at for other 14 indications, such as smoking or weight loss or bulemia and 15 anything during this period of time? 16 A. Yes, sir. Well, it's been approved so far for 17 treatment of obesity, obsessive-compulsive disease and 18 bulemia. Our studies on smoking cessation, I think are 19 terrific. We went from 9 percent of people being able to quit 20 to 18 percent, but other people at Lilly thought it wasn't 21 worth spending all the extra time to get that approved. We 22 also tried it in alcohol abuse, where the investigators 23 published and thought it worked real well, but it only cut 24 down drinking a little bit; it didn't make people teetotalers. 25 127 1 And now it's being tested for trichotillomania, which is 2 pulling out your hair; and for panic attacks. And I can't 3 even keep up with the catalog for all the things that people 4 are publishing on. 5 Q. What else do you need to explain about the chart 6 before you go back to the stand? 7 A. It takes a long time. I've forgotten the date 8 that Doctor Molloy actually made the drug. I think it was -- 9 Q. I believe it was 1972. 10 A. '72. The first human study was May the 11th of 11 1976, because it was exactly the first day of the second 12 century of our company, and so I remember that one. And then 13 the NDA went in in September of '83. It was approved four 14 years and three months later in almost the last day of '87, 15 and it actually went on the market and became available in 16 this country in '88. It had already been marketed in Belgium 17 and in South Africa, as I recall. 18 Q. Is there anything else you need from the chart? 19 A. No. 20 JUDGE POTTER: Mr. Freeman, Mr. Smith. Let me 21 see you-all for just a second. 22 (BENCH DISCUSSION) 23 JUDGE POTTER: While I was doing my math this 24 morning on adding up the number of hours, I just flat missed 25 it. I thought we'd get through somewhere around 12:30. You 128 1 can go ahead and finish it all or if you'd like to take a 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 128 1 break... I just flat did my math wrong. I came out with 2 somewhere around 12:30. 3 MR. SMITH: That's okay. Doctor Thompson's made 4 some mistakes, too. 5 JUDGE POTTER: The one depression thing you put 6 in, they added that one up wrong. 7 (BENCH DISCUSSION CONCLUDED) 8 JUDGE POTTER: Ladies and gentlemen, we're going 9 to go ahead and take a lunch recess at this time. As I've 10 mentioned to you-all before, do not permit anybody to speak to 11 or communicate with you on any topic connected with this trial 12 and any attempt to do so should be reported to me. Don't 13 discuss it among yourselves or form or express opinions about 14 it. We'll stand in recess until 2:00. 15 (LUNCH RECESS) 16 SHERIFF CECIL: All rise. The jury is now 17 entering. All jurors are present. Court is back in session. 18 JUDGE POTTER: Please be seated. 19 Doctor Thompson. I'll remind you you're still 20 under oath. Mr. Freeman. 21 MR. FREEMAN: Judge, at this time we'd like to 22 offer Exhibit No. 171, the chart that has been previously 23 exhibited to the jury and the chart itself. 24 JUDGE POTTER: Be admitted. 25 MR. FREEMAN: We'd also like to offer, 129 1 Your Honor, the approval letter, which is Exhibit No. 170. 2 JUDGE POTTER: No. 170 is admitted. 3 Q. Doctor Thompson, the jury is presently being 4 passed out a copy of exhibit -- Defendant's Exhibit No. 170. 5 Would you tell the Court and jury what that is, please, sir? 6 A. Yes, sir. This is the letter from the Food and 7 Drug Administration to Lilly on December 29, 1987, was when we 8 received it, approving the marketing of Prozac in the United 9 States for depression. 10 Q. For what indication, please? 11 A. I'm sorry. For the indication of depression. 12 Q. All right, sir. Would you go to the document, 13 please, sir, and tell me precisely how the Food and Drug 14 Administration defined what the drug was approved for? 15 A. Well, the best part of the definition is on 16 Page 6 of their letter. 17 Q. Page 6? 18 A. And that's under Indications and Usage. 19 Q. All right, sir. Would you read the pertinent 20 part of that, please, sir. 21 A. Yes. I think it's the second paragraph in the 22 Indications and Usage section: "A major depressive episode 23 implies a prominent and relatively persistent depressed or 24 dysphoric mood that usually interferes with daily functioning 25 (nearly every day for at least two weeks); it should include 130 1 at least four of the following eight symptoms: change in 2 appetite, change in sleep, psychomotor agitation or 3 retardation, loss of interest in usual activities or decrease 4 in sexual drive, increased fatigue, feelings of guilt or 5 worthlessness, slowed thinking or impaired concentration, and 6 a suicide attempt or suicide ideation." 7 Q. All right, sir. Now, those indications which 8 the letter says four out of the following eight, were similar 9 in nature to the symptoms that we put up earlier; is that 10 correct? 11 A. Yes, sir. I think they're just a restatement of 12 the same -- you had nine points, which are the official 13 DSM-III criteria. These are just the FDA's restatement of the 14 same nine but they put the mood first and then they list eight 15 others. 16 Q. Would it or not be surprising to you if any of 17 those symptoms were reported by a physician or person on a 18 1639? 19 A. No, because this illness is made up of these 20 symptoms. You would expect to see reports of these symptoms 21 in various combinations in the people with depression being 22 treated with this drug. 23 Q. All right, sir. Now, does the approval letter 24 or package insert attached and made a part thereof, give a 25 recommended dosage? 131 1 A. Yes, sir. The recommended dosage was 20 to 80 2 milligrams. 3 Q. What is Lilly's recommendation as to the most 4 effective dose? 5 A. For depression it's 20 milligrams, but for the 6 other illnesses it's 60 milligrams. But restricting this to 7 depression and, that is, as we've told everybody to use 20 8 milligrams once a day. 9 Q. All right, sir. I want to talk to you a little 10 bit about dosage and what went into determining that 20 11 milligrams was the best dose for the most people. First of 12 all, I want to ask you is the medication recommended to be 13 given once a day or twice a day or three times a day? 14 A. It frankly doesn't matter, but once a day is 15 perfectly adequate. 16 Q. If it's a 20-milligram dosage, is that what the 17 caplet comes out in? 18 A. Well, now there's a 10-milligram pulvule on the 19 market, but originally there was just a 20-milligram pulvule. 20 Q. All right. Is the recommended dose for Lilly 21 presently what -- 22 A. Twenty milligrams. 23 Q. -- for depression? 24 A. For depression, 20 milligrams a day in virtually 25 all patients. 132 1 Q. And basically it's once a day; is that correct? 2 A. Yes, sir. 3 Q. All right, sir. Now, what does once a day have 4 to do with patient compliance? 5 A. That's a good point, because one of the key 6 problems in taking a chronic medicine is taking it right every 7 day. And if you have a complicated regimen, it makes it more 8 difficult for the patient to take. For example, four times a 9 day is very difficult for any of us to keep up with exactly. 10 Three times a day is a big problem. And I think earlier Mr. 11 Smith brought out the fact that taking something every other 12 day would also be a real problem. So once a day is by far the 13 simplest and best regimen for taking a drug. 14 Q. What tests, if any, had Lilly done prior to 15 making this recommendation to determine that 20 milligrams per 16 day for depression was the best dose? 17 A. Well, at the time we submitted the New Drug 18 Application, most of the patients had actually been treated 19 with either 60 or 80 milligrams, because the clinical trials 20 that we'd done were the standard ones that everyone had done 21 with all psychiatric drugs, which is you start the first day 22 with a small dose and you rapidly titrate upwards. So in the 23 clinical trials in the NDA for Prozac it started at 20 24 milligrams -- I think it was for one day or maybe two, and 25 then go quickly to 40. The investigator by the end of the 133 1 week was already up to 60 or 80 milligrams, and because this 2 drug is so safe in terms of having side effects, most people 3 tolerated these high doses. So that was the standard. 4 Everyone had always done studies that way. When we submitted 5 the NDA, we decided we would try to do fixed-dose studies. 6 Q. And what does fixed-dose studies mean? 7 A. That a given patient would have exactly the same 8 dose from the first day to the end of treatment, and we would 9 treat some patients with 20, some with 40 milligrams a day, 10 some with 60 milligrams a day, and some with sugar pills or 0. 11 And when we designed that study, first of all, the FDA has 12 emphasized it was the first one ever done with a fixed-dose 13 regimen for a psychiatric drug. And I can tell you that 14 Doctor Wernicke and Doctor Zerbe and I were absolutely sure 15 that 20 wouldn't work at all; we thought 40 might work in some 16 people and that we were going to prove that 60 milligrams was 17 the right dose. And when the day came when the statisticians 18 unblinded that study and showed us the data, we were just 19 flabbergasted. We had absolutely no idea that 20 milligrams 20 was going to turn out to be the best dose. We were shocked. 21 Q. All right, sir. Now, what else did you find out 22 before the drug was approved as respects suicide and safety? 23 In other words, can a patient -- tell the jury about whether a 24 patient -- let's back up. 25 At the time Prozac was approved by the FDA, what 134 1 other medications were available by way of type for the 2 treatment of depression? 3 A. Well, there were two basic types, and each type 4 had a number of different drugs in them; one were the 5 so-called monoamine oxidase inhibitors that increased the 6 brain concentrations of norepinephrine, dopamine, as well as 7 serotonin. 8 Q. And the abbreviation for those, the jurors may 9 see in some of the material? 10 A. MAOI inhibitor, MAO -- I means inhibitor. And 11 the other group were called tricyclics because they have three 12 carbon rings that are struck together, and there are a whole 13 host of those. I think the first in this country was Elavil, 14 but there must have been a dozen on the market, and they also 15 were not specific, so they also -- 16 Q. When you say not specific, what does that mean? 17 A. They work on more than one of the chemicals in 18 the brain. Some of them work on six or eight different 19 chemicals in different ways. 20 Q. All right. So if a doctor should prescribe an 21 MAOI for his patient, inhibitor for his patient, could that 22 patient, if they became depressed, take either his or her life 23 with the medication if they took enough? 24 A. That was one of the biggest problems when I was 25 running the ICUs. 135 1 Q. What's the answer to the question, first? Could 2 they take their life? 3 A. Yes, sir. 4 Q. Go ahead and explain it. 5 A. Well, one of the biggest problems I had treating 6 patients who were either suicidal or taking overdoses was that 7 the antidepressants in existence at that time before Prozac 8 were highly lethal drugs and people often died, and they were 9 very difficult to treat because they caused many life- 10 threatening kinds of symptoms. If you just took a week's 11 worth of pills you could die if you didn't get very intensive 12 care. 13 Q. All right, sir. Now, in determining that 20 14 milligrams was the optimum dose for almost everyone, what did 15 Lilly and the FDA take into account on the subject of 16 titration versus undertreatment, or titration and 17 undertreatment, I should say? 18 A. Well, there were two very important things 19 learned when we did fixed-dose studies. One is, you don't 20 want to give too much of the drug because if you cause more 21 side effects with a high dose, people won't take the drug and 22 will stop taking it and then might get in trouble from their 23 underlying disease. And this is the main problem with the 24 other antidepressants and it's why Prozac has been so 25 successful. The second problem is that you don't -- 136 1 Q. Wait just a minute right there. What does it 2 say to you today when you read and see that 15 million persons 3 are taking or have taken the drug as relates to compliance, 4 side effects and that kind of thing? 5 A. Well, the reason it's so successful is because 6 of its safety, the fact that it has fewer side effects. 7 Mr. Smith, as you recall, we've already talked about the fact, 8 unfortunately, it really only cures two-thirds of people with 9 depression, which is the same as the other drugs; the problem 10 is people just can't take tricyclic antidepressants because of 11 all the bad side effects, and if they take too much of them, 12 they can die of an overdose. 13 Now, the other important point you were -- 14 remember I said there were two points about the titration? 15 The other is you don't want to give too small a dose because 16 if you give too small a dose and don't treat this illness, 17 this is a life-threatening illness because people kill 18 themselves. And so you wouldn't want to undertreat this one 19 any more than you'd want to undertreat cancer or a life- 20 threatening infection, because if you don't treat it 21 adequately, people will have very, very bad events, including 22 suicide. 23 Q. Now, earlier you were asked several questions 24 respecting a study that was looked at by Mr. Wood, which was 25 originally, as I recall it, 5, 10, 20, 40 and 60? 137 1 A. No. We were going to just do -- we had done 2 0, 20, 40 and 60, and we were shocked that 20 was the best. 3 Q. All right. 4 A. The European regulators were asking us to show a 5 dose that didn't work. We were all convinced 20 wouldn't work 6 until we did the study. And so then we were trying to do a 7 second study to find a dose that didn't work. And the debate 8 really was about half of the scientific group said let's do 9 10, 20, 40, and the other half said let's do 5, 20, 40. And 10 since none of us knew what either 5 or 10 would do, we knew 11 the right dose in other illnesses was 60 milligrams, and now 12 we knew with depression 20 was about the right dose. There 13 was this huge debate in front of our chairman, and what Mr. 14 Wood said was, "Well, let's see what happens if you choose to 15 use 10 and you're wrong again, you guys told me 20 wouldn't 16 work; suppose you're wrong and 10 works just like 20. Then 17 you're going to have to do a third study to find a dose that 18 doesn't work and you're not even going to know what dose to 19 try. You might go ahead and try 1 milligram or 2 milligrams 20 and we're going to be here arguing about this forever. So why 21 don't you use the lower dose that you-all have recommended, 22 5 milligrams, because you think that won't work, and at least 23 that will keep us from having to do a third study, a fourth 24 study and a fifth study." 25 So it was really about 50-50 among the 138 1 scientists, and his observation that even if we did 10 and if 2 it didn't work, we'd be okay; but if it did work, we'd be in 3 trouble because then we'd have to go and do a third study and 4 we wouldn't even know the dose. So that held the day, and 5 that's why we used 5, 20 and 40, in hopes that 5 would be 6 significantly less effective than 20, and that's the way it 7 turned out, so we didn't have to do another study. 8 Q. Let me get this plain. Five had some effect? 9 A. Yes, sir. 10 Q. But it didn't have the effect that 20 had? 11 A. That's correct. Remember, placebo, sugar pills, 12 have some effect, but 5 is significantly -- it's different 13 than 20. So we found a dose that was less effective than the 14 20 milligrams, although, interestingly, most of the safety 15 side of it looked exactly the same at 5 and 20. 16 Q. Now, you have indicated that this drug has been 17 looked at for a number of conditions such as bulemia, such as 18 smoking cessation, such as alcoholism, such as -- 19 A. Obsessive-compulsive disease. 20 Q. Obsessive-compulsive disorder, which it's been 21 approved for, I understand. Now, have you had an occasion to 22 take the data, for example -- first of all, generally 23 speaking, is a person that is smoking too much generally 24 suicidal? 25 A. Oh, no, sir. 139 1 Q. All right. 2 A. No more than -- 3 Q. Have you had an occasion or has the company had 4 occasion to look at these other indications to make some kind 5 of scientific judgment as to whether in those patients that 6 were not profoundly depressed or had a co-morbid condition, 7 that Prozac produced in any of those people violence or 8 suicidal ideation, suicidal acts or suicide itself? 9 A. No. There's certainly no indication that Prozac 10 produced any of those events in any of those other studies, 11 but the rate even in people treated with sugar pills is very 12 low because the events that you've mentioned, the violence and 13 the suicide, is just not a part of obesity, obsessive- 14 compulsive disease, smoking and so forth; that's just not a 15 part of the illness. 16 Q. In connection with the studies that have been 17 done, when you compare those persons that are on placebo and 18 those persons that have thoughts of suicide with people that 19 are taking Prozac, how does Prozac come out; is it equal with, 20 better than or worse than placebo? 21 A. Well, in depression it's significantly better 22 than placebo. 23 Q. That's what I meant to ask you. I'm limiting it 24 to depression. 25 A. Oh. Just in depression, then, actually across 140 1 17 studies, 3,065 patients, Prozac was significantly, 2 significantly less likely to be associated with emergence of 3 suicidality than sugar pills, and it was much less than with 4 the alternative antidepressants, the tricyclics. The number, 5 Mr. Freeman, is 1.2 percent of people taking Prozac; 2.6 6 percent of people taking sugar pills; and 3.6 percent of 7 people taking tricyclic antidepressants, so those are 8 significant differences. 9 Q. When you talk about significant differences, 10 from a statistical point of view, what are you talking about? 