1 1 IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF WYOMING 2 _ _ _ 3 TOBIN, et al : 4 Plaintiff : : 5 vs. : : 6 SMITHKLINE BEECHAM : Defendant : NO. 00CV0025 7 _ _ _ 8 Videotape Deposition of 9 TADATAKA YAMADA, M.D., taken pursuant to 10 notice, at the office of Stradley, Ronon, 11 Stevens & Young, 2600 One Commerce Plaza, 12 2005 Market Street, Philadelphia, 13 Pennsylvania on Wednesday, January 24, 2001, 14 beginning at approximately 12:56 p.m., before 15 Frances P. Survilo, Registered Professional 16 Reporter_Notary Public and Christopher Nuzzo, 17 Videotape Operator, there being present. 18 _ _ _ 19 APPEARANCES: 20 21 VICKERY & WALDNER, L.L.P. BY: ANDREW VICKERY, ESQUIRE 22 2929 Allen Parkway, Suite 2410 Houston, TX 77019 23 Phone: (713) 526_1100 Representing the Plaintiffs 24 25 SPHERION DEPOSITION SERVICES 1_713_650_3500 2 1 APPEARANCES: (Cont'd) 2 PREUSS, SHANAGHER, ZVOLEFF & ZIMMER 3 BY: CHARLES F. PREUSS, ESQUIRE 225 Bush Street, 15th Floor 4 San Francisco, CA 94104 Phone: (415) 397_1730 5 Representing the Defendant, SmithKline Beecham Corporation 6 STOEL RIVES, LLP 7 BY: JOHN A. ANDERSON, ESQUIRE 201 South Main Street 8 Suite 1100 Salt Lake City, Utah 9 84111_4904 Phone: (801) 578_6930 10 Representing the Defendant, SmithKline Beecham Corporation 11 ALSO PRESENT: Andrea Parry, Esquire 12 In_house counsel for SmithKline 13 14 15 16 17 18 19 20 21 22 23 24 25 SPHERION DEPOSITION SERVICES 1_713_650_3500 3 1 I N D E X 2 _ _ _ 3 WITNESS DR CR RD RC 4 TADATAKA YAMADA, M.D. 5 BY MR. VICKERY 5 __ __ __ 6 BY MR. PREUSS __ __ __ __ 7 8 9 E X H I B I T S 10 _ _ _ 11 NUMBER DESCRIPTION PAGE MARKED 12 Yamada_1 Article on Deliberate self_harm and antidepressant 13 drugs. . . . . . . . . . . . 32 14 15 16 17 T A P E S 18 _ _ _ 19 NUMBER BEGINNING END 20 Tape 1 12:56 p.m. 2:42 p.m. 21 22 23 24 25 SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 4 1 THE VIDEOTAPE OPERATOR: We're 2 now on the record. This is a videotape 3 deposition for the United States District 4 Court for the District of Wyoming. My name is 5 Christopher Nuzzo, and I'm the videotape 6 operator. And I'm employed by Spherion Court 7 Reporting. The court reporter is Fran 8 Survilo. Today's case is as follows: Tobin, 9 et al versus SmithKline Beecham, Civil Action 10 number is 00CV025. This deposition is being 11 taken at Stradley, Ronon, Stevens & Young, 12 2600 One Commerce Plaza, Philadelphia, PA 13 19103. Counsel will now state their 14 appearances for the record. 15 MR. VICKERY: I'm Andy Vickery 16 from Houston, Texas. I represent the 17 plaintiffs. 18 MR. PREUSS: Chuck Preuss, San 19 Francisco representing the defendant. 20 MR. FARBER: John Anderson, 21 Salt Lake City representing the defendant. 22 THE VIDEOTAPE OPERATOR: The 23 deponent for today is Dr. Tadataka Yamada. 24 Today's date is Wednesday, January 24th, the 25 year 2001, and the time is 12:56 p.m. The SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 5 1 court reporter will now swear in the witness. 2 _ _ _ 3 TADATAKA YAMADA, M.D., after 4 having been first duly sworn, was examined and 5 testified as follows: 6 _ _ _ 7 DIRECT EXAMINATION 8 _ _ _ 9 BY MR. VICKERY: 10 Q. State your name for the record, please, 11 sir? 12 A. Tadataka Yamada. 13 Q. Dr. Yamada, we met before, but for the 14 record my name is Andy Vickery and I represent 15 some folks that have a complaint against your 16 company and a lawsuit against your company. 17 You understand that; don't you? 18 A. Yes. Nice to meet you. 19 Q. And you, too, sir. I appreciate your 20 giving us your time. I know it's very 21 valuable. 22 Have you ever been deposed 23 before? 24 A. Once before I was involved in a lawsuit 25 against the University of Michigan. SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 6 1 Q. The lawsuit was against the University 2 of Michigan? 3 A. That's correct. 4 Q. And you were deposed because you were 5 working there? 6 A. Exactly. 7 Q. What generally was the nature of the 8 lawsuit? 9 A. The lawsuit was a medical student who 10 was suing __ I forget the exact __ exact 11 nature of the complaint, but he had failed his 12 medical school year and was seeking to 13 overturn a grade. 14 Q. He was going to overturn his grades with 15 a lawsuit? 16 A. Well, it was kind of that way, and I was 17 the chairman of the department that had failed 18 him. 19 Q. I see. What have you done to prepare 20 yourself for the deposition today? 21 A. Well, yesterday I met with our attorneys 22 for about three or four hours, and essentially 23 they gave me some impression of what might 24 happen here today and the kinds of questions 25 you might ask. SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 7 1 Q. Sure. 2 A. And general impressions of what the 3 purpose of the meeting is. 4 Q. All right. Well, you know I'm not 5 entitled to ask __ Well, I can ask, but you 6 don't have to tell me about your conversations 7 with your lawyers and I suspect you wouldn't, 8 so I won't ask that. 9 Tell me this. Did you read 10 any documents in preparation for your 11 deposition today? 