1585 1 IN THE UNITED STATES DISTRICT COURT 2 FOR THE DISTRICT OF HAWAII 3 4 SUSAN K. FORSYTH, ) Civil No. 95-00185ACK Individually and as ) 5 Personal Representative ) Pages 1,585 - 1,812 of the Estates of June M. ) 6 Forsyth and William D. ) Forsyth, and WILLIAM F. ) 7 FORSYTH, JR., ) ) 8 Plaintiffs, ) ) 9 vs. ) ) 10 ELI LILLY AND COMPANY, ) an Indiana corporation, ) 11 et al., ) ) 12 Defendants. ) __________________________) 13 14 TRANSCRIPT OF PROCEEDINGS 15 The above-entitled matter came on for trial on 16 Thursday, March 18, 1999 at 9:15 a.m. at Honolulu, 17 Hawaii. 18 BEFORE: THE HONORABLE ALAN C. KAY 19 United States District Judge District of Hawaii 20 21 REPORTED BY: TINA M. STUHR, RPR, CSR #360 Notary Public, State of Hawaii 22 PACIFIC REPORTING SERVICES UNLIMITED, INC. 23 733 Bishop Street Suite 2090, Makai Tower 24 Honolulu, Hawaii 96813 (808) 524-PRSU 25 PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1586 1 APPEARANCES: 2 For Plaintiffs: ANDY VICKERY, ESQ. Vickery & Waldner 3 2929 Allen Parkway Suite 2410 4 Houston, Texas 77019 5 KAREN BARTH, ESQ. Baum, Hedlund, Aristei, Guilford 6 & Downey 12100 Wilshire Boulevard 7 Suite 950 Los Angeles, California 90025 8 ROY K.S. CHANG, ESQ. 9 Shim & Chang 333 Queen Street 10 Suite 900 Honolulu, Hawaii 96813 11 For Defendant: ANDREW SEE, ESQ. 12 MICHELLE R. MANGRUM, ESQ. Shook, Hardy & Bacon L.L.P. 13 One Kansas City Place 1200 Main Street 14 Kansas City, Missouri 64105 15 EDMUND BURKE, ESQ. Burke Sakai McPheeters Bordner 16 Iwanaga & Estes 737 Bishop Street 17 Suite 3100 - Mauka Tower Honolulu, Hawaii 96813 18 Also Present: Catherine Itai 19 20 21 22 23 24 25 PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1587 1 I N D E X 2 WITNESS ON BEHALF OF DEFENDANT 3 GARY DENNIS TOLLEFSON, M.D. PAGE 4 Direct Examination by Mr. See 1630 Cross-Examination by Mr. Vickery 1720 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1588 1 (Whereupon, the following proceedings were had 2 in open court out of the presence of the jury.) 3 THE CLERK: Civil No. 95-001858 ACK, Susan K. 4 Forsyth, et al. versus Eli Lilly and Company, et al. 5 MR. VICKERY: Good morning, Your Honor. Andy 6 Vickery and Karen Barth and Roy Chang for the 7 Forsyths. 8 MR. SEE: Good morning, Your Honor. Andy See, 9 Michelle Mangrum, and Ed Burke for Eli Lilly and 10 Company. 11 THE COURT: Good morning. I understand there 12 are more objections. 13 MS. MANGRUM: Your Honor, Mr. Vickery has 14 indicated he intends to read some of his discovery 15 responses, and when we discussed that with the Court 16 at the hearing on March 4th, they were admitted 17 subject to a factual predicate, which would have made 18 them relevant in this case, and our objection to his 19 first set, those he's designated in Plaintiffs' 20 Exhibit 173 is that there is no factual predicate in 21 this case which would make them relevant. 22 THE COURT: 173? 23 MS. MANGRUM: Yes. 24 THE COURT: Which ones are they? 25 MS. MANGRUM: The first one is number nine. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1589 1 THE COURT: How many are there? 2 MS. MANGRUM: In 173 there are nine total. 3 THE COURT: These are only admitted for notice? 4 MS. MANGRUM: Yes, sir. 5 THE COURT: They are only admitted for notice 6 assuming there was a foundation. 7 MS. MANGRUM: Yes, Your Honor. These are all 8 requests that Lilly admits that during certain 9 telephone conferences physicians reported to Lilly 10 certain events their patients had experienced at the 11 same time they were taking Prozac. Number nine, for 12 example, states that a few people have gotten so hyper 13 on the drug that they couldn't even sit still during 14 the day, but there's been no evidence in this case 15 that Mr. Forsyth had that problem, and therefore, 16 Lilly's knowledge of that event is not relevant. 17 THE COURT: Mr. Vickery. 18 MR. VICKERY: Your Honor, all of these matters 19 go to the question of whether or not Mr. Forsyth had 20 akathisia and whether Lilly should have warned about 21 akathisia. As Dr. Healy explained very patiently over 22 a long period of time, this disease or this condition 23 manifests itself in several different ways, and the 24 question is really Lilly's notice that physicians were 25 having patients who experienced these conditions. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1590 1 I'm sorry if I seem a little inarticulate. I 2 had no idea what we were talking about this morning. 3 Ms. Mangrum didn't tell me that she had asked the 4 Court to rule on these or was objecting, so I just 5 learned it when Your Honor walked in. But I -- all of 6 these issues go to restlessness, being hyper, jumping 7 out of their skin, all things that directly relate to 8 akathisia, and so if the question is was Lilly on 9 notice that this drug causes akathisia so as to be 10 under an obligation under Hawaii law to warn about 11 that, these all establish notice. 12 These are conferences in Lilly-sponsored 13 events. These are not random things. It is something 14 that Lilly sponsored in a teleconference, and all of 15 these doctors reported these events. That's why the 16 Court admitted them. 17 I don't recollect, although I will take 18 Ms. Mangrum's word for it, that they were admitted 19 under any kind of condition of predicate at all. 20 THE COURT: Well, you know, as I stated several 21 days ago, it was my understanding that any -- all I 22 was doing was ruling on the other objections, but not 23 on foundation. I mean, for instance, the journal 24 notes of June Forsyth, how could I possibly rule on 25 foundation? I mean, someone would have to establish PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1591 1 that that was her handwriting. There's no way I could 2 have ruled on that. 3 MR. VICKERY: I understand that, and that's not 4 an issue. I mean, we agreed that that was her 5 handwriting. We made no objection. 6 THE COURT: I'm just using that as an example 7 of how could I be ruling on the foundation. On the 8 other hand, as far as, if you had an FDA paper that 9 had been certified by the FDA, then that would come 10 in, but anyway, let's go to the next one. Number 11; 11 is that right? 12 MS. MANGRUM: Yes, Your Honor. 13 THE COURT: This one is the attention span? 14 MS. MANGRUM: Attention span, yes, they 15 couldn't work and could not carry on conversations. 16 THE COURT: Okay. Next one, No. 12. 17 MS. MANGRUM: Three people out of fifty that 18 complained of feeling quite hyper and nervous. 19 THE COURT: Next. Thirteen. 20 MS. MANGRUM: Excuse me, yes, Your Honor, 13. 21 A physician reported that he suspected that Prozac had 22 an amphetamine-like action. 23 THE COURT: What's the relevance of that, 24 Mr. Vickery? 25 MR. VICKERY: I expect that their own witnesses PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1592 1 would readily admit that someone that has an 2 amphetamine-like action is the very kind of 3 nervousness, agitation, akathisia -- I mean, there's 4 so many different terms that are used to describe 5 these phenomena, both lay terms like wired, jumping 6 out of our skin, and more technical terms. Depending 7 on who you're talking to, they might use different 8 verbiage, but we're talking about the same phenomenon. 9 THE COURT: Fourteen is jump out of skin, 10 right? 11 MS. MANGRUM: Yes, Your Honor. 12 THE COURT: Seventeen is the next one? 13 MS. MANGRUM: I believe it's 18, Your Honor. 14 MR. VICKERY: Seventeen. No, I was holding on 15 17, Your Honor. She's right. Seventeen not at this 16 time. 17 THE COURT: Eighteen, restless. Is this a new 18 way of spelling akathisia? 19 MR. VICKERY: (Counsel nods head.) 20 THE COURT: A-C-H-I-S-E-S-I-C. 21 MR. VICKERY: That's right. That's why it says 22 sic after it. It's obviously a misspelling. 23 THE COURT: Nineteen, agitation. 24 MS. MANGRUM: Yes, Your Honor. 25 THE COURT: Twenty-one, bopping other people in PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1593 1 the unit. What about that, Mr. Vickery? 2 MR. VICKERY: It's violence towards other 3 people. 4 THE COURT: Pardon me? 5 MR. VICKERY: It's violence towards other 6 people. Lilly is on notice that people on Prozac were 7 bopping other people. 8 THE COURT: Twenty-two is -- 9 MS. MANGRUM: That one Mr. Vickery has skipped 10 and said the next one is 24 that he intends to read. 11 THE COURT: Twenty-four, wired. 12 MS. MANGRUM: Yes, Your Honor. 13 THE COURT: I think that was the word Dr. Healy 14 used, wasn't it? 15 MS. MANGRUM: It may have been, Your Honor. 16 Plaintiffs only -- Mr. Vickery's argument has been 17 this is relevant to Lilly's notice because plaintiffs 18 claim Lilly should have warned about akathisia and 19 these type of events. Their only expert testimony on 20 the issue of failure to warn was that of Dr. Shlensky, 21 and his only criticism was that the warning should 22 have contained information regarding suicide and 23 violence. Nothing about any of these events. 24 THE COURT: Well, I'm going to allow these, 25 again strictly for notice for that limited purpose, PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1594 1 otherwise I find that they are relevant. 2 Does that cover all of them? 3 MS. MANGRUM: Just a moment, Your Honor. The 4 next one they have designated is Exhibit 174. That's 5 only Request No. 3, which asks that Lilly admit that 6 Fluoxetine is an activating drug, and our objection to 7 that would be the same, lack of factual predicate 8 because there's no evidence in this case that it had 9 that effect on Mr. Forsyth. 10 THE COURT: This portion Lilly admits that 11 technology has not advanced to the point, is that what 12 you're objecting to? 13 MR. VICKERY: I believe that Ms. Mangrum 14 misspoke, Your Honor. No. 3 on 174 is exactly what 15 you're looking at. It has nothing to do with 16 activation. It has to do with the extent of Lilly's 17 understanding and knowledge about what this drug 18 really does to people. 19 The request was that Lilly cannot explain how 20 Prozac works either for treatment of depression or for 21 other behavioral disorders, and I'm certainly willing 22 to leave off that other phrase. 23 THE COURT: What other phrase? 24 MR. VICKERY: The last phrase "or for other 25 behavioral disorders." PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1595 1 MR. SEE: That's fine. Why don't you do that? 2 MR. VICKERY: Okay. I will do that. 3 THE COURT: I'm not sure I see exactly where 4 you're referring to. 5 MR. VICKERY: In the request itself, Your 6 Honor, Request No. 3. 7 THE COURT: Oh, I see. 8 MR. VICKERY: You see the last phrase? 9 THE COURT: Yes. 10 MR. VICKERY: I'm just going to leave that off 11 when I read it. 12 THE COURT: All right. And with that, there's 13 no objection? 14 MS. MANGRUM: That's right, Your Honor. 15 THE COURT: Have we covered everything? 16 MS. MANGRUM: There's three left in 17 Exhibit 178, and that would be request for admissions 18 No. 16 and No. 20, and then Interrogatory No. 17. 19 THE COURT: 178, 16? 20 MS. MANGRUM: Yes, Your Honor. 21 THE COURT: What is the gross revenue? 22 MS. MANGRUM: No, it's request for admission 23 16. It is -- 24 THE COURT: Are we in 178? 25 MS. MANGRUM: Yes, Your Honor. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1596 1 MR. VICKERY: 178 contains both request for 2 admissions and interrogatories, Judge. She's talking 3 about the request for admission No. 16 that Prozac has 4 an activating effect in some people. 5 THE COURT: What's the objection to that? 6 MS. MANGRUM: Again, that there's no evidence 7 that this drug had an activating effect in 8 Mr. Forsyth, so Lilly's knowledge of that or its 9 statement regarding activation is not relevant. 10 THE COURT: What's the Prozac miracle? 11 MS. MANGRUM: A relief of depression. 12 THE COURT: Is that activating or what? 13 MS. MANGRUM: I believe it's relief of the 14 depressive symptoms and a return to normal. That was 15 Dr. Riggs Roberts' phrase. It's not a phrase used by 16 Lilly or coined by Lilly. 17 THE COURT: Yeah, but you say that there was no 18 evidence as to Mr. Forsyth. 19 MS. MANGRUM: Exactly. I mean, no evidence 20 that he was excessively active or pacing, wringing his 21 hands, doing anything other than returning to his 22 normal state by the observations of physicians and 23 family members. 24 THE COURT: Mr. Vickery. 25 MR. VICKERY: Well, I think the Prozac miracle PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1597 1 is exactly activation as is his anxiousness on the 2 following day, the 24th, to get into the hospital. 3 It's again -- the problem that we have and the Van 4 Putten article, if you want to read it, would help is 5 that the terminology has been so loosey goosey with 6 respect to this phenomenon akathisia. They use 7 agitation, activation, nervousness, restlessness, 8 akathisia, jump out of my skin, feeling wired. I 9 could go on and on. 10 THE COURT: Well, I'm going to allow it. I 11 find it relevant. 12 MS. MANGRUM: The last two, Your Honor, are 13 Interrogatory No. 17 -- 14 THE COURT: Is this in 178? 15 MS. MANGRUM: Yes, Your Honor. 16 THE COURT: Interrogatory number what? 17 MS. MANGRUM: One -- or excuse me, 17. Our 18 objection to that is that the number of times the 19 label has been changed is absolutely irrelevant. 20 Several of the changes referenced in there occurred 21 after Mr. Forsyth's ingestion of Prozac, which would 22 make them subsequent remedial measures. And just the 23 number of times that the label has changed has nothing 24 to do with this case. 25 THE COURT: I think someone has already PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1598 1 testified to this anyway, haven't they? 2 MR. VICKERY: No, sir. There has been no 3 testimony on this. 4 THE COURT: I think one of your experts got 5 that in. 6 MR. VICKERY: I believe he said it could be 7 changed, but I don't think anybody has talked about 8 the number of times that it's been changed. My 9 concern, Judge, is that Lilly is going to try to paint 10 this picture that, oh, boy, our warnings are approved 11 by the FDA and they're just cast in stone. They're 12 just cast in stone. So the fact that Lilly changed 13 the label 28 different times over a ten-year period 14 indicates they're not cast in stone at all. 15 Certainly, none of these get into the subject 16 of subsequent remedial measures because there's no 17 question about the substance of any of these changes, 18 but it -- I mean, it clearly indicates that Lilly can 19 and has changed the label for Prozac -- 20 THE COURT: Wouldn't this be more proper for 21 rebuttal then? 22 MR. VICKERY: Well, I don't think so, Your 23 Honor. We're going to have this morning, you know, 24 Lilly's vice president, Dr. Tollefson, who is, you 25 know, is their guy they're bringing and before he PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1599 1 testifies in my case in chief, I want the jury to 2 understand that they can and have changed this label 3 very frequently. Nearly three times a year. 4 THE COURT: Well, you can bring that on 5 cross-examination, can't you? 6 MR. VICKERY: Okay. I'll do that. 7 THE COURT: All right. Next. 8 MS. MANGRUM: That's the last one, except for 9 17 also asks how much it cost to modify the insert, 10 and our objection would be the same, that that also is 11 not relevant at this time. 12 THE COURT: That does not seem relevant for 13 this purpose. 14 MR. VICKERY: Your Honor, they have said time 15 and again with witnesses, isn't there a risk benefit 16 analysis that you have to do in prescribing a 17 medication, and so -- 18 THE COURT: That's to the treating physician. 19 MR. VICKERY: I understand. But they're the 20 ones that have interjected the notion that we balance 21 benefits and risk, and I think the fact that this can 22 be done with no cost, that it's done frequently 23 without any regulatory problems and without 24 significant cost -- 25 THE COURT: Well, what's a significant cost? PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1600 1 MR. VICKERY: I don't know. They won't tell 2 me. 3 THE COURT: You're not going to tell me there's 4 no cost involved. There's some cost. 5 MR. VICKERY: Of course there's some cost. 6 THE COURT: Okay. I rule that irrelevant at 7 this time under 403. It's highly prejudicial and does 8 not have any significant probative value and it would 9 be a waste of time and confusing to the jury. That 10 may become pertinent during the punitive damages 11 phase, if we get to that, though. Have we covered 12 everything? 13 MR. SEE: We have covered all of those, Your 14 Honor. The only other thing we have is really a 15 scheduling matter. I've discussed this with 16 Mr. Vickery. He informs me that other than reading 17 these interrogatory responses and so on that we've 18 just talked about, thereafter, the plaintiffs will 19 rest their case. 20 We do have a motion for directed verdict and 21 would make it, and just -- we kind of would ask the 22 Court's pleasure, if the Court would like to hear it 23 now before the jury comes back, we could certainly do 24 that subject to Mr. Vickery reading -- only reading 25 the interrogatory responses that we've just discussed. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1601 1 If that would be convenient for the Court's schedule, 2 we would offer to do that at this point. 3 THE COURT: That sounds reasonable. Are you in 4 agreement with that, Mr. Vickery? 5 MR. VICKERY: Sure. I think you can take it up 6 whenever you like. 7 THE COURT: All right. 8 MR. SEE: Your Honor, I'll hand up two copies 9 of the pleading. 10 THE COURT: Is that a little epistle here? 11 MR. SEE: It is, Your Honor. 12 THE COURT: This is where Ms. Mangrum was 13 yesterday? 14 MR. SEE: Honestly, I can't testify to that, 15 sir. But I believe I can bottom line what it says in 16 not too long. And they're really -- 17 THE COURT: Well, I can't read much of that, 18 so -- 19 MR. SEE: All right. 20 THE COURT: I've seen it before. 21 MS. MANGRUM: It's 1041 in the book. 22 MR. SEE: It's Exhibit 1041 in our book. It is 23 a blowup of part of the insert. 24 THE COURT: I'm familiar with it anyway. 25 MR. SEE: All right. Your Honor, there are a PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1602 1 few grounds for the directed verdict. The first one 2 is this: Plaintiffs have two experts, Dr. Healy and 3 Dr. Shlensky. They both have testified that Prozac 4 caused akathisia in Mr. Forsyth and that from that, 5 Mr. Forsyth proceeded to these other events, that he 6 became suicidal and he became homicidal. 7 There's no evidence in the case from any of the 8 fact witnesses that Mr. Forsyth, in fact, had 9 akathisia. The Ninth Circuit case, which is U.S. 10 versus Various Slot Machines, which we have in the 11 brief, is very clear. The expert opinion has to be 12 based upon facts. There has to be a fact underlying 13 that opinion. And both the plaintiffs' experts, to 14 get to causation, go through akathisia. 15 And the evidence that we have is very 16 straightforward. There is no evidence from any fact 17 witness, either the hospital records, Dr. Roberts' 18 records, Dr. Neal's testimony, Dr. Roberts' testimony, 19 Bill Forsyth's testimony, Susan Forsyth's testimony, 20 Kim Forsyth's testimony, anyone that observed 21 Mr. Forsyth during anytime he was taking Prozac that 22 he had any sign or symptom of akathisia. 23 THE COURT: Well, it seems to me that Dr. Healy 24 did testify that in reading the record, reading the 25 depositions and the reports that from the facts he saw PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1603 1 in those, that he determined in his opinion, which 2 your experts disagree with, but in his opinion that 3 there was akathisia. 4 MR. SEE: I understand that. 5 THE COURT: And there were symptoms of 6 akathisia. 7 MR. SEE: I understand that. He gave that 8 opinion. 9 THE COURT: Based on the facts he saw from the 10 record. 11 MR. SEE: But let's look at what those facts 12 are and how Dr. Healy gets to his opinion. He put in 13 front of the jury five case reports. He said those 14 case reports show that Prozac causes akathisia. 15 That's the Rothschild, Healy, Wirshing, King and so 16 on. 17 THE WITNESS: Controlled clinical studies. 18 MR. SEE: Some would say. Although 19 Dr. Shlensky would not agree with that nor would 20 anyone else in the medical world, but Dr. Healy does. 21 You look at those five case reports, and what 22 do you see, pacing, hand-wringing, inability to sit 23 down, inability to remain still, the very -- what 24 Dr. Healy claims is the very scientific data upon 25 which his opinion rests, and that's it. Those case PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1604 1 reports. Every one of those people had visible, 2 observable signs of psychomotor movement. Every one. 3 So that's what his opinion is based upon. 4 Now, I know he says, well, I've reviewed the 5 record and I've determined that Mr. Forsyth had 6 akathisia, but that opinion has to be based upon fact, 7 and all of the scientific data that Dr. Healy puts 8 forward, every -- there may be one, every one of those 9 people had active movement. Every one. 10 So Dr. Healy's opinion resting upon that data 11 can't support an opinion that Mr. Forsyth had 12 akathisia. It simply can't do it. Because he says 13 the data is here and it says one thing, but I read the 14 factual record and now I'm ignoring my data, and 15 saying this guy had akathisia when Mr. Forsyth had no 16 symptom that is anywhere close to what was in those 17 five case reports. That's my first ground. 18 My second ground is a proximate cause ground, 19 the Wolf versus Lilly, the Oklahoma case. We heard 20 testimony from the only two prescribers, and their 21 testimony was they did not rely upon what the drug 22 company gave them. They made independent decisions. 23 They did their own research. They looked for the 24 articles themselves and did not rely upon what the 25 drug company told them. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1605 1 THE COURT: But I think that Mr. Vickery did -- 2 you know, I acknowledge he made a strong point there, 3 but on the other hand, I think Mr. Vickery did get 4 them to say that if there was a warning that Prozac 5 caused akathisia or Prozac caused death, then they 6 would have considered the warning. 7 MR. SEE: Well, Dr. Roberts -- 8 THE COURT: I will withdraw the latter. 9 MR. SEE: Dr. Roberts gave no testimony about 10 that. Mr. Vickery didn't ask about that. He asked 11 Dr. Neal, and Dr. Neal said Mr. Vickery sent me all 12 this stuff that's been in this trial, it wouldn't have 13 changed my view at all. 14 THE COURT: I don't know what he sent him. 15 MR. SEE: Well, his testimony was he sent him 16 the exhibits from the trial. 17 The other aspect of the proximate cause 18 argument is that both of these doctors testified that 19 they already knew that there was a possibility of 20 suicide in a patient taking an antidepressant drug 21 including Prozac. Already knew it through their own 22 independent knowledge. That's my second ground for 23 proximate cause. 24 My third ground has to do with the adequacy of 25 the warning, and I think I tried to listen very PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1606 1 carefully to what Dr. Shlensky said about his 2 criticism of Lilly's warning. Dr. Healy, of course, 3 gave no opinion, so the only critique we have is what 4 Dr. Shlensky said, and my notes reflect that what 5 Dr. Shlensky said was Lilly did not warn of the 6 possibility of suicide or violent behavior, and that's 7 my criticism. And my recollection is, and I hope the 8 Court's is too, that that's about all he is said. It 9 was pretty short. 10 The Prozac package insert at the time says, 11 with respect to suicide, "the possibility of a suicide 12 attempt is inherent in depression and may persist 13 until significant remission occurs." The second place 14 is under post-introduction reports. It tells the 15 doctor that "Reports of adverse events temporally 16 associated with Prozac include suicidal ideation." It 17 also says in that section that "Voluntary reports of 18 adverse events temporally associated with Prozac 19 include violent behaviors." 20 And although Dr. Shlensky did not make it part 21 of his criticism, the insert also says, "events 22 observed during premarketing evaluation, akathisia is 23 warned against." 24 Now, I just note that for the Court's own 25 information. Dr. Shlensky did not criticize the PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1607 1 insert about akathisia. He criticized it about 2 suicide, which is here in two places, and he 3 criticized it about violent behavior, which is clearly 4 specified. 5 THE COURT: But his -- wasn't his concern that 6 it didn't warn that, number one, I guess that's a 7 precaution rather than a warning; is that right? 8 MR. SEE: The first suicide warning is in the 9 precaution section. 10 THE COURT: Right. 11 MR. SEE: That's correct. 12 THE COURT: Not the -- there's a warning 13 section, too, isn't there? 14 MR. SEE: There is a warning section. 15 THE COURT: Right. The precaution section is 16 sort of lower case compared to the warning section. 17 MR. SEE: It follows it, but it's not in a 18 lower case. 19 THE COURT: Yeah, but you know what I mean. It 20 doesn't carry the same emphasis as the warning 21 section. 22 MR. SEE: With respect, Your Honor -- 23 THE COURT: I think one of the experts or two 24 of them -- 25 MR. SEE: It's in two different sections. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1608 1 There's no question about that, but with respect, Your 2 Honor, as I wrote down what Dr. Shlensky said, he 3 said, Lilly's warning did not warn about suicide or 4 about violent behavior. Full stop. 5 THE COURT: And did he say with respect to 6 Prozac or with respect to depression? 7 MR. SEE: He said with respect to Prozac, but 8 I'm saying, if you come down to the post-introduction 9 reports section, it says, "Reports of adverse events 10 temporally associated with Prozac, suicidal ideation 11 and violent behaviors." 12 The warning is that those things had been 13 reported in temporal associations with Prozac. So 14 that section of the insert is not a warning about 15 suicide coming along with depression. 16 THE COURT: It's a precaution that what? 17 MR. SEE: It reads, "Voluntary reports of 18 adverse events temporally associated with Prozac that 19 have been received since market introduction and which 20 may have no causal relationship with the drug, include 21 the following: Suicidal ideations and violent 22 behavior." 23 THE COURT: May have no causal relationship? 24 MR. SEE: That's what it says. Dr. Shlensky 25 did not testify that his criticism was that the PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1609 1 warning should say Prozac causes suicide. That was 2 not the tenor of his criticism. It was that the 3 insert did not warn of the risk or possibility of 4 suicide or violent behavior and the fact is, it 5 clearly does. And he really went into no more detail. 6 His warning opinion was very short. So I would submit 7 that the insert, in fact, does warn about exactly what 8 Dr. Shlensky criticized and that's the only opinion in 9 the case about warning. Those are my three grounds. 10 THE COURT: Oh, I thought you said you had 11 more. 12 MR. SEE: I had those three; the causation 13 through akathisia, the proximate cause, both that they 14 already knew about the possibility of suicide and that 15 they may occur in associated events, that's the second 16 one, and the third one is the warning as criticized by 17 Dr. Shlensky is, in fact, adequate. It says exactly 18 what he criticized. 19 THE COURT: Thank you. Mr. Vickery. 20 MR. VICKERY: Your Honor, I, of course, have 21 not had time to read the 13-page brief that 22 accompanies the written motion nor has the Court. I 23 just got it the same time the Court did. 24 THE COURT: Well, do you want to argue this 25 sometime later? PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1610 1 MR. VICKERY: I don't think so. He didn't 2 really rely on the law there anyway, but of the 3 evidence and I'm prepared to address the evidence. 4 I think the Court has in the comments to 5 Mr. See hit the nail on the head with respect to all 6 three. With respect to the first ground, no evidence 7 of akathisia, the problem, of course, is as Dr. Healy 8 explained at some length, the difficulty in discerning 9 this condition if one is not looking for it. 10 If you're not forwarned to look for it, either 11 doctor or patient, it's more difficult to find, but we 12 have the testimony of Dr. Neal that he had a 13 constricted effect. We had the testimony of Kim 14 Forsyth that his hands, indeed, were fidgeting when he 15 was on his way to the hospital and we have the 16 testimony -- 17 THE COURT: His knees? 18 MR. VICKERY: Sir? 19 THE COURT: His knees? 20 MR. VICKERY: No, his hands. 21 THE COURT: I thought you said his hands and 22 knees. 23 MR. VICKERY: No, sir, I said his hands were 24 fidgeting as he was on his way to the hospital. We 25 have the testimony of Dr. Healy -- PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1611 1 THE COURT: Is this something that she did not 2 say in her deposition? 3 MR. VICKERY: That's exactly right. She didn't 4 remember it in her deposition, but the evidence is in 5 the record. I mean, the fact -- 6 THE COURT: I understand. 7 MR. VICKERY: Okay. And then, of course, the 8 testimony of Dr. Healy in looking at the facts, his 9 testimony is based on the facts, on the records, and 10 his opinion can't be ignored, certainly not in the 11 context of a motion for a directed verdict because 12 Mr. See doesn't like the facts he looked at or 13 quibbles with the methodology in which he looked at 14 them. He looked at the records and said based on 15 those records, I believe this man had akathisia. 16 THE COURT: His opinion is based also on the 17 fact that he thought he had mild depression. 18 MR. VICKERY: Exactly. 19 THE COURT: His whole opinion is based on that; 20 whereas, the treating physicians and others thought -- 21 have all opined that it was severe depression. 22 MR. VICKERY: I understand that, and there's a 23 conflict the jury has to resolve based on the 24 credibility that they assess to the various 25 physicians, but that's a traditional jury question. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1612 1 And with that evidence in the record, we're not in a 2 directed verdict context. 3 The second ground -- 4 THE COURT: I just note that the two treating 5 physicians found contrary to Dr. Healy who wasn't even 6 around. 7 MR. VICKERY: You're absolutely right, Your 8 Honor, and for that reason, the jury may choose to 9 give their testimony more credence. I think there are 10 other reasons in which they would tend to discount the 11 testimony of those gentlemen and favor the testimony 12 of Dr. Healy, but my point is quite simply -- 13 THE COURT: And on top of that, as far as the 14 draft warning, which you brought out, in fact, he was 15 being given a sedative along with the Prozac. In 16 other words, there was full compliance. 17 MR. VICKERY: There wasn't full compliance. He 18 discontinued the Xanax. He discontinued the very 19 benzodiazepine. He discontinued that. 20 THE COURT: But he gave him Inderal. 21 MR. VICKERY: He did give him Inderal. 22 THE COURT: And that was to relieve anxiety and 23 he also said that it would relieve any akathisia. 24 MR. VICKERY: I think he said that Inderal 25 would help him sleep. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1613 1 THE COURT: No, he gave him something else for 2 sleep. 3 MR. VICKERY: Okay. I understand the arguments 4 you're making, Your Honor. 5 THE COURT: I'm not making arguments. 6 MR. VICKERY: Or the points. 7 THE COURT: A lot of this doesn't rise to the 8 level of a directed verdict, so go ahead. 9 MR. VICKERY: That's my whole point. I 10 understand the conflicts in the testimony that the 11 Court's pointing out or the conflicts in the evidence 12 from which the jury can go either way on it. My only 13 point is that it's for them to weigh that evidence and 14 decide which way to go. 15 THE COURT: What I have said so far, I think, 16 really undermines the plaintiffs' case, but I'm not 17 sure that it rises to the level of a directed verdict. 18 MR. VICKERY: I agree with you entirely. It's 19 evidence that they brought out that cuts against us, 20 but it's for the jury to decide. 21 The second ground on the Wolf case. As I told 22 the Court before, I was the attorney of record in 23 Wolf. I represented the Wolf children. I understand 24 exactly what happened in that case. 25 THE COURT: You lost on a summary judgment PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1614 1 there? 2 MR. VICKERY: Yes, we did and unfortunately, my 3 clients instructed me to settle the case on appeal, so 4 the Tenth Circuit never got to speak to it. I think 5 the judge was wrong on that case because of the 6 comment Jay presumption, which we've briefed for the 7 Court. I don't think that under Hawaii law that that 8 same result would obtain. I clearly do not, but 9 that's an issue we need not cross at this juncture 10 because Dr. Neal did testify that he would have heeded 11 an appropriate warning from Eli Lilly, so -- 12 THE COURT: Whatever that might be. 13 MR. VICKERY: Whatever that might be. You 14 know, we obviously get into my work product as to how 15 I would argue what that ought to be based on the 16 totality of the evidence, but again, it gets us over 17 the hurdle. 18 THE COURT: I think he did testify he would 19 have acted differently perhaps if the warning had been 20 that Prozac might cause akathisia. 21 MR. VICKERY: Right. 22 THE COURT: And maybe that's in there according 23 to what Mr. See was just saying. 