11 A. I mean that if you did the study over and over 12 and over again, you would most of the time turn up with the 13 same result, that Prozac would be lower than placebo and lower 14 than the tricyclics. If it's not significant, then sometimes 15 it will be lower, sometimesm it will be higher. But this says 16 if you did that same experiment over and over and over again, 17 you'd expect to see Prozac to have the lowest, the lowest 18 likelihood of suicidality, sugar pills in the middle and 19 tricyclic antidepressants as the upper one. 20 Q. What about violent and aggressive behavior? 21 A. Well, there's an excellent study published by 22 Doctor Heiligenstein of that, and what it said is that violent 23 or aggressive behavior in depressed people is 4.3 times more 24 likely on sugar pills than on Prozac. I mean, this isn't that 25 surprising. 141 1 Q. What does that mean in reverse, please? Explain 2 that to me. If it's four point what? 3 A. Three times more likely on placebo, sugar pills, 4 than on patients treated with Prozac. 5 Q. And what does that mean in reverse? Does that 6 mean that it helps that condition or not? 7 A. Well, I think that would be the conclusion, that 8 the disease itself is associated with suicidality and 9 violence. That's part of depression. But if you treat it 10 with Prozac, you decrease the risk of both suicidality and 11 violence and aggressive behavior. That's the way we judge 12 causality. Compared to the disease itself treated with a 13 sugar pill, Prozac improves both suicidality and violent and 14 aggressive behavior. In fact, I know of absolutely nothing 15 that's ever been shown to be better than Prozac in reducing 16 that risk. 17 Q. Now, earlier, talking about statistics and so 18 forth, Mr. Smith asked you a number of questions which I got 19 from the inference from his questions that Lilly and the FDA 20 were in some way trying to say we are going to limit or cap 21 the number of suicidal events by way of ideation, attempts and 22 actual suicides, to a particular number. Now, I want you 23 please, sir, to explain from a statistical point of view what 24 you and Doctor Leber were talking about when you or he or both 25 of you used the word "cap." 142 1 A. Well, Doctor Teischer in his article said that 2 he thought -- 3 Q. Wait a minute. Wait a minute. Wait a minute. 4 I want you to start back with the question. 5 Would you read it back, please? 6 (REPORTER READS THE RECORD) 7 Q. Now, what I'm trying to get at to make it plain, 8 and maybe that's a little long question, but what I'm trying 9 to get at, I'm trying for you to explain what is meant by the 10 word "cap" in terms of statistical projections. 11 A. It's the upper 95-percent confidence limit on 12 the incidence rate, and that actually was described in the 13 first page of that memo. In other words, I have to go back, 14 Mr. Freeman, and tell you about Doctor Teischer. 15 Q. I knew that. I wanted to get that definition 16 first. Now tell me how that came into play in terms of this 17 projection of the upper limit with 95-percent confidence to 18 anything that Doctor Teischer had written or said. 19 A. Well, Doctor Teischer in his article had 20 estimated that the incidence of this intense, very unpleasant 21 suicidal thinking that he described in 6 patients, he said it 22 might occur in 3.5 percent of people treated with Prozac. 23 Well, you know, at this stage we treated lots, thousands of 24 patients with Prozac and we hadn't seen any of these. So he's 25 saying three -- 143 1 Q. Hadn't seen any of what? 2 A. The Teischer-type phenomenon except from Doctor 3 Teischer. 4 Q. All right. All right. 5 A. So Doctor Leber was saying, "I can't understand 6 three and a half percent. That number must be too high 7 because you haven't seen any of it. Can you at least tell me 8 what the maximum incidence could be from all the trials and 9 all the data that you have? Could it be one percent, a half a 10 percent, two percent? Can you give me a cap that shows what 11 that upper limit is." Now, to do that, you've got to have a 12 numerator, the number of events, and you've got to have a 13 denominator, the number of people that are tested. And then, 14 statistically, if you have that numerator and denominator, you 15 can say, well, we've seen one percent. But 95 percent of the 16 time I can tell you for sure it will be less than 1 percent. 17 That's the cap. That's the upper 95-percent confidence limit 18 on the estimate of incidence. 19 Q. Now, very quickly, during the time that clinical 20 trials were going on and up until this time the drug was 21 approved, did the FDA do audits of what was going on in the 22 field by these investigators that were doing the various and 23 sundry clinical trials? 24 A. Oh, my goodness, yeah. The FDA go through the 25 medical records of the investigator to see if they can find 144 1 anything that's not on the case-report form. They come to our 2 files and they check if our copy of the case-report form looks 3 like the investigator's copy. They go to the FDA files to see 4 if the FDA's copy looks like our copy that looks like the 5 investigator. They look at our internal auditing of the data 6 because we audit the investigator, as well. Then we audit our 7 own auditors; then we audit our auditors who audit the 8 auditors within Lilly. I mean, this is a very, very well 9 audited system. 10 Q. Now, you mentioned earlier Doctor Teischer. And 11 are you aware -- you are aware, of course, that Mr. Wesbecker 12 did this shooting on September the 14th, 1989. 13 A. Yes, sir. 14 Q. And you are aware that that got, both locally 15 here in Louisville and elsewhere, tremendous publicity? 16 A. Yes, sir. 17 Q. And you are aware that the Teischer paper came 18 out in February, I believe, of 1990? 19 A. Yes, sir. I think that's right. 20 Q. And, similarly, the Teischer paper both in the 21 the lay press and the medical press got tremendous publicity? 22 A. Yes, sir. 23 Q. Now, as a result of these events, did the FDA at 24 a later time undertake to do yet again another investigation? 25 A. Oh, we've had so many investigations I can't 145 1 even enumerate them but, yes, because of the tragedy here and 2 because of the Teischer paper, the FDA independently on their 3 own did investigations, and they asked us to do reanalyses of 4 data, and they called on experts for the FDA to analyze the 5 data; they even had an advisory committee meeting with experts 6 from all over the world on this issue. 7 Q. Now, I want you to look there at Exhibit 8 No. 172, is it, sir? 9 A. Yes, sir. 10 Q. And tell the Court and jury what that exhibit 11 is, please, sir. 12 A. This is the submission that Lilly made to the 13 FDA in preparation for an advisory committee meeting that they 14 held on September 20th, 1991, to discuss the risk of suicidal 15 ideation and violent behavior with antidepressants, 16 particularly Prozac. 17 MR. FREEMAN: Judge, we did not have this big 18 volume of material made for each juror but wanted them to 19 realize that it would be available for them. We did? I 20 thought we decided not to. 21 You-all want to carry this? 22 We could just make it available to them in the 23 jury room. I don't think anybody wants to carry all this 24 stuff around. 25 JUDGE POTTER: Why don't you leave it there on 146 1 the table, Mr. Freeman. You can put a page up on the screen, 2 if you need it. 3 Q. Now, you have been shown, sir, a number of 4 memoranda both that you wrote and other people at Lilly wrote 5 both by way of E-mail messages, E-mail letters and so forth 6 and so on that occurred after the Wesbecker shooting and after 7 the Teischer paper, have you not? 8 A. Yes, sir. 9 Q. And did Lilly undertake to do its best to answer 10 these questions? 11 A. Yes, sir. We -- we called on experts around the 12 world. We assembled scientists; we asked how to do this; we 13 looked at the literature; we looked at our own data; we did 14 everything I think that you could imagine, both independently 15 of the FDA and with FDA. 16 Q. Now I want you to tell us -- can you see this 17 all right? 18 A. I can see part of it. 19 Q. I want you to briefly tell the jury how the 20 advisory committee came into being and who these people in a 21 general way are, what positions they hold. 22 A. The advisory committee is made up of people 23 outside the Food and Drug Administration. These are usually 24 senior academicians, usually professors, most of them would be 25 physicians, in this case psychiatrists, -- I think there's one 147 1 statistician on this panel -- and they're appointed by the 2 Secretary of Health and Human Services, and they serve on the 3 committee for a few years. And they meet periodically, two or 4 three times a year, and they look at new drugs. Most new 5 drugs in fact go before an advisory committee, like Prozac 6 went before an advisory committee, and they also meet if there 7 are any serious questions raised about a drug, either before 8 or after they're approved. 9 Q. Now, let's make this clear. Was this committee 10 gotten up just to look at the Prozac issue or did it have 11 other functions? 12 A. Oh, no. The committee was a standing committee 13 that met for other functions, but they brought in experts from 14 around the world to add to the regular committee for this 15 hearing. 16 Q. All right. So, now, on Page 1, we have the 17 members of the committee, do we not? 18 A. Yes, sir. 19 Q. And on Page 2, do we have the consultants? 20 A. Yes, sir. Here's Doctor Teischer. 21 Q. Is he the man that wrote the article? 22 A. Yes, sir. 23 Q. All right, sir. 24 A. Doctor Hellander (phonetic) is a member of the 25 Public Citizens Health Research Group, which is the Ralph 148 1 Nader group that had petitioned the FDA to put a black box on 2 Prozac or take it off the market. Doctor Mann; Stuart 3 Montgomery from England; that's Fegler (phonetic), isn't it, I 4 believe, and -- are all psychiatrists, and this gentleman is a 5 real expert in epidemiology of psychiatry. 6 Q. What does epidemiology mean? 7 A. That means in the population at large, who has a 8 disease, what age does it develop, what are the 9 characteristics of it, what's its course. 10 Q. All right. Now, look at the FDA staff. Is that 11 positioned below that, please, sir? 12 A. Yes. Here's Doctor Temple, who was the senior 13 person; Doctor Leber, who heads the division of the 14 psychopharmacological drugs; Doctor Laughren, who works with 15 him; we've mentioned all three of them. And then Doctor 16 Stodel, he comes from a different branch of the FDA, whose job 17 it is to look at adverse events. They're the people who keep 18 all the FD 1639s and do all the analyses of them. And he's 19 the person who analyzed and presented the adverse-event data 20 that Mr. Smith showed, those graphs that had the number of 21 reports of suicidality and hostility. 22 Q. Now, let me ask you about those graphs. You can 23 go back to the stand. On yesterday, I believe it was, or 24 maybe it was on -- 25 A. Friday. 149 1 Q. -- last Friday, a number of graphs were shown 2 that had ball graphs, and they showed fluoxetine, or Prozac, 3 and they showed other comparitors for various conditions. Do 4 you remember that? 5 A. Yes, sir. 6 Q. All right, sir. Now, first of all, who prepared 7 those? Were those prepared by Lilly or by someone else? 8 A. They were prepared by the FDA and Doctor Stodel 9 was the one who presented them and discussed them at that 10 advisory committee meeting. 11 Q. And what was said in explanation to the graphs 12 in terms of whether the numbers were low, high, expected or 13 whatever? 14 A. Well, it's obvious that the raw numbers of 15 reports for Prozac are high, but what the FDA said was that 16 this was not, in fact, a signal that Prozac was causing any 17 problem because there were actually more reports of 18 suicidality associated with Trazodone, a tricyclic, in the 19 first year of its marketing. And they pointed out that early 20 on in the first year or two of marketing a new drug, you tend 21 to see more adverse events, and so they actually found more of 22 them with this tricyclic. 23 Secondly, they said that the publicity 24 surrounding this tragedy and the Teischer paper had caused a 25 lot of people to report similar events. And on those graphs, 150 1 if you recall, there's a W and a T. 2 Q. And what does the W mean on the graphs? Is this 3 the graph that went sort of like that, zigzaggy-looking one? 4 A. The W, of course, is this tragedy here named for 5 Mr. Wesbecker, and the T is the paper published by Doctor 6 Teischer. 7 Q. What did they have to do in FDA's judgment about 8 numbers or about reports? 9 A. Well, it's very important that after those kinds 10 of reports get around, patients and physicians tend to report 11 more and more of the same kind of events. That's why Doctor 12 Leber kept asking us can you go back and use data before the 13 Wesbecker tragedy and before the Teischer paper and look at -- 14 when the FDA did that, they said, well, Trazodone looked even 15 more than Prozac in terms of suicidality. 16 Q. Now, in connection with the case up to the 17 present time, you've heard questions asked by Mr. Smith on 18 numerous occasions about activation and sedation, have you 19 not? 20 A. Yes, sir. 21 Q. Tell the Court and jury whether or not, when you 22 look at this drug from a scientific point of view on studies 23 that have been completed or a study that has been completed, 24 whether or not at 20 milligrams it is either activating or 25 sedating. 151 1 A. Well, I can tell you that definitively because 2 we've analyzed all of the fixed-dose studies that looked at 3 20 milligrams versus 0 in depression for 4 weeks, and here's 4 what the numbers are: 3 percent of people treated with sugar 5 pills have sedating events, 12 percent of people treated with 6 Prozac have sedating events. Now, that's a big difference and 7 it is statistically significant. If you did those same 8 studies over and over and over again, most of the time you'd 9 find out that there are more sedating events on Prozac than on 10 sugar pills. 11 Q. Now, one other question along that line. When 12 the FDA looked at all of these issues, including the labeling, 13 is there a statement that appears in other labels of other 14 antidepressants with respect to watching depression, or 15 depression and suicide? 16 A. Yes, sir. There's virtually the same statement 17 that's in our label. 18 Q. I'm going to ask you to look at this, please, 19 sir, and compare it with the approval letter that you have 20 there, if you would be so kind. 21 A. Yes, sir. 22 Q. Can you see the material that is written on the 23 -- that is shown there on the television monitor? 24 A. Yes, sir. I can see that. Give me a second 25 with the approval letter. 152 1 Q. (To Mr. Myers) Do you have a page site on that 2 as to where that is? 3 A. I have the approval letter. It's actually 4 Page 8 of the approval letter that has the paragraph about 5 suicide, "The possibility of suicide attempt is inherent in 6 depression." 7 Q. Let me show it because I'm not sure they can see 8 this. "The possibility of a suicide attempt is inherent in 9 depression and may persist until significant remission occurs. 10 Close supervision of high-risk patients should accompany 11 initial drug therapy. Prescriptions for Prozac should be 12 written for the smallest quantity of capsules consistent with 13 good patient management in order to reduce the risk of 14 overdose." 15 A. Yes, sir. That's what's in the label, and it's 16 not only in the label for Prozac; essentially the same words 17 are used for every antidepressant I'm aware of in this 18 country. 19 Q. Now, I'll ask you to look at the risk patient 20 labeling that this is information that goes with the medicine 21 to the patient in Germany. 22 A. Well, it's important to remember, this is 23 special patients, not the risk of the drug, it's special 24 patients, and this talks about the risk of suicide and 25 depression. It says -- 153 1 Q. Now, before we get to that, let's make that 2 plain. It says, "Risk patients. Dysfunction of the liver," 3 and then there's a paragraph about that; is that correct? 4 A. Yes, sir. These are special patients you have 5 to have patient thinking about in treating them. 6 Q. Diabetes. Simultaneous treatment. 7 A. Yes, sir. 8 Q. Risk of suicide. 9 A. Yes, sir. 10 Q. Epilepsy. Electric shock therapy and limited 11 function of the heart or respiratory system. 12 A. Yes, sir. 13 Q. Does this document, in your judgment, attempt to 14 assign any causation for any of those conditions to the 15 medication described? 16 A. Oh, heavens, no. These are talking about the 17 patients with depression that are going to be treated. 18 Q. All right, sir. Now, when you get down to the 19 bottom -- the middle of the page and you read risk of suicide, 20 fluctin is Prozac, isn't it? 21 A. Yes, sir. 22 Q. "Does not have a general sedative effect on the 23 central nervous system." Is that correctly read? 24 A. That's what they said. 25 Q. "Therefore, for his/her own safety, the patient 154 1 must be sufficiently observed until the antidepressive effect 2 of Fluctin sets in." Is that what it says? 3 A. Yes, sir. 4 Q. "Taking an additional sedative may be 5 necessary." 6 A. Yes, sir. 7 Q. "This also applies in cases of extreme sleep 8 disturbances or excitability." 9 A. Yes, sir. 10 Q. Now, in connection with Mr. Wesbecker that we 11 are investigating here, was Mr. Wesbecker on Restoril? 12 A. Yes, sir. 13 Q. And was he on Restoril at the time that he did 14 what he did to these people? 15 A. Yes, sir. He had therapeutic levels in his 16 blood of that benzodiazepine. 17 Q. Now, I'm not suggesting that that caused him to 18 do anything, but what is that medication? Does it fit within 19 the categories that they're describing there? 20 A. Some people would call it a sedative; I'd call 21 it more of a -- benzodiazepine is an anxiolytic; it relieves 22 anxiety. 23 Q. Does it have a sedating effect? 