12 A. No, I did not. 13 Q. All right. Do you know anything about 14 the nature of our allegations in this lawsuit? 15 A. Only in a general way. 16 Q. What is your general understanding of 17 what the issues are in this lawsuit? 18 A. That Paxil induced a patient to commit 19 suicide. 20 Q. Okay, sir. Now, you have been with the 21 SmithKline or currently GlaxoSmithKline for 22 only about four or five years, correct? 23 A. That's correct. 24 Q. In that four or five years in the course 25 of doing your ordinary day_to_day job, have SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 8 1 you had any personal involvement with the 2 question of whether or not Paxil causes or 3 contributes to violence or suicide? 4 A. I have not been involved in any personal 5 way with that issue. 6 Q. To your knowledge has that issue been an 7 issue under discussion or investigation within 8 your company during the four or five years 9 that you've been there? 10 A. I do know now that there are lawsuits 11 alleging this association, and I do also know 12 that __ I don't know whether it's in the past 13 four or five years, but at some time in the 14 past our clinicians have looked at reports 15 along those lines. 16 Q. So you learned that prior to the time 17 that you joined the company some effort was 18 made on behalf of the company to look into 19 that issue, correct? 20 A. I don't know when __ when such an 21 investigation or such investigation of 22 occurrences took place, but I am __ I'm 23 familiar with the way that we deal with 24 problems that arise or issues that arise or 25 reports that arise regarding an association SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 9 1 between one of our products and a patient who 2 may have had an untoward event. 3 And, generally, what would 4 happen would be there would be a report and 5 one of our clinicians from the safety team 6 would explore the issue and try to understand 7 the nature of the problem, get as much 8 information as possible and look into the 9 problem that has arisen. 10 Q. Let me follow_up on that for a minute. 11 Any time that there is __ that it comes to 12 your attention that someone has had a bad 13 health outcome and it is associated in time 14 with them being on your drug, that is 15 something that your company wants to know 16 about and is obligated to report to the FDA 17 about; is it not, sir? 18 A. Any time we can obtain information about 19 our compounds, we seek to find as much 20 information as we can. 21 Q. All right. Does your standard procedure 22 in that regard require your people to make a 23 determination regarding the probable causal 24 relationship of your drug to the adverse 25 health outcome? SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 10 1 A. I think the first thing they try to look 2 at is the validity of the concern. Is there a 3 basis for a concern. What are the facts 4 surrounding the circumstances. Are there 5 confounding issues. Is there any scientific 6 reason to expect that a problem may have 7 occurred or might not have __ might have 8 occurred should a normal physiologic effect of 9 the compound have unexpected or undesired 10 effects. 11 Q. Okay. And as part and parcel of that 12 process, to try to determine whether or not 13 your drug contributed in a material way to 14 this outcome? 15 A. Absolutely. 16 Q. Now, let's talk about some of the things 17 that go into that equation and making that 18 decision. One you mentioned is it's 19 scientific basis for it. The bulk of your 20 professional career has been as a teaching 21 doctor in an academic setting, correct? 22 A. Well, teaching was one of my functions. 23 Research, clinical care, administration all 24 were important components of my job. 25 Q. All right. Now, is one of the factors SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 11 1 that is important to know whether or not 2 there's some biologically plausible means by 3 which the drug could cause the bad outcome? 4 A. Are you relating that to a function that 5 I had in the medical school? 6 Q. I'm really talking about generally this 7 process that you've described for me whereby 8 SmithKline Beecham tries to investigate an 9 event to determine whether or not your drug is 10 implicated or to use your words whether 11 there's cause for concern. So I'm really 12 talking about your understanding of SmithKline 13 Beecham's process. Okay? 14 A. Yeah. First of all, I'm not sure I said 15 cause for concern, but what I __ I think that 16 we are always concern when any bad event 17 occurs in somebody who is taking one of our 18 drugs, and it is incumbent upon us to try to 19 determine whether in fact that was a __ that 20 there is validity to any association that may 21 have arisen from an event that's linked to 22 somebody who is taking one of our drugs. 