24 MR. VICKERY: Well, I find Mr. See's statements 25 just now to be somewhat extraordinary. I think that PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1615 1 the world community would be shocked to know that Eli 2 Lilly's lawyer just said in open court that they have 3 warned about suicide and akathisia, because as the 4 Court pointed out, these are not in the warning 5 section. They're in the precaution section. The 6 federal regulations, which are in evidence, both 7 parties have asked the Court to take judicial notice 8 of them, make clear distinctions between warnings and 9 precautions, and the section on temporally associated, 10 they specifically say not caused. 11 It's not even a precaution, Judge. It's 12 merely, oh, yeah, by the way, some people who have 13 taken this pill have reported that, you know, 14 subsequent to taking it, they've had these reactions, 15 but don't worry about it. It doesn't cause -- our 16 pill isn't causing this. 17 Of course, separate and apart from that, 18 there's the interrogatory that we just read that shows 19 that this is not the only way that Lilly informs 20 physicians about problems with the drug. So it -- 21 this isn't even -- 22 THE COURT: What's the significance of that? 23 MR. VICKERY: The significance of that is that 24 Lilly had lots of -- under Hawaii law the warning must 25 be adequate to apprise the prescribing physician of PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1616 1 the dangers, to bring it to his attention, okay? And 2 so something tucked away in the small print of a 3 section that's not even the warning section of the 4 label is not the only way that Lilly has to comply 5 with the common law of Hawaii in giving an effective 6 warning. They use other means. They use dear-doctor 7 letters. They use detail people. It's just 8 abundantly clear that they have not warned about a 9 risk that this drug causes suicide. 10 They've said it's temporally associated with 11 it, but it doesn't cause it. I mean, they've gone 12 beyond not warning to say it doesn't cause it. 13 THE COURT: But on the other hand, you may have 14 that same -- the bottom line is you may have that 15 result, whether it causes it or not. 16 MR. VICKERY: Sure. You may have that result, 17 but it's common sense that if you're getting 18 information from the manufacturer and it is 19 established, as the Court's already noted, in a 20 hierarchical fashion, they're warnings, then they're 21 precautions, and then they're temporally associated 22 events, and where one puts the words in the label is 23 something that is extremely important. 24 THE COURT: That's Exhibit 114; is that right? 25 MR. VICKERY: I haven't looked at it, Judge. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1617 1 MR. SEE: 1041, Your Honor. 2 THE COURT: 1041? 3 MR. SEE: 1041. 4 MR. VICKERY: So for all of these reasons, Your 5 Honor, I think that there is sufficient evidence for 6 the jury to conclude that Mr. Forsyth had akathisia; 7 that the failure to warn and that this drug were 8 indeed a proximate cause of the deaths of June and 9 Bill Forsyth; and that the warning -- I wouldn't even 10 call it a warning. I would say that there's no 11 warning about this issue, but certainly the 12 information in the package insert was not sufficient 13 under Hawaii law. 14 THE COURT: Well, what is your answer to 15 Mr. See's statement that Dr. Shlensky gave a very 16 limited opinion as to the warning, the inadequacy of 17 the warning? 18 MR. VICKERY: My answer to that, Your Honor, is 19 really twofold. Number one is that Dr. Shlensky -- 20 Dr. Shlensky's testimony gets us to the jury. 21 THE COURT: Pardon me? 22 MR. VICKERY: Dr. Shlensky's testimony 23 certainly gets us to the jury, assuming for a moment, 24 that one has to have expert testimony on the issue of 25 inadequacy of warnings. The Court has not addressed PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1618 1 that, but assuming that that's necessary, his 2 testimony would get us to the jury on that. I don't 3 think that's necessary. I've seen no law that says 4 you have to have expert testimony on what a warning 5 should look like to get to the jury. That the jury 6 can determine that themselves from the totality of the 7 evidence. 8 And that's the second point I have. That 9 when -- if you didn't even have Dr. Shlensky's 10 testimony, if you had Dr. Healy's testimony on the 11 causation, and if you have the other documentary 12 evidence that establish that Lilly was aware of this 13 risk and you have the package insert itself which 14 doesn't warn of this risk, if that was all we had, and 15 it's not, but if that was all we had, I still think 16 that takes the case to the jury on an inadequate 17 warning case under Hawaii law. 18 THE COURT: Well, what's your position as to 19 what the opinion was that was rendered by Dr. Shlensky 20 on inadequacy of warning? 21 MR. VICKERY: My opinion is I honestly would 22 like to read that section of the transcript, Your 23 Honor. I think what he said was that there was no 24 warning about -- 25 THE COURT: Mr. See has it for you there. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1619 1 MR. SEE: I have my notes, which are not the 2 record, but I have my notes. 3 MR. VICKERY: I prefer the court reporter's 4 transcript to Mr. See's notes, Your Honor. I can't 5 read his handwriting. I think that -- I don't 6 recollect exactly what he said. I just feel quite 7 comfortable that the evidence is sufficient to take 8 this case to the jury. 9 THE COURT: Thank you. 10 MR. SEE: Could I have 30 seconds, Your Honor? 11 THE COURT: Very well. 12 MR. SEE: I don't know if it's possible for the 13 court reporter to look at this, but Dr. Shlensky 14 testified to this opinion after the 2:15 break. It 15 was the first thing he testified about. And here's 16 what my notes say. He was asked, do you have an 17 opinion whether Lilly gave a fair and appropriate 18 warning about violence or suicide? And he said, no, I 19 don't think they did. And then he said, the insert 20 and the PDR, which is the same thing as the insert, in 21 1993 did not raise the issue of potential suicide and 22 violence. That's his warning opinion. 23 My note was right after the afternoon break, 24 and that's all he said. He didn't say my criticism is 25 it's not good enough to put it down here. You have to PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1620 1 put it up here. He didn't say that. He said that it 2 did not raise the issue of potential suicide or 3 violence, and I submit the insert absolutely, 4 without -- without any possibility of argument does 5 raise the issue of potential suicide and violence. 6 So based upon his opinion and the limitation, 7 the very limited opinion that he gave, didn't say it 8 had to be in the warning, didn't say it needed to be 9 in big black type or red type or whatever. He said it 10 did not raise the issue. And that, by the exhibit, 11 that is really stipulated to be the warning at the 12 time, that's not -- that is absolutely not correct. 13 THE COURT: Although, as Mr. Vickery 14 reiterated, that's raised with respect to the 15 different cause in Prozac. 16 MR. SEE: With respect, Your Honor, the section 17 down here, it says, "the adverse events temporally 18 associated with Prozac." 19 THE COURT: "That have been received since 20 market introduction and which may have no causal 21 relationship with the drug." 22 MR. SEE: Correct. That language, I submit, 23 based upon Dr. Shlensky's opinion that the insert did 24 not raise the issue of the potential for violence, 25 that language covers that. I don't have any note that PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1621 1 Dr. Shlensky said another word about it. That was his 2 criticism and that criticism is absolutely satisfied 3 in the insert. 4 THE COURT: Thank you. Well, I'm not going to 5 rule on this at this point. I want to read 6 Ms. Mangrum's epistle here first. 7 MS. MANGRUM: Thank you, Your Honor. 8 THE COURT: So I think we ought to go ahead and 9 proceed with Defendant Lilly's case. We'll take a 10 short break to allow the jury to come in. 11 (Whereupon, a recess was taken at 9:55 a.m.) 12 (Whereupon, the following proceedings were had 13 in open court in the presence of the jury.) 14 THE CLERK: Civil No. 95-00185 ACK, Susan K. 15 Forsyth, et al. versus Eli Lilly and Company, et al. 16 MR. VICKERY: Good morning, Your Honor. Andy 17 Vickery, Karen Barth, and Roy Chang for the Forsyths. 18 THE COURT: Good morning. 19 MR. SEE: Good morning, Your Honor. Andy See, 20 Michelle Mangrum, and Ed Burke for Eli Lilly and 21 Company. 22 THE COURT: Good morning. Good morning, ladies 23 and gentlemen of the jury. I apologize for the delay, 24 but there was something that we had to resolve. 25 Please proceed, Mr. Vickery. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1622 1 MR. VICKERY: Thank you, Your Honor. At this 2 time, Judge Kay, I would like to offer some responses 3 to both request for admissions and interrogatories and 4 would ask the Court to instruct the jury about the 5 nature of these and then permit me to read them. 6 THE COURT: The Court will instruct the jury 7 that these answers to interrogatories are coming in 8 only for a limited purpose. You may only consider 9 them as to whether -- or as to the fact that Lilly had 10 notice of what is contained in these answers. 11 MR. VICKERY: Thank you, Your Honor. 12 From Exhibit 173 Lilly was asked to admit the 13 following: Admit that on or about November 6, 1989, 14 during a tele-session telephone conference conducted 15 under the sponsorship of Defendant Eli Lilly and 16 Company and Dista Products, a doctor reported that 17 among patients he or she had treated with Prozac there 18 were a, quote, few people who have gotten so hyper on 19 the medication that they couldn't even sit still 20 during the day. 21 Lilly's response was that Lilly admits that the 22 reference document contains the following statement: 23 Quote, a few people who have gotten so hyper on the 24 medication they couldn't even sit still during the 25 day. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1623 1 Request No. 11 in that same set -- 2 MS. MANGRUM: Excuse me, Mr. Vickery. Your 3 Honor, there's also the addition that Lilly denies all 4 other aspects of this request as part of our response. 5 MR. VICKERY: Oh, okay. I'm sorry. I thought 6 Mr. See didn't want me to read that. That Lilly 7 denies all other aspects of this request. 8 In Request for Admission No. 11, Lilly was 9 asked to admit that on or about November 6, 1989, 10 during a tele-session telephone conference conducted 11 under the sponsorship of Defendant Eli Lilly and 12 Company and Dista Products, a doctor reported that 13 three female patients complained after starting to 14 take Prozac, quote, that their attention span was 15 interfered with. That they felt they couldn't 16 concentrate. They couldn't work. They couldn't carry 17 on conversations. 18 Lilly's response was Lilly admits that the 19 reference document contains the following statement: 20 That their attention span was interfered with, that 21 they felt they couldn't concentrate, they couldn't 22 work, they couldn't carry on conversations, and denies 23 the remaining allegations or requests. 24 No. 12, Lilly was asked to admit that on or 25 about November 6, 1989 during a tele-session telephone PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1624 1 conference conducted under the sponsorship of 2 Defendant Eli Lilly and Company and Dista Products, a 3 doctor reported, quote, I have had about three people 4 out of perhaps fifty who have taken Prozac that 5 complained of feeling quite hyper and nervous. 6 Lilly's response was that Lilly admits that the 7 reference document contains the following statement: 8 I have had about three people out of perhaps fifty who 9 have taken Prozac that complained of feeling quite 10 hyper and nervous. Lilly denies the remaining portion 11 of the request. 12 No. 13, Lilly was asked to admit that on or 13 about November 8, 1989, during a tele-session 14 telephone conference conducted under the sponsorship 15 of the Defendant Eli Lilly and Company and Dista 16 Products, a doctor reported, quote, I also suspect 17 that Prozac has an amphetamine-like action. 18 The response was that Lilly admits that the 19 reference document contains the following statement: 20 Quote, I suspect that Prozac has an amphetamine-like 21 action, end quote. And Lilly denies the remaining 22 portions of that request. 23 No. 14, Lilly was asked to admit that on or 24 about November 8, 1989 during a tele-session telephone 25 conference conducted under the sponsorship of PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1625 1 Defendant Eli Lilly and Company and Dista Products, a 2 doctor reported that adverse effects reported by his 3 patients taking Prozac included, quote, severe anxiety 4 and the patient describing that they're about to jump 5 out of their skin. 6 Lilly's response was that Lilly admits that the 7 reference document contains the following statement: 8 Quote, severe anxiety and the patient describing 9 they're about to jump out of their skin. Lilly denies 10 the remaining portions of that request. 11 No. 18, Lilly was asked to admit that on or 12 about October 26, 1989 at 8:30 p.m. Eastern Daylight 13 Time during a tele-session telephone conference 14 conducted under the sponsorship of Defendant Eli Lilly 15 and Company and Dista Products, a doctor reported, 16 quote, I've had to stop Prozac with a number of 17 patients who just complained that they felt so 18 restless, almost akathisic, that they couldn't 19 tolerate it. 20 The response was Lilly admits that the 21 reference document contains the following statement: 22 Quote, I've had to stop Prozac with a number of 23 patients who just complained that they felt so 24 restless, almost akathisic, that they couldn't 25 tolerate it, end quote. Lilly denies the remaining PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1626 1 portions of that request. 2 No. 19, Lilly was asked to admit that on or 3 about October 26, 1989 at 8:30 p.m. Eastern Daylight 4 Time, during a tele-session telephone conference 5 conducted under the sponsorship of Defendant Eli Lilly 6 and Company and Dista Products, a doctor reported, 7 quote, my biggest problem as I said before, and I hope 8 someone will address this, is the question of 9 agitation. 10 The response was that Lilly admits that the 11 reference document contains the following statement: 12 Quote, my biggest problem, as I said before, and I 13 hope someone will address this, is the question of 14 agitation. Lilly denies the remaining portions of 15 that request. 16 No. 21, Lilly was asked to admit that on or 17 about October 25, 1989 during a tele-session telephone 18 conference conducted under the sponsorship of 19 Defendant Eli Lilly and Company and Dista Products, a 20 doctor reported when giving Prozac to schizo-affected 21 patients in a state hospital that, quote, we thought 22 Prozac might help activate them a little bit, and it 23 did activate them, but they started bopping other 24 people on the unit so we had to stop it. 25 Lilly's response was Lilly admits that the PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1627 1 reference document contains the following statement: 2 Quote, we thought Prozac might help to activate them a 3 little bit and it did activate them, but they started 4 bopping other people on the unit so we had to stop it. 5 No. 24, Lilly was asked to admit that on or 6 about October 17, 1989 at a focus group held by or 7 under the auspices of Eli Lilly and Company, a doctor 8 reported that one side effect he had seen is, quote, 9 is the irritability. It, Prozac, just makes them feel 10 wired. 11 The response, Lilly admits that the reference 12 document contains the following statement: Is the 13 irritability. It, Prozac, just makes them feel wired. 14 Lilly denies the remaining portions of that request. 15 That's all from 173, Your Honor. From No. 174, 16 Lilly was asked to admit that Lilly cannot explain how 17 Prozac works either for the treatment of depression. 18 The response was that Lilly admits that 19 technology has not advanced to the point where it is 20 possible to measure serotonin at the level of the 21 synaptic cleft in the brain of a living human being, 22 but states that this mechanism has been observed at 23 work in animals. 24 From No. 178, No. 16, Lilly was asked to admit 25 that Prozac has an activating effect in some people. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1628 1 Lilly's response was, it is admitted that 2 Prozac has an activating effect in some patients, a 3 sedating effect in other patients, neither effect in 4 some patients, and both effects in some patients. 5 Number 20, Lilly was asked to admit that Lilly 6 relies not only on package inserts and other 7 literature, but also on direct communication, both via 8 mails and Lilly agents, sometimes called detailed men, 9 to apprise prescribing physicians of the risks, 10 indications, contraindications, and other pertinent 11 information on Prozac and other Lilly drugs. 12 The response was -- 13 THE COURT: Excuse me a minute. Is this one 14 that was to be read? 15 MR. VICKERY: Yes, it was, Your Honor. 16 MS. MANGRUM: We have no objection, Your Honor. 17 THE COURT: Very well. 18 MR. VICKERY: Lilly admits that it relies on 19 package inserts, medical and scientific literature, 20 direct mail and direct communications consistent with 21 its package inserts by sales representatives to 22 apprise prescribing physicians of the risks, 23 indications, contraindications and other pertinent 24 information of Prozac and other Lilly drugs. 25 That's all from No. 178. And finally, from No. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1629 1 176, Your Honor -- 2 THE COURT: From what number? 3 MR. VICKERY: 176. This is an interrogatory to 4 Lilly. 5 MS. MANGRUM: Wait just a moment, Your Honor. 6 MR. VICKERY: Yes, I can. No. 14. May I have 7 a moment, Your Honor? 8 THE COURT: Yes. 9 MR. VICKERY: No. 14, Lilly was asked the 10 following question: State the number of people known 11 to defendants that have killed another person or 12 persons while on Prozac, Fluoxetine hydrochloride. 13 Lilly's answer, Lilly states that based on 14 incomplete information and as a, quote, approximation, 15 that between March 1, 1983 and November 1992 it 16 reported to the FDA 88 events resulting in fatal 17 outcomes to persons other than patients undergoing 18 Prozac therapy. 19 Your Honor, that concludes our offer. We rest 20 our case. 21 THE COURT: Very well. Mr. See. 22 MR. SEE: Thank you, Your Honor. For its first 23 witness, Eli Lilly and Company will call Dr. Gary 24 Tollefson. 25 THE CLERK: Please raise your right hand. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1630 1 GARY DENNIS TOLLEFSON, M.D., 2 called as a witness on behalf of the Defendant, after 3 having been first duly sworn to tell the truth, the 4 whole truth, and nothing but the truth, was examined 5 and testified as follows: 6 THE CLERK: Please be seated. Please state 7 your name and spell your last name. 8 THE WITNESS: Gary Dennis Tollefson. Last name 9 is T-O-L-L-E-F-S-O-N. 10 DIRECT EXAMINATION 11 BY MR. SEE: 12 Q. Good morning, Dr. Tollefson. 13 A. Good morning. 14 Q. Are you a medical doctor, sir? 15 A. Yes, I am. 16 Q. Do you have a particular specialty? 17 A. Specialty is psychiatry and psychopharmacology. 18 Q. Where are you employed, sir? 19 A. At Eli Lilly and Company, Indianapolis, 20 Indiana. 21 Q. And what is your title? 22 A. I am the product group president for our 23 neurosciences division. 24 Q. And is the neurosciences division the division 25 at Eli Lilly and Company that is responsible for the PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1631 1 antidepressant prescription drug called Prozac? 2 A. Yes, it is. 3 Q. Just a little bit about your background first, 4 Dr. Tollefson. First, would you tell the jury where 5 you come from? 6 A. I was born and raised in a small town called 7 Fairmont, Minnesota, and then I went to the University 8 of Minnesota as an undergraduate. Did my 9 undergraduate work in psychology, where I graduated 10 sum cum laude, and elected to stay on there because it 11 was close to home. Went to medical school also at the 12 University of Minnesota, and then after getting my 13 M.D., I received a Ph.D., a doctoral degree, in 14 pharmacology. Those were all at the University of 15 Minnesota. 16 Q. When did you graduate from college? 17 A. Graduated from college in 1973. 18 Q. And that was with a degree in psychology? 19 A. That's correct. 20 Q. And then medical school, what year did you 21 graduate from medical school? 22 A. 1976. 23 Q. Now, after your medical school, did you go on 24 for additional training as a physician? 25 A. Yes, I did. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1632 1 Q. Would you tell the jury about that, please? 2 A. I did one year of what we call a general 3 internship, which is an experience rotating through 4 different medical specialties; surgery, trauma, 5 pediatrics, neurology, et cetera, for a year, and then 6 I went into what we call a residency in psychiatry and 7 went through that psychiatry residency program in 8 three years at the University of Minnesota. 9 Q. Now, you mentioned having some additional 10 training in psychopharmacology? 11 A. That's correct. 12 Q. First, could you tell us what 13 psychopharmacology is? 14 A. Well, of course, pharmacology is the study of 15 drugs. Psychopharmacology implies the study of 16 medications or drugs that has an influence on the 17 central nervous system, more specifically, I guess I 18 would say, the human brain, so it's a subspecialty of 19 pharmacology. 20 Q. Now, you said you went on and had additional 21 formal education in psychopharmacology? 22 A. Yes, I did. 23 Q. Tell us what that was, please. 24 A. Sure. I did go forward and complete a Ph.D, 25 which is a doctoral degree outside of or in addition PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1633 1 to the medical degree, and it was a cross-disciplinary 2 program. It involved the school of pharmacology at 3 the University of Minnesota, also the School of 4 Biochemistry at Minnesota, and then the department of 5 psychiatry. 6 Q. Now, in your field of psychiatry, have you 7 become what is known as board certified? 8 A. Yes, I have. 9 Q. Could you briefly tell us what that is? 10 A. Board certification in a medical specialty is a 11 specific examination that is provided to physicians 12 that they can elect to take or not to take, and the 13 examination includes both a series of written 14 questions about the field of research and also an oral 15 examination by peers in the field that are already 16 board certified, and if the applicant passes both the 17 written and the oral examinations, if he or she is so 18 fortunate, then they are designated to be board 19 certified. So it is a process, I think, to endorse 20 the training and the knowledge base of the physician. 21 Q. When did you become board certified in 22 psychiatry? 23 A. That would have been, thinking back, probably 24 around 1981 or '2. 25 Q. Now, after you completed your Ph.D. program, PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1634 1 did you then go on and seek employment somewhere? 2 A. I did. My internship, which I had mentioned to 3 you earlier, was at a county hospital, a trauma 4 hospital, and a hospital that provided care for all 5 types of patients in the St. Paul, Minnesota area, 6 called St. Paul Ramsey Medical Center, and I was 7 offered a position to stay on there in the department 8 of psychiatry in an area called consultation liaison 9 psychiatry, and what that is, quite briefly, is when a 10 medical physician, let's say an internist, might have 11 somebody in the coronary care unit or we had a burn 12 unit, a regional burn unit there, if the physician in 13 charge of patient care had a question about their 14 patient, about their psychiatric status or the use of 15 medications, whatever, consultation liaison 16 psychiatrist would be someone who would come in, 17 provide an opinion to the doctor, and help him to 18 manage or follow the case, so I started my career in 19 that area. 20 Q. All right. And did your responsibilities at 21 the St. Paul Ramsey Hospital change after a time? 22 A. It did after I was there approximately five 23 years, and during that time, I was involved also as an 24 assistant professor at that time at the University of 25 Minnesota Hospital, so I was doing teaching as well as PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1635 1 patient care and research. And about halfway through 2 my stint at Ramsey, about five years there, I became 3 the department chairperson, which is the -- 4 essentially, the administrative head of the 5 psychiatric practice group. 6 Q. After you became the chair of the department of 7 psychiatry, did you continue to see psychiatric 8 patients? 9 A. Yes, sir. 10 Q. Would you tell us about that, what kind of 11 patients you saw, and so on? 12 A. We really, at St. Paul Ramsey Medical Center 13 saw a very wide diversity of patients. We were at the 14 forefront in Minnesota of what you have heard of 15 called HMOs or the Health Maintenance Organizations. 16 We had a lot of patients that were members of those 17 programs. We had some satellite clinics so we saw 18 patients from the suburban areas that had traditional 19 insurances like the Blue Cross/Blue Shield programs, 20 but we were also a county-based facility, receiving 21 support from the county, so we would see indigent 22 patients, patients on a variety of government 23 programs. So particularly in the department of 24 psychiatry, we tended to see a lot of patients that 25 had very chronic mental disorders. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1636 1 Q. Can you give us an idea of the kind of mental 2 disorder that you had experience with during your 3 stint there at St. Paul Ramsey? 4 A. They would be typically what we would refer to 5 as the more major psychiatric conditions, 6 schizophrenia, manic depression, or what's called 7 bipolar disorder, you may have heard of, major 8 depression, some of the more serious anxiety 9 disorders. Also did a lot of work with Alzheimer's 10 disease and Parkinson's disease in the sense of 11 patients that might have behavioral or memory problems 12 associated with those disorders as well. So it was a 13 diversity of more serious kinds of neurologic or 14 psychiatric conditions. 15 Q. Dr. Tollefson, there's been testimony in the 16 case about medical and scientific publications in 17 peer-reviewed journals. Have you authored such 18 publications? 19 A. Yes, sir. 20 Q. Tell us how many. 21 A. Approximately 200 papers that have been in 22 peer-reviewed journals. 23 Q. And on what topics generally have you written 24 on? 25 A. Primarily in the area of drugs and PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1637 1 psychopharmacology, but relevant to either depression 2 or psychosis, to a lesser extent, schizophrenia, 3 looking at issues of how drugs work or how drugs are 4 tolerated. 5 Q. Have you had publications in peer-reviewed 6 medical and scientific journals that dealt 7 specifically with research about Prozac? 8 A. Yes, I have. 9 Q. About how many such publications have you had 10 in that area? 11 A. I'd estimate approximately 15 to 20 that 12 specifically dealt with Prozac. 13 Q. In your career, have you been called upon to 14 give speeches and presentations on medical and 15 scientific issues to professional groups and 16 organizations? 17 A. I have. I have had the pleasure to be able to 18 speak internationally, prior to joining Lilly, as a 19 senior academic member of the community and presenting 20 research and particularly being involved in physician 21 education programs. They're called continuing medical 22 education activities, and then since being with Lilly, 23 still involved very much in the academic community 24 with the international meetings, but also doing a lot 25 of things, even at a local level with community-based PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1638 1 physicians because they're the people always in the 2 trenches. 3 Q. Now, at some time, you made a decision to leave 4 the St. Paul Ramsey Hospital and go to work for Eli 5 Lilly and Company? 6 A. That's correct. 7 Q. When was that, please? 8 A. 1991, the middle of the year. 9 Q. What prompted that decision? 10 A. Well, as I mentioned, I had been involved in 11 doing medical education and training programs, some of 12 those sponsored by a variety of different 13 pharmaceutical companies, and I had had a very 14 positive experience interacting with people at Eli 15 Lilly and Company as far as their integrity, their 16 interests in education. I then became involved in 17 consulting with the company, along with some 18 colleagues of mine from academia, on the whole issue 19 of antidepressant medications and symptoms of 20 depression, including suicidal ideation or suicidal 21 attempts, and through that consultation process, I'd 22 been very impressed with the level of scientific 23 integrity of the company. I think they, in turn, 24 appreciated the scientific thinking that I was able to 25 bring, and they were kind enough to offer me a job, PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1639 1 and after I thought long and hard to leave Minnesota, 2 I decided that it was an appropriate time in my career 3 to try something different and to make a different 4 kind of impact in medicine, and so I accepted it. 5 Q. And you've been with Lilly ever since? 6 A. That's correct. 7 Q. Can you tell us just generally what have been 8 your responsibilities with the company? 9 A. Well, I joined the company initially in a 10 position that's called an executive director in the 11 company's medical division, and I was overseeing the 12 area, again, of psychopharmacology and did that for 13 two or three years. 14 At that point, the company promoted me to a 15 vice president within the medical division, and about 16 that time, we began developing a very interesting new 17 medication for schizophrenia, and I had the pleasure 18 of leading a cross-functional team to bring that drug 19 through its final stages of development and into the 20 marketplace. And then more recently, about a year 21 ago, I was promoted to president of the neurosciences 22 product group. 23 Q. Dr. Tollefson, during your career, both when 24 you were in academic medicine and during the time you 25 have been at Lilly, have you personally been involved PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1640 1 in performing clinical research studies using drugs 2 with humans? 3 A. Yes, I have. 4 Q. How many -- just approximately, how many 5 clinical trials have you personally been involved 6 with? 7 A. Since I've been at Eli Lilly and Company? 8 Q. Both before and after. 9 A. Well, I would say it's certainly in excess of 10 100, probably closer to 200 trials. 11 MR. SEE: Your Honor, at this time, Eli Lilly 12 and Company would tender Dr. Tollefson as an expert in 13 psychiatry and in psychopharmacology. 14 MR. VICKERY: Your Honor, Dr. Tollefson is 15 clearly qualified by education and experience to 16 render opinion testimony within the meaning of Rule 17 702. 18 THE COURT: Thank you. The Court finds 19 Dr. Tollefson qualified as an expert in the area of 20 psychiatry and psychopharmacology. 21 Q (By Mr. See) Now, Dr. Tollefson, this case, 22 as you know, involves the disease, major depression. 23 I take it, during your career, you have had experience 24 in diagnosing and treating patients with that 25 condition? PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1641 1 A. Very frequently. 2 Q. Doctor, is suicide one of the risks and one of 3 the possible outcomes of the disease, major 4 depression? 5 A. Well, it is, but I'd even say more so, it is 6 one of the diagnostic symptoms that we look for in 7 reaching the diagnosis of major depression. It's one 8 of the nine critical symptoms that one would observe 9 in order to make the diagnosis. 10 Q. Now, Doctor, we've heard some testimony in the 11 case that suicide is a relatively rare event, and I 12 want to ask you some questions about that, but first 13 has a chart been prepared that would help illustrate 14 your testimony on that point? 15 A. Yes, sir. 16 Q. Let me put up Defendant's Exhibit 1080, and, 17 Doctor, if you'll look in the notebook that's right 18 next to you, there will be a small copy of this at Tab 19 34, so you can see it along with the jury. 20 A. I have it. 21 Q. Now, first of all, the chart indicates that in 22 1993, which is the date -- the year of the deaths of 23 Mr. and Mrs. Forsyth, that there were 31,102 suicides 24 in the United States. Could you tell us, how does 25 suicide rank in 1993 as the cause of death in this PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1642 1 country? 2 A. Well, as the jurors can see in the second 3 point, it was in the top ten. It was the ninth 4 leading cause of death in the U.S. 5 Q. And what does the suicide rate look like when 6 you look specifically at white males who were 55 to 64 7 years old, what does that rate look like? 8 A. Well, it shows that there is an increased risk, 9 and as you can see, the figure goes to 25.7 instances 10 per 100,000 individuals, so slightly more than a 11 doubling. 12 Q. Now, is that 25.7 per 100,000, does that 13 concern depressed people? 14 A. No. That's just a general figure for 15 individuals across our entire population, but within 16 that age bracket. 