24 A. Oh, yes, sir. 25 Q. Is it taken for sleep disturbance from time to 155 1 time? 2 A. Yes, sir. 3 Q. And you tell us that after the autopsy this 4 gentleman, Mr. Wesbecker -- or this man, Mr. Wesbecker, had 5 this in his system, that is, a sedation? 6 A. Yes, sir. The level in his blood was in the 7 therapeutic range. 8 Q. Now, we were talking earlier about the 9 differences in how people practice medicine here and in 10 Germany; is that correct? 11 A. Yes, sir. 12 Q. In Germany they have a statement in the 13 literature about a sedative; is that correct? 14 A. Yes, sir. 15 Q. Here Doctor Coleman knew to give him a sedative 16 with his background, did he not? 17 A. Yes, sir. 18 MR. SMITH: Objection to what Doctor Coleman 19 knew based on his background. 20 JUDGE POTTER: It's also very leading. 21 Sustained. 22 Q. Did Doctor Coleman give him Restoril in this 23 instance? 24 A. Yes, sir. 25 Q. Now, I'd like you, please, sir, to go, if you 156 1 would, to the document that we have -- that we will now 2 introduce. 3 A. Yes, sir. 4 Q. And while we're looking -- going to look at that 5 for just a minute. But while we're talking about that, did 6 the FDA have a public hearing on this issue or these issues? 7 A. Yes, sir. On September the 20th, 1991, after a 8 lot of analysis, not only with FDA personnel but with experts 9 from around the world and with all of the analysis of our 10 data, the FDA had a day-long meeting that was a public forum 11 that investigated and talked about this extensively. 12 Q. CBS News were present or other news media people 13 were there? 14 A. Yes, sir. 15 Q. And there was an audience there? 16 A. Big audience. 17 Q. And there were experts that appeared? 18 A. Yes, sir. 19 Q. Now, what questions during that proceeding was 20 the FDA seeking to have the advisory committee answer? 21 A. First of all, there was the question of is it 22 possible that antidepressant drugs in general could increase 23 suicidality or violent behavior. In other words, we know 24 that's part of the illness; is it possible that the drugs used 25 to treat them could increase the risk. And then the second 157 1 question was: Is there any special drug or class of drugs 2 that seem to have greater risk than the others in terms of 3 being associated with suicidality or violent behavior. 4 Q. Was Prozac specifically looked at? 5 A. Well, the meeting was really called for all 6 antidepressants but, frankly, Lilly was the only company that 7 agreed to appear, and virtually all the discussion or almost 8 all the discussion was about Prozac. And what they said was 9 that Prozac had been studied more than any other drug in this 10 regard, so it was really the primary focus of this meeting. 11 Q. Now, at the end did they ask the question of 12 those assembled? 13 A. Yes, sir. There was a formal vote taken by the 14 committee members. 15 Q. All right. I believe there are two findings in 16 connection with that. Would you ask what the questions were 17 of these group of experts and what their answer was and if it 18 was unanimous or 100 percent? 19 A. Yes. On each of those questions, the first 20 one -- 21 Q. Give me both of the questions again. 22 A. The first one is, is there evidence that 23 antidepressant drugs as a group, any antidepressant drug, 24 increases suicidality or violent behavior or both, and the 25 vote on that was unanimous, ten to zero, that there was no 158 1 evidence of that happening. 2 And then there was a further discussion of are 3 there certain classes of drugs or individual drugs like Prozac 4 that have greater risk of being associated with suicidality 5 and violent behavior, and again the vote there was that there 6 was no evidence that any group of drugs or individual drug was 7 associated with greater risk, and that also was unanimous, ten 8 to zero. And Doctor Teischer, who was sitting there, said 9 that those were honest votes and that he was pleased with 10 them. 11 MR. SMITH: Your Honor, we'd object to that. 12 It's total hearsay, it's self-serving, and request that the 13 jury be instructed to not consider that and request that the 14 Witness be cautioned concerning statements of that nature. 15 JUDGE POTTER: I'm going to sustain the 16 objection. 17 Q. Now, in one place I understood you to say no 18 credible evidence. 19 A. Yes, sir. There were actually two statements in 20 the report of that committee meeting that was made by the FDA. 21 Q. What does the word "credible" mean to you? 22 MR. SMITH: We'd object to this Witness defining 23 credible; that has legal significance. Whether or not -- what 24 the FDA meant by credible is certainly something of a wholly 25 different matter. 159 1 JUDGE POTTER: Objection is overruled. 2 A. Well, credible also has scientific meaning, as 3 well. And I'm not a lawyer, but let me define it from the 4 scientific standpoint, and that is, they said there was no 5 credible evidence of a causal link between the use of 6 antidepressant drugs, including Prozac, and suicidality or 7 violent behavior. That means that if you looked as a 8 scientist at the evidence, none of it was scientifically 9 credible, because, remember, if you whispered to me in the 10 hall that you thought that Prozac caused violence, I guess 11 that's evidence; it's a statement. This says looked at as a 12 scientist there's no credible evidence. But the chairman of 13 the committee, in summarizing the day's meeting, used the 14 word, "There was no evidence showing an increase of 15 suicidality with any of the drugs in depressive or 16 nondepressive patients and, regarding Prozac, we probably have 17 looked more closely and analytically at those data than on any 18 other antidepressant drugs." 19 Q. Did the committee look at violent hostile 20 behavior, as well? 21 A. Yes, sir. 22 Q. And what did they find with respect to that? 23 A. Well, the vote was actually the same because it 24 included suicidality, violent behavior, either or, or both. 25 Q. Ten to zero? 160 1 A. Ten to zero on both votes. 2 MR. FREEMAN: Just a minute, please. Judge, we 3 offer 172 and 173. 4 JUDGE POTTER: Be admitted. If you'll hand them 5 to my sheriff, Mr. Freeman, she'll pass them to the jury. I'm 6 sorry. 7 SHERIFF CECIL: (Hands document to jurors). 8 MR. FREEMAN: That's all we have at this time, 9 Your Honor. 10 JUDGE POTTER: Mr. Smith. 11 12 FURTHER_EXAMINATION _______ ___________ 13 14 BY_MR._SMITH: __ ___ ______ 15 Q. Doctor Thompson, in this data that was submitted 16 to the FDA in -- or to the PDAC in September 1991, there is no 17 mention there, is there, in connection with clinical trial 18 data outside the United States, that Lilly had gone to Europe, 19 reviewed the case-report forms and pulled out mentions of the 20 suicidality out of the case-report forms and reduced the 21 number of suicides seen in the outside-the-U. S. data, is 22 there? 23 MR. FREEMAN: I didn't understand the question. 24 Objection. 25 JUDGE POTTER: Did you understand the question? 161 1 DOCTOR THOMPSON: No, sir. 2 JUDGE POTTER: Mr. Smith, why don't you repeat 3 your question. 4 Q. Let me see if I can break it up and make it more 5 understandable for everybody. 6 After this phenomena arose, Lilly sent a team of 7 investigators to Europe, did they not? 8 A. Yes, sir. 9 Q. And collected case-report forms, did they not? 10 A. Yes, sir. 11 Q. Reviewed case-report forms, did they not? 12 A. Yes, sir. 13 Q. And eliminated what had earlier been described 14 as suicide attempts in those case-report forms. 15 A. I'm not aware of that. 16 Q. You're not aware of that? 17 A. No, sir. 18 Q. Then you don't know of any mention that might 19 have been made of that in Lilly's submission to the PDAC? 20 A. Well, I haven't reviewed this entire document 21 recently, but I wasn't aware, one, that it happened and, two, 22 that that was mentioned in here. 23 Q. All right. You don't know about Doctor Beasley 24 and Doctor Heiligenstein having a table full of case-report 25 forms that mentioned suicide attempts and then, after they got 162 1 through going through those, ending up with one pile of 2 documents about that size? You don't remember that as chief 3 scientific officer of the corporation? 4 A. I wasn't part of that activity. 5 Q. Did you ever talk to Doctor Beasley or Doctor 6 Heiligenstein about their review of the European case-report 7 forms in connection with suicide attempts? 8 A. I know they were struggling to assign causality 9 to the events, but I'm not aware that any case-report forms 10 got deleted from the data base in any way. 11 Q. No. I'm talking about where they went back and 12 decided for analysis purposes that whatever the investigator 13 has called a suicide attempt was not indeed a suicide attempt 14 but was something else. You don't know anything about that, 15 Doctor Thompson? 16 A. I know that the reverse occurred a lot, that 17 they went back and called investigators up to check to see if 18 something in fact was a suicide attempt. I'm sure, I guess, 19 the other side happened, as well. I don't know. They 20 followed up on a lot of those adverse events. 21 Q. You don't know about Doctor Catherine Mesner -- 22 Mrs. Catherine Mesner and a bunch of clinical research 23 administrators going to Spain and Europe to collect this data 24 from Europe in connection with the Lilly clinical trials? 25 A. I don't remember Spain, but we sent a team over 163 1 to get the original data on the case-report forms. 2 Q. And the reason that they went over there was to 3 review that data in connection with suicide, wasn't it, Doctor 4 Thompson? 5 A. It was about that issue and violence that we 6 were sending them over to collect the data, yes. 7 Q. And don't you know, sir, that what they in fact 8 did was reduce the number of suicides that had been reported 9 by citing that these weren't suicide attempts at all? 10 A. No. I know that they were interested in trying 11 to look at causality, but I'm 100-percent sure they would not 12 change the data on the case-report forms. 13 Q. Well, did they assign causality, then, to any of 14 those suicide attempts? 15 A. I hope so. 16 Q. And did they assign that causality as being 17 related to the ingestion of Prozac? 18 A. I don't remember if they assigned any of those 19 as being more than possibly related. I don't think any of 20 them fell into the probable box. 21 Q. Wait a minute. Let's see if we understand this, 22 Doctor Thompson. You sent a team to Europe to investigate 23 this issue, to review the European case-report forms, and you 24 were hoping and it was your understanding that they were 25 reviewing causality, is your term; is that right? 164 1 A. They were going, first of all, to get the data 2 because we didn't have it in the U. S. computer data base and 3 we wanted all the data we could get. 4 Q. You said they were reviewing causality, didn't 5 you, Doctor Thompson? 6 A. As part of their analysis. The first thing they 7 were doing was -- 8 Q. Let me get my question here. Was there a 9 determination that any of those suicide attempts were causally 10 related to Prozac? 11 A. I don't believe so. 12 Q. All of them were not related by their 13 investigators -- by your investigators; is that what your 14 testimony is? 15 A. Now, by my investigators, do you mean the 16 original investigators treating the patients or do you mean 17 the Lilly personnel? 18 Q. I'm talking about Doctor Beasley, Doctor 19 Heiligenstein and Doctor Wheadon, the individuals that 20 reviewed these case-report forms, the Lilly psychiatrists. 21 Did they determine causality to any instances of attempted or 22 completed suicides or violent-aggressive behavior in 23 connection with Prozac? 24 A. My best recollection is that none of those 25 events from the clinical trials were judged to be causally 165 1 related, either individually or certainly not collectively. 2 Q. Didn't find a one that was judged to be related? 3 A. That's my best recollection of the data from the 4 clinical trials as you've talked about. 5 Q. Well, anything. I thought -- were you looking 6 at just clinical trial data or were you looking at 7 postmarketing events, too? 8 A. Well, in the exercise that you're describing, 9 the case-report form would only come from a clinical trial. 10 Q. What about postmarketing data? 11 A. Independently we were also looking at all the 12 adverse events reported worldwide in marketing use, yes. 13 Q. Did you independently investigate any of those 14 postmarketing adverse events? 15 A. Yes, sir. 16 Q. Did you determine whether any of those were 17 causally related to the ingestion of Prozac? 18 A. We've already been over that in great detail. 19 Several of them were checked possibly causally related, and 20 we've gone over that in great detail. 21 Q. My question is: Did you advise the PDAC of 22 that? 23 A. I have no idea whether that was in here or not 24 because the FDA had every single one of those FD 1639s 25 describing the adverse events in detail, and the FDA forbade 166 1 us, forbade us, for making causality judgments and told us to 2 report them all, because the FDA didn't want causality 3 judgments. 4 Q. No, Doctor Thompson. I'm talking about your 5 submission to the committee. Did you advise the PDAC that you 6 had determined that some were causally related to the use of 7 Prozac? 8 A. This is the submission to the Food and Drug 9 Administration. The Food and Drug Administration had the 10 computer records of those FD 1639s and, as you know -- 11 Q. Then why make any submission, Doctor Thompson? 12 MR. FREEMAN: Let him finish, please. 13 A. -- on the margin of those reports, even though 14 the FDA doesn't want it, there was a note that a couple of 15 them were judged to be possibly causally related; it was put 16 on there for foreign regulators, but as you know from the 17 copies you've shown me of those documents, the FDA got the 18 same documents, so they had had that for some time. Now, this 19 was added to -- this was an analysis added to and summarizing 20 all the data the FDA already had. To my knowledge, there's no 21 new data in this report that the FDA had never seen, their 22 analyses of the data. 23 Q. But, see, Doctor Thompson, what I don't 24 understand is if this special committee is investigating this 25 issue and Lilly has made a determination in some instances 167 1 that Prozac was causally related to suicidality and violent- 2 aggressive behavior, why didn't you mention it in the 3 submission to the committee? 4 A. Because the committee works for the Food and 5 Drug Administration and most of the information the committee 6 is given comes directly from the FDA. 7 Q. I thought you told us the committee was 8 independent of the Food and Drug Administration, that they 9 were eminent psychiatrists, world renowned and that they were 10 here conveyed -- and looking at this special matter. 11 A. Mr. Smith, the committee members are not 12 employees of the Food and Drug Administration. 13 Q. That's correct. They're academicians, you said. 14 A. And they're paid by and appointed by the 15 Secretary of Health and Human Services. They work over a 16 period of years with that part of the FDA. It's a standing 17 committee. They meet three times a year. Some of them are 18 called in on special questions. They're paid by HHS. They in 19 fact have all kinds of data submitted directly from the FDA. 20 This was a submission we voluntarily made, showing some 21 detailed new statistical analyses of data that they had 22 already seen from the Food and Drug Administration. 23 Q. Then why submit it to them? 24 MR. FREEMAN: He's not finished with his answer. 25 JUDGE POTTER: Well, objection is overruled. 168 1 A. We had no requirement to make the submission, 2 and the submission went to the Food and Drug Administration 3 for the purposes of both the FDA and the advisory committee 4 reviewing it. 5 Q. You say here, "Enclosed for distribution to the 6 committee members in advance of the meeting are 30 copies of 7 the summary report of our presentation." You made one up for 8 each member of the committee, didn't you? 9 A. There are only ten members of the committee and 10 this letter goes to the FDA, goes specifically to Michael 11 Bernstein. 12 Q. But you gave it -- I mean, it says that they're 13 for the committee members, doesn't it? 14 A. We're forbidden by regulation and law to 15 communicate directly with the committee members, so we submit 16 things to the FDA and the FDA decides what they will give to 17 the committee. We are not allowed to in any way communicate 18 directly with the committee members. 19 Q. Doesn't this sentence right here say, Doctor 20 Thompson, "Enclosed for distribution to the committee members 21 in advance of the meeting are 30 copies of a summary report of 22 our presentation"? 23 A. Mr. Smith, look who the -- yes. The answer is 24 yes. Look who it was addressed to. 25 Q. I understand that, but didn't you expect them to 169 1 give this and didn't you expect this to be seen by members of 2 the committee, Doctor Thompson? 3 A. I hoped so, yes. 4 Q. Okay. That's my point. Did you tell -- did you 5 mention in here that you had assigned causality as reasonably 6 probably related already to incidences of violent-aggressive 7 behavior and suicidality? 8 MR. FREEMAN: That's a misstatement of the 9 Witness's testimony. 10 JUDGE POTTER: I think it is a misstatement, Mr. 11 Smith. He used a different term. 12 Q. Did you tell them that you made any assignment 13 of causality? 14 A. Oh, yes, we did. But you're talking about 15 apples and oranges. You're asking me did we specifically call 16 attention to the two of the thousands of reports on which we 17 had checked "possibly related." The causality analysis here 18 was extremely detailed, and I've already read you what the 19 committee felt about the causality because the committee would 20 not, frankly, be interested in our causality assessment on any 21 individual adverse event or even on a whole bunch of them. 22 They were only -- 23 Q. Why wouldn't that committee be interested in 24 that? Isn't that what they were looking at? And aren't you 25 the manufacturer of the drug? And aren't you the ones that 170 1 conducted the clinical trials? And aren't you the one that 2 paid the investigators? And aren't you the one that 3 investigated these instances of these adverse events on these 4 drugs? Who else would have closer information concerning 5 whether or not any particular event is related to the drug 6 than Eli Lilly themselves? 