23 Q. Okay. That's what I understood you to 24 say, and what I want to do is kind of explore 25 with you some of the factors that might __ SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 12 1 A. Yes. 2 Q. __ make it valid or invalid. Okay? 3 A. Uh_huh. 4 Q. Is one of those factors to know whether 5 or not there is some biologically plausible 6 reason to say if our drug is causing this, 7 this is probably how it's doing it? Is that 8 one of the things you look at? 9 A. Well, let me give you an example. I 10 think if we observed that in our dog studies 11 or in our rat studies a drug caused 12 abnormalities in the liver and then after we 13 launch a product we find that we had patients 14 that got liver problems, that would be a 15 validation of what we observed in our animal 16 experiments. That would concern us greatly. 17 Q. Okay. 18 A. And so there, there would be a 19 scientific basis for what we observed. That's 20 a very important linkage. 21 On the other hand, if we 22 observe an event in the clinic or in the __ in 23 the marketplace in patients that are taking 24 the medication, an event that was not in any 25 way predictable by anything that we observed SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 13 1 in our preclinical studies and for which we 2 would have no scientific explanation, then we 3 have a problem in a sense because we're not 4 certain exactly whether the event was related 5 or not related to our medication. 6 We look for as much detail as 7 we can under those circumstances and try to 8 come up with some kind of clinical evaluation 9 as to the validity of the association. 10 Q. Would it be fair to say, Dr. Yamada, 11 that if we're looking at an adverse health 12 event that manifests itself in a purely 13 physical or biological way, that like the 14 liver example you used, that it's probably 15 easier to determine a cause and effect 16 relationship between the drug and that adverse 17 health event than say if we're looking at 18 something like human behavior? 19 A. I think that's fair. Human behavior is 20 __ we know so little about it, and therefore, 21 to try to speculate on a mechanism for human 22 behavior is very difficult. 23 Q. And yet your company makes drugs that 24 are designed to alter brain chemistry with a 25 specific ultimate goal on being a modification SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 14 1 of human behavior; isn't that true? 2 A. That's correct. 3 Q. And one of those is, of course, Paxil? 4 A. Yes. 5 Q. And so to the extent that it is 6 difficult to determine whether a drug will 7 either help or hurt someone, in spite of that 8 difficulty it is something your company 9 does __ 10 A. Yes. 11 Q. __ in the marketplace? 12 A. Yes. 13 Q. What has been your role, if any, since 14 joining SmithKline with regard to Paxil? 15 A. Well, Paxil was developed long before I 16 became as chairman of research and development 17 in the company. We have had several studies 18 ongoing for additional indications for Paxil, 19 but those studies were undertaken and designed 20 before I became the chairman of research and 21 development. 22 I have chaired a committee 23 that oversees decisions as to whether or not 24 we can take a study's results forward to a 25 file with the FDA based upon the data that's SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 15 1 available, and in that context I have seen a 2 presentation of Paxil and certain new 3 indications for the compound. That's 4 generally been the focus of my participation 5 and discussions on Paxil. 6 Now, there is another aside to 7 this, and that is that our worldwide clinical 8 safety officer, I think you probably met him, 9 Ian Hudson. 10 Q. I didn't meet him but I got to ask him 11 some questions. 12 A. Okay. Ian Hudson the worldwide clinical 13 safety function also reports into our head of 14 clinical development. This is actually in the 15 old SB structure I'm defining now, not 16 necessarily the new GSB structure. 17 But, in that capacity, I would 18 meet with Ian Hudson on a regular basis, and 19 we would discuss key issues that might have 20 arisen around compounds. 21 The focus of our attention was 22 on compounds that we had specific concerns 23 about related to what we observed in the 24 frequent setting and what had been experienced 25 in the clinic after __ after launch. SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 16 1 Q. Had you ever discussed with Dr. Hudson 2 the issue of whether or not Paxil causes or 3 contributes to violence and suicide in some 4 percentage of patients? 