17 Q. Now, could you also tell the jury, when you 18 look at persons of the male gender only, what 19 percentage of suicides are involved in people who are 20 males? 21 A. Males commit four out of every five suicides in 22 the U.S. 23 Q. Now, in your work, in your career, you're 24 familiar with medications that had been developed to 25 treat major depression? PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1643 1 A. Yes, sir. 2 Q. And we've had some testimony in this case about 3 tricyclic antidepressants or abbreviated as TCAs. Are 4 you familiar with that group? 5 A. Yes, I am. 6 Q. Now, Dr. Tollefson, would you tell the jury, 7 please, with respect to using tricyclic 8 antidepressants in depressed patients who may be 9 suicidal, is there any particular risk of those 10 medications? 11 A. Well, there are two related risks that are 12 really quite significant, and which why, I think, 13 explain why, in general, these tricyclics or TCAs have 14 become less and less popular with physicians. Number 15 one, they require significant dose escalation or dose 16 titration, which means starting low with a small dose 17 and needing to work up. 18 The literature, our medical literature is quite 19 replete that all too often, patients cannot tolerate a 20 necessary dose to treat their depression with these 21 older drugs because they have so many side effects, so 22 they don't receive what we call a therapeutic dose of 23 the medicine, but even more importantly, they are 24 highly toxic in an overdose, so you're confronted with 25 a patient that might have a risk of suicide as part of PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1644 1 depression who now, at least historically in the past, 2 you had to give a medication where, if they consumed 3 five, six, seven days' worth, just a week's worth of 4 their prescription, it could be enough to kill them. 5 And so with the introduction of newer 6 medications, it had a much wider margin of safety. Of 7 course, physicians could be much more comfortable and 8 effectively and aggressively trying to treat this very 9 serious disease. 10 Q. All right. Now, let's turn to the development 11 of Prozac, Dr. Tollefson, and again, is there a 12 graphic chart that we prepared that would help 13 illustrate your testimony -- 14 A. Yes. 15 Q. -- on the development of the drug? 16 A. Yes, there is. 17 THE COURT: What's the number on that? 18 MR. SEE: That is Exhibit 1077, Your Honor. 19 THE COURT: Thank you. 20 Q (By Mr. See) I'll put it up on the easle, 21 Doctor, and if you would turn -- if you would turn in 22 your book to Tab 35, there's a small copy there that 23 you can refer to. 24 A. I have it. 25 Q. First, on the chart we're looking at, there's a PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1645 1 word called synthesis. What's that mean? 2 A. Synthesis is a term that we would use relative 3 to the chemical process of manufacturing the 4 medication, so it undergoes a process of being 5 synthesized. 6 Q. All right. Can you tell us what year was 7 Prozac actually discovered, the compound? 8 A. 1972. 9 Q. Now, we've heard a little testimony about how 10 Prozac works, and I'd like to ask you if you could 11 tell the jury, briefly and in lay language that we 12 will be able to understand, how does Prozac work? 13 A. Well, I'll do my best. Maybe just as a 14 preface, the older antidepressants that we referred to 15 as the tricyclic antidepressants or the TCAs, I 16 mentioned that they had a very large number of side 17 effects that were often problematic for patients, one 18 of the reasons for that is that those medications 19 affected many different chemical sites within the 20 brain, and Prozac and its family of medications that 21 are called selective serotonin uptake inhibitors. The 22 term "selective" means that they're targeted just for 23 one site, a serotonin-based site in the brain. 24 Q. I want to stop you there for a second. You 25 used the phrase, selective serotonin reuptake PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1646 1 inhibitor. Is that abbreviated SSRI? 2 A. Yes, it is. 3 Q. And is that the family of antidepressant 4 medications that Prozac belongs to? 5 A. Yes, it is. 6 Q. And there are others that belong to that family 7 now? 8 A. That is correct. 9 Q. Okay. Would you go on, please? 10 A. Sure. So with the specific targeting that this 11 medication has, it goes to a site in the human brain. 12 And remember, the brain is comprised of literally 13 billions and billions of nerve cells, and those nerve 14 cells have a site on them where serotonin, which is a 15 chemical messenger, a way of communicating from one 16 cell to its neighbor, they go specifically -- a drug 17 like Prozac -- to this, what's called, reuptake site, 18 a place where the brain chemical goes back up into the 19 nerve cell. 20 And, essentially, this class of medications 21 blocks that site. It doesn't allow serotonin, the 22 chemical, to go back into that nerve cell, which means 23 more of it is around in the area between the two nerve 24 cells to continue the communicating process. And it's 25 our belief in the field of psychiatry that one of the PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1647 1 factors that contributes to the biological, the 2 medical aspect of depression, is, relatively speaking 3 having too little serotonin. So by blocking, it's 4 being taken back up into cells where it would be 5 destroyed or stored, but not able to be an effective 6 communicator. A drug like Prozac keeps more of the 7 serotonin in that area so it can continue to 8 communicate, so it's making up, essentially, for a net 9 deficit or a shortage of that chemical during an 10 episode of what we call major depression. 11 Q. Doctor, what prevents their being too much 12 serotonin in this area of the brain that you're 13 talking about? 14 A. Well, of course, the human body is a very 15 marvelous organism and it has checks and balances in 16 how the body works, and one of those examples of a 17 balance system is that same nerve cell also has some 18 receptors on its external surface that are sensitive 19 to monitoring how much serotonin is out there, and if 20 you began to have an increase in serotonin, those 21 sensors would send off a signal and they would tell 22 that nerve cell to stop releasing serotonin into that 23 area again of communication we call synaptic clef. 24 And the origin of serotonin, we've talked a 25 little bit about that and it may seem like a bit of a PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1648 1 foreign term, serotonin, this brain chemical 2 actually -- its origin is from dietary amino acids, 3 and specifically an amino acid we call tryptophan; 4 that when we eat foods that have tryptophan in them, 5 it is converted in the body, this chemical serotonin, 6 and it's stored in these particular nerve cells and it 7 can be released then with an appropriate signal within 8 the brain. 9 Q. Now, coming back to our chart on drug 10 development. First, there's indicated that there's a 11 process in the chemical lab. What happens there? 12 A. From the chemical lab, basically, we're going 13 from that early stage of having synthesized or created 14 this particular chemical, and what we do is we 15 continue to try to refine it and understand more about 16 its chemical properties. 17 Q. There then is the phase called pharmacology or 18 toxicology. Is that the phase when studies with 19 animals are done? 20 A. That is correct. 21 Q. And why are studies with animals done? 22 A. Well, initially, it's important, with the new 23 medication, to characterize it in several different 24 ways. We call it pharmacology. What we're really 25 talking about are four areas of understanding the drug PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1649 1 and they're sometimes called ADME. I can briefly tell 2 you what those are. One is, is the drug absorbed, 3 that's A, and, of course, if you're going to take a 4 medication orally, it's important that it gets 5 absorbed and gets into the system. 6 Number two, D is the disposition of the 7 medication. Where does it go in the body and at what 8 rates does it go into those areas of the body? M is 9 the metabolism. How is the medication broken down by 10 the body and ultimately cleared from the body, through 11 the kidneys, through the liver, a combination of both. 12 And then that last stage is the E, that's the actual 13 excretion, the actual route that the drug leaves the 14 human body. 15 Q. Now, there's a label on our chart called IND 16 filing. Can you tell us, please, what is an IND? 17 A. When a pharmaceutical company has a drug that 18 they believe is a promising candidate to be evaluated 19 for a health care problem, and they've done this 20 preliminary toxicology and pharmacology, it is 21 necessary to file this particular drug with, in the 22 case of the U.S., the Food and Drug Administration, 23 and you are, essentially, filing that you have an 24 investigational drug, this is what you know about it, 25 and you then wait for the FDA, essentially, to review PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1650 1 that and give you a thumbs up that it's okay to begin 2 to move further on in the drug development process. 3 Q. So IND stands for Investigational New Drug? 4 A. Yes. 5 Q. And is that the application filed with the FDA 6 before the actual studies with human beings start? 7 A. Yes, it is. 8 Q. And when was that filed with Prozac? 9 A. It was approximately 1976, I believe. 10 Q. Now, we now have it in, the yellow indication 11 on the chart, a bunch of phases. 12 A. Um-hum. 13 Q. Tell us, what is phase one? 14 A. Well, phase one is moving into -- it's, 15 essentially, a replication of what we just talked 16 about, the pharmacology, but is now done in humans, so 17 we replicate and try to understand exactly, again, how 18 is the drug absorbed, distributed, metabolized, and 19 excreted within humans. There also is the opportunity 20 to observe any general properties of that medication. 21 These are typically done in volunteers, not in 22 patients with a particular disease state in phase one. 23 Q. Now, tell us, what is the involvement of the 24 FDA when clinical studies; that is, studies in human 25 beings are going on? PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1651 1 A. The FDA is, of course, constantly interested 2 and vigilant for what is going on and it's necessary 3 for pharmaceutical sponsors to provide periodic 4 updates as to the progress of that work, and so it's 5 undergoing, really, constant scrutiny and observation 6 by the agency. 7 Q. In other words, if you do a study in phase one, 8 do the results get sent to the FDA? 9 A. Yes, sir. 10 Q. Now, tell us about phase two. What happens 11 there? 12 A. Phase two is typically when you begin to move 13 into patients that might have a disease state, so you 14 could be studying a drug, let's say, for cancer or for 15 diabetes. You'd now begin to test the properties of 16 that drug in treating the disease of interest, and 17 those studies are designed to look at two things: 18 One, is the medication efficacious? Does it work? 19 How well does it work? And on what features of the 20 disease is it working? 21 And then there's also a phase, of course, 22 evaluation of the safety of the medication, what kind 23 of side effects might someone have? How severe are 24 they? How well tolerated is the medication relative 25 to a comparator, a comparison? PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1652 1 Q. With the case of Prozac, a drug that was 2 intended to treat depression, what kind of patients 3 are involved in the studies in phase two? 4 A. These were patients almost exclusively who met 5 the criterion for what we call a major depressive 6 episode. 7 Q. Now, the studies done during phase two, are 8 those results sent to the FDA? 9 A. Yes. 10 Q. Now, we have phase three. What happens in 11 phase three? 12 A. Phase three is an effort to expand into much 13 larger patient samples and -- 14 Q. What is a patient sample? 15 A. I'm sorry. A group of patients that have the 16 disease, and -- in phase three, so number one, the 17 number of study participants or patients with the 18 illness is much larger and there's an effort to go 19 into more diversities of individuals to look at the 20 benefits and the safety or tolerability of a 21 medication based on age, gender, ethnicity, all those 22 relevant factors that reflect the diversity of our 23 society. 24 Q. Now, there's a point here on the chart that's 25 called NDA submission. First tell us, what does NDA PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1653 1 mean? 2 A. NDA is a term that stands for a New Drug 3 Application. 4 Q. What is that? 5 A. It's a very laborious task of collecting 6 clinical reports from all of the preclinical phase 7 one, phase two, phase three experiences with the 8 medication, complying it into multiple, multiple 9 volumes and submitting that to the Food and Drug 10 Administration in the case of the United States, 11 requesting their evaluation of whether or not they 12 find, based on your data, that the drug is both safe 13 and effective for the proposed indication. 14 Q. So is it the case that when the NDA is 15 submitted, the data from all of the studies that had 16 been done to date are submitted to the FDA at one 17 time? 18 A. There is, indeed, a summary of all information. 19 Q. And with Prozac, was there an NDA filed? 20 A. Yes, there was. 21 Q. And when was that done, sir? 22 A. I believe it was in about 1983. 23 Q. Now, after the NDA is filed, does the research 24 stop? 25 A. Absolutely not. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1654 1 Q. What goes on? 2 A. One would continue to do a variety of clinical 3 studies with the medication. We work very closely, 4 for example, with academic medical centers and with 5 leading people in the field to continue to look at 6 what would be some of the scientific questions that 7 they might have about the medication, about the 8 disease state. Obviously, medical technology is going 9 leaps and bounds every year, and so there are new 10 technologies that we can employ in the study of 11 medication, so it's a constant iterative-like learning 12 process that goes on throughout the life cycle of a 13 product. 14 Q. Now, when all of this information on these 15 studies is submitted to the FDA, what does the FDA do 16 with it? 17 A. Well, the FDA spends significant amounts of 18 time reviewing those application materials in great 19 depth. They have many different components that would 20 review it. They have toxicology reviewers. They have 21 what are called biostatisticians, people that look at 22 all the numbers. They have clinicians that review the 23 materials, and so there's a fairly long extensive 24 process of reviewing the materials, generating 25 potential questions, sharing those questions with the PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1655 1 company or the sponsor. There is a dialog of back and 2 forth in trying to understand and really fully 3 characterize the profile of what that data means. 4 Q. Did there come a time when the NDA for Prozac 5 was approved by the FDA? 6 A. Yes. 7 Q. When was that, please? 8 A. That was in December of 1987 in the U.S. 9 Q. So the FDA took, what, about four years or so, 10 four or five years -- 11 A. Yes. 12 Q. -- to review the information that was 13 submitted? 14 A. That is correct. 15 Q. Now, what does it mean when the NDA gets 16 approved? What happens? 17 A. When the NDA is improved, that means now that 18 the company has authorization to begin to market that 19 product for the treatment of the specific disorder 20 that was applied for. So in the case of Prozac, for 21 the treatment of major depression. 22 Q. So Prozac began to become available for doctors 23 to prescribe to their patients, and you said the 24 approval was in December of '87, so it was '88 -- 25 A. I believe it was January of '88. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1656 1 Q. Now, there's one last element on the chart 2 here. It says, "Post-approval phase four." Tell us 3 what that means. 4 A. Well, post-approval means the NDA has been 5 approved by the FDA; that is, they have found the drug 6 to be both safe and effective for treatment of the 7 disorder. So it's post-approval activities, and those 8 clinical studies, again, as I alluded to earlier, 9 would be the ongoing investigation of interest, both 10 of the company and the academic community, and the 11 exploration of further properties of the medication, 12 how it can be used in the treatment of either the 13 disorder that's already been approved, in other words, 14 additional studies in depression, or in the case of 15 Prozac and many other medications, other possible new 16 indications that one might look at. 17 Q. Dr. Tollefson, I want to ask you about the 18 clinical studies done by Lilly during the development 19 of Prozac. Have we prepared another chart that shows 20 that? 21 A. Yes, sir. 22 MR. SEE: Your Honor, this is Exhibit 1089. 23 THE COURT: Thank you. 24 Q (By Mr. See) Dr. Tollefson, I think a small 25 copy of this one is in your book at 36. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1657 1 A. A very small one. 2 Q. First of all, can you tell us what this 3 represents generally? 4 A. Yes. This is really looking at a chronology of 5 the studies that were going on from the earliest, sort 6 of phase one, phase two work that we mentioned, out 7 throughout continued development of this product, and 8 it goes out through, if I can read this properly, 9 through 1996. 10 Now, of course, that work is continuing to go 11 on, but it's, I think, designed to try to portray both 12 the breadth and depth of clinical work that went into 13 the document, first of all, that the FDA reviewed, and 14 then secondly, points to the continued post-approval 15 or phase four work that is ongoing with this molecule. 16 Q. So each of the sort of orange lines represents 17 a study? 18 A. Each of these orange bars represents a specific 19 study protocol, and to your left would be the point 20 when the first patient was enrolled in the trial, and 21 to your right, the end of the orange bar, would 22 represent the last patient visit in an individual 23 protocol. So the sum total of the protocols would be 24 the number of horizontal bars you see. 25 Q. So it appears as if there are smaller and PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1658 1 shorter clinical trials starting here around 1976, and 2 then clinical trials ongoing right on through 1996; is 3 that right? 4 A. That is correct. 5 Q. And did you say there are clinical trials being 6 sponsored or performed by Lilly that are going on 7 beyond that date? 8 A. Yes, there are. 9 Q. Are there clinical trials of Prozac being 10 sponsored by Lilly going on right now? 11 A. Yes, there are. 12 Q. Why is that? 13 A. Well, as I mentioned earlier, this particular 14 molecule really has the potential to treat a number of 15 other indications, and I think some of you that may 16 have, you know, followed a little bit about the 17 history of Prozac, know it was approved in the U.S. 18 for an eating disorder that often affects adolescents 19 called bulimia. It also has been approved for 20 obsessive compulsive disorder, and we're continuing to 21 pursue some other very interesting, serious clinical 22 problems where we think this drug could really help 23 people. 24 Q. And is it correct that there are ongoing 25 clinical trials that also deal with patients who have PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1659 1 major depression? 2 A. Oh, absolutely. 3 Q. Now, I would also like you to tell the jury 4 about the numbers of patients involved and the number 5 of clinical trials involved with patients with 6 depression, and is there another chart that has been 7 prepared that will help you illustrate that? 8 A. Yes. 9 MR. SEE: This, Your Honor, is 1088. 10 THE COURT: Thank you. 11 MR. VICKERY: May I have a question on voir 12 dire about this, Your Honor? 13 MR. SEE: It is the small one at Tab 37 of your 14 book, Doctor. 15 THE WITNESS: Thank you. 16 THE COURT: You may. 17 MR. VICKERY: Dr. Tollefson, are all of these 18 trials here in depressed people or are some of them in 19 people who are not depressed? 20 THE WITNESS: These trials would include 21 patients with depression and may well include people 22 that have other psychiatric disorders or we call them 23 co-morbidities with depression. 24 MR. VICKERY: Okay. So your testimony is not 25 limited to just depressed patients; is that right? PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1660 1 THE WITNESS: Correct. 2 MR. VICKERY: Okay. Very well. 3 Q (By Mr. See) Have you got the small one? 4 A. I do. 5 Q. Now, first it indicates number of worldwide 6 protocols. First, tell us what a protocol is. 7 A. A protocol is a written document that, 8 essentially, summarizes the purpose of a study, how 9 the study should be conducted, how the study will be 10 analyzed statistically, and then really what are the 11 primary reasons for the study to be done, so it's a 12 summary document. 13 Q. All right. And then it says, length of 14 exposure -- well, first of all, the number of studies 15 designed, that's 504? 16 A. Correct. 17 Q. Then length of exposure, what does that mean? 18 A. This would be how many -- the range of days or 19 years that a patient was actually exposed to the study 20 medication. 21 Q. Okay. And that would be anywhere from a day to 22 over a year in the Prozac study? 23 A. Correct. 24 Q. And then it says, "Number of investigators 25 participating in clinical trials worldwide," and PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1661 1 that's listed at more than 1200. First, would you 2 tell us what does "investigator" mean? 3 A. An investigator would be a health care 4 professional, more often than not in these cases, a 5 psychiatrist who would be charged with carrying out 6 the protocol at his or her research site at a hospital 7 or medical center. 8 Q. Then we have a number of patients in the 9 worldwide clinical trial and that's more than 51,000, 10 and the number of Prozac patients listed is more than 11 27,000, and does that number indicate the number of 12 patients that actually took Prozac during the clinical 13 trials sponsored by Lilly? 14 A. The latter number, 27,000, does. 15 Q. Now, Dr. Tollefson, a stipulation was read to 16 the jury earlier that patients who had a current high 17 risk for suicide were excluded from outpatient studies 18 of Prozac. The stipulation also said that neither the 19 plaintiffs' experts nor the defense experts criticized 20 that, but I want to ask you about it. 21 Does that mean that patients who had suicidal 22 thinking or who had a history of suicide attempts were 23 excluded from the studies with Prozac? 24 A. No, it does not. 25 Q. Would you explain that to us? PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1662 1 A. First of all, if I could provide a little 2 background on it. Many of these protocols, but not 3 all, eliminated patients that were defined by having 4 a, quote, serious suicidal risk. That degree of 5 seriousness was at the discretion of the physician, 6 the investigator, to make the decision whether or not 7 the patient was eligible or not. Why that was in 8 outpatient protocols, of course, was the risk that 9 patients might be exposed to a placebo or sugar pill, 10 so I think it's fairly obvious why that would be a 11 concern. 12 But as far as patients having a risk of 13 suicide, we had approximately 36 percent of our entire 14 patients, inpatients or outpatients, that had suicidal 15 thinking at the time that they entered the study, or, 16 in fact, may have had recently a suicide gesture or 17 even an attempt, and because in European trials, 18 placebos are not often used, we had the opportunity of 19 doing trials in inpatients or doing these trials 20 without that particular issue of the physician 21 excluding serious suicide risk, so we had, you know, 22 approximately 30 to 35 percent of the protocols 23 outside of the U.S. where that wasn't an issue, and 24 approximately a quarter of the patients in trials 25 outside of the U.S. who had absolutely no exclusion PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1663 1 written into the protocol regarding their suicide 2 status. 3 Q. So in that number of the Prozac clinical 4 studies, patients with a -- did you say a serious risk 5 of suicide? 6 A. Patients that -- more than a third of patients 7 that participated in all of our trials had at least 8 suicidal ideation, thoughts of taking their life, at 9 the time that they entered the trial. 10 Q. That would be before they took any drug, right? 11 A. Exactly. 12 Q. They came to the study with that history? 13 A. Which is expected. That's one of the symptoms 14 of this disease. We expect to see it. 15 Q. Dr. Tollefson, have any of the clinical trials 16 conducted by Lilly on Prozac been published in 17 peer-reviewed medical journals? 18 A. Yes, very many. 19 Q. Okay. Can you give us an idea of approximately 20 how many? 21 A. Well, I would argue that Prozac is probably the 22 most well-published of any medication used in 23 psychopharmacology over the last 25 years. There are 24 over 11,500 publications in the medical literature 25 that mention Prozac, and just to put that in some PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1664 1 context, if you were to take the next three 2 competitors in the same class that we have, 3 medications called Zoloft, Paxil, or Salexa 4 (phonetically), and look at how many times they have 5 appeared in the medical literature and add up all 6 three of those drugs, they're still less than the 7 number of citations around Prozac. 8 Q. Now, has Lilly been the only person or body 9 that has conducted clinical studies with Prozac? 10 A. Definitely not. 11 Q. Well, who else has done them? 12 A. A large, large number of academic 13 professionals. We see studies conducted, for example, 14 by the National Institutes of Mental Health, private 15 research foundations. Really quite a wide variety of 16 investigators have looked at this molecule. 17 Q. For example, have competitors of Lilly, other 18 drug companies, done clinical studies using Prozac? 19 A. They have. One of the disadvantages of being 20 the most widely prescribed medication for depression 21 is that you're often a target for a competitor to want 22 to do a comparison study to see how their medication 23 compares with yours. 24 Q. And have studies, clinical studies on Prozac, 25 comparing Prozac to another antidepressant, studies PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1665 1 performed by other drug companies, have those been 2 published in peer-reviewed medical journals? 3 A. Yes, they have. 4 Q. Dr. Tollefson, to your knowledge, has there 5 ever been a controlled clinical trial comparing Prozac 6 to another antidepressant when the trial was sponsored 7 by another drug company, a competitor of Lilly, has 8 there ever been a study like that published that you 9 know about, that comes to the conclusion that Prozac 10 causes an increased risk of suicide? 11 A. I'm not aware of any such conclusion from any 12 trial. 13 Q. Now, we've had some testimony from Dr. Healy 14 and Dr. Shlensky, who were expert witnesses for the 15 plaintiffs, about an article that was published in 16 February of 1990 by a Dr. Teicher from Boston. Are 17 you familiar with that article? 18 A. I am. 19 Q. Did you see it when it first came out? 20 A. Yes, I did. 21 Q. And were you at Lilly at that time? 22 A. No. I was at St. Paul Ramsey and the 23 University of Minnesota. 24 Q. Now, we've also heard testimony that this 25 article that came out by Dr. Teicher is a type of PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1666 1 publication called a case report. Would you tell us 2 what a case report is? 3 A. Well, most major journals have a section at the 4 back of the journal that's referred to as case 5 reports, and it is an opportunity for clinicians to 6 write about an observation that they have made, 7 typically in one to three or four patients, and it 8 really -- case reports serve the purpose to share that 9 observation with the medical community and potentially 10 generate what we call a hypothesis or an educated 11 guess about your observation, and so they can set the 12 stage for future research that might be done in a more 13 sophisticated way to try to answer whether or not that 14 hypothesis was correct or perhaps not correct. 15 Q. Dr. Tollefson, are you familiar with the 16 prevailing thought in the medical and scientific 17 community about whether a case report can be used to 18 establish that a drug caused the adverse event that is 19 reported? 20 A. Yes. In the medical community, a case report 21 is not felt to be a method that would demonstrate 22 whether or not there is a causal effect. It really 23 only characterizes an observation of seeing event A 24 occurring in a patient at a particular point in time, 25 but it does not address causality or whether or not PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1667 1 the observation was merely coincidental. 2 THE COURT: I think we better take a break now. 3 Please be back at 20 after 11. I want to meet with 4 counsel a minute. 5 (Whereupon, the following proceedings were had 6 in open court out of the presence of the jury.) 7 THE COURT: Mr. See, how long do you anticipate 8 your case is going to take to put on? 9 MR. SEE: The whole case? 10 THE COURT: I think earlier you told me four or 11 five days. 12 MR. SEE: I did. If -- depending upon the 13 cross-examination, we could be finished at the end of 14 the day on Tuesday or perhaps going over to the 15 morning of Wednesday. That would be my best estimate. 16 Could be wrong, but that's what I would anticipate. 17 THE COURT: Thank you. And, Mr. Vickery, do 18 you anticipate much rebuttal? 19 MR. VICKERY: I don't anticipate much rebuttal 20 at this time, one to three witnesses at most. 21 THE COURT: Well, maybe a day? 22 MR. VICKERY: A day maybe. 23 THE COURT: I assume your local counsel has 24 told you that a week from this Friday, that Friday, 25 the Court will not be open. It's a state holiday. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1668 1 MR. VICKERY: Mr. Chang keeps me well informed 2 on that, Your Honor. 3 THE COURT: Okay. It's a new policy. Let's 4 take a break. 5 (Whereupon, a recess was taken from 11:10 a.m. 6 to 11:28 a.m.) 7 THE COURT: Please proceed, Mr. See. 8 Q (By Mr. See) Dr. Tollefson, I was asking you 9 about the case report that came out from Dr. Teicher 10 in February of 1990. My question is: Had there been 11 reported in the medical literature before that time 12 case reports of patients taking other antidepressants 13 who had been observed to become suicidal? 14 A. Yes, there have. 15 Q. Now, in that light, what was the significance, 16 if any, of the case report from Dr. Teicher? 17 A. Well, the observation, again, or the case 18 reports go back some 35 years and include a variety of 19 antidepressants, they even include patients receiving 20 psychotherapy, no medication, that they may experience 21 an increase in suicidal thinking during therapy. And 22 I think, reflecting back when I was at the University 23 of Minnesota, what probably drove a lot of the 24 interest about this specific set of case reports was 25 the already existing significant media interest in PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1669 1 Prozac, and so I think this played into a lot of 2 interest in the -- to the lay public about the 3 molecule. 4 Q. Now, the case reports, that had been in the 5 medical literature before the Teicher article, that 6 talked about patients observed being suicidal while 7 taking some other antidepressant, did those stand for 8 the proposition that those other antidepressants 9 caused suicidality? 10 A. They did not. 11 Q. And did and does the Teicher case report stand 12 for the proposition that Prozac causes suicidality? 13 A. It does not. Again, it's only a hypothesis 14 that was generated. 15 Q. Now, based upon your own personal knowledge, 16 what did Lilly do when the Teicher case report came 17 out in February of 1990? 18 MR. VICKERY: Excuse me, Your Honor. May I 19 have a question on voir dire at this point? 20 THE COURT: Voir dire? 21 MR. VICKERY: Yes, sir. 22 THE COURT: No. You'll have an opportunity to 23 cross-examine. 24 MR. VICKERY: All right. Very well. 25 THE WITNESS: Well, initially, there was a PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1670 1 group of academic experts, I was one of them as a 2 consultant from the University of Minnesota, that were 3 invited in to work with Lilly. At that time, there 4 had been a significant amount of person hours already 5 gone into exploring the particular question or 6 hypothesis raised in the Teicher communication. There 7 were some very exhaustive discussions and 8 recommendations that our consulting group offered to 9 the company that were implemented, additional 10 analyses, ways to study the question with existing 11 data. This group was brought back on a couple of 12 occasions. 13 The company also took those results of those 14 data and analyses. They were provided to the Food and 15 Drug Administration for their consultation. And I 16 recall having been at the University of Minnesota in 17 late August of 1990, a company also electively sent 18 out what's called a Dear Doctor letter, an educational 19 letter to physicians all throughout the United States, 20 psychiatrists, general practitioners, et cetera. I 21 received one of those at the University of Minnesota, 22 basically acknowledging the Teicher case report, 23 discussing the issues of suicidality as part of 24 depression, and the morbidity and the mortality with 25 the disease state, reviewing the relevant literature PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1671 1 on the subject, as well as Lilly's own data analyses 2 and echoing just what is already in the package insert 3 at that time, the significant importance of observing 4 patients with depression regardless of their treatment 5 for suicide. 