7 A. We presented data from a huge number of 8 controlled clinical trials in which it's possible to 9 scientifically make a judgment of causality. The Food and 10 Drug Administration, Doctor Stodel specifically, presented the 11 data from the spontaneous reports that you've already shown me 12 and the jury, and Doctor Stodel described his analysis of the 13 totality of all of the adverse-event reports. So we focused 14 primarily upon the controlled clinical trials, and the FDA and 15 the FDA staff focused primarily on their data base about 16 postmarketing adverse events because, remember, they had 17 events that came in from other people than Lilly, so their 18 data base was bigger than our data base. 19 Q. Let me ask you this, Doctor Thompson: Is there 20 any mention in there that the German government saw this as 21 being a problem in 1984 or '85? 22 A. I sure doubt it, because by this time it no 23 longer was a problem in the minds of any of the foreign 24 regulators and after this meeting it no longer was a problem 25 in the minds of the FDA. 171 1 Q. Did you mention in there that Doctor Schenk had 2 said as long as this product is used in Germany in accordance 3 with the package inserts, that is, with concomitant use of 4 tranquilizers and sedatives in agitated or suicidal patient, 5 that there shouldn't be any question about the benefit/risk 6 ratio? 7 A. I hope to goodness we didn't say that, Mr. 8 Smith, and I bet we didn't mention the cats from 1977, either. 9 At the time this was done, we had submitted 2.5 million pages 10 of analysis. We had data of tens of thousands of people in 11 controlled trials and millions of people that had taken the 12 drug, and there had been four thousand scientific publications 13 on Prozac. And looking at all of those data, all of those 14 data, I read you what the committee concluded unanimously. 15 Q. Is this -- did you expect that the data would be 16 reviewed in this summary form by members of the committee or 17 did you expect that they would review the 2.5 million pages? 18 A. Well, I know they went back and reviewed data 19 that the FDA showed them that's outside of this submission. I 20 know that. 21 Q. My question is simple: Did you expect that they 22 had reviewed and were conversant with that data, Doctor 23 Thompson? 24 A. Not all 2.5 million pages, but whatever the 25 pieces were that the FDA thought were significant for them to 172 1 see, the FDA presented to them in advance and at the meeting. 2 Q. Did you tell or did you mention in that 3 presentation Doctor Seymour Fischer's study? 4 A. I don't think so. 5 Q. Did you mention the Taiwanese study? 6 A. I don't think so. 7 Q. Did you mention Doctor Frankenfeld's work? 8 A. I don't know who that is. 9 Q. The medical examiner, I believe, in North or 10 South Carolina who found an abnormally high incidence of 11 violent suicides in connection with Prozac use. 12 A. I'm sorry. That's the first I've heard of that, 13 sir. 14 Q. Did you mention in here that the FDA had 15 suggested that a rechallenge study be done? 16 A. No, sir. I expected the FDA to tell them that. 17 Q. Did you mention in here that there was a request 18 from a large -- for a large prospective study? 19 A. No. I expected the FDA to tell them that. 20 Q. Using a new instrument to measure suicidality? 21 A. The document speaks for itself in terms of its 22 content. 23 Q. Was there any mention made about the fact that 24 Doctor David Dunner was on this committee and had also been a 25 Lilly investigator and has also been on the Lilly psychiatric 173 1 advisory board? 2 A. Yes. At the beginning of the meeting there was 3 an extensive discussion of any possible conflict of interest, 4 and for each of the members of the committee, they described 5 in detail their relationships with all drug companies making 6 antidepressants. 7 Q. Did -- wasn't Doctor Tollefson there and made a 8 presentation orally? 9 A. Yes, sir. 10 Q. And didn't he say that, "We view the data that 11 are generated from spontaneous-event reporting and case 12 reports to be hypothesis generating. We have chosen to test 13 these hypotheses based on the remaining three methods of 14 studies that I've cited. These alternatives include 15 prospective suicide specific trials, epidemiologic data bases 16 and detailed studies drawn from controlled double-blind 17 clinical trials in consultation with the Food and Drug 18 Administration and noted external experts in the field of 19 depression and suicidality. We have already generated a 20 series of protocols to better characterize patients who 21 experience an increase in suicidal ideation during 22 pharmacotherapy and other forms of treatment." 23 A. I think Doctor Tollefson said something like 24 that. 25 Q. Listen to this: "The first of these protocols 174 1 has already been initiated." Do you remember him saying that? 2 A. He probably did. 3 Q. That's not true, is it? 4 A. You'd have to ask Doctor Tollefson. 5 Q. It wasn't done, was it? 6 A. Wait a second, Mr. Smith. You'd have to ask 7 Doctor Tollefson what he was referring to, because we've done 8 hundreds of prospective blind studies and I don't know which 9 one he was referring to. 10 Q. Well, would it surprise you, Doctor Thompson, to 11 know that this protocol that Doctor Tollefson mentions before 12 the PDAC, that he represents to the PDAC as being done, was 13 never done? 14 A. I don't think you read it as being done. I 15 thought you said initiated. 16 Q. Initiated. 17 A. Most people would say that the letter that you 18 showed me earlier, to Doctor Dunner saying, "Will you do this 19 study, here's a protocol," most people would say that 20 initiated the study. I wouldn't use that term, but most 21 people in our industry would use that term. 22 MR. SMITH: Your Honor, I just have a couple 23 minutes. 24 JUDGE POTTER: Okay. Go ahead. 25 Q. You have mentioned that the BGA questions were 175 1 sent to the FDA in February 1985; correct? 2 A. Yes, sir. 3 Q. And the question that was characterized as 4 intensification of CNS side effects was characterized by 5 Doctor Talbott in his letter as, quote, please explain the 6 alleged intensification of CNS side effects; correct? 7 A. Is that the submission to the IND that we saw 8 earlier? 9 Q. I think it's in evidence. I don't have it 10 marked. It's the BGA questions. 11 A. Well, give me just a second to pull that out 12 again, if you would. 13 Q. Certainly. Okay. 14 A. Okay. I've got them now. This is the Page 15 13,986 or whatever it is of our IND files. Would you tell me 16 which number you were reading? 17 Q. Seventeen. 18 A. Seventeen: "Please explain the alleged 19 intensification of CNS side effects, paren, which resemble 20 symptoms of depression, i.e., insomnia." Yes, sir. That's 21 what we sent the FDA. 22 Q. All right. That's what you told the FDA the 23 BGA's questions were; correct? 24 A. Yes, sir. 25 Q. But actually if you'll look at Plaintiffs' 176 1 Exhibit 63... 2 A. Give me a second. 3 JUDGE POTTER: I don't think he has that, Mr. 4 Smith. 5 A. I don't recall it. What is it? 6 JUDGE POTTER: Mr. Myers will give him a copy. 7 It was introduced earlier. 8 Q. I'm sorry. 9 A. Yes, sir. This is the 1984 May letter from 10 von Keitz to me and a bunch of other people. Okay. 11 Q. Well, I don't know. Let's see. Yeah. Page 3. 12 A. Yes, sir. 13 Q. Actually what the BGA said was, "In 15 to 20 14 percent of cases, side effects occur which involve the central 15 nervous system, as most of them resemble the clinical picture 16 of an underlying disease, even from theoretical reasons one 17 has to expect an intensification and not an improvement of 18 symptoms." Correct? 19 A. Yes, sir. 20 Q. That's not what is said under Item 17 that was 21 sent to the FDA, is it, Doctor? 22 A. But the FDA got all of the analysis we sent to 23 the BGA and they already had all of the case-report forms and 24 all the analysis of those CNS symptoms. 25 Q. Look then at Item 18 of what Doctor Talbott 177 1 purportedly told the FDA about the BGA questions. Do you see 2 that? 3 A. Yes, sir. 4 Q. 18, it says that the BGA was asking, "Please 5 provide an in-depth analysis of suicide and suicide attempts 6 patients by patient, timing, symptomatology and trial entry, 7 phase of trial and any other clinically relevant comments." 8 Correct? 9 A. Yes, sir. 10 Q. That's what Doctor Talbott said the BGA was 11 asking them; right? 12 A. Yes, sir. 13 Q. Actually, what the BGA said was, "During the 14 treatment with the preparation" -- if you turn back to Exhibit 15 63 on Page 3, what the BGA really said on suicide was in the 16 third-from-the bottom paragraph, they said, "During the 17 treatment with the preparation, 16 suicide attempts were made, 18 2 of these with success. As patients with a risk of suicide 19 were excluded from the studies, it is probable that this high 20 proportion can be attributed to an action of the preparation 21 in the essence of the deterioration of the clinical condition 22 which reached its lowest point." 23 A. Do you mean the BGA didn't ask for this detailed 24 analysis, patient and timing and symptomatology and phase of 25 trial and clinically relevant data? 178 1 Q. They did in one item, but they certainly in the 2 medical concerns said more than that, didn't they, Doctor? 3 A. Well, but remember, the attempts on Prozac were 4 in fewer patients than the attempts in patients treated with 5 placebo. The numbers themselves aren't significant. 6 Q. Oh, the numbers themselves aren't significant? 7 A. If you wanted to define a risk, wouldn't you 8 like to know how many patients attempted suicide out of 100 9 patients treated with placebo and 100 patients treated with 10 Prozac? The answer is fewer people treated with Prozac had a 11 suicide attempt; that's not even including the fact that they 12 were treated for a lot longer with Prozac. So you can't just 13 compare apples and oranges; you need to look at the 14 denominators. 15 Q. Was the BGA off that bad, Doctor Thompson? What 16 were they doing, employing idiots? 17 A. Oh, no, sir; not at all, but they look at 18 summaries. 19 Q. Yeah, but, see, this is their -- 20 MR. FREEMAN: Please let him answer the 21 question. 22 JUDGE POTTER: Let him answer, Mr. Smith. 23 A. In the data you already showed me from Germany, 24 and I don't remember whether it came directly from the BGA or 25 whether it came from our affiliate, you had the numbers of 179 1 patients that had been exposed and the number that had made 2 suicide attempts, and that's what I was telling you about the 3 16. The 16 is not very impressive in terms of the drug doing 4 anything because the incidence is less than in people treated 5 with sugar pills. 6 Q. Then why did it take a two-volume response to 7 the BGA, and why did you still end up with a caution in risk 8 patients that the use of concomitant medication should be 9 used, Doctor Thompson? 10 A. Two questions, you'll get two answers. The 11 first one is, this is clearly a very concerning event, and we 12 did every analysis possible and it took two volumes to 13 describe all the analyses. Any fatal event, be it anaphylaxis 14 or loss of bone marrow, or suicide is of extreme concern to 15 Lilly. The second thing is the wording in our label looks 16 just like the wording in other antidepressants in Germany, 17 just like the wording in the Prozac label in America looks 18 like the wording of other antidepressants in America. 19 Q. I don't want to continue arguing with you, but 20 then if any event is so serious, why didn't you just tell the 21 PDAC that you had already determined that there were a number 22 of instances of violent-aggressive behavior and suicidality 23 that were reasonably causally related to the use of Prozac? 24 A. Because after thousands of man hours, tens of 25 thousands of patients in controlled trials, by the time we got 180 1 to the advisory committee, it was crystal clear that there was 2 no evidence or no creditable evidence of a causal relationship 3 between Prozac and risk of either suicidality or violent 4 behavior. From a careful scientific analysis, there was no 5 evidence. Now, why would I tell them about cats? Why would I 6 tell them about excitement in the first few patients treated 7 with the drug? Or why would I tell them about a causality 8 assessment that the FDA tells us not to make? Why would I do 9 that? We've got all of these data that they're looking at as 10 scientists. Would they even care if I made a causality 11 judgment on an individual case? The answer is no. 12 Q. Why did they hold the meeting if they didn't 13 care what you thought? 14 A. Because it was a very serious concern. 15 Q. Then why did you have a response if you didn't 16 think they cared what you said? 17 A. There was intense publicity about this. No one 18 had ever examined in this depth before. Remember what they 19 said, Prozac was studied at the advisory committee more than 20 any other drug ever before. We had in fact a lot of data on 21 the subject. It deserved a public hearing, I agreed with that 22 and, in fact, I thought it ought to get a public hearing so 23 that people, good scientists, objective scientists would look 24 at this and make a determination. They did. 25 Q. Doctor Thompson, the response -- do you have the 181 1 response there that you filed with the BGA? 2 A. Yes, sir. 3 Q. The two-volume response? 4 A. Yes, sir. This one right here. The one that -- 5 now, what I've got is the IND submission in 1985, that 6 includes what we sent to the BGA. Is that what you're talking 7 about? 8 Q. I thought there was some two-volume response 9 submitted to the BGA. 10 A. I don't have that here on the table, I don't 11 believe. What I think I've got is a copy of -- in English -- 12 the submission made to the BGA that addressed that question 13 about suicidality. 14 Q. Okay. Let's be certain we're talking about the 15 same thing. In fact, of that two-volume response, isn't there 16 just six pages that have to do with suicidality in that entire 17 response? 18 A. I don't know that I've ever seen what our German 19 affiliate sent to the BGA. 20 Q. Okay. Well, then, why don't you turn to 21 Page PZ 909 474. 22 A. I don't have 474; I've got through 395. But 23 this thing that went to the IND, what I've got is Pages 24 908 172 and then 908 1344 and then 909 2 through 395. 25 Q. Well, do you have anything there that responds 182 1 to Question 18, suicidality? 2 A. Let me find it. 3 MR. FREEMAN: The Witness may be looking at the 4 second volume rather than the first volume. I think they're 5 both up there. 6 A. Well, I'm sorry. I've got -- I'm sorry. Here's 7 October of '84. What I was looking at was the IND submission. 8 MR. FREEMAN: Second volume. 9 A. Okay. Sorry. Let me go find the second one. 10 Thank you. 11 Q. So that's what was submitted to the German 12 government right there in your right hand? 13 A. I haven't reviewed this, so let me tell you what 14 I think I've got. I think what I've got here is an IND annual 15 report of February 12th, 1985, and I think it had a whole 16 bunch of stuff in it, including a copy of what was sent to the 17 BGA. 18 Q. All right. Now, set that aside a minute. 19 A. I think that's all part of the same thing. 20 Q. Okay. Now pull out what was the response to the 21 BGA that was sent as a part of that safety update. Where is 22 the part that's the response to the BGA? 23 A. Okay. There is a question on Page -- IND Page 24 14365, BGA Response 9A, that has to do with ophthalmology, it 25 talks about patients with eye changes, ophthalmology, 183 1 phospholipidosis. These were all questions that the BGA had 2 raised, if you recall. 3 Q. Go to 18. 4 A. I'm getting there. Do you know what page it's 5 on? 6 Q. Yeah. 7 A. I'm sorry. 8 Q. PZ 909 474. It might be marked as Page 14438. 9 A. Okay. Give me a second and I'll get there. 10 Okay. This is 17, the review comments that are: "Many of the 11 CNS adverse experiences reported by patients taking fluoxetine 12 treatment was resulting in intensification rather than 13 improvement of symptoms." That's the part you wanted me to 14 talk about; right? 15 MR. SMITH: Can I look, Your Honor? 16 JUDGE POTTER: Certainly. 17 Q. Right here, BGA response. 18 A. That's what I've got. That's what I just read. 19 Q. You're reading 17. I'm talking about 20 suicidality. 21 A. Not the intensification of symptoms? Because 22 they're related, I mean. Okay. I've now got 14438. "The 23 reviewer expressed concern over the number of suicide attempts 24 made by patients treated with fluoxetine." 25 Q. Where does that stop? 184 1 A. Okay. It looks like it stops on -- it looks 2 like it's six pages, as you said, on that aspect of it. 3 Q. Six pages? 4 A. Yes, sir. 5 Q. The response to the BGA on the suicide issue was 6 six pages long? 7 A. Well, remember there were other questions that 8 bore on that same issue, but you're right. 9 Q. Six pages? 10 A. Yes, sir. 11 Q. And that is in two volumes of materials that was 12 sent to the BGA; is that right? 13 A. Well, there are a lot of other data that bore on 14 that question, sir, as you know. 15 Q. Okay. What other data bore on that question? 16 A. Well, there are whole compilations of adverse 17 events, which would include all kinds of adverse events. 18 Q. Whether or not it's stimulating or activating 19 would bear on that issue? 20 A. Yes. Bipolar affective disorders, inpatient 21 versus outpatient, et cetera, et cetera. 22 Q. And that was -- in order to be submitted to the 23 FDA, that was in the 1985 IND safety update? 24 A. It was in the IND. The thing I can't testify to 25 is whether in fact this is all that was sent to the BGA; first 185 1 of all, it's in English. 2 Q. Show the jury the stack of paper that was 3 submitted to the FDA in which these six pages were contained. 