5 A. I don't recall ever having discussed 6 that particular issue with Ian Hudson. 7 Q. Okay. Let's __ You used a couple of 8 initials there, and so our record is clear. 9 The company that you went to work for in 1996 10 is SmithKline Beecham, correct? 11 A. That's correct. 12 Q. And within the past few months it has 13 had a merger? 14 A. That's correct. 15 Q. And what's it called now? 16 A. It's called GlaxoSmithKline, GSK. 17 Q. Your role with GlaxoSmithKline is what, 18 sir? 19 A. I am chairman of research and 20 development. 21 Q. As such, are you in essence the top 22 scientific officer in the company? 23 A. No, not __ There is a complexity and I 24 should explain it. There is a position called 25 chief science and technology officer in the SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 17 1 company who actually runs information 2 technology __ 3 Q. Okay. 4 A. __ and is not part of research and 5 development. I do not report to him and he 6 does not report to me. So I am the 7 administrative head of the research and 8 development function in SmithKline Beecham. 9 Q. So if we want to talk about the question 10 of research and development regarding Paxil __ 11 A. Yes. 12 Q. __ at least during the last four or five 13 years, you're the top guy there? 14 A. Right, during the last two years. 15 Q. Last two years? 16 A. Yes. 17 Q. What were you doing from '96 until '98? 18 A. I was the president of a division of the 19 company called healthcare services which 20 incorporated two major businesses. One was 21 referenced clinical laboratory called 22 SmithKline Beecham Clinical Laboratories, and 23 a pharmaceutical benefit management company 24 called Diversified Pharmaceutical Services. 25 Q. Okay. Dr. Yamada, let me get back to SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 18 1 the question of drug effects and is there a 2 causal relationship from the drug to the bad 3 outcome. Is one of the factors that you would 4 look at whether there is a dose response 5 relationship? 6 A. Not necessarily. Traditional toxic 7 effects are dose related but some are 8 idiosyncratic. In fact, some of the most 9 difficult problems are not dose related. 10 There could be allergic responses in which the 11 most minute dose can exert a bad outcome. 12 Q. Sure. Sure, I understand that, but as a 13 general proposition, when bad things happen to 14 people on drugs and they are caused by the 15 drugs, there's usually a dose response 16 relationship; isn't there? 17 A. You see I __ No, I'm trying to explain 18 this. I think there is a class of adverse 19 reactions that is dose related and then there 20 is a class of adverse reactions that is not 21 dose related. The dose related ones are often 22 easier to deal with because they're 23 predictable. 24 Q. I understand. 25 A. The more difficult ones are the ones SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 19 1 that are unpredictable are usually not dose 2 related. You know, for example, if you were 3 allergic to Penicillin and I gave you an 4 injection of Penicillin, it wouldn't matter 5 how much I gave you. 6 Q. I understand that completely, but in the 7 mix __ Separate and apart from that, by and 8 large at least in sort of the traditional 9 analysis of it there's a dose response 10 relationship between a drug and an effect that 11 would be seen in people who were not allergic 12 to it; isn't that true? 13 A. There is absolutely a class of effects 14 that are adverse that are dose related. 15 Absolutely, I agree with that. 16 Q. All right. Now, in doing the analysis 17 your company does on reports of adverse 18 events, is one of the things you look at 19 whether or not the adverse event stops when 20 you take the drug away and comes back when you 21 give the drug again? 22 A. No, that's always a tricky proposition, 23 and I think this is why we do randomize 24 control trials. In other words, what you like 25 to see is what happens under the circumstances SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 20 1 when you have a drug that has a known 2 biological activity and a dummy drug, and it 3 is possible __ For example, let's say we are 4 doing a research on drug X and the first five 5 patients who get drug X get headache. It's 6 possible that the drug causes the headache or 7 it's possible that the population of patients 8 we're studying happens to get headaches. 9 Q. I understand that. 10 A. We wouldn't know that unless we had __ 11 we were able to unblind the study and see 12 whether those patients, all five, were on the 13 drug or all five were on the placebo or there 14 was an equal distribution of people on the 15 drug or on the placebo. 