6 Q (By Mr. See) Dr. Tollefson, did the Food and 7 Drug Administration come out with its own statement 8 with respect to the Teicher report and its view about 9 Prozac? 10 MR. VICKERY: Objection. This calls for a 11 response of a non-final agency decision that has been 12 excluded by the Court. 13 THE COURT: I thought it was already in 14 evidence. 15 MR. VICKERY: Oh, okay. This one. I'm sorry, 16 I thought he was talking about another one. 17 Q (By Mr. See) Let me show you the blowup, 18 Doctor, so the jury can see it. 19 THE COURT: What number? 20 MR. SEE: It's 1138. 21 Q. And, Doctor, that would be in your book up 22 there at Tab 39. Now, Exhibit 1138 is dated July 31, 23 1990, and I think you said this was the FDA's initial 24 response to the Teicher article coming out; is that 25 right? PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1672 1 A. And a review of Lilly's data, yes. 2 Q. So by this time, Lilly had already made a 3 submission of data and analysis to the FDA about the 4 issue raised in the Teicher article? 5 A. That is my understanding. 6 Q. And let's just read it together. Prozac's 7 labeling -- 8 A. From the time -- 9 Q. I'll just read it. 10 A. I'm sorry, you said the word "together." 11 Q. I'll read it and I'll ask you questions about 12 it. That was a misleading way to say it. "Prozac's 13 labeling, from the time of approval, has warned of the 14 general risk of suicide in depressed patients and 15 recommended close supervision of high-risk patients. 16 On the evidence currently available, there appears to 17 be no basis to conclude that the use of Prozac is 18 associated with any unreasonable or unexpected risk." 19 Now, in the FDA statement, they're talking 20 about the general risk of suicide in depressed 21 patients. What significance, if any, did that have to 22 you as it specifically relates to the Teicher case 23 report? 24 A. Well, I think it goes back to the point I made 25 earlier that suicidal thinking, gestures, actual PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1673 1 attempts, are one of the cardinal symptoms necessary 2 in evaluating a diagnosis of major depression, and 3 regrettably, major depression carries a significant 4 risk of suicide with it. So it would be nice today if 5 we, in the medical profession, had a cure for major 6 depression or a medicine that worked 100 percent of 7 the time. Regrettably, we do not. That means that 8 some patients, even patients receiving treatment, may 9 not be getting better. Their illness may continue to 10 progress. That means the signs and the symptoms may 11 progress. One of those signs or symptoms could be 12 suicidality, and so it is not unexpected that, in some 13 patients, you may see an increase in their symptoms, 14 such as suicidality, if they are not optimally 15 responding to the particular treatment that the doctor 16 has started. But that's very similar, I would argue, 17 to many of the medications that we have available in 18 medicine. 19 Q. Doctor, after the FDA came out with its initial 20 statement on July 31, 1990, did Lilly continue to look 21 at the data and perform analyses that were eventually 22 submitted to the FDA? 23 A. Yes. There were many analyses that were 24 conducted and those analyses were submitted to 25 regulatory agencies, as well as published scientific PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1674 1 articles for the academic and clinical communities. 2 Q. Now, Doctor, to your own knowledge, did the 3 Food and Drug Administration also consult directly 4 with Dr. Teicher about what he had reported in his 5 article? 6 A. The Food and Drug Administration did to the 7 best of my knowledge. 8 Q. Now, I want to ask you about after the July 9 time frame of 1990. You indicated that additional 10 information was submitted by Lilly to the FDA? 11 A. That's correct. 12 Q. And I want to ask you about the FDA's 13 conclusion of that and we'll show another blowup and 14 this one is 1061. And, Doctor, that is in your book 15 at Tab 40, 4-0. Do you have that there? 16 A. Yes. 17 Q. Now, this talks about a citizen petition. 18 First tell us, what is a citizen petition to the FDA? 19 A. Well, one of the rights that a citizen of the 20 United States of America would have would be to 21 petition the Food and Drug Administration regarding a 22 particular concern they might have, for example, 23 around a medicinal product, a medication, and I 24 believe that was the case here. 25 Q. And the date of the FDA statement is July 26, PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1675 1 1991? 2 A. Correct. 3 Q. And at that time, the FDA stated, "The data and 4 information available at this time do not indicate 5 that Prozac causes suicidality or violent behavior." 6 Now, the question I want to ask you is, was the 7 conclusion of the FDA consistent with the conclusion 8 of Eli Lilly and Company; that is, that the scientific 9 data simply did not indicate that Prozac caused 10 suicidality or violent behavior? 11 A. That's correct. 12 Q. And now I want to put up another blowup. This 13 one is 1067, and that should be at Tab 41 of your 14 small copies there. Now, 1067 is dated August 1 of 15 1991. And this also refers to the citizen's petition 16 that the last one talked about? 17 A. Yes. 18 Q. And the FDA has indicated in its communication, 19 and I'll read the quote, "The data and information 20 available at this time do not indicate that Prozac 21 causes suicidality or violent behavior." And that 22 would be consistent with all of the information that 23 Lilly submitted to the FDA? 24 A. Yes. 25 Q. Now, the statement goes on. It talks about, PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1676 1 "The FDA's review revealed no basis for concluding 2 that Prozac caused these adverse clinical events." It 3 goes on to say, "Depression itself is highly 4 associated with suicide." Is that the concept you 5 were talking about before, that suicide is both a 6 symptom and the result of a major depression? 7 A. Yeah, I think it's very similar as an analogy 8 if you had angina or heart disease and you experienced 9 chest pain, a natural symptom. It's certainly 10 possible, while the doctor may prescribe you a 11 medication, that you might have an episode of chest 12 pain on the medication. It's a symptom of underlying 13 illness. I believe that's the concept that the FDA is 14 trying to illustrate. 15 Q. It goes on to say that, "An analysis of 16 controlled clinical trials that allowed a direct 17 comparison of the incidence of emergent suicidal 18 thoughts and actions among individuals on Prozac, 19 placebo" -- that's a sugar pill? 20 A. Correct. 21 Q. -- "or other antidepressants, fail to find any 22 greater risk among those on Prozac." Would you tell 23 the jury, when looking at a question like this, why is 24 it, as the FDA has stated, it is important to look at 25 the results from controlled clinical trials? PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1677 1 A. Controlled clinical trials are an exercise that 2 are designed essentially to investigate one question, 3 and the control refers to controlling other variables 4 that might influence or bias the outcomes of the 5 results. So in this case, for example, having a 6 placebo group does provide a chance to observe the 7 natural course of the illness absent the medication, 8 and to compare what's being observed as part of the 9 disease with the study group that's actually receiving 10 the medication, but all other variables are kept equal 11 across the two groups so that they are truly 12 comparable, apples and apples rather than apples and 13 oranges. 14 Q. Dr. Tollefson, Prozac has been a product about 15 which you have had responsibility for some years now 16 right up until today; isn't that right? 17 A. That's correct. 18 Q. Now, would you tell the jury, please, whether 19 the FDA has ever changed its conclusion that it 20 expressed in this FDA statement of August 1, 1991? 21 A. To my knowledge, it has not. It has never. 22 Q. Just a couple of concepts about the Food and 23 Drug Administration. Does the Food and Drug 24 Administration have the power and authority to order 25 that any prescription drug be removed from the market? PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1678 1 A. Yes, they do. 2 Q. And does the Food and Drug Administration have 3 the power and authority to order that different 4 warnings be placed in the information for doctors that 5 the drug company sends out? 6 A. They certainly do have that. 7 Q. And in your experience, does the FDA actually 8 exert that power and authority? 9 A. Yes, they do. 10 Q. Dr. Tollefson, has the Food and Drug 11 Administration ever required Eli Lilly and Company to 12 warn doctors that Prozac causes suicide or violent 13 behavior? 14 A. They have not. 15 MR. SEE: If I may approach the witness, Your 16 Honor? 17 THE COURT: You may. 18 Q (By Mr. See) Doctor, let me hand you 19 Defendant -- or Exhibit 1042. And my question for you 20 is, is that a copy of the Dear Doctor letter that you 21 referred to earlier? 22 A. Yes, it is. 23 Q. And that's the letter in August of 1990 Lilly 24 sent out to doctors in the United States to inform 25 them about the Teicher article? PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1679 1 A. Yes, sir. 2 MR. SEE: Your Honor, at this time, I offer 3 1042. 4 MR. VICKERY: No objection at all. 5 THE COURT: 1042 is admitted. 6 (Whereupon, Exhibit 1042 is admitted into 7 evidence.) 8 Q (By Mr. See) Since the time of the FDA's 9 submission by Lilly to information -- or to FDA of the 10 information, and then the FDA's conclusions that the 11 information and the data simply do not indicate that 12 Prozac causes suicidality or violent behavior, has 13 Lilly done any other monitoring or any other analysis 14 of information about this issue? 15 A. Yes, we have. 16 Q. And, in fact, has the data from the clinical 17 trials that Lilly has conducted with Prozac been 18 examined and evaluated to see if there's information 19 that may show whether there is any issue about Prozac 20 and suicidality? 21 A. That database has been examined in great detail 22 and it has generated a number of publications in the 23 scientific literature addressing the question, looking 24 at it from many different perspectives. 25 Q. Let me show you the blowup. It's 1092, which PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1680 1 should be in your book at Tab 42. All right. Do you 2 see that? 3 A. Yes, sir. 4 Q. Now, would you tell us what this represents? 5 A. Well, there are two plots of data, as you can 6 see. If you look to your left, it is comparison of 7 patients that have been randomized to receive Prozac 8 versus those who were receiving placebo. 9 Q. And placebo again is the sugar pill? 10 A. Correct. And then to your right you have 11 trials where patients received either Prozac or one of 12 these older tricyclic antidepressants or TCAs, and 13 then across the bottom for both pairs of groupings, 14 you see that four types of analyses were conducted; 15 suicidal acts, whether or not a patient, at any time 16 during the trial, had an increase in suicidal 17 ideation, which is the second column. Whether or not 18 that ideation worsened significantly, we called it the 19 emergence of substantial ideation, again, at any time 20 during the trial. And then lastly, from the other 21 perspective, remembering that this is a symptom of the 22 disease, we were interested in where suicidal ideation 23 actually improved from the patient's first visit to 24 the patient's last visit in a clinical trial. 25 Q. And this analysis was conducted as of what PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1681 1 date? 2 A. These analyses were ongoing kinds of work done 3 up to our database of May 1995. 4 Q. Now, let's look first to the comparison of 5 Prozac and the sugar pill. First of all, with respect 6 to suicidal acts, what does this really show? 7 A. In controlled clinical trials, the rate of acts 8 overall was relatively low and there was no difference 9 between the incidence of acts with the sugar pill, or 10 placebo, and that of Prozac. 11 Q. Now, the Prozac here is indicated in the sort 12 of orangish color or the peach color? 13 A. Yes. 14 Q. And the placebo would be in the light blue? 15 A. Yes, sir. 16 Q. So with respect to, for example, suicidal 17 ideation worsened, what does our chart show? Which, 18 either Prozac or placebo, produced the worsening of 19 suicidal ideation that was worse? 20 A. Well, you can judge that by the relative height 21 of the bar, and the bar for placebo shows that's 22 slightly over one in five individuals or 20 percent 23 had the worsening of suicidal ideation during the 24 trial. That was a numerically larger figure than with 25 the treatment with Prozac. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1682 1 Q. And let's talk about the improvement of 2 suicidal ideation. How did Prozac compare with people 3 just taking -- these are depressed people now, right? 4 A. Correct. 5 Q. And how did Prozac compare to the people taking 6 the sugar pill? 7 A. Here you can see that the Prozac bar in that 8 golden color is significantly higher, which means a 9 large number. In fact, I believe that's in excess of 10 70 percent of patients receiving the medication had an 11 improvement, that is a reduction in suicidal thinking, 12 that was statistically significantly more than was 13 received among the patients receiving the sugar pill 14 or placebo. 15 Q. All right. Now, can you tell us generally what 16 was the significance of the results when the Prozac is 17 compared to the tricyclic antidepressant? 18 A. Sure. The first comparison against placebo, 19 remember, was looking at the base rate of change in 20 suicide as a symptom of depression while receiving the 21 placebo, looking at the natural history of the 22 disease. 23 Now, the second comparison of Prozac versus 24 another medication allows one to address whether 25 there's an effect that is unique to Prozac or how does PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1683 1 it compare relative to other antidepressant 2 medications. So we now have introduced a comparison, 3 not against the sugar pill, but the conventional older 4 antidepressants called the TCAs. 5 Q. And what's the general conclusion that you can 6 draw? 7 A. Both antidepressants, Prozac or the tricyclic 8 class, look comparable across each of the four 9 measures. 10 Q. Now, Dr. Tollefson, based upon this analysis 11 from the data from the clinical trials, are you able 12 to draw a conclusion about whether Prozac causes 13 suicidal acts or ideation? I mean, can you draw a 14 conclusion based upon that data? 15 A. Yes, sir. 16 Q. What is that conclusion? 17 A. I think there are two here. Number one is 18 there appears to be no evidence that antidepressants, 19 in general, induce suicidality at a rate higher than 20 seen with the sugar pill, and relative to Prozac 21 specifically, evidence that Prozac is actually 22 associated with a lower likelihood of that occurring 23 and a greater probability that patient's suicidal 24 thinking will get better than the sugar pill. 25 Q. Now, did Lilly also do an analysis of the PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1684 1 Prozac clinical trial data looking at the question of 2 violence? 3 A. Yes, they did. 4 Q. Let me put up the blowup for this marked 1098, 5 and that should be in your book at Tab 43. 6 A. I have it. Thank you. 7 Q. Now, on this chart here, placebo is indicated 8 in the light blue and Prozac is in the peach color? 9 A. Correct. 10 Q. Now, what does this chart show us? 11 A. This is looking at a comparison of the 12 incidence of acts that were representative of either 13 anger, hostility, or overt violent behaviors. 14 Q. And, again, the patients that you looked at 15 with respect to this data, these were people who had 16 major depression? 17 A. That's correct. They were very rigorously 18 diagnosed with major depressive disorders. 19 Q. And what conclusions can you draw from this 20 chart on the question, does Prozac cause anger, 21 hostility, or violent behaviors? 22 A. These data would propose two conclusions; one, 23 is, as you can see in the blue, that acts of anger, 24 hostility, or violence occur in the context of major 25 depression; that is, the patients receiving, again, PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1685 1 the sugar pill allowing us to look at the natural 2 history of the illness. 3 When we look at Prozac, the second observation 4 here is, number one, patients receiving the drug had a 5 much lower incidence, looks like about seven-fold 6 lower, but also that was a statistically significantly 7 lower incidence, which also leads one to believe that 8 there may be a protective effect. Not an absolute, 9 but a relative protective effect against the emergence 10 of those behaviors. 11 Q. Now, we've heard testimony, Dr. Tollefson, that 12 suicide is, in fact, a risk in people who are 13 depressed. The question I want to ask you is, have 14 you done studies in patients who do not have the 15 diagnosis of major depression to see whether there is 16 evidence that Prozac is related to suicidality in 17 those people? 18 A. Yeah. In our consideration of what were 19 different kinds of studies that we could conduct to 20 try to address this question, again from many 21 different directions, one of them was to look at 22 patients with depression relative to those who did not 23 have depression, both of whom received either, again, 24 the sugar pill or Prozac. 25 Q. All right. Would you turn to Tab 24 in your PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1686 1 book? 2 THE COURT: What number? 3 MR. SEE: I'm sorry. I'm just going to ask him 4 about a medical article, Your Honor, that's not an 5 exhibit. 6 THE WITNESS: I have it. 7 Q (By Mr. See) Just hang on one second. What 8 is that, Dr. Tollefson? 9 A. This is a photocopy of a peer-reviewed article 10 entitled, "Evaluation of Suicidality During 11 Pharmacologic Treatment of Mood and Non-Mood 12 Disorders." 13 Q. And who is the author of that article? 14 A. I'm the lead author on that paper. 15 Q. Now, you said it is analysis of suicidality in 16 mood disorders. What did you mean by mood disorders? 17 A. Mood disorders in this case principally reflect 18 patients, again, with major depression, as we've 19 talked about already. 20 Q. And the non-mood disorders part would be 21 patients who did not have major depression? 22 A. That is correct. 23 Q. Who were also given Prozac? 24 A. That is correct. 25 Q. Now, what did you generally conclude based upon PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1687 1 that study? 2 MR. VICKERY: Objection. Your Honor, the Court 3 has excluded testimony from my expert, Dr. Healy, 4 regarding people who were not treated for depression 5 on Mr. See's objection. Now he's trying to get 6 testimony from his expert on grounds that mine was 7 excluded from testifying about. 8 THE COURT: I think we better take this up at 9 side bar. We'll excuse the jury at this time. Please 10 be back at one o'clock. 11 (Whereupon, the following proceedings were had 12 in open court out of the presence of the jury.) 13 MR. VICKERY: Your Honor, if I may, I think I 14 may jog your recollection about this. Dr. Healy was 15 going to testify about a letter written by a gentleman 16 to a Mr. Noone at Lilly. It involved a patient who 17 was not depressed at all and who became suicidal. The 18 very significant fact that he wanted to bring out to 19 the jury was, here is a man who is pro Lilly, the 20 doctor that was writing the letter. It was a patient 21 who was not depressed and yet became suicidal on this 22 drug. We had a side bar conference. Mr. See objected 23 and said, Judge, this is a non-depressed patient, 24 don't let Dr. Healy talk about that, and the Court 25 sustained Mr. See's objection and did not allow PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1688 1 Dr. Healy to go into that. 2 Now, Mr. See, as he's done already with several 3 other respected studies, is going into aspects that my 4 experts were specifically precluded from doing based 5 on his motions in limine and his objections during the 6 trial. 7 I've let several of them slide, Your Honor, 8 because, quite frankly, I'm delighted he's opened the 9 doors to them, but with respect to this one, you know, 10 I'm really hamstrung by it because it was his 11 objection that said don't let him do that, Judge, and 12 you didn't, and now he wants to do exactly the same 13 thing that he urged the Court not to let me do. 14 MR. SEE: Exhibit 102, Your Honor, concerns -- 15 I mean, the reference is that certain eating disorders 16 may be associated with a higher incidence of suicide, 17 and I think that was the exclusion. I was not asking 18 Dr. Tollefson about any other disorder at all. Only 19 that there were patients, who had not had depression, 20 who were given Prozac to see whether suicidality 21 emerged. 22 THE COURT: I think that's what Mr. Vickery is 23 speaking to. He's not speaking to 102; is that right? 24 MR. SEE: No, I thought he was speaking to 102. 25 MR. VICKERY: What I'm talking about, Your PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1689 1 Honor, is 102 is the letter that Dr. Healy wanted to 2 talk about, okay? 3 THE COURT: Okay. 4 MR. VICKERY: The significance of this letter 5 to Dr. Healy was that here is notice to Lilly from a 6 physician, whom we don't know his name, but whom is 7 obviously pro Lilly from the tenor of the letter, who 8 is reporting that a patient who is getting Prozac for 9 an eating disorder became suicidal. And what it does, 10 and the enormous significance of it to Dr. Healy was, 11 that it takes depression out of the equation. It 12 takes the Lilly strategy of blaming the underlying 13 disease out of the equation and says, here guys, you 14 had notice here that a patient who was not depressed 15 became suicidal, and we wanted to talk about this 16 letter, but we were precluded by virtually Mr. See's 17 objection, and the basis of his objection was that 18 this letter is about a person who had an eating 19 disorder, not about someone who's depressed. 20 MR. SEE: Your Honor, I was asking 21 Dr. Tollefson about that issue based upon Your Honor's 22 October 16, 1998 ruling, and it indicates that the 23 Court's order addresses only evidence that Lilly 24 researched non-indicated uses of Prozac. It does not 25 address evidence of the results of such research to PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1690 1 the extent that results show reactions to suicide, 2 homicide, or other violence from taking Prozac. 3 So I mean, my only intent of asking him about 4 this particular study is that here depressed people 5 were given Prozac, and they were observed to see if 6 suicidality emerged; and there were also people, who 7 did not have depression in these studies, who were 8 given Prozac to see whether suicidality emerged. 9 THE COURT: But Mr. Vickery's objection is not 10 with respect to the order, but with respect to your 11 objection with respect to Dr. Healy's testimony on 12 someone becoming suicidal who did not have depression. 13 And the Court did not allow -- as I recall, I did not 14 allow Dr. Healy to speak to that and now, evidently, 15 you're asking your witness almost the same question. 16 MR. SEE: I honestly don't have a recollection 17 of it. I'll have to go back and look at my notes, and 18 I certainly will. 19 THE COURT: We'll break for now and 20 reconvene -- well, if you want to pursue it -- I think 21 you better withdraw the question, but if you want to 22 pursue it, then we'll pursue it at side bar at one 23 o'clock. 24 MR. SEE: Very good. Thank you. 25 (Whereupon, a lunch recess was taken from PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1691 1 12:03 p.m. to 1:15 p.m.) 2 THE COURT: Please proceed, Mr. See. 3 MR. SEE: Thank you, Your Honor. 4 Q. Dr. Tollefson, we've talked about controlled 5 clinical trials done with Prozac, and now I'd like to 6 change gears for just a second and ask you about 7 epidemiology studies. 8 THE COURT: Excuse me, are you withdrawing your 9 last question? 10 MR. SEE: I do. 11 Q. I'll ask you about epidemiology questions or 12 studies. First, would you tell the jury what is an 13 epidemiology type study? 14 A. These tend to be what we call naturalistic in 15 that there is no formal randomization of people to one 16 drug or the other, so they look at large populations 17 and they observe particular events or circumstances in 18 a more normal context or real world context perhaps. 19 Q. Now, Dr. Tollefson, if you will, would you turn 20 to Tab 16 in your book. We have had testimony in the 21 trial already about a study by Dr. Hershel Jick. Are 22 you familiar with that study? 23 A. Yes, I am. 24 Q. And do you have it before you now? 25 A. I do. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1692 1 Q. Now, the one thing we haven't heard is the 2 conclusion in the study, and if I could, I'd ask you 3 to turn to Page 218 of the study. 4 A. I have it. 5 THE COURT: What exhibit is this? 6 MR. SEE: It is a medical article, Your Honor. 7 It's not numbered as an exhibit. 8 THE COURT: Oh. 9 Q (By Mr. See) If you would look on Page 218 in 10 the right-hand column under conclusions. 11 MR. VICKERY: Excuse me, Mr. See. What tab was 12 that? 13 MR. SEE: Sixteen. 14 Q. Under the conclusions there's, about halfway 15 down, a sentence that reads, "Though the suggestion," 16 do you see that? 17 A. Yes, I do. 18 Q. Would you read that to the jury, please? 19 A. In the author's conclusions he says, "Though 20 the suggestion has been made that fluoxetine, Prozac, 21 may trigger an emotional state, which itself increases 22 the risk of suicide, this suggestion has not been 23 supported by formal evidence." 24 Q. And that is the conclusion of the author of the 25 Jick study? PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1693 1 A. Yes, it is. 2 Q. Now, would you turn to Tab 10 in your book, 3 please. 4 A. I have it. 5 Q. And is that a study entitled, "Suicidality and 6 Fluoxetine, Is There a Relationship?" by a Dr. Fava? 7 A. Yes, it is. 8 Q. You're familiar with that study? 9 A. Yes, I am. 10 Q. And is that an epidemiology type survey study? 11 A. It is a survey study, that's correct. 12 Q. Would you turn over to Page 110 of that study 13 under the title, "Discussion," right up at the top. 14 Do you see that? 15 A. I do. 16 Q. And would you read the first sentence of that 17 discussion, please? 18 A. "New onset suicidal ideation of the intensity 19 and severity described by Teicher and associates did 20 not emerge in the course of treatment with either 21 fluoxetine alone or any other antidepressant in our 22 sample of depressed patients." 23 Q. And, again, that was the conclusion of 24 Dr. Fava, the author of this study? 25 A. Yes. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1694 1 Q. Would you turn to Tab 28 in your book? 2 A. I have it. 3 Q. Is that an epidemiology study by Dr. Meredith 4 Warshaw? 5 A. Yes. 6 Q. And the title of that is, "The Relationship 7 Between Fluoxetine Use and Suicidal Behavior in 654 8 Subjects with Anxiety Disorders," correct? 9 A. Correct. 10 Q. Now, in that study Dr. Warshaw and the other 11 author studied patients who had both major depression 12 and anxiety; isn't that right? 13 A. Correct. 14 Q. Now, would you look on the first page of that 15 article, on the left-hand side where it says, 16 "Conclusion"? 17 A. I have it. 18 Q. You see that? Would you read the first 19 sentence of that conclusion? 20 A. "We found no evidence that fluoxetine use is 21 associated with increased risk of suicide attempts or 22 gestures." 23 Q. And would you look down at the bottom of that 24 page and tell the jury what journal that was published 25 in and the date? PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1695 1 A. This was published in the Journal of Clinical 2 Psychiatry in April of 1996. 3 Q. And is that a peer-reviewed journal? 4 A. Yes, it is. 5 Q. Would you turn to Tab 18 of your book? And is 6 that another epidemiology type study by Dr. Andrew 7 Leon and others? 8 A. Yes, it is. 9 Q. And the title of that one is, "Prospective 10 Study of Fluoxetine Treatment and Suicidal Behavior in 11 Affectively Ill Subjectives;" is that right? 12 A. Correct. 13 Q. Now, affectively ill means what? 14 A. Affective disorders, that's with an A, A-F-F, 15 affective disorders represent a synonomous term with 16 mood disorders and refers to depressive illness. 17 Q. Now, Doctor, I'd like you to tell the jury the 18 source of the data from Dr. Leon's article, and that 19 is right in the method part. Do you see that? 20 A. Yes. 21 Q. Would you read that about the source of the 22 data from this study? 23 A. Sure. The data in this study come from the 24 National Institutes of Mental Health Collaborative 25 Depression Study which was a prospective naturalistic PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1696 1 follow-up of persons who presented for treatment of 2 affective disorders. 3 Q. Would you turn over to Page 200 of that 4 article? And on the left-hand column under 5 "Discussion" down at the bottom, there's a sentence 6 that starts out, "Results indicate," would you read 7 the next two sentences, please? 8 A. Sure. "The results indicate that although 9 fluoxetine was prescribed to more severely ill 10 subjects, their risk of suicidal behavior was not 11 elevated. Instead, there were non-significant 12 protective effects of fluoxetine and other somatic 13 antidepressant treatments in the absence of 14 fluoxetine." 15 Q. In summing that up, does that mean that people 16 that got prescribed Prozac were, in fact, sicker 17 before they started out, but they did better on 18 Prozac? 19 A. It says that Prozac, on average, was prescribed 20 to patients that had higher risks of suicide by virtue 21 of the severity of their illness and, in fact, the 22 rates that were observed here were lower than expected 23 for the average patient. 24 Q. Let me point out one more study. Would you 25 turn over to Tab 19, please? And is that the study by PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1697 1 Fiona Mackay? 2 A. Yes, it is. 3 Q. Now, underneath the author's name, it indicates 4 that these authors are from the Drug Safety Research 5 Unit in the United Kingdom. Are you familiar with 6 what that is? 7 A. That is a group that's devoted to 8 pharmacoepidemiology or the study of drugs in large 9 human populations based in the U.K. 10 Q. Could you look down at the bottom of the page 11 and tell us when this article was published or maybe 12 up at the top of the page? 13 A. It was probably published in 1997. 14 Q. And the journal? 15 A. The journal is entitled, Pharmacoepidemiology 16 and Drug Safety. 17 Q. Would you turn over to Page 245 of that 18 article? In the left-hand column under, "Selected 19 Events" -- 20 A. Yes. 21 Q. -- the third paragraph, would you read that 22 conclusion, please? 23 A. Yes. "There was no statistical significance 24 between the number of suicides and the SSRI taken. It 25 has been suggested that fluoxetine might promote PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1698 1 suicidal ideation. Our data do not support this 2 view." 3 Q. Now, there has been some suggestion by 4 Dr. Healy that Eli Lilly and Company has not studied 5 the question of Prozac and suicidality in large groups 6 of people. Is that correct? 7 A. Prozac has been studied in very large groups of 8 people as illustrated by some of these 9 pharmacoepidemiology articles. 10 Q. Let me specifically refer you to Tab 8 of your 11 book, and draw your attention to the article by 12 Dr. Ditman. 13 A. I have it. 14 Q. Are you familiar with the article by 15 Dr. Ditman? 16 A. Yes, I am. 17 Q. Will you tell the jury what that is? 18 A. This was an extremely large epidemiological 19 survey conducted by our Lilly affiliate in Germany 20 that surveyed just short of some 20,000 patients being 21 treated in Germany being cared for by either 22 psychiatrists or primary care doctors. 23 Q. And what were the conclusions of this study by 24 Dr. Ditman in Germany? 25 A. They concluded that the efficacy and the safety PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1699 1 seen in this population, this very large population of 2 German subjects, was consistent with the clinical 3 experience that has previously been discussed; that it 4 was an effective therapy and that whether it was in a 5 general practice or psychiatric setting, that the 6 incidence and risks for suicide was diminished as 7 depression was diminished by treatment. 8 Q. And was the large Ditman study conducted in 9 Germany funded by Eli Lilly and Company? 10 A. Yes, it was. 11 Q. Are you familiar with an organization called 12 the American College of Neuropsychopharmacology? 13 A. I am. 14 Q. That's also called the ACNP? 15 A. That's correct. 16 Q. Are you a member of that group? 17 A. I am. 18 Q. Would you turn to Tab 2, please, of your book. 19 A. I have it. 20 Q. Are you familiar with the consensus statement 21 by the ACNP of March 2, 1992? 