4 MR. FREEMAN: Can we approach the bench, Your 5 Honor? 6 (BENCH DISCUSSION) 7 MR. FREEMAN: I understood that this was going 8 to be 10 to 15 minutes; it's already been way over 30. 9 JUDGE POTTER: Just get your man to hold up the 10 two stacks and it will probably be close to the end of it, 11 won't it? 12 MR. SMITH: Yes, then just one more question. 13 JUDGE POTTER: Make him hold them up, Mr. Smith. 14 (BENCH DISCUSSION CONCLUDED) 15 MR. SMITH: Hold up the papers that you 16 submitted to the FDA. 17 A. That's the total annual report to the IND. One 18 year's worth of new data. 19 Q. And in there was this six pages concerning this 20 issue? 21 A. Yes, sir. 22 Q. Now, is it your testimony that that properly 23 advised the FDA about the seriousness of this issue which the 24 BGA had expressed was a serious issue? 25 A. The FDA had never raised the issue. We had no 186 1 obligation to even send this to them; we just included it for 2 completeness. The question is: Is it a proper response to 3 the BGA. They asked the question. They approved the drug 4 after they got it; I guess it must have been the proper 5 response to them. I don't know. 6 Q. Aren't you responsible to tell the FDA 7 everything there is to know about the safety and efficacy of 8 the drug? 9 A. We've gone through that before. They changed 10 the requirements under the IND and NDA regulations. At the 11 time of this submission, there was absolutely no -- absolutely 12 no regulatory requirement to give them any questions submitted 13 from anywhere, including any of the 74 other regulatory 14 authorities looking at this drug. 15 Q. And you weren't and you didn't? 16 A. We did. I told you, we gave them this huge set 17 of stuff that we had sent to Germany, of which six pages 18 addressed that one question. 19 Q. All right. What evidence do you have that there 20 were therapeutic levels of Restoril in Joseph Wesbecker if you 21 haven't seen his medical records, like you testified Friday? 22 A. Well, I've seen the analytical report done of 23 his postmortem blood sample because I'm an expert in that 24 area, and the SmithKline-Beecham report shows the 25 concentration to be 240 nanograms per milliliter, and I know 187 1 the therapeutic range to be 50 to 1,000. 2 Q. Did they show you the other path report that 3 showed only trace amounts of Restoril? 4 A. Yes. But they didn't deem it as a method that 5 would quantify it. 6 Q. That's the explanation for that? 7 A. That's why the first lab sent it off to the 8 second lab so they could have better methodology to quantify 9 the fluoxetine. 10 Q. How do you know that? 11 A. I was told that, in fact, because the first lab 12 could not quantify and obviously from their report had not 13 quantified a number of those drugs, they sent it to a 14 reference lab, which is the one we use for getting 15 quantitative blood levels. 16 Q. Oh, this is your lab? 17 A. No. It's owned by SmithKline-Beecham. I wish 18 we owned it but we used to use it as a lab for our clinical 19 trial samples. 20 Q. Is it your testimony, Doctor Thompson, that 21 Joseph Wesbecker should have been on a concomitant sedative? 22 A. Oh, I'm sorry. I don't think I ever testified 23 to "should." First of all, I wasn't treating him; secondly, I 24 have not examimed his entire medical record. 25 Q. Okay. You're just going to give us a piece of 188 1 information about that. 2 A. Well, but I'm an expert in the analysis of 3 drugs, and so that's why I was asked to review the reports 4 from those labs, because I have, in fact, expertise in that 5 area. 6 Q. When were you asked to do that, Doctor Thompson? 7 A. Well, over the last few days. 8 Q. Over the weekend? 9 A. Well, last week and -- now, all those 10 discussions about those laboratories goes back to the time of 11 this event when I recall talking with the coroner here, I 12 think, and a conversation with Doctor Masica and some other 13 people about analyzing what was in his blood. 14 Q. You're coming back, aren't you? 15 A. I hope so, sir. 16 Q. All right. 17 JUDGE POTTER: Thank you very much, Doctor. You 18 may step down. 19 Ladies and gentlemen we're going to take the 20 afternoon recess. As I've mentioned to you-all before, do not 21 talk to anybody about this case or let anybody talk to you. 22 Do not form or express opinions. We'll stand and take a 23 15-minute recess. 24 (RECESS) 25 SHERIFF CECIL: The jury is now entering. All 189 1 jurors are present. Court is back in session. 2 JUDGE POTTER: Please be seated. Ladies and 3 gentlemen of the jury, the Defendants have asked that you be 4 given copies of that document that was introduced so my 5 sheriff put it on your seats. Tomorrow you-all are going to 6 get a second folder so you-all can start leaving things on the 7 cart, if you want. You don't have to, but, I mean, didn't 8 Denise bring over a series of second folders with your names 9 on it so you don't have to carry everything in and out. If 10 you need any more tablets or anything, let me know. And if 11 any of you-all have any suggestions about how this paper work 12 ought to be handled, mention it to my sheriff and we'll see if 13 we can't accommodate you. 14 Mr. Smith, do you-all want to call your next 15 witness. 16 MR. SMITH: Yes, Your Honor. At this time we'd 17 call Doctor Peter Breggin, M.D. 18 JUDGE POTTER: Is he in the courtroom? 19 MR. SMITH: I think my legal assistant has gone 20 to get him, Your Honor. I'm sorry. Ms. Zettler's legal 21 assistant. 22 JUDGE POTTER: Sir, could I ask you to step down 23 here and raise your right hand, please. 24 25 190 1 PETER BREGGIN, M.D., after first being duly 2 sworn, was examined and testified as follows: 3 4 JUDGE POTTER: Would you please have a seat. 5 Would you keep your voice up. Would you spell your first and 6 last names and then state it loudly for the jury, please. 7 DOCTOR BREGGIN: My name is Pete Roger Breggin, 8 and Breggin is spelled, B-R-E-G-G-I-N. 9 10 EXAMINATION ___________ 11 12 BY_MR._SMITH: __ ___ _____ 13 Q. How old a man are you? 14 A. Fifty-eight. 15 Q. And what do you do for a living, sir? 16 A. I'm a psychiatrist. 17 Q. Would you tell the jury where you live? 18 A. Bethesda, Maryland, which is just outside of 19 Washington, D.C., and two blocks from the National Institutes 20 of Health and the Library of Medicine. 21 Q. How long have you lived at that location, Doctor 22 Breggin? 23 A. More than 20 years. 24 Q. Are you a married man? 25 A. Yes, sir. 191 1 Q. Do you have children? 2 A. I have four children, ages 15 to 32. 3 Q. How long have you been practicing psychiatry, 4 Doctor Breggin? 5 A. I've been in full-time private practice since 6 1968, but practicing before that as a resident and at the 7 National Institute of Mental Health, but private practice 8 since '68. 9 Q. Would you tell the jury basically what your 10 educational background is, Doctor Breggin, beginning with high 11 school, where you graduated and when you graduated. 12 A. I went to Widmere High School on Long Island and 13 graduated in 1954. And then I went to Harvard College, to 14 Harvard, for four years. And there I actually began to work 15 in the field of mental health just as a student, very 16 intensively. We developed the Harvard-Radcliff Mental 17 Hospital Volunteer Program and I probably put 25, 30 or more 18 hours a week sometimes, working in the state mental hospital 19 during my four years there; I led the program for a couple of 20 years. Did summer research through Harvard through the 21 National Institute of Mental Health in the hospitals, and 22 actually we wrote our first book then, developed our first 23 book, which was later published, about the use of volunteers 24 as case aid workers in the state mental hospitals. 25 Q. Was that when -- when you were at Harvard, was 192 1 that when you got your interest in psychiatry in mental 2 health, Doctor Breggin, or had you had that interest even as a 3 high school student? 4 A. Well, I had always been interested in psychology 5 and in philosophy, but I think I was actually a major in 6 American history and literature when a friend asked me to go 7 out to the mental hospital and volunteer. And it was really 8 through that that I ended up getting involved so deeply in 9 psychiatry, going to medical school. 10 Q. When did you start medical school and where did 11 you go? 12 A. I went directly from Harvard to Western Reserve, 13 which is now called Case Western Reserve Medical School in 14 Cleveland. By then, I already knew I wanted to be a 15 psychiatrist through my college experience. In addition to 16 the regular medical curriculum, I took a special psychiatry 17 clerkship, and I also did four years of research on the 18 physiology of the brain in relation to adrenaline, which is 19 one of the hormones of the body. I did animal research with 20 rats, and I also drew conclusions for human physiology and 21 wrote several papers, actually two papers, out of medical 22 school on the function of the brain and its relationship to 23 this particular medication we were using, which was 24 adrenaline. 25 Q. When were you at Case Western Reserve, Doctor 193 1 Breggin? 2 A. Let's see, high school I graduated '54, and 3 college in '58, and then Case Western Reserve, '62. 4 Q. So you would have been there before Doctor Leigh 5 Thompson was at Case Western Reserve. Did you know he was -- 6 I believe he was on the faculty there. 7 A. You mentioned it in passing, but I must have 8 been before him because I don't remember. 9 Q. I think you are an older fellow than he is. 10 A. I'm an older fellow. Thank you. 11 Q. Did your course work at Case Western Reserve -- 12 did you take courses in psychiatry in medical school? 13 A. Well, since I had my interest I took more than 14 was required. I took a special intern -- I forget we called 15 them clerkships in psychiatry as well as the four years of 16 research, which was like a dissertation, in a sense. 17 Q. Was that four years of research that you did 18 into brain physiology and the adrenaline function of the 19 brain, was that while you were in medical school or after you 20 graduated from medical school? 21 A. That was in medical school. 22 Q. And so you graduated from medical school in 23 1962? 24 A. That's correct. 25 Q. And what did you do in connection with 194 1 postgraduate training after you got your M.D. work? 2 A. Well, the first thing you have to do is an 3 internship, and there was one place in the United States where 4 you could take half your internship in psychiatry; there may 5 have been one or two other places, but I was eager to get into 6 psychiatry. So for that and some other reasons I went to the 7 State University of New York, Upstate Medical Center in 8 Syracuse, and took half a year of neurology and pediatrics and 9 medicine and half a year of psychiatry. 10 But I had been to Harvard, and I wanted to go 11 back to Harvard, and I went the following year for my first 12 year of actual psychiatric training at Harvard. There I had 13 the official title of Teaching Fellow at Harvard Medical 14 School, but it wasn't as fancy as it sounds; I was in training 15 and we did some teaching. And then I went back and finished 16 my three years of residency, the standard amount, back at the 17 State University of New York in Syracuse. 18 Q. Did you work part time or anything of that 19 nature or is internship and residency full-time work, Doctor 20 Breggin? 21 A. Well, it was full time. I think I did insurance 22 physicals part time to help pay. Pay in those days was very, 23 very low, I mean, like literally two or three thousand a year 24 in those programs, so I think I did insurance physicals. But 25 basically I continued my training and I wrote. I've always 195 1 written ever since I've been very young, so I was publishing 2 out of college, and then in medical school, and then in my 3 training. 4 Q. Then after you finished your residency at the 5 New York Upstate Medical Center, where did you go next? 6 A. I went to the National Institute of Mental 7 Health for two years, and that's a uniform -- that was as a 8 uniform service. That was the United States Public Health 9 Service. 10 Q. Did you know Doctor Leigh Thompson at the 11 National Institute of Mental Health? 12 A. I don't think so. 13 Q. When was -- I believe actually Doctor Thompson 14 was in with the National Institutes of Health and you were 15 with the National Institute of Mental Health. 16 A. Right. 17 Q. Can you tell us, sir, is that the same 18 organization or a different group? What's the difference in 19 that? 20 A. It's a more complicated question than you 21 realize. Over the years -- the two are separate. There is a 22 National Institutes of Health and then there is a National 23 Institute of Mental Health. At times they have been separate, 24 and at times the National Institute of Mental Health has been 25 one of the branches the National Institutes of Health. It's 196 1 now back to being a branch. When I was there, it was an 2 autonomous body, its own institute. Now it's under Health. 3 But they're separate, administratively separate. One focuses 4 on mental health, and the other has a huge range of other 5 things, from cancer and heart disease and neurology and 6 stroke. 7 Q. Are they both housed in that same facility there 8 in Bethesda, Maryland? 9 A. Well, yes, but they're housed all over the 10 United States and all over the area, but there is a central 11 office in Rockville. And then what you see on television 12 sometimes where they're showing you research buildings with 13 the latest breakthroughs, that is housed in Bethesda, research 14 facilities. 15 Q. What did you do at the National Institute of 16 Mental Health? 17 A. The first year, I was in Charlottesville, 18 Virginia. They had abolished the job I was going to in 19 Washington, D.C., in Bethesda, near Washington, so I was in 20 Charlottesville, Virginia, and I was responsible for helping 21 communities throughout the southeast build and staff mental 22 health centers. Say that Louisville or any other town wanted 23 to have a community mental health center in the '60s, they 24 would petition the federal government, and then I would go, 25 particularly in North Carolina, and I would sit down with 197 1 people and say these are what you need in the way of emergency 2 room or general hospital or to back up your clinic, and this 3 is what you have to have in your psychiatric clinic. And then 4 they would develop that, and then we would examine it and 5 carry on discussions with them about how to build a community 6 mental health center. That's what I did for the first year. 7 But I wanted to -- 8 Q. How about the second year? 9 A. I wanted to go back to Washington, so I was 10 fortunate and got assigned to Washington, D.C., for my second 11 year, and then I was working in a center for mental health and 12 education. What we did there was to help develop new programs 13 that would support the mental health of children up through 14 college, new kindergarten programs, right on up through 15 college, sometimes developing classrooms that were thought to 16 be healthier places, sometimes programs for kids who were 17 already in trouble, wide variety of things that year. I got 18 to like that. I actually was asked to stay and agreed to stay 19 in the mental health of children field, but then I decided at 20 the last minute I wanted to go into private practice rather 21 than taking a career ladder into the government, so I went 22 into private practice. 23 Q. When you were with the National Institute of 24 Mental Health, did you have some army or military rank or 25 designation? 198 1 A. Well, yes. I mean, it was very much like being 2 in the army except we didn't wear uniforms. It was an 3 official uniformed service, the United States Public Health 4 Service, so technically I was a veteran at the end of that 5 period of two years, but I really was not in a military kind 6 of setting, I was always in a health setting. 7 Q. Did your -- 8 A. They called us surgeons -- the rank was surgeon, 9 which I was not a surgeon, which was the equivalent of 10 lieutenant commander in the navy. That was the standard rank. 11 Q. Did that serve as your military service, your 12 time at the National Institute of Mental Health? 13 A. Yes. That was my military service. It was a 14 volunteer military service. 15 Q. Is that the reason you did it, to fulfill your 16 military service or was there other reasons? 17 A. Well, I did it for two reasons, one was to 18 fulfill the military service; that was the good fortune of 19 being in the U. S. Public Health Service, but to go to the 20 National Institute of Mental Health at that point in my career 21 was probably the most outstanding opportunity there was in the 22 world at that point, so it was something I very much wanted to 23 do. It was very hard to get into. It was the most 24 competitive program, postgraduate program, that you could get 25 into. 199 1 Q. Had you done anything to distinguish yourself in 2 medical school or in your residency that had gotten you into 3 the National Institute of Mental Health? 4 A. Well, I suppose what was different than maybe 5 some other students was that I was already publishing. I had 6 already been involved in innovative programs in psychiatry 7 ever since I was 18 years old, so that was very unusual, and 8 it was very unusual to be published, but I suppose it's mostly 9 recommendations of your professors. I mean, I haven't really 10 thought about that, but I'm sure what really was the final 11 decider was the recommendations you got. 12 Q. Well, did you have any particular kind of 13 outstanding grades in medical school in psychiatry that 14 qualified you for that service, Doctor Breggin? 15 A. We did have one place that -- my school was pass 16 and fail, and I didn't fail so I passed. We didn't have a 17 regular grading system at Case Western Reserve, but we did 18 have a national exam at the end of the year that almost 19 everyone took throughout the United States to qualify you for 20 licensure; instead of having to go to every state, we would go 21 and take this one board. And it had a section in psychiatry, 22 and I did get -- I missed 1 out of 100 questions, and it was 23 the highest grade that anyone had ever seen in the school on 24 any subject area. It was a raw score of 99 and a percentile 25 of 99.99 or something along that line. I guess that's what 200 1 you're asking about. 