16 Q. We will talk about randomize clinical 17 trials and placebo controls __ 18 A. Sure. 19 Q. __ before we're done I promise, but if 20 you took your five patients and they were all 21 given your drug and they all developed 22 headaches, that would at least raise the 23 possibility that there was an association 24 between the drug and the headache, right? 25 A. Yes. In that setting if there is in SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 21 1 fact a controlled group that's on placebo and 2 they did not get it, then I would __ I would 3 be very concerned about our drug. 4 Q. But even if there's not a placebo 5 control and there are five of you sitting on 6 the other side of the table here for me today, 7 if I gave drug X to all five of you and you 8 all five got headaches, that would raise the 9 reasonable possibility that the drug triggered 10 the headache, correct? 11 A. Well, you know, I'm a scientist. That 12 would be hard for me. 13 Q. I'm not saying that it did. I'm just 14 saying that it would be pos __ it's something 15 that's worthy of further investigation? It's 16 possible? 17 A. I would say it's possible. 18 Q. Okay. 19 A. Yeah, I would say it's possible. 20 Q. Now, just bear with me because I 21 understand that you're a scientist and that 22 you would like the absolute proof positive as 23 would I on the issues we're here to talk about 24 today. 25 A. Sure. SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 22 1 Q. But I don't think either one of us have 2 it. Okay? 3 A. Okay. 4 Q. If to follow my line of reasoning the 5 five of you got headaches when I gave you drug 6 X but then when I took away drug X the 7 headaches went away, would that strengthen the 8 reason for concern? 9 A. It would provide some evidence, but the 10 evidence would have to be taken into context 11 and the knowledge that other medications __ 12 there was no placebo control. 13 Q. I understand that. 14 A. Okay. 15 Q. We will talk about placebo control. 16 A. Okay. 17 Q. But if five people develop the problem 18 on the drug and then it goes away when the 19 drug is taken away, that sort of strengthens 20 the possibility and moves us further along in 21 our thinking that we've got to be concerned 22 about a causal relationship here; doesn't it? 23 A. Yeah, I mean if in fact the headaches 24 could be validated. 25 Q. Because, as you said earlier, one reason SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 23 1 for concern early on would be well maybe these 2 five people were just predisposed to getting 3 headaches. 4 A. That's right. 5 Q. But if their headaches went away when 6 the drug was taken away, that sort of suggests 7 that maybe that's not the situation, maybe the 8 drug is at play here; doesn't it? 9 A. That would be one piece of evidence but 10 it would be very weak. 11 Q. Okay. Well, how about if I give the 12 same drug, drug X to the five people again the 13 next day and they all get headaches again, is 14 that stronger? 15 A. It still would be evidence. I mean 16 I __ Let me try to think of an example that 17 might be __ Let's say I'm a gastroenterologist 18 and I've been involved in ulcer research, and 19 for many years we all believed that acid 20 caused ulcers. And, of course, the heritage 21 of Glaxo and SmithKline Beecham was that they 22 had ulcer medications that were predicated on 23 diminishing the amount of acid. 24 Q. Okay. 25 A. So these drugs reduced acid, ulcers SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 24 1 healed, and so we had a cure; ergo, acid 2 caused ulcers. 3 Q. All right. 4 A. But it turned out that we were all 5 wrong. It was an infection that caused the 6 ulcer. None of us knew this at the time, and 7 so, you know, there's sort of a causal 8 relationship between acid and ulcer was one 9 that we inferred from data in which probably 10 didn't have the appropriate controls. 11 Q. If the health outcome is something that 12 is life threatening, is it ethical to give a 13 placebo or sugar pill? 14 A. If the health outcome __ If there is a 15 known effective therapy, I think it's 16 increasingly difficult to do so. I don't 17 believe __ For example, if there is a known 18 treatment for diabetes and I am trying to test 19 my new medication for diabetes and I don't 20 give as a control another diabetes medicine, 21 then I would think it's unethical. 22 Q. You in your very impressive resume have 23 published in the field of ethical implications 24 for medical research; haven't you? 25 A. I have not. SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 25 1 Q. I saw something down there. Maybe it 2 was just the title that got me, but there was 3 something about ethical conduct of research? 4 A. I'm not sure what specifically you're 5 talking about. 6 Q. Okay. Well, maybe on the break I'll dig 7 it out, but. 8 A. I have one recognition for something 9 along those lines, but I'm not sure it was a 10 paper. 