22 A. Yes. 23 Q. First of all, Doctor, would you turn over to 24 Page 7 of the ACNP consensus report and I want to ask 25 you about the second paragraph on that page that PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1700 1 starts out, "In conclusion," do you see that? 2 A. Yes. 3 Q. Now, that paragraph is talking about case 4 reports, is it not? 5 A. Yes, it is. 6 Q. Would you read that paragraph to the jury of 7 what the ACNP says about case reports? 8 A. It starts out, "In conclusion, case reports 9 suggest that a small minority of patients may 10 experience emergent suicidal thoughts or event such 11 behavior during the pharmacological treatment of 12 depression. These reports do not distinguish between 13 the relative potential contribution of the disease 14 process, external stressors, or the medication. Of 15 significance, there is evidence that such emergent 16 suicidality is not specific to any one type of 17 antidepressant and may, therefore, be largely a 18 manifestation of the natural course of the illness." 19 Q. Will you tell the jury what that means as far 20 as whether case reports can be used to come to 21 conclusions about whether a drug causes an adverse 22 effect? 23 A. Essentially, they cannot be used to reach that 24 conclusion. 25 Q. Would you turn over to Page 9 of the ACNP PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1701 1 consensus report, and I'd like to ask you about the 2 conclusion that is under Paragraph 6C right in the 3 middle of the page. Do you see that? 4 A. Yes. 5 Q. Would you read that conclusion to the jury? 6 A. "There is no evidence that antidepressants such 7 as the selective serotonin reuptake inhibitors, for 8 example, fluoxetine, trigger emergent suicidal 9 ideation over and above rates that may be associated 10 with depression and other antidepressants. What is 11 clear is that most patients receive substantial 12 benefit from treatment with this drug and related 13 antidepressants." 14 Q. Now, Doctor, as a member of this organization, 15 of the ACNP, are you familiar with the official 16 positions and stands that that organization takes on 17 issues from time to time? 18 A. Yes. 19 Q. Now, Dr. Healy testified in front of the jury 20 that he believed that the ACNP would, in fact, reject 21 this consensus statement because it's old and out of 22 date. Would you tell the jury what you know about the 23 consensus statement and its current position today? 24 A. I think the position of the ACNP would be 25 consistent today as it was when the position paper was PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1702 1 provided. There have not been any subsequent 2 discussions to overturn these conclusions. There has 3 not been any data introduced to the ACNP that would 4 cause them to reconsider their conclusions. 5 Q. Are you familiar with the Harvard Mental Health 6 Letter? 7 A. Yes. 8 Q. Would you turn to Tab 12 of your book, please? 9 Dr. Tollefson, is the Harvard Mental Health Letter a 10 reliable authority on issues dealing with mental 11 health and medications to treat psychiatric illness? 12 A. I think many clinicians consider this to be an 13 authoritative reference. 14 Q. And do you? 15 A. Yes. 16 Q. And what is the date of the Harvard Mental 17 Health letter in front of you? 18 A. This is January of 1995. 19 Q. Would you turn over to the second page, and I'd 20 like to ask you about the conclusion that is at the 21 end of the first paragraph on the left-hand column. 22 It starts out, "On the other hand." Do you see that? 23 A. Yes, I do. 24 Q. Would you read that to the jury? 25 A. Yes. "On the other hand, critics have also PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1703 1 claimed that fluoxetine causes suicides. The evidence 2 against that claim is strong. Antidepressant drugs in 3 general, as one would expect, reduce the danger of 4 suicide and the SSRIs are no exception." 5 Q. Now, Dr. Healy gave some testimony that he 6 believed that Professor Stuart Montgomery, in the 7 United Kingdom, had consulted with Lilly about doing a 8 study regarding Prozac and suicide, and Dr. Healy said 9 that he believed that that was unpublished. And my 10 question for you is, has, in fact, Professor Stuart 11 Montgomery published an article concerning that very 12 research? 13 A. Yes, he has. 14 Q. Would you turn to Tab 20, please, of your book? 15 Now, I'd like to ask you about the first full 16 paragraph on Page 214. 17 A. I have it. 18 Q. The one that starts out, "It is clear." Do you 19 see that? 20 A. Yes. 21 Q. Would you read that down through the reference 22 to the Teicher article? 23 A. Okay. "It is clear that in this study, 24 fluoxetine neither increased nor decreased the suicide 25 attempt rate. The absence of provocation of suicidal PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1704 1 behavior by fluoxetine, in this group of high-risk 2 patients, contradicts the suggestions that have been 3 made on the basis of anecdotal reports that fluoxetine 4 provokes suicidal behavior," and then in parentheses 5 it gives the reference, "Teicher, et al. colleagues, 6 1990." 7 Q. Now, if I could ask you to turn down to the end 8 of that paragraph and read the rest of it starting, 9 "The high suicide attempt rate." Do you see that? 10 A. Yes. 11 Q. Would you read that, please? 12 A. "The high suicide attempt rate observed on 13 placebo emphasizes the danger of bias in interpreting 14 open report of suicidal behavior in those with a 15 history of suicide attempts and makes it clear that 16 judgments that particular treatments are likely to 17 cause suicide attempts should only properly be made on 18 the basis of randomized placebo controlled study." 19 Q. Would you explain for the jury, please, what 20 Professor Montgomery is saying about the use of either 21 case reports or controlled clinical trials as 22 information to come to causal conclusions? 23 A. Again, he is emphasizing that case reports 24 cannot serve the purpose to establish causality, and 25 he goes on to emphasize that the best way to address PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1705 1 this, particularly when you're talking about a symptom 2 like suicide, which is part of depression, is through 3 these randomized controlled clinical trials, where you 4 have one group receiving medication, one group 5 receiving the placebo or sugar pill, that that would 6 be the best way to address the question. 7 Q. Now, Dr. Tollefson, in his questioning of 8 Dr. Healy, Mr. Vickery referred to Exhibit 58. 9 MR. SEE: If I may approach the witness, Your 10 Honor? 11 THE COURT: You may. 12 Q (By Mr. See) And I'm going to put a copy of 13 Plaintiffs' Exhibit 58 in front of you, and 14 specifically refer you to Page 18 of that document. 15 First of all, do you know what it is? 16 A. Yes. 17 Q. All right. That is in evidence as a 18 preliminary report of a Professor Herman in Germany. 19 Is that your understanding? 20 A. Yes. 21 Q. Now, Mr. Vickery, in questioning Dr. Healy, 22 made reference to a statement in that exhibit that 23 says that Prozac is, from a purely mathematical basis, 24 5.6 times more likely to have a suicide attempt or 25 suicide than the comparative antidepressants. Do you PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1706 1 see that part? 2 A. I do. 3 Q. Now, what does the reference "purely 4 mathematical" mean? 5 A. I think what the writer is saying here is that 6 if you only looked at the absolute number of events in 7 one group versus another group without any other 8 comparisons or corrections, that the absolute number 9 in one group was 5.6 times higher than the absolute 10 number in a second group. 11 Q. Now, from a scientific viewpoint, is that the 12 fair or scientifically valid way to look at those 13 numbers? 14 A. I'd say that it is neither fair or valid. 15 Q. All right. Let me ask so we all understand, 16 Professor Herman, the author of that document, is he a 17 Lilly employee? 18 A. He was not at that time and he is not 19 presently. He has not been. 20 Q. Now, Doctor, can you explain for the jury why 21 it is not scientifically appropriate to look at that 22 5.6 times number? 23 A. Sure. Any time that you're doing work that 24 involves, like here, epidemiology, you start, and I'd 25 emphasize start, with an observation in one group PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1707 1 versus another. How many events do you see, but it's 2 critically important that you then consider how many 3 opportunities have there been in one group versus the 4 other for the event to have occurred. How many 5 exposures, how many opportunities, again, that 6 something might have occurred, and are they equal or 7 not equal and to control, in essence, for those 8 differing lengths of exposure or risks. 9 Q. Has a chart been prepared, Dr. Tollefson, that 10 will help you illustrate and explain this concept to 11 the jury? 12 A. Yes. 13 THE COURT: What number is this? 14 MR. SEE: Your Honor, this is purely for 15 illustrative purposes. It's not on the exhibit list. 16 It has been displayed to Mr. Vickery per our 17 agreement. I have a copy that the Court can look at 18 while we're discussing it with the witness. 19 THE COURT: Thank you. 20 Q (By Mr. See) Dr. Tollefson, I think there's a 21 small version of that at Tab 49 in your book. 22 A. I have it. 23 Q. Now, first of all, it's got Player A and Player 24 B and games and home runs. It looks like baseball and 25 not medicine. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1708 1 A. Right. 2 Q. Can you explain what it is that you want to 3 communicate with this? 4 A. This is an effort to provide you, I guess, with 5 an analogy when we talk about looking at events, and 6 then needing to put it in the context of either 7 exposures or opportunities for that event to have 8 occurred. 9 Q. So we have Player A and Player B, and HR stands 10 for home runs? 11 A. Home runs. 12 Q. All right. Now, explain the analogy, please. 13 A. Well, picture yourself perhaps as the manager 14 of a baseball team, and you're looking to compete with 15 the Yankees, so you need a power hitter, somebody who 16 can hit home runs. You might start, if you were 17 looking at two players that you could sign as a free 18 agent, you might start by saying, how many home runs 19 have they hit. And as you can see, Player A has hit 20 ten home runs and Player B has hit only two home runs. 21 If you were to stop at this point, you'd say, well, 22 obviously Player A is the power hitter. 23 Q. And is that where you stop? 24 A. Absolutely not. 25 Q. All right. What's the next step? PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1709 1 A. To try to get at this concept of opportunities 2 or exposures, you then have to ask a very reasonable 3 question, well, how many games did Player A play in? 4 How many games did Player B play in? You can see here 5 that Player A participated in ten games, Player B in 6 only two games. This allows you now to go one step 7 further and that's to say, well, how many home runs 8 have been hit per game that the player had an 9 opportunity to participate in? You see, all of a 10 sudden now that ratio, ten divided by ten becomes one, 11 two divided by two also becomes one for Player B. 12 Now, all of a sudden, you're puzzled and you're 13 saying, gee, they look like equivalent power hitters. 14 Now I don't know which one I might want to sign. 15 Q. Now, let me ask this question: In looking at 16 the home runs per game box, can you yet tell which 17 player is the better home-run hitter? 18 A. You cannot. You've not gone far enough in the 19 analysis. 20 Q. All right. Now, let me ask this: Let's apply 21 it back to the case that we're talking about. 22 A. Yes. 23 Q. The 5.6 times suicide risk that is referred to 24 in Exhibit 56 that Mr. Vickery questioned Dr. Healy 25 about, where would that 5.6 times number go in your PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1710 1 group of boxes? 2 A. That would be a ratio that would be analogous 3 to going under the home runs per game, the middle 4 column. 5 Q. So let me ask you again, is that where the 6 analysis stops? 7 A. It should not. 8 Q. All right. Go on with the baseball analysis. 9 What would you look at next? 10 A. Well, if you're a good manager, you would then 11 want to ask the question, all right? I know how many 12 home runs have been hit, I know how many games the 13 player was in, but how many times did the player 14 really have a chance to come to bat and really have an 15 opportunity to hit a home run? So then you ask how 16 many at bats were there? 17 You can see for Player A, in his ten games that 18 he participated in, he had 30 at bats, 30 19 opportunities to hit a home run. Player B, on the 20 other hand, only had two at bats in the two games that 21 he played in. So now you can calculate how many home 22 runs did a player generate per at bats, per 23 opportunity, and you see all of a sudden, Player A, 24 who started out looking like the most productive 25 home-run hitter, now has a ratio of only one to three; PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1711 1 that is, one home run every three times at bat. In 2 contrast, Player B has one home run every time he got 3 a chance or she got a chance to bat. 4 And so when you work all the way through the 5 calculation, all of a sudden we see that Player B is 6 the more productive home-run hitter per opportunity to 7 hit. 8 Q. Now, let me ask you this: What is the value or 9 the data relating to Prozac in this 5.6 number that 10 should go into the at bat column? 11 A. These are the actual number of days that a 12 depressed patient would have been receiving Prozac, 13 and so the analogy is with depression, as a very 14 serious disease state, which we call morbidity and 15 mortality, that is the risk of suicide, how many days 16 was that patient taking the medication where they may 17 have had an increase in suicidal thinking or actually 18 have attempted or completed a suicide. So it's days 19 of therapy on medication. 20 Q. So this would be sometimes calculated in terms 21 of patient days on therapy? 22 A. Patient days. Patient years. 23 Q. Patient years on therapy? 24 A. That's correct. 25 Q. And that corresponds to the at bats in the PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1712 1 baseball analogy; is that right? 2 A. Correct. 3 Q. Now, Dr. Tollefson, when the patient days or 4 years on therapy is taken into account, is there any 5 significant difference between the suicide risk for 6 Prozac as compared to the suicide risk for the 7 comparative drugs? 8 MR. VICKERY: Objection. This is beyond the 9 scope of this man's report. There's no disclosure, 10 there's no discovery supplementation that he was going 11 to, in any way, redo the data from Professor Herman. 12 THE COURT: I haven't seen the reports so how 13 should I know? 14 MR. VICKERY: We'll be glad to provide them to 15 the Court. 16 MR. SEE: May we discuss at side bar, Your 17 Honor? 18 THE COURT: Yes. 19 (Whereupon, the following proceedings were had 20 at side bar out of the hearing of the jury.) 21 MR. VICKERY: Your Honor, I'm sure the Court 22 recalls the number of different times Mr. See objected 23 and the number of different objections the Court 24 sustained regarding testimony that I was trying to 25 induce that was beyond the scope of the expert's PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1713 1 report. 2 THE COURT: I recall. 3 MR. SEE: Mr. Vickery has used the 5.6 times 4 document to offer to the jury evidence that Prozac 5 causes suicide. Dr. Tollefson's report clearly shows 6 that he will be testifying on that issue, in fact, 7 that Prozac does not cause suicide, and he is simply 8 responding to Dr. Healy's use of that 5.6 number 9 saying that it does not cause suicide, that Dr. Healy 10 was taking it out of context and presenting it in a 11 misleading way. 12 MR. VICKERY: Judge, this is a 1985 Lilly 13 document. It's marked as their exhibit. The final 14 version is marked as their exhibit. They've known 15 about this document for 14 years. This man references 16 everything that he's relied on. There's 73 different 17 medical articles that he's relied on, which I have 18 read or analyzed, and there is nothing in there about 19 him doing a reanalysis of Professor Herman's data. 20 This is something they're making up in the middle of 21 trial and it is beyond the scope of the report. 22 MR. SEE: It is simple response to Dr. Healy's 23 testimony using this number in a very misleading way 24 suggesting to the jury that this data shows that 25 Prozac causes suicide. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1714 1 THE COURT: Well, I'll allow it. 2 Q (By Mr. See) Just so you'll recollect the 3 question, Dr. Tollefson, is once the patient days or 4 years on therapy is taken into account, is there any 5 significant difference between the result of suicides 6 on Prozac versus the suicides on the comparative 7 drugs? 8 A. There was no statistically significant 9 difference. 10 Q. Now, Doctor, what I want to ask you now is 11 this: All of the data that went up to make that 5.6 12 times calculation, was all of that data that was in 13 Exhibit 56 that Mr. Vickery talked about with 14 Dr. Healy, was all that data submitted to the 15 regulatory agency in Germany regarding the application 16 for Prozac's approval in that country? 17 A. Yes, it was. 18 Q. And did Lilly then submit the patient days or 19 patient years of exposure also to that regulatory 20 agency in Germany? 21 A. I think, consistent with standard practice in 22 epidemiology, that was the way the data was shared 23 with the BGA, the Germany regulatory authority. 24 Q. And after all those patient years and patient 25 dates of exposure was submitted, what was the ultimate PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1715 1 decision of the German regulatory agency in Germany 2 about whether Prozac should be approved for use in 3 that country? 4 A. The German authority found that Prozac was safe 5 and effective and approved it for marketing in Germany 6 and it continues to be marketed in that country today. 7 Q. Was the data that went up to end up with that 8 5.6 times calculation also submitted to the FDA in 9 this country? 10 A. Certainly. 11 Q. And was the same patient days or patient years 12 of exposure information also submitted to the FDA? 13 A. Yes, they were. 14 Q. And I think you've already said, but what was 15 the FDA's conclusion about whether Prozac should be 16 approved as a safe and effective drug for use in this 17 country? 18 A. They approved it as well. 19 Q. Now, Dr. Tollefson, you are familiar with the 20 package insert -- well, let me ask you this, Doctor: 21 Has Prozac been approved for use in treating 22 depression in countries other than the United States 23 and now, as we've heard, Germany? 24 A. Yes. 25 Q. And is there a chart that illustrates that? PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1716 1 A. Yes, there is. 2 Q. This is Exhibit 1122, and I'll put 1122 up in 3 front of the jury, Dr. Tollefson, and ask you, is that 4 a representation of the countries in the world who 5 have approved Prozac for use in treating depression in 6 their countries? 7 A. It is, and it reflects approximately 90 8 countries around the world who have approved Prozac 9 for the treatment of depression. 10 Q. Dr. Tollefson, are you familiar with the 11 package insert for Prozac that was in effect in 1992? 12 A. Yes. 13 Q. And have we got a chart that blows up part of 14 that? 15 A. We do. 16 Q. And it is 1041. I'll put that up in front of 17 the jury. I think that's in your book at Tab 46, sir. 18 Do you have it there? 19 A. Yes, I do. 20 Q. All right. First of all, under "Precautions," 21 Lilly has provided information to the prescribing 22 physicians with respect to the question of suicide and 23 depression, isn't that so? 24 A. Yes. 25 Q. Okay. And going down into "Other events PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1717 1 observed during premarket evaluation of Prozac," what 2 does that mean? 3 A. These would be events that occurred during the 4 context of the clinical trial, but they are 5 categorized here independent of whether or not they 6 were causally related to the drug the patient was 7 receiving. So they were observational events. 8 Q. All right. And with respect to those events, 9 the insert for Prozac that was in effect in 1992, 10 provides the prescribing physician information that 11 events observed during the time that patients were 12 taking Prozac and the clinical trials included the 13 event of agitation and included the event of 14 akathisia, right? 15 A. That is correct. 16 Q. So if the prescribing physician has reviewed 17 the insert, he or she would be in a position to know 18 that during the clinical trials for Prozac, these 19 events were observed, correct? 20 A. That is correct. 21 Q. Now, we go down to another section in the 22 insert which is entitled, "Post-introduction reports," 23 do you see that? 24 A. Yes. 25 Q. Now, that reads, "Voluntary reports of adverse PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1718 1 events temporally associated," what does "temporally 2 associated" mean? 3 A. Happened to occur at the same time someone was 4 receiving medication. 5 Q. Okay. "...temporally associated with Prozac 6 that had been received since market introduction and 7 which may have no causal relationship with the drug, 8 include the following," and then there is indicated, 9 "suicidal ideation." Is that the medical term for 10 suicidal thinking? 11 A. Yes. 12 Q. And also the term, "violent behaviors," 13 correct? 14 A. That is correct. 15 Q. Now, would you explain for the jury what does 16 this mean when the prescribing physicians are being 17 notified that there had been reports of these events, 18 but they may have no causal relationship with the 19 drug? What does that mean? 20 A. I think it harkens back to our earlier 21 discussion of what a case report is. These, 22 essentially, represent even weaker evidence of a case 23 report; that is, there is a reporting system available 24 that if a physician happens to observe event A in a 25 patient receiving a medication, he or she can choose PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1719 1 to notify the company, the FDA, like a case report, an 2 observation, as it mentions here, temporally 3 associated with the drug, and that would then be added 4 in this post-introductory report section as an 5 educational tool or an informative tool for future 6 prescribers that, independent of causality, this event 7 has been reported to occur during treatment. 8 Q. Now, the question I have is, the listing of 9 suicidal ideation and violent behaviors in this 10 section of the insert, does that mean that Lilly 11 believes that Prozac causes those things? 12 A. Absolutely not. 13 Q. Well, if that's the case, would you tell the 14 jury why does Lilly then inform prescribing physicians 15 of that information? 16 A. Again, I think it is an effort to remind 17 physicians about the association of suicidality with 18 depression, and it goes back up to the precaution 19 section of labeling around suicide and depression. It 20 is good medical practice to have physicians aware of 21 that observation. 22 Q. Now, Dr. Tollefson, I have just a couple more 23 questions, and my questions are addressed to you, Gary 24 Tollefson, as a physician, a psychiatrist, and a 25 pharmacologist, and they are this: Doctor, do you PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1720 1 have an opinion, based upon all of the scientific 2 research that you have personally conducted as well as 3 the research that you have reviewed with respect to 4 Prozac, an opinion whether Prozac causes suicide, 5 suicidal behavior, or violent behavior? First, do you 6 have an opinion? 7 A. Yes. 8 Q. Would you tell us what your opinion is? 9 A. Well, my opinion on this is based on extensive 10 studies that have been done in many, many different 11 methodological ways by academic professionals, the 12 National Institute of Mental Health, reviews of 13 regulatory agencies, and those have consistently -- 14 those large-scale control types of trials have 15 consistently failed to show any association, so it is 16 my opinion that there is absolutely no medically sound 17 evidence of an association between any antidepressant 18 medication, including Prozac, and the induction of 19 suicidal ideation or violence. 20 MR. SEE: Thank you very much, sir. I pass the 21 witness. 22 THE COURT: Mr. Vickery. 23 MR. VICKERY: Thank you, Judge. 24 CROSS-EXAMINATION 25 BY MR. VICKERY: PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1721 1 Q. Good afternoon, sir. 2 A. Good afternoon. 3 Q. We have never met until today, but I met you 4 earlier. My name is Andy Vickery, and I represent 5 Bill and Susan Forsyth. 6 Dr. Tollefson, would you do me a favor, and 7 that is, just visit with me straight one on one. In 8 other words, when I ask you a question, would you just 9 look at me and answer my question? 10 A. I'd be happy to look at you. 11 Q. Thank you. Now, I want to talk to you first 12 about your company's position. I take it that your 13 level in the company is high enough that you sort of 14 speak for Eli Lilly here in this courtroom and in this 15 trial on this matter; is that true? 16 A. That's true. 17 Q. We heard -- right before you started, we heard 18 an admission by Lilly, your company -- I think it was 19 an interrogatory, I'm sorry -- and we said to you, 20 tell us how many people have been taking Prozac where 21 other people died, and it was 88, 88 times where, not 22 the patient, but someone else died. And my question 23 to you, sir, in all fairness is, in each of those 88 24 circumstances, is it the position of Eli Lilly and 25 Company that it was the underlying drug -- I mean, the PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1722 1 underlying disease, that it couldn't have possibly 2 been your drug that contributed in any material way? 3 A. I think it would be our -- 4 Q. Excuse me. I'm sorry. I thought we had this 5 agreement you were going to talk to me. 6 A. I didn't know it was exclusive. 7 Q. Well, you see, these folks have an important 8 role over here, but I think that they -- 9 MR. SEE: Your Honor, I object to the badgering 10 of the witness and arguing. 11 THE COURT: Sustained. 12 THE WITNESS: What our opinion would be is that 13 there is no credible scientific evidence or proof that 14 there is any association between antidepressant 15 medications and suicide or violence. 16 Q (By Mr. Vickery) And when you -- you say 17 those and you've thrown in some kind of terms of art 18 when you say that, haven't you? 19 A. That's your definition. Could you give me an 20 example? 21 Q. Sure. Association. That's an epidemiological 22 term, isn't it? 23 A. It can be. I don't think it's exclusive to 24 epidemiology, but it could be. 25 Q. And epidemiologists look at nine different PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1723 1 factors, including the strength of association to 2 determine if there is causation, don't they? 3 A. They can. 4 Q. I mean, you're familiar with the Bradford Hill 5 criteria, aren't you? 6 A. I am. 7 Q. And aren't those, sort of, the way that 8 epidemiologists look to determine whether an inference 9 of causation is appropriate? 10 A. That is one method. 11 Q. Okay, sir. Now, when you say that there is no 12 proof of an association, what you were talking about 13 is an association to a statistically significant 14 degree, aren't you? 15 A. I am talking about the absence of any medical 16 information that would suggest that there is evidence 17 of causality between an antidepressant and violence 18 and suicide. 19 Q. What kind of evidence would be acceptable to 20 Dr. Gary Tollefson? 21 A. Well, I think not just exclusively to me, but 22 the field as a whole has indicated that the best way 23 to evaluate causality is through a randomized 24 controlled clinical trial. 25 Q. Well, now, that's not what your subordinate, PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1724 1 Dr. Beasley, concluded in the spring of 1990, is it? 2 A. I would be very surprised if Charles would not 3 agree that the best way to establish causality is 4 through a randomized clinical trial because 5 Dr. Beasley has conducted many of those and published 6 them. 7 Q. But are you not familiar with the draft 8 protocol that he did in which he considered three 9 ways; a randomized clinical trial, epidemiology, or 10 rechallenge, and chose rechallenge? 11 A. I think you're misstating or perhaps 12 misunderstanding. Dr. Beasley did not choose 13 rechallenge. Dr. Beasley did an extensive evaluation 14 of the different methods available to answer the 15 question and evaluated the strengths and the 16 weaknesses of each. 17 Q. And in his document, did he not, sir, conclude 18 that rechallenge was the way -- I mean, that's the 19 method that he set up to do was a rechallenge with 200 20 patients, wasn't it? 21 A. I'm not sure which document you're referring 22 to, sir. 23 Q. Okay. Let me show it to you. 24 MR. VICKERY: May I approach the witness, Your 25 Honor? PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1725 1 THE COURT: You may. What exhibit? 2 MR. VICKERY: It's not an exhibit. I'm going 3 to show it to him and see if it refreshes his 4 recollection. 5 Q. Dr. Tollefson, for the record, what I've handed 6 you is a document on Lilly letterhead, isn't it? 7 A. It is. 8 Q. The date is March 29, 1991, right? 9 A. That's correct. 10 Q. That's about three months before you arrive at 11 Lilly? 12 A. As a full-time employee, that's correct. 13 Q. And as soon as you arrive, Dr. Beasley becomes 14 your subordinate, right? 15 A. Correct. 16 Q. And it's a letter to the Food and Drug 17 Administration, isn't it? 18 A. It is. 19 Q. And it's signed by Dr. Talbott, who's the 20 director of regulatory affairs at Lilly, isn't it? 21 A. That's correct, at the time. 22 Q. Now, attached to that is a draft study plan, a 23 protocol, one of those protocols you were telling us 24 about, as to how Lilly via Dr. Beasley intended to 25 study this issue. Have you seen this document before? PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1726 1 A. I've not seen the cover letter, but I've seen 2 the protocol. 3 Q. And tell us what method the protocol chooses. 4 A. Well, I think, first of all, as I look at the 5 cover letter, it says that this is a draft protocol, 6 so it means that it's something under review or under 7 consideration. It says it is being refined by Lilly, 8 and it is yet to have been reviewed by expert 9 consultants outside of Lilly, and then it goes on to 10 request a meeting with the FDA representatives to 11 discuss this as a protocol. 12 So to me, my understanding would be this is one 13 potential way of evaluating a question that is being 14 discussed, had not yet been discussed with external 15 experts, nor had it been discussed with the Food and 16 Drug Administration. 17 Q. I appreciate that information, but that wasn't 18 my question. 19 A. I'm sorry, could you restate that? 20 Q. My question was, which of the three methods did 21 Dr. Beasley choose, random -- real simple. It's A, B, 22 or C, randomized clinical trial, epidemiology, or 23 challenge/rechallenge? Which did he choose? 24 A. I think you forgot D, which is all of the 25 above. Dr. Beasley was involved conducting all of PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1727 1 those types of studies. Rechallenge was one of the 2 three, so the answer was D, all of the above. 3 Q. In this document? 4 A. Not in this particular document. This document 5 is focusing on one of the options being evaluated, 6 rechallenge. 7 Q. Okay. Can we agree that he chose rechallenge 8 in this instance? 9 A. We cannot agree on that. 10 Q. We can or cannot? 11 A. I think you said earlier, if I understood you 12 correctly, sir, that it was his preferred or 13 recommended approach, I don't believe that's contained 14 in the document. 15 Q. Does this document contain a study protocol to 16 do a challenge/rechallenge test? 17 A. Yes, it does. 18 Q. Now, did Lilly ever do that test? 19 A. Lilly did not do the specific protocol. 20 Q. In fact, has Lilly ever done, in all of these 21 clinical trials that you've done all over the world, 22 has Lilly ever done a prospective trial where going 23 in, what we're going to study here is, does our pill 24 make people become homicidal or suicidal? Have you 25 ever done that? PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1728 1 A. Yes, we have. 2 Q. When? 3 A. You asked me if we've ever done a prospective 4 study to evaluate whether this pill, as you call it, 5 causes people to be suicidal or homicidal and yes, we 6 have. Those have been prospective randomized trials, 7 epidemiological trials, mood and non-mood disorder 8 trials, high-risk special population trials, et 9 cetera, et cetera. 10 Q. Well -- 11 A. Many studies. 12 Q. Can you just point me to one, because quite 13 honestly, I have never seen one where that's what you 14 were studying going in. I'm not talking about whether 15 you were studying whether this drug will help somebody 16 with depression, and you go back later and look at it 17 and say, well, now let's look and see if it helped or 18 if it affected suicide. I'm talking about where up 19 front, you said this is what we're going to study. 20 A. I think we've reviewed with the jurors today a 21 number of those studies that included prospective 22 trials. 23 Q. Maybe we're not communicating, Dr. Tollefson. 24 Those prospective trials were trials to see where the 25 hypothesis -- you know how the scientific method PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1729 1 works, right? 