2 Q. So after your time with the National Institute 3 of Mental Health did you go directly into private practice, 4 Doctor Breggin? 5 A. Yes, I did. 6 Q. And have you continued in private practice? 7 A. Yes. I've been in full-time practice, 8 literally, since 1968. The first few years, I saw patients 9 about a third of the time and I did consulting work that had 10 developed while I was at the National Institute of Mental 11 Health. I was on the faculty at the University of Maryland 12 and at a local graduate school and at the Washington School of 13 Psychiatry, mostly relating to the work I had done in mental 14 health and education. Gradually, I left that behind and I 15 remained in full-time private practice. 16 May I get a drink of water? 17 Q. Certainly. We've already gotten you thirsty, is 18 that it? 19 A. It's a little warm. 20 Q. You say you taught at the University of 21 Maryland; any other places that you've taught at? 22 A. Well, in those years, yeah, I taught in the 23 graduate school of counseling at the University of Maryland; I 24 taught at the graduate school of what was called Antioch 25 Putney; and in Washington, D.C., there's an organization 201 1 called the Washington School of Psychiatry, which is an old, 2 established private psychiatric facility; it publishes a 3 well-known journal; it has its own faculty. And I taught 4 there for a few years, too. But we're going back a long time 5 now. 6 Q. Are you currently doing any teaching, Doctor 7 Breggin? 8 A. I teach part time at George Mason University, 9 which is a very large and really fine state university in 10 northern Virginia, and I'm a professor, an adjunct professor, 11 which means very part time, in the graduate department of 12 conflict analysis and resolution. 13 Q. Well, now, what is -- is that psychiatry? 14 A. It draws on psychiatry but it's its own field; 15 it's a relatively new field, maybe 10 or 15 years old. And 16 the idea behind it is to study human conflict on every level, 17 from the family and domestic conflict and domestic violence on 18 up to violence between countries. And many members of the 19 department will go overseas, which I do not do, and do 20 political conflict resolution, not as politicians but by 21 sitting down with opposing sides, Israelis and Arabs or 22 northern Ireland and England, and sit down and help resolve 23 conflict. And it's a model that enormously appeals to me, so 24 I've been very pleased to teach there. I teach a required 25 Ph.D. course called Mind and Conflict, and so I can bring to 202 1 bear biology and psychiatry and sociology and just a whole 2 wide variety of areas to sitting down in a seminar setting and 3 having really very nice discussions with very advanced 4 students. It's really a privilege, actually. 5 Q. All right. Tell the jury about -- you say at 6 one time a third of your time was occupied with private 7 practice; how about now? 8 A. Well, that third was only for a few years when I 9 was also doing consultation, but I'd say after the mid '70s, 10 probably, it's been full time. Right now I'm probably 11 actually sitting with patients 35 hours a week. That doesn't 12 include the paper work and telephone calls and records. I'm 13 actually that many hours on the average, I would say, seeing 14 patients. It's been more at times; it's been less at times. 15 It usually comes out to about 35 hours. 16 Q. Now, how many patients will you see a week, 17 approximately? 18 A. Well, I don't see too many people more than 19 once, and I see families and couples. 20 Q. You mean more than once a week? 21 A. Right. More than once a week. So I'm seeing 22 more than 35 people probably during that week, with families 23 or families and kids. And I do a lot of consultation now. 24 People call me and want to come and see me for special 25 consultations, usually on psychiatric medication, and so I'll 203 1 have a -- any week I'll have several people that I'm only 2 seeing once or twice, but that's in addition to the numbers 3 that I'm describing. 4 Q. In your practice over the years, what is it, 26 5 years that you've been in private practice? 6 A. I haven't counted. Yeah. I think it's over 25 7 now, yeah. 8 Q. Have you seen individuals who were suffering 9 from the diagnosis of major depressive disorder? 10 A. Well, that's very common, yes. You know, major 11 depressive disorder simply means seriously depressed; it's a 12 category to indicate serious depression. And it's one of the 13 most common things probably in anyone's private practice. I 14 may see a few more than some other people. 15 Q. So you see depressed individuals? 16 A. Oh, very much so, yes. 17 Q. And have done that through the entire time of 18 your practice? 19 A. The entire time, but probably more seriously in 20 recent years. As I've gotten older and you get better known 21 and people become familiar with your work, you get to see more 22 serious patients than when you're 35 years old. So I see a 23 higher percentage of seriously upset or disturbed patients 24 now. 25 Q. Do you see patients who are manic depressive or 204 1 bipolar? 2 A. Definitely, yes. 3 Q. Do you see patients who are suffering from the 4 disorder of schizoaffective disorder? 5 A. Yes. 6 Q. Do both manic depressive and patients with 7 schizoaffective disorder have manifestations of depression at 8 some point in their illness? 9 A. By definition, yes. You wouldn't get that 10 label, that diagnosis, without having a depressed element to 11 your experience. 12 Q. You're the first full-time psychiatrist that's 13 testified in this case, Doctor Breggin. Why don't you tell 14 the jury basically what psychiatrists do. I mean, we all have 15 heard of shrinks. You're a shrink. Give us generally how you 16 set about to help people suffering from a mental disorder. 17 A. Well, there's a wide spectrum of approaches in 18 the field right now, and, so, any individual psychiatrist 19 could be behaving, you know, really quite differently with the 20 same patients. Most psychiatrists use a combination -- maybe 21 I should start from a little earlier than that and say what a 22 psychiatrist is, because it's sort of suggested that everybody 23 knows, and people get very confused about psychiatrists, 24 psychologists, social workers. Would it be worth doing that? 25 Q. Briefly. Maybe we can draw a distinction there. 205 1 A. Psychiatrists have medical degrees, and that's 2 one of the keys, and have medical training. Most of my 3 training has been hospital and clinics. Psychologists are 4 trained basically in the academic community and they get a 5 Ph.D., rather than an M.D., and then there are different 6 branches. We've got clinical psychologists who work doing a 7 variety of things that are similar to psychiatrists, but right 8 now they can't prescribe medication, and in some places they 9 can't see people in hospitals; in other places they can. It 10 depends on the state. Different places in the country give 11 different rights or privileges to psychologists. So 12 psychiatrists have medical degrees and tend often to use 13 medical approaches. So the average psychiatrist will probably 14 be seeing people and giving medication and also seeing people 15 and talking to them about their difficulties, doing 16 psychotherapy, working with couples, working with families. 17 It's really quite a broad spectrum. Yes. 18 Q. I'm sorry. We've heard the terms psychotherapy 19 and psychopharmacology. Can you explain for us the 20 distinctions between those two terms? 21 A. Generally, there's a sharp division between 22 psychotherapy, meaning fundamentally some form of nonmedical 23 talking, some form of communication therapy where you're 24 either developing a relationship with the person that's going 25 to be supportive emotionally or morally supportive, or you're 206 1 giving insight and understanding or you're helping people 2 resolve conflicts. I like the conflict model. I think of 3 people as being in conflict with themselves, being in conflict 4 with other people. It could involve group therapy. It could 5 even be in a hospital where you would do group therapy or 6 individual therapy, but basically communication is at the 7 heart of psychotherapy. 8 Q. Do you have to be trained to do that? I mean 9 just to talk to somebody? I mean, friends and family members 10 talk to people and help them through difficult situations. 11 What's the difference in that talk that a psychiatrist gives 12 and a friend or a loved one might give? 13 A. It's a very good question and it's one that a 14 lot of people have wondered about and discussed and debated. 15 But basically as a therapist we get to see people that other 16 persons can't communicate with anymore, at least about the 17 particular issues in a person's life, so that often, 18 particularly if you're seeing people who are having a lot of 19 difficulty, you need the personal skills to relate to somebody 20 who's frightened to death or feeling horribly helpless and 21 hopeless or perhaps imagines things that are very unreal, that 22 they're being controlled by radio waves or by your computer, 23 my computer in the office. So you have to be prepared to deal 24 with a lot of fear, a lot of hopelessness. You have to be 25 comfortable with that. You have to have some idea about how 207 1 to make people comfortable when they're feeling terrible about 2 themselves. 3 Then beyond that, there's many different things, 4 and I think probably every psychotherapost brings a somewhat 5 different viewpoint to it. I do a combination of helping 6 people develop better principles of living, helping them see 7 what they're doing in their approach at work or at home or 8 with other people that's getting them into difficulty, causing 9 them anguish, disturbing their lives. And, also, I try to go 10 back into childhood, not in a Freudian psychoanalysis where 11 you spend four days a week with somebody talking about 12 childhood, but I try to systematically go back and say maybe 13 you learned something in childhood that isn't working anymore. 14 Maybe you got hurt a lot, sexually abused, so now you approach 15 all people fearfully. You don't have to do that anymore; this 16 happened in childhood. Or maybe you lost -- well, in Mr. 17 Wesbecker's case, maybe you lost your father when you were one 18 or two. And, believe it or not, that can leave a gloom, that 19 can affect a person. Maybe we could talk about that, maybe we 20 could get some understanding of that and help you get past 21 that. It's more likely to produce serious effects at age two 22 or three or four than younger. 23 So I do a combination of work like that, but I 24 think that psychotherapists each -- because it's so personal 25 -- has their own particular view of it, but I think that's a 208 1 good summary that most therapists would be comfortable with. 2 Q. Do you receive training in that in medical 3 school? 4 A. You receive some training, I did, because I was 5 interested in psychiatry and I, you know, took some special 6 opportunities. It's usually in your residency in psychiatry 7 that that training begins. 8 Q. I guess that's what I mean. I mean, are the 9 questions that you as a psychiatrist are directing to a 10 patient and the way you're guiding that patient, is that done 11 just in some regimen or based on some type of specialty 12 training as opposed to questions I might ask you as a friend 13 when you're having a difficult time? 14 A. Well, yes. You're definitely trained in terms 15 of not only how to communicate but also what to look for, 16 where to focus attention, what to look out for in terms of 17 dangers of someone being violent, someone being suicidal, how 18 to look for also how medications may be affecting an 19 individual, which is another thing; that's the 20 psychopharmacology. 21 So you did have very specific training. It 22 varies in intensity from program to program throughout the 23 United States. When I was in training in the '60s, there was 24 more emphasis on psychotherapy than now. I would say there's 25 been an increasing emphasis toward medication probably in 209 1 recent years, but, yes, it requires a lot of training -- 2 Q. All right. 3 A. -- and experience and supervision. I think the 4 most important thing is talking to older people who have been 5 doing it longer, and that's called supervision; you talk about 6 what you're doing and what experience you had and how things 7 went wrong and how things went well and how you can approach 8 things differently. Supervision I think is very key. 9 Q. Do you make people lie down on a couch? 10 A. I don't have a couch. In fact, people walk into 11 my office and they smile with relief and they say, "You don't 12 have a couch." I don't. I prefer face to face. I like to 13 encourage strength and I like to encourage people to feel in 14 charge as much as possible, so I have never encouraged the 15 patient to lie down while I sit up. It's face to face. 16 Q. In your experience, Doctor Breggin, is 17 psychotherapy useful in the treatment of mental disorders? 18 A. Yes. I think it's very useful. It's a subject 19 of controversy within the profession as to how useful it is 20 with people who are diagnosed manic depressive or people who 21 are diagnosed schizophrenic, but I find it very useful really 22 with all diagnostic groups of people. And there's a lot of 23 literature, a lot of research to support that it can be used 24 with even the most seriously upset people, but I think it 25 takes experience, it takes a certain comfort in working with 210 1 people who are very upset. 2 Q. Explain to the jury psychopharmacology. 3 A. Psychopharmacology. Psycho refers to the soul 4 or the mind, and pharmacology refers to medication, and it's 5 the medication and treatment of individuals with psychiatric 6 or psychological problems. And some doctors specialize in 7 that completely and some doctors specialize completely in 8 psychotherapy, and the vast majority of psychiatrists do both. 9 The vast majority do both. 10 Q. Do you do both, Doctor Breggin? 11 A. I do both, but a little differently. The 12 patients that I see who I'm giving medication to have already 13 been begun on medication by other people. I myself specialize 14 in helping people through communication, through talking, 15 through support, through family work, couples work. I'll even 16 work with members of the community to help an individual get 17 stronger and be able to function in the family and in the 18 community. But I see many people on medication because 19 they've already been on it when they come to me, and I either 20 let them stay on it, that's what they want, or very frequently 21 people come to me for help in coming off of medication. 22 I have specialized in my practice and in my 23 writings in the adverse effects of medication, so I'm known as 24 somebody who looks at and understands adverse effects. So 25 people who are having difficulty with medication frequently 211 1 come to me, so I end up working with them, with their 2 medication and, if they wish and if possible, helping them 3 come off the medication. That's not always possible. 4 Q. Well, do you believe that there's -- that even 5 though you don't use psychopharmacological treatment 6 generally, do you believe it's always bad? 7 A. I don't believe it's always bad, but it isn't 8 what I prefer. 9 Q. All right. Let's get to the point more 10 directly, Doctor Breggin. Do you have any criticism of 11 Doctor Lee Coleman's treatment of Joseph Wesbecker with 12 respect to the use of psychotropic medications generally? 13 A. No. He was performing, as best as I could tell 14 by the community standard, as we say. He was behaving as a 15 good doctor, I thought, in what he was doing in terms of 16 trying to evaluate his patient, but doing it differently than 17 I would, because I would be putting much more emphasis on 18 getting family in, working even with somebody in the community 19 since he was having so much trouble in the community on and 20 off at times, at least at work. I would have been involved 21 more in that process, I think, but certainly what he was doing 22 is very acceptable. 23 Q. But simply by virtue of the fact that Doctor 24 Coleman was prescribing psychotropic medications doesn't mean 25 that you have an automatic criticism of Doctor Coleman's 212 1 practice? 2 A. No, not at all. 3 Q. It's just not what you prefer? 4 A. No. 5 Q. Do you believe that Joseph Wesbecker -- and this 6 question may be a little premature, but I think we need to 7 address it now since we're talking about psychopharmacological 8 treatment. Do you believe he would have benefited from any 9 psychopharmacological treatment? 10 A. Well, he -- I think so. He wanted it and he 11 felt it was helpful. The doctor was doing it in a rational 12 manner, you know, and it certainly is a -- he was certainly 13 operating by standard practice. But, again, it's not how I 14 would have approached it. I would have taken a different 15 approach. 16 Q. All right. Is hospitalization acceptable 17 psychiatric practice for psychiatrists? 18 A. Definitely. Some psychiatrists have basically 19 hospital practices where most of their patients are 20 hospitalized. Many psychiatrists don't do any hospital 21 practice. There's a wide variety, but certainly it's 22 acceptable and can be very important. 23 Q. Have you in your practice or in your training or 24 your experience, Doctor Breggin, had any experience in 25 examining the effects of psychoactive medications on human 213 1 beings? 2 A. Yes. Oh, a lot. 3 Q. Tell the jury when you first got interested in 4 that and bring us up to date on what background you have in 5 studying psychoactive medications. 