2 A. I think so. 3 Q. There's a hypothesis and that's, let's study 4 this, let's see if this drug does this. Is that what 5 an hypothesis is? 6 A. A hypothesis is an educated guess to be 7 evaluated. 8 Q. So one hypothesis would be this drug will help 9 people with depression become better, right? 10 A. Yes. 11 Q. And Lilly did lots of studies on that 12 hypothesis, correct? 13 A. That's correct. 14 Q. And one hypothesis would be this drug will help 15 people with bulimia, right? 16 A. That is correct. 17 Q. And Lilly did lots of prospective studies with 18 that hypothesis, correct? 19 A. We did several. 20 Q. And one hypothesis would be this drug helps 21 people with obsessive compulsive disorder, right? 22 A. Right. 23 Q. And Lilly has done lots of studies on that? 24 A. Yes. 25 Q. Now what I'm talking about is something PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1730 1 different. I'm talking about a study where the 2 hypothesis is this drug causes people to kill 3 themselves or conversely, this drug doesn't cause 4 people to kill themselves. Has Lilly ever done that? 5 A. Lilly has conducted those trials. Lilly has 6 sponsored trials conducted by reputable outside 7 academic centers to investigate those associations. 8 Q. Please tell us which one or ones because, quite 9 frankly, we're very familiar with the ones you just 10 went over and none of them fall in that category, do 11 they? 12 A. I'll give you another example. We conducted a 13 trial -- in fact, we talked earlier about the American 14 College of Neuropsychopharmacology, the ACNP. In 15 their consensus paper, they identified four types of 16 trials that would help address this question. They 17 were randomized prospective clinical studies that were 18 reviewed under a meta-analysis, which Lilly has done. 19 They suggested looking at epidemiological studies, as 20 you've heard about, which were done by Lilly. The 21 third suggestion was to evaluate Prozac in disorders 22 where depression wasn't prominent, to evaluate whether 23 there was a drug effect. That was done as well. And 24 lastly, they suggested looking in high-risk 25 populations. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1731 1 I'll give you an example. I published a paper, 2 first author, in looking at what's called agitated 3 depression. People who, at baseline, had severe 4 depression and were highly agitated, and we built into 5 that prospective double-blind trial of fluoxetine, 6 Prozac, against a tricyclic antidepressant, 7 Imipramine, a suicide evaluation scale called the ASIQ 8 or the Adult Suicide Inventory Questionnaire. 9 Q. Well, I'm looking right here at your article on 10 baseline agitation. Can you tell me what the 11 hypothesis was that you were testing when you did this 12 article? 13 A. We were -- I'm not sure if you have the same 14 article I'm talking about or not, but the one I'm 15 referring to was a hypothesis that patients with 16 agitated depression would show an ability to tolerate 17 a newer antidepressant, the SSRI, in this case Prozac, 18 better than the older tricyclic antidepressants, 19 Imipramine. 20 Q. I'm looking right at it and there's nothing in 21 the hypothesis that you're studying that this is to 22 test suicide. 23 A. That was part of both the efficacy -- remember, 24 this is a symptom of the disease. It was part of the 25 efficacy analysis outlined in the paper, as well as a PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1732 1 safety evaluation where we used the adult suicide 2 inventory. 3 Q. Let's talk about meta-analysis. That's kind of 4 a big ten-penny medical word. Can you tell us, is 5 meta-analysis something you do going in or is it 6 something you do looking back? 7 A. Meta-analysis is one form of going back and 8 looking at a large number of studies, pooling those 9 studies to get a larger patient sample to improve the 10 validity of the statistical analysis. It is referred 11 to -- it is a statistical term called meta, meaning 12 more than one, analysis. 13 Q. Now, so what Dr. Beasley did in the 14 meta-analysis in 1990 is he went back and he looked at 15 some of the 27,000 patients, I believe you said. 16 A. Is that a question? 17 Q. No, sir. I'm just going on. Don't worry, I'll 18 finish. When Lilly was making a report to the FDA 19 about this in 1990, Dr. Beasley went back and he 20 reanalyzed or did a meta-analysis of some of these 21 27,000 patients that had taken Prozac, didn't he? 22 A. He did. 23 Q. And tell us how many of those 27,000 patients 24 Dr. Beasley looked at when he did this analysis. 25 A. Well, the number of patients that Dr. Beasley PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1733 1 looked at was defined by, first of all, the principles 2 of meta-analysis, and it's an area -- if I could just 3 take a moment to explain to you. To do a legitimate 4 meta-analysis, the protocols that you -- 5 Q. Excuse me, Doctor. Would you just answer my 6 question? How many patients did he look at? I'm sure 7 Mr. See will ask you if he wants you to explain 8 meta-analysis. 9 A. There were approximately 3500 patients with 10 major depression out of this group that met the 11 criteria for an appropriately conducted meta-analysis. 12 Q. And how many of those 3500 were actually on 13 Prozac? 14 A. I don't remember the exact number. I would say 15 it's probably about half. 16 Q. Wasn't it just 600 and some odd? 17 A. I doubt that. I'd have to refer to the paper. 18 Q. And when Dr. Beasley did this meta-analysis, 19 did he call the clinical investigators that had been 20 hired by Lilly and talk to those fellows and say, we 21 see that you've reported a suicidal event, you know, 22 tell us about that patient. Give us your clinical 23 feedback. Did he do that? 24 A. The analysis was done looking at several 25 different things. One was the written statement on PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1734 1 the part of the physician about the event, another was 2 looking at the rating scales used by the physician, 3 yet another was what was called drug epidemiology 4 network which is checking and cross-referencing with 5 the reporting system to the FDA that might have been 6 generated by the physician. So there were three 7 sources of physician information that were reviewed. 8 Q. Dr. Tollefson, is it not true, sir, that 9 Dr. Beasley and other folks at Lilly simply did not 10 contact the doctors who had reported the initial 11 phenomenon when they did the meta-analysis? 12 A. I'm sure that if they had any questions when 13 they reviewed the written documents, that they would 14 have felt comfortable calling. Whether they did or 15 did not, I can't answer, but I know Dr. Beasley 16 routinely has discussions with investigators. 17 Dr. Beasley talked with Dr. Teicher about this 18 phenomenon to make sure that he understood it. 19 Q. Have you not seen Dr. Beasley's deposition 20 testimony where he said he didn't call any of them? 21 A. I have not seen that. That must mean that he 22 was clear on his review of their textural comments. 23 Q. Now, tell me this, is an adverse reaction 24 that's associated with a higher serotonin potency -- 25 that's what you're talking about Prozac doing, giving PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1735 1 a higher serotonin potency, isn't it? 2 A. I don't think I said that. What serotonin 3 uptake inhibitors do is attempt to normalize the 4 amount of serotonin in the brain. Again, we said 5 earlier, depression is associated with a reduction, a 6 net deficit. Serotonin uptake inhibitors try to 7 normalize that back to what hopefully all of us here 8 have an opportunity to enjoy. 9 Q. Is a side effect of Prozac akathisia? 10 A. I do not believe that it is a side effect that 11 has been demonstrated to be caused by Prozac. I base 12 that on analyses of looking at the incident rates of 13 akathisia. Again, in patients with placebo versus 14 those receiving Prozac, there is no statistically 15 significant difference in the incident rates. 16 Q. Did you, Dr. Tollefson, publish an article in 17 1991, right before you went to work for Lilly, called, 18 "Antidepressant Treatment and Side Effect 19 Consideration"? 20 A. Yes. 21 Q. And did you in that article write, and I quote, 22 "However, adverse reactions associated with a higher 23 5-HT, or serotonin, potency include nausea, headache, 24 nervousness, and akathisia." Did you write that? 25 A. I'd like to see it. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1736 1 Q. Sure. 2 MR. VICKERY: May I approach the witness, Your 3 Honor? 4 THE COURT: You may. 5 Q (By Mr. Vickery) I'll take you there in just 6 a minute. Is this the article that you wrote? 7 A. It is one. 8 Q. And you're not the first author on this one, 9 you're the only author, aren't you? 10 A. That's correct. 11 Q. Now, over on Page 6, on the bottom left-hand 12 corner, do you say the following, "However, adverse 13 reactions associated with a higher 5-HT" -- 14 A. I'm sorry, could you show me where you are, so 15 I can follow along? 16 Q. Yes, sir. You see Page 6, there where it has 17 figure four, five, and six? 18 A. Yes. 19 Q. And if you'll come in the right-hand column, 20 down five lines. 21 A. Starting with? 22 Q. Where it says, "However." 23 A. Okay. 24 Q. Would you read that sentence out loud for us? 25 A. Let me make sure that I have the right one PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1737 1 here. "Some of the newer second-generation agents, 2 however," is that what you're referring to. 3 Q. No, sir. "However, adverse reactions" -- 4 A. And you're in the left column? 5 Q. No, sir, the right column. 6 A. Sorry. Okay. I have it. 7 Q. Would you just read that line for us, that 8 sentence, please? 9 A. Sure. "However, adverse reactions associated 10 with higher 5-HT potency include nausea, headache, 11 nervousness, and akathisia." 12 Q. Okay, sir. Now, later in that same article you 13 say that other drug treatment side effects involving 14 the central nervous system include extrapyramidal side 15 effects, and we've talked about that big word, and 16 akathisia or nervousness, don't you? 17 A. Again, I'd like to see the section just to put 18 it in context. 19 Q. Okay. Turn over to Page 8. 20 A. Okay. 21 Q. Right-hand column, two-thirds of the way down 22 where it starts, "Hypomania." 23 A. Okay. 24 Q. Why don't you just read it for us where it 25 says, "Other drug treatment side effects." PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1738 1 A. "Other drug treatment side effects involving 2 the central nervous system include sedation, 3 extrapyramidal side effects," in parentheses it says, 4 "uncommon; tardadyskinesia," in parentheses, "reported 5 with use of tricyclics but uncommon," end of 6 parenthesis; "weight gain, cognitive impairment, 7 akathisia or nervousness, and possibly iatrogenic 8 suicidal ideation." 9 Q. Now, does Prozac, as a side effect, cause 10 akathisia? 11 A. I do not believe that it causes it. We said 12 that it is included in labeling. It has been observed 13 during clinical trials, but again, where it's 14 positioned in labeling that the FDA has issued is not 15 as a causally related event, but an event observed 16 during treatment. That's really what I tried to 17 capture in this paper is these events have been 18 occasionally or seldomly observed. I don't think I 19 inferred that they had been demonstrated to be 20 causally related. There's a difference. 21 Q. If we skip all that stuff in the middle and if 22 you just read with me, "Other drug treatment side 23 effects involving the central nervous system include 24 akathisia or nervousness." Now, do you mean to say 25 when you say other drug side effects include PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1739 1 akathisia, that you don't really mean that akathisia 2 is a side effect of the drug? 3 A. I mean to say it is a side effect that has been 4 observed in patients receiving antidepressants. I do 5 not mean to say that it has been definitively 6 demonstrated with one agent to be causal. There's a 7 difference. I hope that it is clear. Again, it is 8 the difference between -- 9 Q. I'm sorry. 10 A. -- coincidentally observing and demonstrating a 11 cause. Those are two different concepts. 12 Q. I'm sorry. It's not clear to me. Let's try 13 one more time and if you can't help me, maybe it's 14 clear to other people. But when you say other -- 15 MR. SEE: Your Honor, with respect, I object to 16 the commentary and ask that it be stricken. 17 THE COURT: Sustained. 18 Q (By Mr. Vickery) When you say, "Other drug 19 treatment side effects include akathisia," I interpret 20 that to mean that akathisia is another drug side 21 effect. Do you mean something else? 22 A. I mean it is a side effect or an experience 23 that can be observed during the course of treatment. 24 Q. Okay. Well help us out with something else 25 then. Now, you say "Other drug side effects include," PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1740 1 and at the end of that list, would you give me the 2 phrase? 3 A. "And possibly iatrogenic suicidal ideation." 4 Q. Iatrogenic is a big medical word that merely 5 means caused by the physician or the treatment of the 6 physicians, correct? 7 A. Correct. 8 Q. So what you're saying in May of 1991 is that 9 other drug side effects include possibly drug-induced 10 suicidal ideation, aren't you? 11 A. Keep in mind this paper was published in May of 12 1991. That's about two or three months after 13 Dr. Tiecher's report and it was a case report that was 14 hypothesis generated. That's why I refer to it as 15 possibly. At that point it was a hypothesis that was 16 well understood in the medical literature. It was a 17 point of discussion, so I think it deserved to be 18 mentioned. 19 Q. Well, if we're going to keep that in mind, 20 could we keep in mind that it was 15 months after the 21 Teicher article instead of three? 22 A. Yes. 23 Q. Thank you. 24 A. The issue, I mean, was still contemporary. 25 Q. Okay. Sometime between May of 1991 and -- PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1741 1 A. Can I point out, though, correction. This 2 paper was written shortly after the Teicher paper 3 published. It's very important, I think, for the jury 4 to recognize when you write a paper, it undergoes peer 5 review. It has to go out. It has to be reviewed by 6 multiple physicians. It then comes back to the 7 physician that authored it to be revised. It then 8 goes back to the journal, and it's reviewed by the 9 journal. It then goes into a cue or a line before 10 it's ever published. 11 So just to clarify, I wrote this paper 12 originally at the time, right around, proximal to 13 Teicher. Yes, it published 15 months later. That's 14 an artifact of the journal publishing practices. I 15 hope that's clear. 16 Q. I'm not sure what question you were answering, 17 but thank you for telling us. 18 A. You're welcome. 19 Q. Sometime between 1991 and 1999, Dr. Gary 20 Tollefson has concluded that other drug side effects 21 do not include drug-induced suicidal ideation, hasn't 22 he? 23 A. I'm not sure what you just said. Could you 24 repeat it for me? 25 Q. Yes, sir. I'm saying that sometime between the PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1742 1 time that article was published and today when you sat 2 on the stand and raised your hand and said I'll tell 3 the truth and gave your opinions, you have come to the 4 conclusion that it is not possible, it is impossible, 5 that this drug could have caused William Forsyth to 6 kill his wife and himself or any of these other 88 7 people to die or any of the other suicides? You've 8 concluded that it's just impossible, haven't you? 9 A. That is not what I said. I think I said that 10 based on the extensive burden of scientific research 11 that has gone into this question, there is no credible 12 scientific evidence of this association. 13 Q. Well, now, Dr. Tollefson, if we're going to 14 talk about this being written in response to Teicher, 15 did I understand you earlier to say that when the 16 Teicher article came out, that Lilly hired outside 17 consultants, such as yourself, to help them sort of 18 get handle on it and respond to that issue? 19 A. They asked us to both look at the data that 20 they had already generated and to share with them 21 thoughts about what other kinds of things might be 22 done to address the question. 23 Q. And can you tell us what was one of the very 24 first things you did as a paid Lilly consultant to 25 respond to the Teicher article? PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1743 1 A. I suggested that one way they could evaluate 2 their already existing data was to look at the gold 3 standard rating scale for depression that was used as 4 their primary instrument to measure change in 5 depressive signs and symptoms, the Hamilton Depression 6 Rating Scale, and I suggested on there, there was an 7 item that the clinician evaluated in a semi-structured 8 interview with his or her patient, item three, which 9 taps degree of suicidality that the patient has 10 demonstrated over the past seven days. It is a 11 snapshot, a cross-sectional view, and I said that that 12 could be a useful tool to explore whether patients 13 receiving Prozac, older tricyclics, or the placebo 14 sugar pill showed significantly different rates of 15 this phenomenon described by Teicher. 16 Q. That's not all you did, is it? 17 A. That was the principal recommendation at the 18 time I consulted to what would be useful to do with 19 the existing database. 20 Q. Didn't you write the journal? Did you write a 21 letter to the editor of the journal that published the 22 Teicher article? 23 A. I wrote a critique, a response, which is a 24 standard thing one sees, that if there is an article 25 published in a medical journal, there is an area in PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1744 1 the journal, which is called, "Letters to the editor," 2 where it provides an opportunity for any clinician to 3 express an opinion either in favor or raising 4 questions about a paper that's appeared in the 5 journal. It's, again, a method to keep dialog on the 6 subject open. 7 Q. And one of the things that you said didn't 8 really have anything to do with the science of it, it 9 had to do with the legal ramifications, didn't it? 10 A. I raised that as one possible consequence of 11 going from a case report, as a hypothesis, to assuming 12 that there was causality, and there was a strong 13 inference of causality, I felt, personally in the 14 Teicher report and subsequent comments. 15 Q. When you criticized Dr. Teicher and Dr. Cole, 16 was one of the things that you said is, hey guys, if 17 you publish this, you'll cause legal problems? Isn't 18 that true, sir? 19 A. I think one of the points, and it was only one, 20 suggested that it could create a lot of confusion 21 around this issue until the hypothesis had been 22 tested. 23 Q. Now, Dr. Cole was a very senior and respected 24 physician, was he not? 25 A. He was. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1745 1 Q. And he was what Lilly calls an opinion leader, 2 correct? 3 A. That's correct. 4 Q. And within the corporate jargon of Lilly, tell 5 us what is an opinion leader? 6 A. Someone who is trained in a particular 7 discipline who has, like we all do, opinions, and an 8 opinion leader would suggest that those opinions may 9 be influential. 10 Q. Is this someone who's got enough experience, if 11 you will, to have some gray hair and has a real 12 reputation in the field? 13 A. Well, I don't think opinion leaders have to 14 have gray hair, but some do. 15 Q. Okay. And do you recall, without my showing it 16 to you, what response you got from the authors to your 17 letter saying, hey, this is going to cause legal 18 problems? 19 A. They -- I don't remember the exact details, but 20 they were not particularly concerned about that. 21 Q. Let's look at it. Let's do that. What I'm 22 going to show you, sir, is not marked as an exhibit, 23 but it's from the December 1990 issue of the American 24 Journal of Psychiatry. It includes the letter that 25 you wrote criticizing the Teicher and Cole article and PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1746 1 their response, okay? And we're just going to look at 2 several portions of it. 3 It's on fluoxetine and suicidal ideation. It 4 starts, "Sir, in a recent article, Martin Teicher and 5 colleagues presented six case reports," et cetera. 6 The end of the first paragraph, it says, "In my 7 opinion, this is not well substantiated and may 8 introduce a medical-legal precedent." What was your 9 concern, Dr. Tollefson? 10 A. Well, it was not well substantiated at that 11 time, and I would argue today it has been 12 substantiated, there is no medical evidence to support 13 their hypothesis. My concern was that that 14 hypothesis, that there may be a relationship, could 15 lead people to misconstrue that there was a 16 relationship, and there is, I would argue, a big 17 difference in how that could be seen by an individual. 18 Q. I understand that. That's the medical part. 19 Tell me about the legal part now. Was your concern 20 that some people were going to file some lawsuits 21 against Eli Lilly that was paying you as a consultant? 22 A. Let me just make a point. I have spent my 23 entire career in psychiatry trying to help people with 24 serious mental disorders. Depression represents one 25 of the most significant public health concerns this PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1747 1 country faces. It is a disease that's been 2 stigmatized for many, many years. People don't go to 3 get help. If they get help, they don't stay with 4 treatment adequately. These kinds of issues can 5 further stigmatize the disease. 6 So yeah, I have a concern that if 7 antidepressants somehow all of a sudden were 8 inappropriately, at that time based on case reports, 9 viewed as drugs that cause people to kill themselves, 10 what would you do as a depressed patient who's kind of 11 sitting on the fence, should I get help? Should I get 12 help? My doctor said I should take this medicine. I 13 don't think I will. That was my concern, this whole 14 concept of stigmatization of mental disorders. And, 15 yeah, I was concerned that a case report, only a case 16 report, was going to somehow become established as 17 causal proof that antidepressants were deadly and 18 dangerous, and I did not believe at that point in 19 time, and I certainly don't believe today, that that's 20 the case. 21 Q. You didn't answer my question, Doctor. The 22 question was, were you concerned when you said legal 23 precedent, that the existence of this report from 24 these very prominent physicians, one of whom was an 25 opinion leader and a clinical investigator for Lilly, PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1748 1 would cause people to file lawsuits against Eli Lilly? 2 Is that what you meant legal precedent? 3 A. Absolutely not. 4 Q. Tell us then, what did you mean by "legal 5 precedent"? 6 A. Just what I thought I tried to say and that is 7 that it would be construed that that report, that 8 preliminary observation would be used to demonstrate 9 inappropriately a causal association, be it in a 10 medical arena, a legal arena, or the public domain. 11 That was my concern. 12 Q. All right. Let's flip on over. In your letter 13 over on the next page, you say, "The concomitant 14 medications, benzodiazepines also confound analysis." 15 That's a lot of big words in there. Help me break it 16 down. Concomitant, what does that mean? 17 A. Taking a second or additional medications on 18 top of whatever the first medication was. So more 19 than one agent at the same time. 20 Q. Now, benzodiazepine is a sedative, is it not? 21 A. It's a minor tranquilizer used for anxiety 22 typically. 23 Q. Is Xanax one of those? 24 A. It is. 25 Q. And you know that Bill Forsyth, Sr. was on PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1749 1 Xanax for a period of time, and you know that it was 2 discontinued, don't you? 3 A. Yes. 4 Q. And you say it was confounding analysis, does 5 that mean make it more difficult to get a handle on 6 it? 7 A. Absolutely. 8 Q. Now, answer this question for me: When the 9 clinical trials were done, all of this clinical data 10 you talked about that had been reanalyzed later, could 11 the physicians that were giving the patients the pill, 12 give them benzodiazepines which would counteract these 13 very side effects we're concerned about? 14 A. That only occurred in the first couple of 15 trials, and one has to remember that we're talking 16 about early investigation of a serious disease, 17 depression. You've got patients going on placebo, so 18 there was an ethical concern about giving them just 19 the sugar pill if they were in severe distress, so 20 some of the early protocols did include an option for 21 the physician to either use or not use a 22 benzodiazepine or a minor tranquilizer. That 23 accounted for only about 8 percent of the entire 24 population study, and remember, that 8 percent could 25 include somebody who only received one dose one time PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1750 1 on one day in a six-week period of time and yet it was 2 8 percent. 3 So yes, in a couple of the very early trials, 4 when we were trying to understand this medication and 5 recognizing the severity of depression and the 6 treatment with the placebo, it was permitted. 7 Q. Follow a hypothetical and maybe we can 8 illustrate it. Let's say -- accept for just the 9 purposes of my question that Prozac might give me 10 akathisia and that might make me suicidal, but what 11 you did in those early clinical trials is the doctor 12 that was giving me this medicine to test how it 13 worked, would, in addition to that, give me a 14 benzodiazepine which would mask the very symptom that 15 I'm so concerned about now. Isn't that exactly what 16 happened? 17 A. Not exactly. Let me just reiterate. 18 Physicians, at their discretion, could choose to use 19 one of those medications in the first early three 20 studies or not, and they did that based on their 21 clinical judgment. Now, the point is one can analyze 22 patients, who either receive or did not receive those 23 benzodiazepines concomitantly, and prepare those 24 analyses to eliminate, as you point out, that 25 confound. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1751 1 Q. Tell me this then, Dr. Tollefson, when you 2 wrote in to the Journal of Psychiatry, instead of 3 saying, "The concomitant medications confound 4 analysis," why didn't you say, as you have just here, 5 don't worry about the fact that there was some 6 concomitant benzodiazepines. It was only 8 percent. 7 We can get rid of those. That's not a problem? 8 A. Well, here you've helped illustrate for me the 9 major difference between a case report and a 10 randomized controlled trial. A case report is 11 completely uncontrolled. That's why when you have 12 four or five drugs on board, you can't assess the 13 contribution of drug one, two, three, four, or five in 14 isolation because they're all in the system at the 15 same time. 16 In a randomized controlled clinical trial, you 17 have the opportunity to look at where these 18 medications were used, you can look at patients as a 19 group that are homogenous, who either had or had not 20 used it. You can do an appropriate analysis to 21 determine whether that was a factor or not and, in 22 fact, we did do that and it was not a factor. 23 Q. Now, one of the things Dr. Healy told us about 24 control, one of the things he said in his opinion made 25 the Tiecher report a controlled study was the PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1752 1 seniority of the men that did it, the judgment and 2 experience of Dr. Martin Teicher and Dr. Jonathan 3 Cole. Do you put credence in their judgment and 4 experience? 5 A. I would not put credence in the statement that 6 just based on how old you are or how long you've been 7 in the field, that that all of a sudden transcends a 8 case report into something more than that. Case 9 reports, regardless of whether you're male, female, 10 Asian, Caucasian, young or old, are nothing more than 11 case reports. 12 Q. Okay. Let's go down just a little bit more 13 here. "The authors correctly pointed out that 14 serotonin has a modulatory role in violent suicidal 15 and obsessional behavior and fluoxetine," which we all 16 know is Prozac, "is a potent and selective 17 serotonergic reuptake inhibitor." 18 We've heard about all of these words but 19 modulatory. What does it mean when you say that 20 serotonin has a modulatory role in violent and 21 suicidal behavior? 22 A. There have been a number of investigators that 23 have put forward data to suggest that, independent of 24 medications, individuals with markedly low levels, 25 abnormally low levels of serotonin, more in a measure PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1753 1 of metabolite, a breakdown product of serotonin, if 2 that is in a very low concentration, it is correlated 3 with a high risk towards violent behavior. 4 Q. So are you saying, Dr. Tollefson -- let me show 5 you what I wrote when we very first started this 6 trial. 7 When we very first started this trial, in the 8 opening statement I wrote that early on, before 9 Prozac, that there was some relationship in the 10 literature that was positive between serotonin and 11 suicide. And is that exactly what you're saying here 12 when you say that there is a role, a modulatory role 13 between serotonin and violent or suicidal behavior? 14 A. There's a relationship that's been written 15 about in the literature, that's correct. 16 Q. And one of the people that wrote about that in 17 the literature in 1984, before Prozac was ever on the 18 market, was a guy named Gary Tollefson; isn't that 19 true, sir? 20 A. Yes. 21 Q. Okay. So you yourself, even before this drug 22 came out, knew that there was some relationship 23 between serotonin and violence and suicide, right? 24 A. It had been reported in the literature. 25 Q. Okay. We can go on. You say here, "The PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1754 1 authors advised clinicians to query patients carefully 2 about suicidal ideation, particularly if they are not 3 responding well to treatment, fluoxetine. Such advice 4 is sage for all of us dealing with any depressed 5 patient receiving any treatment modality. Inherent in 6 the treatment process is informed consent; i.e., a 7 relative risk/benefit analysis." 8 What do you mean by "informed consent"? 9 MR. SEE: Your Honor, I object. Relevance. 10 MR. VICKERY: Would you like me to respond? 11 THE COURT: Yes. 12 MR. SEE: May we approach? 13 THE COURT: Let's take a break. Please be back 14 at ten of. 15 (Whereupon, the following proceedings were had 16 in open court out of the presence of the jury.) 17 THE COURT: My video is still not working and 18 my eyesight is not as good as Dr. Tollefson's. 19 MR. VICKERY: We'll get on that right away, 20 Your Honor. 21 THE COURT: What's the relevance? 22 MR. VICKERY: The relevance is that what 23 Dr. Tollefson is telling -- is saying in this article 24 is that he's telling physicians that they need to 25 discuss this with patients, so it's relevant to the PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1755 1 fact that Lilly needs to warn physicians to warn 2 patients. It's not as Mr. See is about to object, 3 this is about direct warnings between Lilly and the 4 patients. That's not what I'm saying at all. What 5 I'm saying is that this man has said that it is 6 important for the patients to know and the patients to 7 be quizzed and the patients to be warned, and in order 8 for the doctors to know to do that, then Lilly has to 9 alert them to do that. That's the relevance. 10 MR. SEE: It's just like the ACNP document that 11 Your Honor has already ruled upon. It's one doctor 12 talking to another doctor, and the implication that 13 that means the drug company should talk directly to 14 patients simply doesn't follow. It's not the law. 15 It's an implication that somehow Lilly has a duty to 16 warn patients directly and it just doesn't follow. It 17 violates the lawyer intermediary doctrine. 18 THE COURT: This is Dr. Tollefson acting as an 19 agent for Lilly? 20 MR. SEE: He's talking to doctors. I think it 21 is before he joined Lilly as well, so I don't think he 22 was acting as an agent for Lilly. 23 THE COURT: Well, wasn't this when he was 24 engaged as a consultant for Lilly? I thought that's 25 what -- PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1756 1 MR. VICKERY: That's what he said. 2 MR. SEE: It is before the Teicher article came 3 out. 4 MR. VICKERY: No, this was in response. 5 THE COURT: I thought this was in response. 6 MR. SEE: I'm sorry. I misunderstood. It says 7 December of 1990, Dr. Tollefson was not an employee of 8 the company, if that's what Your Honor is asking. 9 THE COURT: I thought he testified that he had 10 been hired by Lilly as one of the consultants to 11 respond to the Teicher report. 12 MR. SEE: I believe his testimony was he was 13 hired by Lilly to provide Lilly advice on what Lilly 14 ought to do, what kind of research Lilly ought to do, 15 not to be a spokesperson for Lilly, and he gave advice 16 to Lilly on what, in his opinion, was a valid 17 scientific methodology that the company ought to think 18 about following. 19 THE COURT: And this is a letter that he wrote 20 to a journal? 21 MR. SEE: It is a letter he wrote to a journal. 22 THE COURT: May I see the letter? 23 MR. SEE: Sure. It's the one right on the left 24 side. 25 THE COURT: It seems to me that this is PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1757 1 referring to the concern that any depressed patients 2 are prone to suicide. 3 MR. VICKERY: Right. But the importance of it 4 to us, Your Honor, and the relevance of it is here is 5 a man, who was hired by Lilly to respond to the 6 Teicher article, who writes a letter to Lilly -- I 7 mean, to the journal responding to the Teicher article 8 who agrees with Teicher and Cole that patients need to 9 be well informed. I'm not saying that this man -- 10 THE COURT: Dr. Neal said the same thing and he 11 said there was no difference in the Lilly warning 12 because everyone knows that people with depression are 13 prone or susceptible to suicide. 14 MR. VICKERY: Oh, I understand that. This is 15 step one of a sequence, Your Honor, which I'd rather 16 not entirely divulge to Mr. See and Dr. Tollefson, but 17 step one is, does Dr. Tollefson agree with 18 Drs. Teicher and Cole that patients need to be 19 involved in the information loop. 20 MR. SEE: Well -- 21 MR. VICKERY: That is not to say that Lilly has 22 to be the one directly communicating with the 23 patients. 24 MR. SEE: And if it doesn't go to that, then 25 it's not relevant to anything. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1758 1 MR. VICKERY: Well, of course it is. If Eli 2 Lilly doesn't tell physicians those things that they 3 need to be alert to and things that they need to quiz 4 their patients about, then how are they going to know? 5 You've seen Dr. Neal testify. For goodness gracious, 6 if this man didn't have Lilly telling him what to look 7 for, he wasn't going to look for it. 8 MR. SEE: First Mr. Vickery says, oh, it's not 9 going to an argument that Lilly should have done X in 10 warning and now he says, oh, yeah, it does go to his 11 argument. 12 MR. VICKERY: Maybe I'm not clear to him. Let 13 me be clear to the Court. It's not going to whether 14 Lilly should inform patients directly. It does go to 15 whether Lilly should tell doctors, doc, you need to 16 share some information with your patients. You need 17 to query your patients about the phenomenon that 18 they're undergoing. It is a three-party line of 19 communication; from the drug company to doctor to the 20 patient, and if the first leg of that journey is not 21 made, then the second one is not going to be made. 22 MR. SEE: As I read it, it goes to depression 23 and whether you query your patient about suicide if 24 you have a depressed patient. I mean, Dr. Shlensky 25 testified that the package insert is not intended to PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1759 1 be some kind of textbook on how to diagnose 2 depression. It has -- the insert has to do with the 3 drug. I mean, it's very clear Mr. Vickery is making a 4 step-by-step argument that somehow Lilly should be 5 saying something in the insert that this inquiry 6 should be made directly to the patient. I mean, it is 7 clear that that's where the reasoning process is 8 going. 9 THE COURT: Is this referring to clinical tests 10 because it refers to clinicians? 11 MR. VICKERY: This is very simply 12 Dr. Tollefson's letter to the journal about the 13 Teicher and Cole article, and then we're going to get 14 to Teicher and Cole's response. 15 THE COURT: I'll allow it. 16 MR. VICKERY: Thank you, Your Honor. 17 THE COURT: Let's take a break. 18 (Whereupon, a recess was taken from 2:44 p.m. 19 to 3:00 p.m.) 20 THE COURT: Please proceed, Mr. Vickery. 21 MR. VICKERY: Thank you, Your Honor. We have 22 solved the mystery of the Court's monitor. Hopefully 23 it will be working now. 24 THE COURT: Pardon me? 25 MR. VICKERY: I said, we've got your monitor PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1760 1 fixed. 2 THE COURT: Oh, great. 3 Q (By Mr. Vickery) Before the break, 4 Dr. Tollefson, I was going to ask you, "Inherent in 5 the treatment process is informed consent, a relative 6 risk/benefit analysis." What did you mean, sir, when 7 you wrote that "informed consent was inherent 8 treatment of a patient?" 9 A. What I meant is that when you have -- when you 10 sit down across from a patient that, in this case, has 11 major depression, it's important that you talk about 12 several things. One is the disease itself, the 13 seriousness of it; that is, what are the risks if it's 14 not treated effectively, what might happen, so that 15 you understand the consequences of the disease itself. 16 Then to go over the discussion, what are the potential 17 treatments that might be available for that disorder 18 and what, in turn, are their relative strengths and 19 weaknesses, so that ultimately the patient, in 20 discussion with his or her doctor, could decide on 21 what the best course of action for that individual 22 patient should be. 23 Q. So the doctor informs and the patient consents, 24 is that the way it goes? 25 A. I think it's a back-and-forth process. It's a PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1761 1 dialog. It's a relationship as I'm sure many of you 2 have with your doctor. 3 Q. And is it important that before the patient 4 consents to take that pill, that they understand what 5 it might do to them even though, if it's statistically 6 insignificant in the overall scheme of things, what it 7 might do to them? 8 A. They need to be informed of the benefits of 9 treatment, the potential risks of treatment, and weigh 10 that relative to the potential risk of the disease. 11 Q. Okay. And, of course, the physician doesn't 12 know as much about your drug as your company does, 13 does he? 14 A. For clarification, you're talking about the 15 company as a collective? 16 Q. Yes, sir. I'm talking about Eli Lilly and 17 Company in Indianapolis, Indiana. 18 A. Clearly they know different things. I think 19 the physician has the experience of working with the 20 individual patient and knows probably best that 21 individual and what medication he or she might want to 22 use in that individual better than Eli Lilly and 23 Company. On the overall totality of the scientific 24 database, it depends on the individual physician how 25 well read they are or are not. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1762 1 Q. Have you ever met any physician anywhere in the 2 world that knows more about Prozac, let's say Prozac, 3 than Eli Lilly and Company altogether? 4 A. I think there are physicians that know the 5 basic issues, back to your point about informed 6 consent, that would understand those basic issues 7 about the product as well as people at the company 8 would. 9 Q. So you think it is possible that maybe there is 10 a physician somewhere that knows more than Eli Lilly 11 and Company? 12 A. No, I think I wanted to say that there are 13 probably physicians, I hope many, that understand the 14 basic issues around this molecule and the treatment of 15 depression as well as we do. I think it's our effort 16 to make sure that they have available to them that 17 information. 18 Q. Do you think, perhaps, Dr. David Healy is one 19 of those physicians? 20 A. I don't know. 21 Q. Okay. Let's see what Teicher and Cole had to 22 write back to you. Let's go up to the start, if you 23 would. Dr. Teicher and associates' reply. "Sir, 24 Dr. Tollefson expresses his opinion that our 25 hypothesized association between fluoxetine," or PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1763 1 Prozac, "and the emergence of suicidal ideation is not 2 well substantiated by our cases or by the literature, 3 that our report is potentially counter-productive and 4 may introduce a medical-legal precedent. First, from 5 our perspective, these cases were convincing." 6 Now, when they wrote back a second time and 7 told you, from their perspective with their collective 8 experience, Martin Teicher and Jonathan Cole and said, 9 no, we were serious, we thought that this was 10 convincing, did you believe them then? 11 A. No, I did not. 12 Q. Okay, sir. "Second, support for our hypothesis 13 is emerging in the literature. Fava and Rosenbaum 14 recently presented that the emergence of suicidal 15 ideation in 1,017 patients treated with a variety of 16 antidepressants. In the patients without suicidal 17 thoughts, prior to treatment, suicidal ideation 18 emerged 3.5 percent during treatment." 19 I want to keep on reading about Fava and 20 Rosenbaum, but I want to ask you this about them: 21 Fava and Rosenbaum, first of all, were Lilly 22 consultants, were they not? 23 A. They have been. 24 Q. So it's not surprising to you that their 25 conclusion in their article is in favor of Prozac, is PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1764 1 it? 2 A. I don't see the relationship. 3 Q. Well, you were asked about the ACNP document, 4 the American College of Neuropsychopharmacologists, 5 and that document points out that the Fava and 6 Rosenbaum data that other people who weren't Lilly 7 consultants looked at the data from Fava and Rosenbaum 8 and said there's a problem. You know that, don't you? 9 A. I don't think they said there was a problem. I 10 don't believe that's what they said. I think that 11 there was a subsequent analysis done, I believe, by 12 Dr. Teicher or at least his colleagues, where -- and 13 we've already talked about the Fava paper. I believe 14 I read the conclusion that Dr. Fava and Dr. Rosenbaum 15 did not see any associated risk with Prozac that was 16 different than other agents being used in their 17 survey. 18 My understanding of the chronology was then 19 that Dr. Teicher or colleagues of his went back and 20 looked at a separate group of patients. These were 21 patients not receiving one antidepressant, but 22 receiving two. And they made the point or the 23 observation that patients receiving Prozac plus 24 another drug, in this case, lithium, had an even 25 higher rate than those receiving a single drug. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1765 1 Dr. Fava came back and said, duh? I mean, 2 basically, this is what we would expect because the 3 patients receiving multiple antidepressants are more 4 severely ill, they're more refractory, they carry a 5 much more profoundly high risk of suicide. That's why 6 they're on two drugs and, in fact, that, I believe, 7 has been the general opinion of the clinical world, is 8 that to take patients that are particularly refractory 9 and at exceptionally high risk, you can't compare that 10 group with patients receiving standard single-drug 11 therapy. 12 Q. Dr. Tollefson -- 13 A. It's an inappropriate comparison. 14 Q. -- does the clinical world include Dr. David 15 Graham, an epidemiologist at the Food and Drug 16 Administration? 17 A. I would -- that's fine, yes. 18 Q. And have you seen Dr. Graham's memorandum when 19 he did the same thing when he went through the Fava 20 and Rosenbaum data and analyzed it to determine 21 whether there was a positive correlation between 22 Prozac and suicidality? 23 MR. SEE: Objection, Your Honor. Based on the 24 Court's prior ruling. 25 MR. VICKERY: This is cross-examination. I'm PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1766 1 entitled to ask this man if he's seen a document. 2 Just because the document's not in evidence -- 3 THE COURT: We better have a side bar. 4 (Whereupon, the following proceedings were had 5 at side bar out of the hearing of the jury.) 6 MR. VICKERY: The question -- 7 THE COURT: What is the objection? 8 MR. SEE: The question relates to the document 9 the Court has already excluded from evidence. It is 10 an internal FDA document that's a non-final opinion, 11 non-final decision, and that's what he's asking about. 12 THE COURT: I thought that Dr. Graham's memo 13 had been admitted. 14 MR. SEE: I don't think, Your Honor. That's 15 excluded. 16 MR. VICKERY: The Court has excluded the 17 document in substance. 18 THE COURT: Then why are you standing up and 19 asking about it? 20 MR. SEE: If the information contained in the 21 document should be excluded, then he shouldn't be able 22 to ask questions and, essentially, tell the jury in 23 his question about it. 24 MR. VICKERY: Your Honor, there's all kinds of 25 things that aren't admitted in evidence. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1767 1 THE COURT: There was a reference to 2 Dr. Graham's epidemiological letter to the FDA and 3 that it expressed concern about Prozac and, in fact, 4 had been admitted. 5 MR. SEE: I'm pretty sure this one he's talking 6 about was not admitted. 7 MR. VICKERY: I think Mr. See is right. 8 THE COURT: Never mind. 9 MR. VICKERY: It should have been admitted. 10 No, I'm not saying it was properly excluded. I'm just 11 saying it was excluded, okay. But whether it's in 12 evidence or not, an expert can base their opinion on 13 things that aren't in evidence. 703 specifically says 14 so. And in cross-examining an expert, I can ask him 15 about other documents that are not admitted in 16 evidence, but which might impact his opinion or not. 17 THE COURT: The question was? 18 MR. VICKERY: Whether he's seen the memo from 19 Dr. Graham and if that changed his opinion. 20 MR. SEE: Your Honor, the whole purpose of 21 excluding these documents that have to do with 22 non-final FDA determinations is the fact that it gives 23 weight because the guy was with the BGA, but it wasn't 24 the FDA's personal position. It was his personal 25 position and under -- wait. Under 403 it has exactly PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1768 1 the same effect as putting the document in. 2 THE COURT: I'll sustain the objection. 3 (Whereupon, the following proceedings were had 4 in open court in the presence of the jury.) 5 THE COURT: Please proceed, Mr. Vickery. 6 Q (By Mr. Vickery) Drs. Teicher and Cole have 7 looked at the data from Fava and Rosenbaum and they 8 conclude, bottom line, we continue to suggest that 9 Prozac or fluoxetine may induce or cause suicidal 10 ideation, correct, sir? 11 A. That's what they said at that time. 12 Q. Let's see what they said further down about 13 your criticisms of them. It says, "We are concerned 14 by Dr. Tollefson's comment that our report may be 15 potentially counter-productive and may introduce a 16 medical-legal precedent." Incidentally, did you ever 17 talk to either of these guys, either on the telephone 18 or face to face about this? 19 A. I had an opportunity to discuss this with them. 20 I don't know the timing, if it was before or after the 21 letter, but I do know John Cole. 22 Q. Okay. It says, "He appears to be arguing that 23 we should not have published this report because our 24 findings were preliminary, because fluoxetine is a 25 highly selective drug with a low index of lethality, PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1769 1 and because ongoing monitoring of suicidal potential 2 is already a cardinal point in the treatment with 3 antidepressants of any patient. These arguments are 4 only superficially true and wither on deep 5 reflection." 6 "First, the presumed neurochemical selectivity 7 of fluoxetine is illusory." Big words, what they're 8 saying is Prozac isn't quite as selective in 9 pinpointing a drug as Eli Lilly claims it is. True or 10 false? 11 A. That's what they're saying. I would also point 12 out, though, I don't see a reference with that. 13 Typically in a case report, if you're trying to speak 14 to science, you provide a reference for your reader. 15 It's a statement they made that's unreferenced and 16 unsubstantiated. I personally do not agree with it. 17 Q. Well, let me follow up on that a minute. Kind 18 of put a finger in the page on that, and we'll come 19 back to it. How about that Harvard Newsletter you all 20 are so proud of, doesn't even have anybody's name on 21 it, does it? 22 A. I believe it represents the institution. 23 Q. The Harvard Medical School? 24 A. Harvard Newsletter, I presume, has to have a 25 connection with Harvard. I don't know which PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1770 1 departments. 2 Q. Okay. Let's come back to this then. "This 3 agent binds specifically to the serotonin uptake port, 4 but in doing so, it affects serotonin turnover and 5 post-synaptic receptors located on other 6 neurotransmitter systems. The net effect is 7 alterations in a number of neurotransmitters, 8 including dopamine and norepinephrine." 9 Now, we haven't heard about dopamine or 10 norepinephrine. Are those other brain chemicals up 11 here that affect human behavior? 12 A. They are. 13 Q. And does Prozac, in addition to affecting 14 serotonin, affect those other brain chemicals too? 15 A. That has not been conclusively demonstrated. 16 There is data saying both yes and no. I think the 17 preponderance of scientific information would say 18 there's absolutely no direct effects. 19 Q. Was there a secondary effect? 20 A. Some people have postulated the possibility of 21 a secondary and direct effect, but again, it has not 22 been demonstrated repeatedly. I don't think that it's 23 generally accepted. 24 Q. Is Eli Lilly's position on that, doesn't cause 25 it or you guys can't prove it? Which is it? PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1771 1 A. I don't think the ownership is just on us. I 2 don't think the scientific community as a whole, 3 inclusive of Lilly or other pharmaceutical 4 manufacturers of the SSRIs, have been able to show 5 that there is that effect. 6 Q. Well, let me ask you this: If there is an 7 effect on dopamine and norepinephrine, is it going to 8 be a good thing or a bad thing? 9 A. Both of those chemicals are involved in 10 depression, so it certainly could be a good thing. 11 Q. Could it also be a bad thing? 12 A. It's conceivable. 13 Q. We know, for example, from your 1984 article, 14 that serotonin is related to suicide, right? 15 A. The prevailing literature suggests that 16 patients that have markedly low levels of serotonin 17 may carry a higher risk for externally directed 18 violence or aggression. The serotonin uptake 19 inhibitors work in the opposite direction to return 20 those levels to normal. So I just want to make the 21 point that, yes, the literature has suggested the 22 relationship with serotonin, but it has suggested that 23 it's related to a marked deficit in serotonin. 24 Q. Okay. Let's read on and see what else they 25 say. "We do not necessarily believe that these mildly PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1772 1 depressed, non-suicidal, low-risk patients will be 2 carefully monitored for emergence of suicidal 3 ideation, and the simple dosing strategy and low 4 initial side effect profile of Prozac" -- we're going 5 to say Prozac whenever we see fluoxetine -- "may 6 inadvertently result in less frequent visits and less 7 careful monitoring. We have now received information 8 about the suicides of ten patients." And they're not 9 talking about people trying suicide or thinking about 10 it, they've now got information on ten folks. Did 11 Dr. Jonathan Cole share that with you in person? 12 A. That they had that information? 13 Q. Yes, sir, about ten deaths. 14 A. That does not surprise me. This is a -- 15 thinking where they work. They work at what's called 16 a tertiary care center. They get patients that are 17 referred with serious, often refractory medical and 18 psychiatric conditions, so I am sure that they do see 19 patients there who unfortunately die with suicides. 20 Q. Are 10 deaths, is that significant in the 21 overall scheme of things, or since there have been 22 27,000 clinical trials, is that 10 out of 27,000, 23 that's not too bad? 24 A. Any death is bad and it is unfortunate, but 25 that reflects the seriousness of these psychiatric PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1773 1 illnesses. 2 Q. Well, let's read on what they said about those 3 folks. You said they were in a tertiary care facility 4 where there are really sick people, but let's see what 5 they say. "We are following up on these leads, but so 6 far, it appears that eight patients were at relatively 7 low risk; that is, were not affectively ill or had 8 their first episode of mild to moderate outpatient 9 depression although they had an intact family, a 10 career, and ongoing treatment before starting 11 fluoxetine." 12 Now, you know, in the case of Bill Forsyth, he 13 had an intact family, don't you? 14 A. I don't know that, but I have no reason to 15 question you. 16 Q. And he had had a good career, but he was 17 retired very successfully. Would you accept that? 18 A. Sure. 19 Q. And he certainly had ongoing treatment for a 20 couple of months before Dr. Roberts ever put him on 21 Prozac, all right? But it sort of sounds like he -- 22 depending on how serious his depression is, and 23 there's conflicting testimony about that, but that he 24 was like these other folks, that he was at a 25 relatively low risk, this was his first depression, PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1774 1 would you accept that? 2 A. I'll have to accept that it was his first 3 depression. I can't accept, without significant 4 detail, that it was at a relatively low risk. Suicide 5 is multi-faceted. There are a lot of things that 6 determine risk. 7 Q. Let me ask you this: If it is true, and I'll 8 represent to you that it is, that he was seen in 9 therapy by a psychologist who's licensed by the State 10 of California to keep people in jail for this very 11 reason, so they won't harm themselves or others, that 12 he was seen by a very well-trained, a Harvard-trained 13 psychiatrist for a couple of months, and that he was 14 seen daily by another doctor right here at Castle 15 Medical Center on the island of Oahu, and that none of 16 those three people ever -- with all of those under the 17 DSM criteria, none of them ever saw suicidality. If 18 that's true, would you think that this man must have 19 been at a relatively low risk of suicide? 20 A. No. 21 Q. Okay. They say, "We thus continue to urge 22 caution in the use of this agent and suggest that 23 patients be informed about this possible hazard." 24 Do you think patients should be informed about 25 this possible hazard? PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1775 1 A. It's not clear to me what the hazard is. 2 Q. The hazard of the article they were talking 3 about, that people who had never been suicidal before 4 might, in the early period of time on this drug, 5 become suicidal. 6 A. I think you may be confused. I believe the 7 cases that Teicher and Cole reported did have a 8 positive history, at least several, if not all, had a 9 positive history of past suicidal ideation, so these 10 are not individual cases where there had never been 11 suicidal thinking or acts. 12 Q. Okay. I stand corrected. 13 A. Thank you. 14 Q. The article was on treatment emergent suicide 15 and the cases they reported were people who, shortly 16 after taking Prozac, began to have very violent 17 thoughts of killing themselves. That's what the cases 18 were, right? 19 A. These are patients who had often failed 20 previous therapy. They were obviously medically ill, 21 otherwise they wouldn't be candidates for therapy. 22 They reported that during the course of observing them 23 receiving a therapy, Prozac, that they did report this 24 intense feeling. They did not act upon the feeling in 25 those cases, as I recall, but they reported PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1776 1 psychologically having those thoughts. But, again, 2 these were patients, as I understood, who had suicide 3 in the past. This is consistent with the literature I 4 mentioned of 35 years ago when patients were observed 5 on old antidepressants, on psychotherapy, to have 6 emergence during treatment. 7 When you start treatment, the next day, you're 8 not cured. The treatment process takes time. Some 9 people take four to six weeks to begin to get better. 10 During those four to six weeks, you are still at risk. 11 Some people, regrettably, never fully recover and 12 continue to be at risk. That's back to the baseball 13 analogy. They have multiple days of risk to have 14 suicide occur. It has nothing to do with causality of 15 the drug. These were case reports. 16 MR. VICKERY: Tina, would you mind reading my 17 question back to this gentleman so that he can answer 18 it? 19 THE COURT: Let's move on. 20 Q (By Mr. Vickery) My question, Doctor, should 21 patients be informed about the hazard that they would 22 suddenly begin to have violent suicidal thoughts 23 shortly after taking this drug? 24 A. Patients need to be advised of the fact that 25 their symptoms may increase or decrease during the PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1777 1 course of treatment. 2 Q. Has Eli Lilly ever warned doctors that they 3 should tell patients, hey, you might, after taking 4 this drug early on, before the antidepressant part 5 kicks in, you might have some really bad, nasty, scary 6 thoughts about killing yourself? Has your company 7 ever warned doctors that they, in turn, should share 8 that information with patients? 9 A. Well, first and foremost, I think we've already 10 seen it's in the precaution section of the label for 11 Prozac and for other antidepressants, and secondly, 12 we've also heard about the Dear Doctor letter. I 13 think that was a specific effort to also do the same 14 thing, but the label clearly points that out in the 15 precaution section as an educational tool. 16 Q. Dr. Tollefson, you are familiar with federal 17 regulations concerning labeling of drugs, are you not? 18 A. I have a familiarity with it, yes. 19 Q. And you understand you are here under oath? 20 A. Yes, sir. 21 Q. Is there a section dealing with warnings and a 22 section dealing with precautions? 23 A. Yes. 24 Q. And are they very different? 25 A. Yes. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1778 1 Q. A warning is much stronger, isn't it? 2 A. Yes. 3 Q. A warning is in bold print, isn't it? 4 A. Yes, it may. 5 Q. A warning is in a box, what they call a box 6 warning, because they draw little lines around it to 7 catch the eye's attention, isn't it? 8 A. No, most warnings are not. That's a particular 9 subset that you rarely see, but they can be displayed 10 that way. The majority are not. 11 Q. What kinds of things give rise to box warnings, 12 life or death dangers? 13 A. They need to be extremely serious, so yes, it 14 could be life or death, and there needs to be a 15 reasonable association with the drug in question. If 16 there is not that reasonable association, something 17 would not appear in a warning's section. 18 Q. Like you wouldn't put a box warning about -- 19 your warning about a rash, would you? 20 A. A warning around a rash, if the rash could be 21 life threatening. In other words, a serious systemic 22 allergic response to a drug, then obviously, yes, you 23 would. 24 Q. Is your rash warning a boxed warning? 25 A. A boxed warning is a very select subtype of PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1779 1 warnings. There are no boxed warnings for Prozac. 2 Q. Okay. Well, let's read on to what Drs. Teicher 3 and Cole had to say. "There are three fundamental 4 missions of academic medicine that prompted us to 5 publish this preliminary report. These guiding 6 principles are devotion to patient care, research, and 7 teaching. The possibility that Prozac may produce a 8 potentially life-threatening side effect made 9 publication a necessity, as primum non nocere takes 10 precedence over medical-legal concerns." That's a big 11 latin phrase. Tell us what it means. 12 A. I don't know. You may have to help me. 13 Q. Doesn't it mean -- isn't that part of the 14 Hippocratic oath that says, first of all, do no harm? 15 A. Yes. 16 Q. Thank you. And they said that the Hippocratic 17 oath to do no harm is more important than Dr. Gary 18 Tollefson's concerns about medical-legal precedence, 19 didn't they, sir? 20 A. That's what they said, but again, I want to 21 point out, my concern was the potential damage that 22 the article might do to depressed patients and this 23 whole concept of stigmatizing patients prematurely. 24 When they did their case report, typically what I 25 would like to see as a physician is balance; that is, PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1780 1 this is what I've observed, here are the limitations 2 of what I observed. 3 I didn't feel, and it's the only reason -- I've 4 written these kind of letters probably no more than 5 once or twice in my life. My concern was -- and this 6 was before I consulted with Eli Lilly and Company on 7 suicide. My concern was they didn't have fair balance 8 in this article. They didn't lay out the strengths 9 and the weaknesses of their observations to let the 10 physician be objective and to vote his or her view 11 based on an objective opinion. That was my concern. 12 That's why I wrote the letter. 13 Q. What happened when Teicher and Cole 14 dechallenged the people with Prozac, the six patients? 15 A. I believe some of them improved, although, I 16 believe, it was also in the course of receiving a 17 completely different class of antidepressant drug, so 18 I would presume their underlying illness was also 19 improving. And I believe that, indeed, is what they 20 said. At least in the majority of those cases, that 21 they did receive treatment, they did improve, and they 22 did not, at least during his observation, have a 23 return of suicide. 24 Q. What does it suggest to you, sir, when somebody 25 is challenged with a substance, they had developed PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1781 1 violent suicidal thoughts, then that substance is 2 taken away and the thoughts go away, dechallenge. 3 Does that suggest anything to you? 4 A. It suggests to me that, number one, there may 5 have been a variation in the course of their disease, 6 that would be my first consideration. 7 Q. Would another consideration be the one that you 8 wrote about in 1991, that maybe, possibly, there was a 9 drug-induced suicidal ideation? Would that be one 10 that you would consider? 11 A. It's one that I would consider, but I can give 12 you the example of a paper that was published long 13 before Teicher, et al., by two authors, Damluji and 14 Ferguson. They reported patients that had this sort 15 of similar phenomenon receiving an old tricyclic, 16 dezipramine, and low and behold, they did exactly what 17 you said, they dechallenged them, they took away the 18 dezipramine and treated them with Prozac. Both 19 patients got clinically better. Their depression 20 improved. They had absolutely no return. 21 So I would say, yeah, they were not only 22 dechallenged, they were challenged again with Prozac 23 and their depression resolved and they had no 24 suicidality. 25 Q. Let's look at the footnotes. They say there PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1782 1 are other reports that suggest they -- look right 2 here. "Along with other reports (1, 4, 5) it 3 introduces the concept of antidepressant-induced 4 suicidal ideation." Now, let's see, one, four, and 5 five are their footnotes, aren't they? 6 A. They're references. 7 Q. And let's look at those references. Look at 8 that, number five, Damluji and Ferguson. That's the 9 very article you're talking about, isn't it? 10 A. That's correct. 11 Q. And, apparently, Drs. Cole and Teicher disagree 12 with you on the significance of the Damluji and 13 Ferguson article, don't they? 14 A. Damluji and Ferguson may disagree with Teicher. 15 That's part of what is in academics, opportunity to 16 have an opinion. 17 Q. Are Damluji and Ferguson Lilly consultants? 18 A. Absolutely not. I don't know either of them 19 personally. 20 Q. Let's go back up and read the rest of their 21 conclusions. "We think that this is a real 22 phenomenon, but we lack definitive evidence. Rather 23 than burying our heads in the sand to await further 24 proof, we felt it important to risk being wrong and to 25 tolerate criticism by our colleagues in order to PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1783 1 elicit their aid in researching this possibility both 2 quickly and effectively." 3 Now, I want to ask you, sir -- you can cut that 4 off -- did Eli Lilly and Company ever do the Charles 5 Beasley rechallenge protocol study? 6 A. Eli Lilly and Company reviewed that along with 7 a number of other options and had discussion with 8 external consultants with the Food and Drug 9 Administration, and the consensus was that that was 10 not a good way to progress in answering this question. 11 Other protocols, other methods were identified. Those 12 were conducted and carried out by Eli Lilly and 13 Company. 14 Q. Let's look then. Let's look at the document to 15 the FDA on that issue. Just bear with me just a 16 minute, Doctor. We're going to look at Exhibit 112. 17 MR. SEE: Would you give us just one second to 18 find it? 19 MR. VICKERY: Sure. 20 MR. SEE: Your Honor -- oh, I beg your pardon. 21 MR. VICKERY: Are you with me? 22 MR. SEE: Yes, sir. 23 Q (By Mr. Vickery) Okay. Ms. Barth, go up and 24 show us the top of this document if you would. These 25 are minutes of a meeting between the FDA and Lilly to PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1784 1 talk about this issue, and this is dated September 25, 2 1990. You weren't working for Lilly at that time, 3 right? 4 A. Correct. 5 Q. But Dr. Beasley was working for Lilly, right? 6 A. Correct. 