6 A. Well, I went through several phases of work with 7 medications. During my training, of course, we used 8 medication extensively. We were working in mental hospital 9 settings where just about everyone was on medication, and that 10 was at least three and a half years with my residency and my 11 internship. But also in medical school we worked with 12 medication because I was on a state hospital -- I guess it was 13 the city hospital -- the city hospital ward in Cleveland, so 14 we used medications extensively. 15 When I was with the National Institute of Mental 16 Health, I was not doing clinical work except the little bit 17 that was allowed part time in the evening, so I wasn't using 18 medication. Then when I began my practice for the first 19 several years, I saw very few people on medication and I never 20 prescribed any. I didn't prescribe any medication, didn't 21 feel I needed to, liked to work with people without it, until 22 about 1983. 23 At that time I wrote my first medical book -- my 24 second medical book, actually, my first medical book on 25 medication. I was concerned that people were not looking 214 1 enough at the hazards of medication, so I wrote a book, 2 Psychiatric Drugs, Hazards to the Brain, that is, the problems 3 that these drugs can give to the brain. It's a medical book 4 written for physicians by a medical publisher. And as a 5 result of my writing a book about what I saw as an 6 overemphasis on medication and the need to look at its 7 hazards, many people started to come to me and say, "I can't 8 get off medication, can you help me, can you work with me?" 9 So after 1983, and more and more every year, 10 I've been working with people I guess more than ten years now, 11 more than ten years, with medication. And on any given day 12 I'm likely to be seeing someone either in a consultation about 13 medication or one of my own patients who's on medication. 14 Q. Well, when did you become interested in people 15 who have problems as a result of psychiatric medications? Was 16 that in '83, or was that even earlier? 17 A. Well, that was probably 1954. 18 Q. Tell the jury about that. 19 A. When I began to work in the state mental 20 hospitals in 1954, I noticed how many of the patients were 21 being heavily medicated. We were just beginning to get into 22 the most powerful drugs that we have now, those actually come 23 into North America, they're called the neuroleptic drugs or 24 the antipsychotic drugs that you read about in the newspapers. 25 One of the more recent drugs is clozapine or Clozaril, Haldol, 215 1 Thorazine. Thorazine was just coming in in 1954, so I saw the 2 hospitals just about before they came in and then over the 3 next four years. 4 And it struck me that while these medications 5 made the hospitals quieter and made the patients more subdued 6 and made the management of the hospital easier, that it was 7 not getting the patients out and, in fact, the reduction in 8 the state mental hospital population doesn't begin for ten 9 years. It was not, as some people believe, the result of 10 bringing in the drugs because it literally didn't happen for 11 ten years. What the drugs did was made it easier to manage 12 the patients, and I didn't feel that was right from the 13 beginning. I remember meeting and talking with people and 14 wishing they weren't so drugged and wishing that they could 15 relate more and be helped more. So I began early believing 16 more in the psychological and the social approaches, but I 17 didn't write about medications till '83; I wrote about the 18 psychosocial approaches before then. 19 Q. When did you start studying the effects of 20 psychoactive medications? 21 A. Well, I was actually doing -- I was actually on 22 a research project, that's how -- one of the summers that I 23 worked in a program in the state mental hospital, one of the 24 summers I was assisting a clinical investigator on a 25 medication treatment for elderly patients in the state mental 216 1 hospital. So right from the beginning it was an interest of 2 mine and something I really thought a great, great deal about 3 very early on. 4 Q. Did you begin to pay particular attention to 5 psychoactive medications and specifically from a medical 6 standpoint how they worked? 7 A. Yeah. I would say that it would -- that when I 8 decided to do a book on it in '83, which meant a lot of years 9 of research before then, it's a very heavily researched and 10 documented book, so I'd say in the early '80s is when I became 11 especially intensely interested and kind of developed a 12 subspecialty in the adverse effects of drugs, that would be in 13 the early '80s. 14 Q. Generally, what did you do? Did you go back and 15 take some refresher courses in pharmacology? Did you go study 16 rat brains and things of that nature? How did you go about 17 becoming, Doctor Breggin, specifically familiar with the 18 effects of psychoactive medications? 19 A. Well, I had already had my training, to begin 20 with, and then I began to research the existing available 21 information. I just read everything I could get my hands on. 22 I think my first book has hundreds and hundreds of references 23 to the ongoing research. I began to see patients in large 24 numbers, but probably not until after the book was published. 25 I have over the years taken courses, advanced courses in 217 1 pharmacology. Last year I took a full-day course given by the 2 Food and Drug Administration on medication and both 3 postmarketing tracking of medication, but also on the effects, 4 the hazards associated with medication. So it's been a 5 combination of different things. In recent years, it's been 6 seeing a lot of patients, talking to doctors. I give 7 workshops all over the country. 8 Q. Are you a member of any professional 9 associations or societies, since we're talking about 10 workshops? 11 A. Yes. Quite a few. 12 Q. All right. Generally tell us what they are. 13 A. Member of the American Psychiatric Association, 14 have been since I was very young. I'm a member of the 15 Canadian Psychiatric Association because I go to Canada 16 occasionally to give workshops. I'm a member of the Royal 17 Society of Medicine in England because I go to England 18 sometimes and give workshops. I do have a full-time practice, 19 though. It's a little stressful because I do travel, but I'm 20 not away every week or even every month, necessarily. I'm a 21 member of several scientific organizations. I'm a member of 22 the American Ortho Psychiatric Association, which has to do 23 with youth and children and preventive mental health. And 24 also I think an unusual thing. I'm also a member of the 25 American Psychological Association, which very few physicians 218 1 are. You have to be specially elected on the basis of doing 2 research that they consider to be to the standard of 3 psychologists who are much more research oriented than 4 psychiatrists in many ways. I mean, I had to submit research 5 papers and show that I had been working in a way that they 6 thought was appropriate. So I'm also a member of the American 7 Psychological Association. A few others, I'm sure. 8 Q. Let's go back to psychotropic medications. Have 9 you got any idea, any estimate, Doctor Breggin, on how much 10 literature you reviewed in connection with how psychotropic 11 medications work, neurotransmission, neurotransmitters, 12 neurobiology, brain anatomy, et cetera? 13 A. It would be I think hard to estimate. I mean, 14 just the bibliographies in my books would be thousands. I'm 15 sure it's tens of thousands by now. I haven't ever tried to 16 calculate that. Don't know. 17 Q. Have you since 1983 attempted to keep yourself 18 well informed and knowledgeable concerning the developments in 19 psychopharmacological treatments in mental disorders? 20 A. Yes, I have. I'm not a psychopharmacologist, 21 which is a very specialized area of exactly how the brain 22 works and exactly how the drugs on a very close-in level work 23 on the neurotransmitters. I'm not a psychopharmacologist. 24 But for a psychiatrist, I've read an awful lot in that area, 25 yes. 219 1 Q. Well, would you say you're as knowledgeable 2 concerning psychoactive medications as any psychiatrist, other 3 than a psychiatrist that might also be an neuropharmacologist? 4 A. Well, yeah, the person being a -- 5 MR. FREEMAN: Object to that, Your Honor. It's 6 self-serving in nature. 7 JUDGE POTTER: I'm sorry. 8 (BENCH DISCUSSION) 9 JUDGE POTTER: I apologize, Mr. Smith. You were 10 rolling along so smoothly I really wasn't listening to your 11 question that closely. 12 MR. FREEMAN: He asked him was he as 13 knowledgeable as any psychopharmacologist in this particular 14 area. 15 MR. SMITH: That is absolutely not what I said. 16 I said, "Are you as knowledgeable as any psychiatrist in this 17 area other than someone who has a neuropharmacological 18 expertise." 19 MR. FREEMAN: Could I have a continuing 20 objection to opinions and the renewal of our motion in limine 21 rather than jump up every time he gives an opinion? 22 JUDGE POTTER: I tell you what. He's probably 23 not going to get into much today. I mean, don't you think 24 maybe qualify him and it will be a good time to break for the 25 evening? 220 1 MR. SMITH: I was going, depending on the time, 2 to go into very briefly two charts on the serotonin system. 3 But I could defer that, if you wanted to. 4 JUDGE POTTER: No, you pick a good time to break 5 around 5:00 and then we'll talk about objections and so forth. 6 Go ahead, Mr. Smith. 7 (BENCH DISCUSSION CONCLUDED) 8 Q. My question to you, Doctor Breggin, was, do you 9 think you're as knowledgeable as any psychiatrist concerning 10 the effects of psychotropic medication, except maybe for a 11 psychiatrist that also had a neuropharmacology Ph.D. or 12 something of that nature? 13 A. I mean, it's hard to compare. I think I've 14 written more about the hazards and adverse effects of drugs 15 than perhaps almost anyone I know of. Whether I know more, 16 I'm sure there are people that know a lot more than I do about 17 a lot of things. I mean, I'm sure of that. I have focused a 18 great deal, however, in that area, probably written as 19 extensively as anyone there is. 20 Q. And read as extensively? 21 A. Certainly had to to write. Yes. 22 Q. Give us your background in connection with 23 neurotransmitters and generally how we classify 24 neurotransmitters. And do it briefly. The jury's heard some 25 of this, but give us the basic theories of neurotransmission, 221 1 for instance. 2 A. All right. Briefly. Briefly. I mean, an 3 interesting way to think about it is that we started in life 4 as a one-celled animal and then evolved. 5 Q. You mean in the mother's womb? 6 A. No. Way back. Just one-celled animals in the 7 ocean, and then the cells got together. They aggregated, they 8 became bodies, and the problem for the cells was how to 9 communicate. So it didn't start out with an organized 10 network. It didn't start out with here we are; it evolved. 11 And so one cell had to communicate with another cell. 12 Q. Wait a minute. Did God have any part in this? 13 A. I think so, but I'm not an expert on that. 14 Q. Okay. I just want to make sure we weren't 15 turning this into some evolutionary trial. 16 A. I'm staying within the narrow limits of science 17 and certainly acknowledging its narrow limits. I'm the first 18 to acknowledge its very narrow limits. But at any rate, the 19 cells need to communicate, and a network developed for 20 communicating among the cells. And it developed by fits and 21 starts over a long period of time. And there are many 22 different ways that the cells in the controlling network, in 23 the brain, the brain is the controlling network, there are 24 many ways in which the cells in that brain talk to each other, 25 basically saying carry a message or don't carry a message. 222 1 Every cell in the brain -- there are billions -- I'm talking 2 about the neurons, the actual communicating brain cells, there 3 are billions of brain cells -- is being influenced by one or 4 more other cells, sometimes hundreds of other cells, it's 5 incredibly complex, and the cells are communicating in a 6 variety of ways. 7 They put out some substances that are rather 8 free floating to communicate and they put out some that are 9 very specific neurotransmitters calculated to tell the next 10 cell to fire or not fire, to influence the next cell. 11 If you think of a brain cell as having an arm 12 that reaches out to the next cell, and at the end would be 13 like a hand, and that hand is dropping packets of chemicals, 14 neurotransmitters, into an infinitesimally small space where 15 the next hand is grabbing it, and this is the free synaptic 16 nerve dropping the packets. I think there's been discussion 17 already of serotonin and neurotransmitters, it's one of dozens 18 dropping that packet, which is being received by the other 19 nerve and, in this case, telling the other nerve to fire and 20 send a message yet further along the route. 21 And it's in that space between that is 22 infinitesimally small, very, very small, that's called the 23 synaptic cleft that a lot of discussions about the effects of 24 Prozac have gone on. It's not really terribly complicated in 25 some ways; in some ways it's horribly complicated; in some 223 1 ways it's beyond my expertise, but I got enough I think to 2 communicate to you about it to understand the process. 3 When the serotonin is put out by this cell, say 4 this shoulder is the cell and it's got an arm and it's putting 5 out the packet. Whether or not it affects and how it affects 6 the other receiving cell will depend in part on how long the 7 serotonin stays there. 8 Q. Let me interrupt you, Doctor Breggin, and ask 9 you this: We've heard a lot about serotonin and things of 10 that nature. And you mention there were a dozen other? 11 A. Dozens. 12 Q. Dozens other neurotransmitters. Does 13 neurotransmission of these other neurotransmitters act 14 generally in the same way that serotonin neurotransmission 15 works? 16 A. Well, there are many that do act in that general 17 way, yes. 18 Q. That is by crossing between the synaptic cleft? 19 A. Yes. By dropping a packet of chemicals into the 20 synaptic cleft. It's really like sparks. You think of them 21 as sparks, but they're individualized sparks, so that the 22 serotonin spark only is going to fire a serotonin receptor. 23 But this is so complicated. This nerve may have receptors for 24 lots of other specialized chemicals. So we're just looking at 25 one tiny part of a vastly complex system. We really don't 224 1 know, for example, how that system generates a thought or an 2 activity or an action. We're a long way away from that. 3 We're just beginning to try to decipher the connections and 4 some of the general theory of how it works. 5 Q. Are you saying, Doctor Breggin, that there may 6 be neurotransmission of serotonin and, at the same time, may 7 be neurotransmission of norepinephrine, dopamine or some 8 other? 9 A. Yes. Absolutely. In fact, the same cell may be 10 getting bombarded -- bombarded; may not feel bombarded, 11 influenced -- by a whole variety of other influences. In 12 fact, one cell may put out more than one neurotransmitter. It 13 gets very complicated. 14 Q. Well, will there be numerous neurotransmitters 15 within the same synaptic cleft between two neurons, or do we 16 just have, say, for instance, serotonin neurons going to 17 serotonin -- presynaptic and postsynaptic neurons? 18 A. Generally, the term synaptic cleft is used to 19 describe that particular interface between the particular kind 20 of neurotransmitter. 21 Q. Would there be maybe more than one neuron at the 22 end of a nerve? 23 A. Yes. But it would be sending something to a 24 different set of receptors. It's all -- they're specialized 25 in who they receive from. 225 1 Q. Would you like a chart that we've got to help 2 you describe this? 3 A. Sure. 4 Q. Why don't you come down here, Doctor Breggin. 5 And this looks like a pretty good brain we've got here. 6 A. I drew it myself. It's from one of my 7 publications, but it's based on anatomical textbooks. This is 8 showing something more gross than I was just describing to 9 you. 10 Q. Well, is it appropriate to start with that or do 11 you want to start with the other one? 12 A. No. We can back up a little bit, get a little 13 change of pace. This is describing where the serotonin nerves 14 go, the nerves that are releasing serotonin and that are 15 primarily affected by Prozac. And I was trying to illustrate 16 -- they begin in an area that's black, the raphe nuclei. All 17 of them have their bodies there. If you remember from 18 biology, a cell body with the nucleus, mitochondria, and all 19 the activities that are going to keep it alive, which is the 20 cell. But then it reaches with this long arm called the axon, 21 the long arm that I described to you, and I wanted to show 22 that serotonin goes virtually everywhere. 23 So it is affecting synapses and other nerves 24 where all these little dots are throughout the entire brain. 25 It is affecting the temporal lobe and memory that's very 226 1 important; it's affecting the frontal lobes where the seed of 2 civilization is, in a sense, our ability to love and to hate, 3 to be angry, to care, to plan, to think; it's affecting those 4 lobes. It's going all the way around to the parietal lobe, 5 which is a lobe that is generally associated with personality 6 and character and artistic creativity. 7 By the way, these distinctions are somewhat 8 arbitrary. This whole organ works together. It's an 9 orchestra, but we're sort of talking about the violins. It 10 goes to the limbic system in here, which is associated with 11 the emotions, with the color of emotions, the intensity of 12 emotions. It even goes to the cerebellum, which has a lot to 13 do with balance, and goes down into the spinal cord and 14 affects nerves to come out in the spinal cord and affect the 15 body, and particularly it has an effect on the intestines. It 16 affects the pituitary gland, and it does this through part of 17 the brain called the hypothalamus. So your thyroid hormone, 18 sexual hormones, the stress hormones that you read about, are 19 all being affected by the serotonin system and, hence, by 20 Prozac when it affects the serotonin system. 