7 Q. And once you came and became educated as to 8 what had happened before you got there, you learned 9 about them having met with the FDA, didn't you? 10 A. Yes. 11 Q. Okay. Let's look down here. "The firm," and 12 that's the way the FDA talks about drug companies like 13 you guys, isn't it -- 14 A. Yes. 15 Q. -- they call you the firm? "The firm contended 16 that prospective trials were hampered by their 17 inability to reach agreement with Dr. Teicher on 18 operational criteria for the phenomenon referred to in 19 his article. Nevertheless, two types of prospective 20 trials were discussed." There's a large two, 21 something, I can't read it, "randomized double-blind 22 parallel group study," and then "two, an in-hospital 23 rechallenge of patients who met predefined criteria 24 for suicidal acts or ideation on either Prozac or a 25 standard tricyclic antidepressant." PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1785 1 Now, that study that was discussed with the FDA 2 in September of 1990 was never done, was it? 3 A. It was not done for a variety of reasons. 4 Q. And, in fact, Eli Lilly has never done any form 5 of challenge, dechallenge, rechallenge test, have 6 they? 7 A. We have not because, as I said, based on our 8 discussions with the FDA, we felt, and they did as 9 well, that this was an experiment that would not 10 answer the question, that there would be a marked 11 expectational bias; that is, if you were a patient 12 who's taking a medication and had a serious side 13 effect, who's going to volunteer to do it over again, 14 essentially? And it was felt that it would be very 15 difficult to do. And then you introduce the concept 16 of how diverse human behavior is, think of all the 17 different factors that could, on one day, at one 18 snapshot in time, cause you to be suicidal. How would 19 you, a week later, a month later, a year later, ever 20 recreate all of those variables to give someone a drug 21 a second time and be able to definitively say that it 22 was the drug the second time that caused it, not the 23 fact they were having a problem in a relationship, 24 that they had lost their job, that their depression 25 was more severe, that they started consuming alcohol, PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1786 1 any of the myriad of things that can cause 2 suicidality. 3 This is a complicated behavioral disorder that 4 may be difficult for a non-physician to understand, 5 but you can't do a rechallenge experiment and expect 6 to have credible data come up. Rechallenge is 7 something that's fine in the field of dermatology. If 8 you're talking about an allergy to a cat fur, I can go 9 back and inject that allergin in your skin and see a 10 reaction. That's a rechallenge. It's fine if you're 11 talking about an allergy as a dermatologist. It is 12 not a tool endorsed by the FDA or major organizations 13 in the field of psychiatry as a tool to definitively 14 answer this question. 15 We looked at it. We looked at it seriously. 16 We discussed it with consultants. It fell to the 17 bottom of the list as the most valid ways to answer 18 the question. We did the things that we felt, in 19 discussion with the FDA, would best address this 20 question and I think it has. 21 Q. Answer me these things very specifically if you 22 would. Did Dr. Beasley's draft propose a rechallenge? 23 A. Dr. Beasley -- you showed me here in '91, he 24 had a protocol. In order to consider this as an 25 option -- PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1787 1 Q. Excuse me, Doctor. 2 A. -- you have to have a protocol. 3 Q. Excuse me. My question was just, did he do it? 4 It doesn't call for a long explanation. 5 A. Please restate your question, then, sir. 6 Q. Did his draft propose a rechallenge? 7 A. Dr. Beasley wrote a rechallenge protocol. 8 Q. Did Dr. Beasley -- are you familiar with the 9 letter that Dr. Healy wrote to the British Journal in 10 response to the meta-analysis paper done by Beasley 11 and Beasley's response to Healy's letter? 12 A. Yes. 13 Q. And did Dr. Beasley say in that response 14 rechallenge is a good way, that's a good way 15 scientifically to study? 16 A. Not quite in those words. He said that 17 rechallenge is a scientifically accepted procedure. 18 He did not relate it back to psychiatry, suicide, and 19 this question. 20 Q. Did Dr. Healy -- wait a minute. Excuse me. 21 You mean when he was writing a specific response to 22 Dr. Healy's specific criticism about his study of 23 suicidality and he said rechallenge is a good 24 scientific method, are you meaning to suggest to us 25 that he meant for dermatology? PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1788 1 A. That's where it has been more commonly used. I 2 think he was suggesting that this was one of a series 3 of options. He did not say in that letter, and 4 correct me if I'm wrong, that it was best, that it was 5 the preferred method. It was one that was 6 scientifically acceptable methodologically, but would 7 it best address the question, I don't think that was 8 the content of his letter to Dr. Healy. 9 Q. Okay. You know the works of Hershel and Susan 10 Jick, don't you? 11 A. I do. 12 Q. And you're familiar that in '92, before they 13 did the study we've all talked about so much in this 14 case, they wrote another study, the conclusion of 15 which -- the very last part of which said, the way to 16 study this is by rechallenge? You know they wrote 17 that, don't you? 18 A. To be honest, I don't remember that. I'd have 19 to look at it. 20 Q. Okay. Well, I'll dig it out for you because I 21 want to move on to some other things. Forgive me for 22 being blunt, but isn't the truth of the matter that 23 Eli Lilly never did these prospective tests because 24 you knew what the answer was going to be and you chose 25 instead to stick your head in the sand rather than PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1789 1 have the scientific proof, proof positive, proof 2 beyond a reasonable doubt? Isn't that true, sir? 3 A. That's not true. 4 Q. Okay. Now, I want to take you back to your 5 1991 article. I believe you still have it up there, 6 don't you? 7 A. Yes. 8 Q. And I've written down another quote from that 9 article. 10 MR. SEE: Could you give me a reference? 11 MR. VICKERY: Let me find the specific page on 12 that and give it to counsel and myself. 13 Bear with me, Doctor. I've got all of your 14 articles right here. Somewhere I have this. Let me 15 just find this. If it would have been a snake, it 16 would have bit me, Doc. 17 Q. Turn on Page 10, if you would. You see the 18 topic, "Drug Toxicity?" 19 A. Yes. 20 Q. You wrote, "One aspect" -- the second sentence 21 there, "One aspect of the toxicity issue is the 22 question of whether emergent suicidality is a drug 23 side effect," correct? 24 A. Yes. 25 Q. And then later down there, about seven or eight PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1790 1 lines lower, you wrote, and I've written it up here 2 and just check me out, "Another question to answer is 3 whether the potential of suicidal ideation is 4 secondary to another drug side effect, such as an 5 unpleasant akathisia." And then you go on to describe 6 other kinds of side effects. 7 A. Um-hum. 8 Q. A few questions about that. In your opinion, 9 sir, does akathisia lead to violence or suicide? 10 A. In my opinion, no. I think this article 11 captured that there were a couple, again, of case 12 reports describing this, so I wanted to be fair and 13 have balance, so I included that possibility, but it 14 is derived from a couple of case reports. Personally 15 I haven't seen that direct relationship, nor have I 16 seen clinical trials to support it, but I have, 17 certainly, read articles where people have 18 hypothesized. 19 Q. Now, you say an unpleasant akathisia. Is there 20 such a thing as a pleasant akathisia? 21 A. Typically, akathisia is very unpleasant, and it 22 involves very profound restlessness, that if you were 23 seeing a hundred people in a crowd, it would be very 24 evident to you which one of those hundred had this. 25 It's both a very subjective unpleasant feeling and PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1791 1 it's a very profound motor overt restlessness. 2 Q. Okay. Further down there, in the last sentence 3 under that topic, you say, "In a very small minority 4 of patients, suicidality may, on occasion, be a 5 true" -- there's that word again -- iatrogenic or 6 drug-induced event." And I had to stop writing 7 because the jury was coming in, but you said, "perhaps 8 due to a paradoxical serotonin response, but there are 9 currently no available studies to support this 10 hypothesis." What is a very small minority of 11 patients? 12 A. I would say, you know, 10 percent or less. 13 Q. Is that a tolerable risk of suicide? 14 A. I'm not sure I understand your question. 15 Q. Well, if the risk is suicide -- if the adverse 16 health event is not a rash or nausea, but suicide, is 17 that a significant number of people? Is it tolerable, 18 from Eli Lilly's standpoint, to subject that 19 percentage of people to that kind of risk? 20 A. Number one, I don't think that there is any 21 evidence that such a risk exists, but as we said 22 earlier, any risk of any drug has to be put in the 23 context of alternative medications available and their 24 risks and the risks of the disease itself. So that's 25 between the physician and the patient to weigh the PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1792 1 decision to treat or not to treat and what to treat 2 with. 3 Q. Is Prozac a psychoactive drug? 4 A. Yeah, I think it would fall under that 5 category. 6 Q. So in other words, it's something that affects 7 the chemistry in our brain, which in turn, affects our 8 behavior, right? 9 A. If it's an antidepressant, it would have to do 10 that. 11 Q. And earlier, when we were talking about your 12 medical-legal concerns, you said you had a concern 13 that maybe enough people wouldn't take the drug; that 14 maybe if word got out of this suicidality problem 15 Teicher and Cole were talking about, that there would 16 be some people who just wouldn't get the benefit of 17 the drug because they would be scared off. I know you 18 didn't use those exact words, but am I capturing the 19 gist of what your concern was? 20 A. Well, you said "the drug." I said that there 21 has been a historic problem with depression being 22 stigmatized where people don't seek treatment or 23 aren't compliant with treatment. I would not want to 24 see something happen that would push us back 10 or 20 25 years where people that have a life-threatening PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1793 1 disease, for the wrong reasons, aren't considering the 2 option of trying treatment with medications. 3 Q. Is it your position, Dr. Tollefson, that if a 4 mistake is going to be made, we're all human, we all 5 make mistakes, that you'd rather someone make a 6 mistake and give this drug to a patient rather than 7 make a mistake and withhold this drug from a patient? 8 Is that your position? 9 A. With all due respect, I don't think -- I think 10 that's a very individual case-by-case decision. I 11 really wouldn't be comfortable with a global 12 generalization. 13 Q. One of the things about being a vice president, 14 and now president, is that sometimes you get to speak 15 to the media and make public statements, don't you? 16 A. That's correct. 17 Q. And I want to ask you whether you recently made 18 the statement that "The real hope was that through 19 early intervention" -- and you're talking specifically 20 about giving Prozac -- "you can significantly alter a 21 course that will otherwise lead a child to difficult 22 social and parental relationships, poor academic 23 performance, substance abuse, even suicide, Tollefson 24 said." 25 MR. SEE: Your Honor, I object to the relevance PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1794 1 of the statement. There's no relevance in this case. 2 MR. VICKERY: This is offered for impeachment, 3 Your Honor. 4 THE COURT: Impeachment? 5 MR. VICKERY: Yes. I haven't finished the 6 quote. I'm about to get to the impeaching statement. 7 THE COURT: Well, let's get to whatever is 8 relevant here. 9 Q (By Mr. Vickery) "The potential, particularly 10 when you're talking about a drug that's safe and 11 effective, is to err on the side of using it too 12 liberally." Is that what you want, you want people to 13 err on giving this drug -- if they're going to make a 14 mistake, by all means, make a mistake of giving this 15 drug rather than not giving it? 16 A. I don't believe that that's a correct quote. I 17 don't think I would have ever used the term "too 18 liberally." I think that must be your introduction. 19 Q. It's in quotation marks. Would you like me to 20 show it to you? 21 A. I guess I would like to see the source 22 documents to put it into context. 23 Q. It's the Star Tribune Newspaper of Twin Cities, 24 Minneapolis, St. Paul, and it's an article about kids 25 on Prozac. Do you remember giving that interview? PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1795 1 A. I don't remember it, no. Where would you -- 2 where is the quote? I would be happy to look at it 3 that you had in question. In fact -- 4 Q. Right there. It's highlighted in yellow. 5 A. Can I take a moment to look at it? 6 Q. You may indeed, and I need to show Mr. See 7 where it is. 8 A. I don't remember the specific quotes. I can 9 speak to what the content was. 10 Q. Have they misquoted you or not? 11 A. I honestly do not recall -- 12 Q. Okay. 13 A. -- but the concept that's here is certainly one 14 that I may have said. I just don't know about the 15 specific words. I don't remember this particular 16 article or source. 17 Q. Well, you told us this morning that there were 18 other studies you all had done for eating disorders 19 and obsessive compulsive disorders and things like 20 that. You didn't mention it, but another one you've 21 done is for children, isn't it? 22 MR. SEE: I object, Your Honor. Relevance. 23 MR. VICKERY: Your Honor, if it wasn't 24 relevant, Mr. See wouldn't have asked him about those 25 other studies. That's all I can say. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1796 1 THE COURT: He didn't ask him. He volunteered 2 it. I'll sustain the objection. 3 Q (By Mr. Vickery) Okay, sir. Let's move on to 4 something different, shall we? When was the Ham-D 5 Item 3 developed? 6 A. I don't remember the exact year. I think it 7 probably goes back to the early sixties, the Hamilton 8 Scale. 9 Q. So it was in existence certainly in 1982 when 10 you wrote a suicide article and said, quote, There's 11 no conclusive documentation of an accurate method to 12 predict suicide risk," wasn't it, sir? 13 A. There is no tool that exists that is able to 14 predict. In other words, when you say predict, I 15 think looking out into the future, weeks or months 16 down the road. I know of no tool, clinical or an 17 instrument, that can predict. Otherwise, obviously, 18 we'd be a lot more successful in preventing. 19 Q. Well, earlier you were talking about how 20 complex this was and how multi-facet this issue was, 21 and yet when you all have analyzed it, you relied on 22 the simple zero to four scale. One question, zero to 23 four; isn't that true? 24 A. Well, I think perhaps you misunderstand, 25 Mr. Vickery. We have never used or said that the PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1797 1 Hamilton Item 3 predicts future suicide risk. We have 2 used it as a snapshot in time to look at this day when 3 the physician saw the patient, what was that 4 assessment as of today, how did that compare the next 5 time the doctor saw the patient on that day? That is 6 distinctly different than using a tool to predict a 7 year from now whether someone will or will not commit 8 suicide. 9 Q. Is that snapshot an old black and white or is 10 it a brand new three-dimensional color snapshot that 11 really gives us a good picture of it? 12 A. Well, it's like that Kodak film that comes in 13 the yellow and the gold box. It's gold because the 14 Ham-D is the gold standard for the assessment of 15 depression. 16 Q. Are you a suicidologist? 17 A. How do you define that? 18 Q. A guy like Dr. Ron Maris sitting out here, who 19 has written about nine books on it. 20 A. I'm a psychopharmacologist that investigates 21 the aspects of diseases like depression and the 22 effects of drugs, so suicide ideation or attempts is 23 one aspect of that, but I have not devoted my life 24 exclusively to that practice, so I would defer on the 25 quantity of effort to Dr. Maris. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1798 1 Q. Okay. Well, tell me this, when Dr. Beasley was 2 going to study this with the rechallenge, when he 3 proposed that idea that got rejected by others, was he 4 going to use this little gold film, this Ham-D, or was 5 he going to use a much more sophisticated measurement 6 tool to assess suicidality? 7 A. Number one, Dr. Beasley did not propose the 8 rechallenge. It was one of a series of things he was 9 considering, as was our entire group. As far as how 10 they were going to measure it, of course, they were 11 going to use the Hamilton. There were efforts to look 12 at whether or not other scales could be modified to 13 try to capture what Dr. Teicher had described. In 14 fact, Lilly, I know, prior to joining the company, had 15 discussions, tried to work with Dr. Teicher to 16 understand how this could be done. 17 Q. The scale that he's going to use, according to 18 that protocol, is called the Beck Scale from 1979, 19 isn't it? 20 A. That was one that was mentioned, yes. 21 Q. Now, is that one that just measures zero to 22 four or does it have a whole bunch of different 23 variables to really give you a clear picture of this 24 issue? 25 A. It has variables, you're correct, but it has PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1799 1 one fundamental difference, and that is, it's 2 something that the patient, essentially, completes as 3 opposed to the Hamilton, which is a semi-structured 4 interview that the doctor conducts with the patient. 5 One of the things, at least my opinion in the 6 field, and I'm sure that Dr. Maris would have an 7 opportunity to share his opinion, but many patients 8 who do have suicide do not volunteer that they have 9 it, and so there's a question about the reliability 10 and validity of a self-reporting instrument. My 11 personal feeling is to err on the side of the doctor 12 interviewing the patient as opposed to a form that the 13 patient might fill out. 14 Q. Can you tell me this: I guess when Beasley or 15 someone else monitors a medical study, that's under 16 your purview because you're his boss; is that right? 17 A. It was at that time. 18 Q. And did he have the study going up in Boston 19 where he was trying to spend a bunch of Lilly's money 20 trying to get a doctor to come up with yet a better -- 21 even better than the Beck Scale to measure this? 22 A. I think that's what I alluded to. We were 23 working with a Dr. Ivan Miller to see if an existing 24 scale might be modified to capture this Teicher 25 phenomenon. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1800 1 Q. And what are the status of those efforts? 2 A. Well, I believe Dr. Miller published the scale 3 eventually. It took several years for him to validate 4 it. Subsequently, of course, this issue has been 5 reviewed by the Food and Drug Administration in great 6 detail and we felt, as the FDA and the scientific 7 bodies have, is that the Hamilton data was compelling 8 and convincing from a scientific viewpoint. 9 We've used other suicide scales. We've used 10 that scale. We have used the adult suicide 11 questionnaire I mentioned earlier. We've tried some 12 of these other scales. They have been consistent in 13 showing a lack of association with the Hamilton. I'd 14 lastly point out, as far as I know, all of these 15 scales, to one degree or the other, has been validated 16 against the Hamilton Item 3. That's how you create 17 the new scales. You've got to go back and validate it 18 against this so-called gold standard. These scales 19 have been validated against the Hamilton. 20 Q. Okay. We've heard lots of evidence, and I 21 think some from you, that suicide is an inherent risk 22 of the disease of depression, right? 23 A. Undoubtedly. 24 Q. And I think we've heard some figures that 25 that's about 15 percent of depressed people commit PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1801 1 suicide sometime in their lives, right? 2 A. One of the more commonly cited figures for 3 lifetime risk of suicide for major depression is 15 4 percent. Many people will use a range. 5 Q. Now, that doesn't mean 15 percent a year. What 6 that means is that 15 percent of people who have a 7 major clinical depression will, at some time over the 8 course of 20 or 30 years of their life, end their life 9 by suicide; isn't that true, sir? 10 A. That's true. 11 Q. Okay. How about homicide, is that an inherent 12 risk of depression? 13 A. I think that in that literature, and I would 14 submit I'm not an expert in that particular domain, 15 but my reading of that literature is that while it is 16 not a substantial risk, not equal to that of suicide, 17 which is internally directed violence, that there is a 18 slight increase in depression, particularly severe 19 depression, and especially certain, more severe 20 subsets of depression, that yes, you can see an 21 increase in violence or aggression, but not to the 22 same robustness or relative degree that you would see 23 suicide. So it's not the 15 percent figure you cited. 24 Q. Dr. Tollefson, I want to know, sir, whether or 25 not the idea of blaming the underlying disease, let's PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1802 1 blame depression, whether that is something that you 2 really believe is medically and scientifically 3 warranted or conversely, whether that is simply a 4 public relations and legal strategy that was devised 5 by Eli Lilly back in 1990 to deal with this issue and 6 make it go away? 7 A. It is not a position of Eli Lilly and Company. 8 This is a position of credible clinicians, 9 psychiatrists, organizations such as the American 10 Psychiatric Association. It is not a position of Eli 11 Lilly and Company, and clearly predates this issue. 12 The discussions around depression and suicide go back 13 years and years and years, even before drug therapy 14 was available. 15 Q. Did you ever work at Lilly at the same time as 16 Leigh Thompson? 17 A. A brief overlap. 18 Q. And tell the jury who this man was, Leigh 19 Thompson. 20 A. He is a physician, professor of medicine, 21 internationally known critical care specialist who 22 worked for a period of time at Lilly in charge of its 23 medical division. 24 Q. Top scientist at Lilly, right? 25 A. Yes, for a period. PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1803 1 Q. And were you aware that in September of 1990, 2 when he was going to talk about this issue, that he 3 was cautioned by Dr. Beasley and Dr. Heiligenstein, 4 both of whom worked for you, and said, don't blame the 5 underlying disease. Don't do that, boss, because we 6 ourselves have reported this as being probably related 7 to the drug. Were you aware of that? 8 A. Well, I'm aware of what you're talking about. 9 I think you misrepresented what was said. 10 Q. Then let's look at it because other folks need 11 to decide whether I'm misrepresenting that or you. 12 A. Sure. 13 Q. This is Exhibit No. 110. 14 MR. VICKERY: Are you ready, Mr. See? 15 MR. SEE: Yes, thank you. 16 Q (By Mr. Vickery) September 14, 1990. You've 17 seen this document before, haven't you? 18 A. I can't see it right now, but I'll take your 19 word for it that I've seen it before. 20 Q. Well, would you like to come down so you could 21 see? Would that help you? 22 MR. VICKERY: Could he do that, Your Honor? 23 THE COURT: If he could read it any closer. It 24 is not reproduced very well. Go ahead. 25 THE WITNESS: Do you have a paper copy? PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1804 1 MR. SEE: If I may, Your Honor. I'll give him 2 a paper copy. 3 THE WITNESS: Thank you. 4 Q (By Mr. Vickery) Now, let's read first what 5 Dr. Thompson writes. This an E-mail. This is a print 6 of an E-mail, isn't it? 7 A. Yes, it appears that way. 8 Q. And this is his name down here, L-E-I-G-H, 9 Leigh, right? 10 A. Correct. 11 Q. And can you tell us who all these guys are, Dan 12 Masica? 13 A. These were all Prozac medical physicians within 14 Lilly having different roles. 15 Q. Okay. "Comments. Thank you for your comments, 16 but they're late. I gave the drafts to Dan and Bob 17 early Monday morning with a request for them to proof 18 and verify the numbers. The verbatims are just for 19 Mr. Wood. The slides are" -- what's that word? 20 A. Made. 21 Q. -- "made. I showed them yesterday afternoon. 22 The proofs have been shown repeatedly to Wood, et al. 23 and I'm not sure at this date changes can be made in 24 the slides. I do not understand the changed numbers 25 as I took these entirely from the materials you've PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1805 1 given me. I didn't make up any numbers at all." Why 2 did he say that? Did Dr. Thompson have a tendency to 3 make up numbers? 4 A. Not at all. He was very strict and by the 5 book. 6 Q. "Because of the importance of this 7 presentation, I'm very upset that I get on Friday 8 morning this response to my Monday morning request, 9 especially when these slides were made entirely from 10 the materials that Dan gave me Friday afternoon." 11 Now, let's look at their response. Oh, no, 12 this isn't their response. That was his response to 13 their comments. So we're looking at their comments. 14 "To Dr. Leigh Thompson from Charles Beasley and John 15 Heiligenstein and Dan Masica and Dave Wheadon." All 16 those guys worked for you when you came to Lilly, 17 didn't they? 18 A. Yes. 19 Q. "Charles, David, and I have reviewed your 20 presentation and offer the following comments: 21 Verbatim number four, we feel that caution should be 22 exercised in a statement that, quote, suicidality and 23 hostile acts in patients taking Prozac reflect the 24 patients' disorders and not a causal relationship to 25 PZ. Post-marketing reports are increasingly fuzzy and PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1806 1 we have assigned reasonably related on several 2 reports. Our physician letter summarizes the 3 experience to say that ongoing analyses to date of the 4 prospective randomized double-blind depression 5 clinical trials, they taken at whole do not support 6 the hypothesis of a causal relationship between 7 fluoxetine and suicidality." 8 Now, tell me, if you would, what do you 9 interpret these educated men to mean when they say, 10 "exercise caution?" Don't say that it's the 11 underlying disease. Don't say that, boss. Isn't that 12 the way you read that? 13 A. Not quite. I mean, putting this in the proper 14 time perspective, this is September 1990, and so this 15 is shortly after the Teicher reports were issued, and 16 these physicians are physicians who are involved in 17 reviewing spontaneous reports, the kinds of things 18 that go into that post-introductory report in 19 labeling, and they're required by international 20 criteria to unless -- and remember, at this point in 21 time, no one at Lilly is trying to say we know 22 definitively. They're saying exactly as these doctors 23 said, based on all the scientific data we have at that 24 point, September '90, we see no scientific evidence. 25 What they are saying, that when they have to PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1807 1 fill out these post-marketing reports that increased 2 around the time, there was a lot of media around 3 Teicher's report, that they're mandated to, basically, 4 say is it reasonably, possibly causally related? And 5 so keeping an open mind at this point, they felt 6 rather than saying no, it's completely impossible, as 7 good physicians, as good scientists, they were saying, 8 well, it could be reasonably, possibly related. 9 So they are counseling back to Leigh, 10 Dr. Thompson, saying, rather than definitively saying 11 it is only the disease, why don't you say, based on 12 all the scientific evidence that we've accumulated to 13 this point, there is no evidence of the relationship. 14 So they're taking, I think, a more objective 15 scientific position at that point in time, so they're 16 mediating Dr. Thompson, which is, you know, what their 17 job is, to work with Leigh. Leigh was the senior 18 management person. They're down working with the data 19 every day and they offered that opinion to Leigh. 20 Q. And they were doing the same thing that you 21 were doing at about the same time when you were 22 writing the article that was eventually published in 23 May of '91 that said, "In a very small minority of 24 patients, suicidality may, on occasion, be a true 25 drug-induced event." They were just saying the same PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1808 1 thing you were, weren't they? 2 A. They were acknowledging the existence of these 3 case reports, these hypotheses. 4 Q. Now, let's see what they said about the 5 clinical trials on the next page if you would. Page 6 5, under "Suicidal thinking and clinical trials. You 7 may want to note that trials were not intended to 8 address the issue of suicidality." Also in Paragraph 9 2, "Patients were excluded who were a serious suicidal 10 risk." Now, they didn't say only 8 percent of the 11 patients. They said patients were excluded who were a 12 serious suicidal risk, didn't they? 13 A. Well, my hard copy has that completely blacked 14 out. So I'm sorry, I don't know why, sir. 15 Q. Let me hand you the original. 16 A. You see what I'm referring to? 17 Q. Yes, sir. I'm quite familiar with that. 18 A. You want this back, sir? 19 Q. I've handed you the original that will be 20 available for the jury. 21 A. Okay. Thank you. 22 Q. They say also in Paragraph 2, "Patients were 23 excluded who were serious suicidal risks. One patient 24 who made an attempt was randomized with no further 25 attempt." PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1809 1 What do you make of the fact that these men, 2 these four men together were saying, hey, boss, our 3 clinical trials weren't designed to assess suicide 4 and, in fact, we excluded people from the clinical 5 trials that were a suicidal risk? What do you make of 6 that? 7 A. Well, again, one has to look at which -- and I 8 don't know what database Dr. Thompson was looking at, 9 but if he were looking at this point only the U.S. 10 trials that involved placebo or sugar pill, those 11 trials did have an exclusion for serious suicide risk, 12 not for the presence of suicidal thinking, but for 13 serious risk. 14 The additional trials done outside of the U.S., 15 as I mentioned, many of them did not have that 16 exclusion. So my first reaction is they're probably 17 talking about the U.S. placebo trials only. And let 18 me just read it again. 19 I would disagree. I know -- I think I know 20 what they're saying. When they say, "The trials were 21 not intended to address the issues of suicidality," 22 what they're saying is that that hypothesis really 23 wasn't there when the trials were initially conducted. 24 However, these trials, for their primary objective in 25 the protocol, were looking at the safety and the PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1810 1 efficacy of the drug. Part of the safety and the 2 efficacy of this drug is suicidality, so it was 3 certainly within that umbrella of what the objective 4 of the protocol was. Not having had the hypothesis at 5 the time the protocol was written, one could argue 6 that it wasn't highlighted as the singular thing to be 7 looked at, but it was certainly one of the things 8 looked at. 9 Q. But this same man, Dr. Beasley, that was one of 10 the authors of this, looked at the same clinical trial 11 later when he said to the FDA, don't worry about it. 12 Not a problem. I did a meta-analysis. No risk. He 13 did go back and assess a suicidal risk after the fact 14 even though he acknowledged right here, the trial 15 wasn't intended to do that, didn't he, sir? 16 A. Number one, the trial was intended to look at 17 the safety and efficacy of the molecule, including 18 suicidality. Yes, Dr. Beasley's meta-analysis, as we 19 talked about meta-analyses before, was a 20 retrospeculative review of that data, clinical trial 21 database that was part of what was discussed with the 22 Food and Drug Administration. 23 They agreed and they issued, you know, an 24 opinion on that concurrent with what Dr. Beasley had 25 indicated, no credible scientific relationship between PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1811 1 Prozac and the induction of suicidality. 2 MR. VICKERY: I promise tomorrow to visit with 3 you about the FDA and European data. It's after four. 4 Do you want me to continue? 5 THE COURT: Correct. Let's break for now. Be 6 back at nine o'clock tomorrow. 7 (Whereupon, the proceedings were adjourned at 8 4:10 p.m. to be reconvened on Friday, March 19, 9 1999 at 9:00 a.m.) 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU 1812 1 C E R T I F I C A T E 2 --ooOOoo-- 3 I, TINA M. STUHR, Official Court Reporter, 4 United States District Court, District of Hawaii, 5 Honolulu, Hawaii, do hereby certify that the foregoing 6 is a correct partial transcript of proceedings in 7 Civil No. 95-00185ACK, Susan K. Forsyth, et al. vs. 8 Eli Lilly and Company, et al., at Honolulu, Hawaii, on 9 March 18, 1999, before the Honorable Alan C. Kay, 10 United States District Judge. 11 DATED: December 23, 1999. 12 13 ______________________________________ TINA M. STUHR, RPR, CSR #360 14 15 16 17 18 19 20 21 22 23 24 25 PACIFIC REPORTING SERVICES UNLIMITED, INC. (808) 524-PRSU