21 Now, there aren't -- the serotonin system is the 22 most widespread one of all the neurotransmitters. There are 23 some neurotransmitters that have more actual cells, but none 24 of them go more places in the brain than serotonin. 25 Q. Okay. Are you saying, then, that there will be 227 1 serotonin -- the serotonin system will be in more areas than, 2 say, dopamine or epinephrine and things of that nature? 3 A. That's right. 4 Q. Why is that? Do you know? 5 A. I don't know why that is. I don't know if 6 someone else would know. I suspect that it's more a question 7 of you have to go back and look at embryology and the whole 8 evolution of organisms in the brain. That is out of my area. 9 Q. All right. But you do know that the serotonin 10 system affects more brain parts than any other system? 11 A. It's at least, yes, more widespread. The net of 12 all these nerves, these are bundles of little tiny axons 13 reaching around and affecting the synapses in all these 14 multiple places, very widespread. 15 Q. Do you mean that I might have a serotonin 16 nucleus down in the base of my brain that might go all the way 17 up over into the front of my brain? 18 A. Yes. You certainly do have axons from deeper in 19 the brain in the blackend area of raphe nuclei going all the 20 way up around to the very frontal -- and also the cortex, the 21 surface where intelligence is deeply affected. You have them 22 going really everywhere, but particularly heavier in these 23 higher functioning areas, higher in the sense of our being 24 different from other animals, more of the thinking, feeling 25 and spiritual processes. 228 1 Q. Well, you mean that you could, if I were dead, 2 dissect one of my serotonin nerves out of my brain? Is that 3 what you're saying? 4 A. Well, you would have a lot of trouble dissecting 5 out something that small, but you could actually see slices of 6 this under an electron microscope and you could also go into 7 the brain and, through biochemical methods that some of Lilly 8 researchers have been key in developing, you could find some 9 of the general concentrations of serotonin in the various 10 parts of your brain on autopsy. 11 Q. All right. But the nerve itself that carries 12 the serotonin would be microscopic from the start to the end? 13 It would just be a long thing? 14 A. That's right. Short and long. Some are coming 15 out, some are going all the way. But they're unbroken. They 16 go all the way unbroken till they reach the point where they 17 drop into the synapse of the serotonin. 18 A. All right. Now, you have arrows pointing in all 19 of these directions, but you don't have anything receiving 20 these. Is it just not drawn on here or are they getting from 21 one spot to the other by virtue of these neurons? 22 A. I'm not sure I understand your question. I have 23 not drawn in the receiving neurons. That would be infinitely 24 complex. 25 Q. Okay. This is just a simple diagram to 229 1 illustrate the areas of the brain affected by the serotonin 2 system? 3 A. Yes. And it is anatomically correct. 4 Q. It's really pretty, too. 5 A. Close to what you would see a diagram of in an 6 anatomy textbook. 7 Q. Okay. Now, do we have another diagram we can do 8 in the next ten minutes to show a more closeup view of this 9 synaptic cleft? You want to do that now? 10 A. Sure. 11 Q. We're talking about serotonin, reuptake, 12 postsynaptic, presynaptic cleft, neurotransmission, things of 13 that nature and give us five minutes and help us all 14 understand how all that works, five minutes, before we get out 15 of here. 16 A. This is -- I've noticed for the first time 17 there's a copyright by a man's name I don't recognize, which 18 must be the artist who drew it for my book. But this is from 19 a drawing that I made from other expert thinkers on how these 20 systems work. The purpose of this was to make it clear to 21 both physicians and laypersons, I mean, the publication was 22 meant for both physicians and laypersons, how the 23 neurotransmission takes place at the cleft. I've talked about 24 the arm and the hand reaching out. Now, the nerve eventually 25 breaks down -- here's the nerve starting and this would be 230 1 down in your -- this piece here -- 2 Q. Let me set this up here, Doctor Breggin. 3 A. This piece is the cell body and that's this 4 blackened area here, so the cell is beginning in there; that's 5 where the body is and this is its stretch. Remember its 6 stretch, its axon, could be stretching to your frontal lobes 7 or your cerebellum or your hypothalamus. This is the stretch. 8 It would be infinitesimally small or it could be long enough 9 to reach around much of your brain. And this is one of those 10 release points focused in on, but every nerve has a lot of 11 them. 12 This is one of the release points that the 13 serotonin is being put into. This is called the presynaptic 14 nerve, this is called the postsynaptic nerve. This is just 15 bringing the magnification up in a way we can never see, at 16 least at this point. We don't have a picture this clear. 17 This is a combination of looking at electron microscopes, but 18 more than that, imagining from the biochemical information 19 what this must look like. The shapes are fairly arbitrary. 20 Putting little arrows on to show people how they fit is 21 totally arbitrary; it really doesn't look at all like that. 22 The Ss, that's not the usual abbreviation of serotonin. 23 That's usually 5-HT, but I put S on it because I wanted not 24 just doctors but laypeople to read the book. 25 These are serotonin molecules that are being 231 1 released from the serotonin nerve, and they are caught in the 2 receptors, and that fires the next nerve. That's 3 neurotransmission, and in this case the whole operation is 4 serotonergic neurotransmission. That's a specialized function 5 of the brain. 6 Q. Okay. How does this presynaptic nerve end or 7 neuron know to release serotonin? 8 A. Well, the whole picture is certainly beyond our 9 understanding, so let me make that clear. I mean, you'd have 10 to go back to the beginning and say what's getting the nerves 11 firing in the first place. But what there has been a great 12 deal of research about lately has been the regulatory 13 mechanisms right at this point, what's regulating it at this 14 point. And a lot of the research came out of the laboratories 15 that are interested in developing medications along this line. 16 Q. Lilly being one? 17 A. Lilly being one, and there are others, too. 18 Now, this is carefully regulated. One of the regulatory 19 mechanisms is called reuptake. The serotonin isn't allowed to 20 linger indefinitely here, just firing, like a spark that just 21 keeps on firing, and it's not put out here. It is instead 22 brought back in. Some of them may be put out there, but 23 they're brought back in by reuptake through a receptor, which 24 I could have drawn just like this one, but I didn't want to 25 confuse anybody, and back into the original cell where they 232 1 are reused or broken down into some more fundamental 2 substance, in which case it could be secreted -- excreted in 3 the body, but it's brought back into the cell for reuse, can 4 also be destroyed. 5 Another mechanism -- now, if -- I'm not sure how 6 much detail to get into here. People are shaking their heads 7 already. 8 Q. Well, there's one, two, three, four, five, six, 9 seven, eight, nine, ten -- I believe ten or eleven of these 10 serotonin cells out in the synaptic cleft. 11 A. They're not cells, they're either packets of 12 biochemicals or just the molecules, however we want to manage 13 it. 14 Q. Has anybody counted the number of serotonin 15 molecules in the synaptic cleft? 16 A. No one has figured out a way to measure the 17 concentration of serotonin in the synapse. It's too fine. 18 So, how these mechanisms work has a certain amount of 19 guesswork behind it, simply because we don't know the 20 concentrations in there. Brain can be ground up and you can 21 measure the serotonin that's outside the cell, but that 22 doesn't mean it's inside the synapse; it doesn't mean it's in 23 that working place. So you can get a general idea of the 24 amount of serotonin that's in some tissue that you're grinding 25 up, and then there are methods -- and this gets out of my 233 1 expertise except for the general principles -- there are 2 methods whereby you can say it's not in the cell; it's outside 3 the cell. But it could be diffusing here or there, it could 4 be in a variety of different places. We can't measure what's 5 going on right here; it's all an inference. 6 Q. Is that important to you, Doctor Breggin, the 7 fact that we can't measure this here in determining -- 8 A. It's very important. It's very important. Let 9 me explain one more thing to you before I show you the 10 importance of it. The idea behind Prozac and a number of 11 other medications is to keep the serotonin in here longer so 12 that these cells are being bombarded or, in a sense jacked up, 13 just like in a sense if you were flooding your carburetor 14 getting more in and trying to get the system to go faster. 15 And the way that serotonin is influenced is that Prozac gets 16 into this reuptake process and competes with the little Ss; it 17 takes up room. 18 Let's say you had a train of cars going along 19 like the old cars we used to play with and they were filled 20 with coal, and let's say that's your reuptake system and 21 that's reuptaking these little cars and reuptaking serotonin 22 and serotonins are jumping into the car. Well, if Prozac is 23 jumping in, too, there's just so much room. So Prozac 24 competes in the reuptake system; that is, it jumps into that 25 system because of its chemical similarity somewhat with this 234 1 chemical, at least enough to get up into the reuptake system. 2 Prozac isn't firing. Prozac is keeping the serotonin in the 3 nerve longer. 4 Now, the nerve doesn't in a sense like that, 5 because this is an intrusion into the metabolic processes of 6 the brain, so the brain kicks in with compensatory mechanisms. 7 One thing it does is it has receptors here, and when they get 8 a sense there's too much serotonin they shut the nerve down. 9 So the Prozac is keeping the serotonin in the cleft longer, 10 but the nerve has stopped producing it. That happens in the 11 first week or ten days or so. Eventually that wears out. 12 Q. Wait a minute. Is that your idea? Did you come 13 up with that idea? 14 A. No. Hardly. I'm not able to do that kind of 15 research. That's out of the Lilly labs and other places, but 16 Lilly was one of the pioneers of that. 17 Q. My question, is there any controversy about this 18 down regulation; is that what it is, down regulation? 19 A. No. This is a shutdown mechanism, compensatory 20 shutdown mechanism, whereby the nerve itself is either putting 21 out fewer packages of serotonin or none. Now, this only goes 22 on for a while. After a while that breaks down and it just 23 doesn't control anymore. It just only can do it for a while. 24 There's no controversy about that. The controversies are much 25 more technical and complex as to what the ultimate outcome is, 235 1 but there's no controversy about the shutdown of this nerve. 2 But another thing happens because the brain, 3 whether alcohol is being taken into the brain or whether a 4 psychiatric drug is being taken into the brain, the brain 5 greets it as an intrusion. The brain didn't evolve or wasn't 6 God given to accept Prozac or to accept alcohol or to accept 7 any of the things that people often like to try to put into 8 it. So another thing that happens is when there's a lot of 9 serotonin in there, these receptors begin to disappear. It's 10 as if they're saying we're not going to have so many catchers 11 up because there's so much of this stuff being thrown at us. 12 It's too much. So this shuts down but comes back to life 13 eventually. This stays; that is, during the life that the 14 Prozac is being given, these begin to disappear because the 15 brain is saying too much serotonin, I'm not going to receive 16 it, I won't take it. 17 Q. What's that called, Doctor Breggin? 18 A. This is down regulation. It results in 19 something called subsensitivity, a lesser sensitivity that can 20 occur either by fewer of these or these not working as well, 21 not as well, but not being as sensitive. In the case of the 22 Prozac research so far, they're fewer in number. You can 23 count them 60 percent less in some areas of the brain the 24 receivers, because the serotonin is flooded. I hope this is 25 clear. I wish I could ask you whether you're following. 236 1 Q. You can't. Is this your idea or is this 2 something, this down regulation, this sensitivity, is this 3 something that's been demonstrated and accepted from a 4 scientific standpoint? 5 A. Oh, yes, sir. It's definitely demonstrated and 6 accepted. It doesn't happen with -- even the receptors have 7 different classes and kinds. It doesn't necessarily happen 8 with all kinds of receptors, but it happens with many 9 receptors, serotonin is one. 10 Q. Here's a question that I have. 11 A. Actually I just thought of coming back to your 12 original question, which is, why does it matter what's in 13 here. 14 Q. Uh-huh. 15 A. Because, actually, we're only guessing as to 16 what the overall effect is. It's not like when you give 17 insulin and you watch the blood sugar go down, or you stop the 18 insulin and the blood sugar goes back up. We haven't got 19 anything tiny enough to go in there and know what the overall 20 effect is on this system. We can make general judgments about 21 it. If the person is agitated and excited or overexcited, 22 there's perhaps too much going on. Most probably there's an 23 excess, at least, a super amount of serotonin that is revving 24 up the system and in this case has an agitating effect on it. 25 And that's a very good probability that that's how the 237 1 agitation that you've heard about develops, but we can't 2 actually get in there and measure that specific amount. 3 Q. So is there, Doctor Breggin, a baseline 4 serotonin level or concentration in the synaptic cleft of 5 living human beings? 6 A. Well, there may be a baseline, but we wouldn't 7 know what it is. And it may shift from day to day, but we 8 have no way of measuring. It's all indirect. We measure by 9 the effect on the pituitary, for example. You can look in the 10 blood and see the pituitary is changing what it's putting out, 11 but that's very indirect from knowing what's going on in each 12 of the millions of synapses in the brain. Some may be up, 13 some may be down; there's no way to know. It's a very 14 complicated kind of discussion I'm giving you. I hope very 15 much it's getting across. 16 Q. All right. Well, they've heard it in a couple 17 of forms in a couple of ways. 18 It's five after five, Your Honor. It might be 19 an appropriate time to stop. 20 JUDGE POTTER: Okay. Thank you, Mr. Smith. 21 Ladies and gentlemen, we're going to take the 22 evening recess. I tell you it's 9:00 tomorrow morning. And I 23 again mention the admonition applies to talking about this 24 case or letting anybody communicate with you on this case to 25 absolutely everybody. We're talking about your friends, your 238 1 family, and you probably got them pretty well trained by now. 2 They don't even ask you when you get home. But the people we 3 don't have trained and there's no way to train them because 4 they're in the business of publishing newspapers and saying 5 things on TV, are the media. I again emphasize that you 6 shouldn't let anybody in the media communicate with you by 7 watching their programs or whatever. Do not permit anybody 8 speak to or communicate with you on any topic connected with 9 this trial. Don't discuss it with each other and don't form 10 or express opinions about it. We'll stand in recess till 11 9:00. 12 (JURORS EXCUSED AT 5:07 P.M.) 13 JUDGE POTTER: I asked Mr. Freeman if we needed 14 to take anything up, and he thought we could take most of it 15 up tomorrow morning if you-all would -- he's wanting Mr. 16 Stopher to be here. If you-all would tell him what your plans 17 are about witnesses and really as far as depositions and 18 things go, this guy provides a little bit of a lull not for 19 Mr. Smith, but for you, Ms. Zettler. 20 MR. SMITH: She's sleeping at night now, Your 21 Honor. 22 JUDGE POTTER: That's the point is you've got to 23 keep going. Who is going to be your next witness after this 24 witness? 25 MS. ZETTLER: Talbott or Zerbe. 239 1 JUDGE POTTER: By deposition; right? 2 MR. SMITH: You're not going to bring Max 3 Talbott down here? 4 MR. FREEMAN: I don't see any reason to bring 5 him down and ruin your case. 6 JUDGE POTTER: But you and Mr. Myers will have 7 that. I'll see you-all at quarter of nine. Okay. 8 MR. SMITH: I think Breggin is probably going to 9 take a substantial part of the week. 10 JUDGE POTTER: Week? Okay. Well, we'll see. 11 MR. FREEMAN: How much longer are you going to 12 take with him? 13 MR. SMITH: Day, day and a half. You think 14 you'll take half a day? 15 MR. FREEMAN: You think you'll take all day 16 tomorrow with him? It is awfully hot. If you believe you'll 17 take the rest of tomorrow -- 18 MR. SMITH: I think we've got a lot of stuff to 19 cover. 20 JUDGE POTTER: I promise you-all I've sent notes 21 out to the heating people, and they tell me the heat is not 22 on. 23 MR. FREEMAN: The weather just changes so much. 24 JUDGE POTTER: See you-all in the morning. 25 (PROCEEDINGS TERMINATED THIS DATE AT 5:10 P.M.) 240 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 witnesses 8 were first duly sworn; that said testimony was taken down by 9 me in stenographic notes and thereafter reduced under my 10 supervision to the foregoing typewritten pages and that said 11 typewritten transcript is a true, accurate and complete record 12 of my 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 241 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