11 Q. To use your example of diabetes, it 12 would be unethical because to give a sugar 13 pill to someone who had diabetes __ 14 A. Oh, I know what it is. Actually it's 15 a __ I'm sorry. 16 Q. That's okay. 17 A. It was a university policy on the 18 ethical conduct of research. I was actually 19 the chairman of a committee at the University 20 of Michigan Medical School that formulated a 21 policy on actual conduct of research at the 22 university. 23 Q. Okay. You wouldn't give a placebo to 24 someone who had diabetes because of the fear 25 that that person would go into insulin shock SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 26 1 and die, correct? 2 A. I don't think it's ever ethical to 3 conduct a study in which you deprive somebody 4 of medication that is known to be effective 5 for the treatment of a condition that is 6 harmful. 7 Q. All right. And we know that for many 8 years there are __ there have been medications 9 that were treatment __ that were effective in 10 the treatment of depression before the SSRIs 11 ever came on the market; don't we? 12 A. Yes, but there were some very strong 13 side effects with those medications. 14 Q. You're talking about what class of 15 medication? The tricyclics? 16 A. The tricyclics. 17 Q. What were the side effects? 18 A. Well, people had significant side 19 problems. They would have both cardiovascular 20 problems and cognitive problems associated 21 with them. 22 Q. Dr. Yamada, did you as a practicing 23 physician or a physician in an academic 24 setting ever prescribe Paxil or any other SSRI 25 drug to a patient? SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 27 1 A. I've never prescribed Paxil or an SSRI 2 when I was a physician. 3 Q. Did you ever teach the doctors that were 4 under your tutelage about SSRI medications? 5 A. We discussed on rounds patients who were 6 on those medications, and in the course of the 7 discussions of the patients, we would discuss 8 the medications themselves. 9 Q. You are Board_Certified in internal 10 medicine, correct? 11 A. Yes. 12 Q. And your subspecialty within internal 13 medicine is gastroenterology? 14 A. That's correct. 15 Q. Do you believe that doctors whose 16 specialty is internal medicine should be 17 prescribing SSRI drugs like Paxil? 18 A. I do. I believe depression is a 19 condition that cuts across many medical 20 specialties, and I believe that it's a 21 condition that in fact is probably treated in 22 the vast majority of cases by generals, family 23 practitioners, general internists. That's the 24 setting in which depression is most often 25 seen, diagnosed, and treated. SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 28 1 Q. And that is the majority of the market 2 for Paxil; isn't it? 3 A. I believe it is. 4 Q. Now, is one of the risks of depression 5 suicide? 6 A. Yes, I believe it is. 7 Q. Is one of the risks of depression 8 violence towards other people? 9 A. Violence towards other people? Not in 10 the same way that other psychiatric illnesses 11 would be associated with that problem. 12 Q. Okay. So if we know that depressed 13 people have some greater risk of suicide and 14 we know that prior to the SSRIs coming out 15 there was a class of drugs called tricyclic 16 antidepressants or TCAs that were effective in 17 ameliorating some of those symptoms of 18 depression, would it be ethical to conduct 19 research in which you had a placebo controlled 20 population of depressed people on sugar pills? 21 A. You know, I hate to speculate on what 22 kind of decision making went on back in those 23 days and what specific actions or discussions 24 took place at the FDA. 25 One of the biggest concerns in SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 29 1 a way is that the FDA is a great champion of 2 placebo controls. They believe that you can't 3 show real efficacy unless there's a clear 4 enhancement over a placebo effect. 5 The European regulatory 6 agencies actually would like to have active 7 comparatives. So they're in __ And to some 8 extent we as a company are at the mercy of 9 what our regulators ask us to do in our 10 clinical trials. 11 So I __ You know, I __ it 12 would be very difficult for me to speculate on 13 the ethics of a decision that occurred in '92 14 because I wasn't privy to the discussions with 15 the FDA and the kinds of concerns that may 16 have been raised at the IRVs over the design 17 of the trials. 18 Q. Well, I'm really talking about the 19 studies that have been done since you joined 20 the company. 21 A. Uh_huh. 22 Q. There have been ongoing Phase II, Phase 23 III clinical trials for other indications for 24 Paxil other than depression during your tenure 25 as head of research and development; haven't SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 30 1 there? 2 A. There have been. 3 Q. Okay. Now, you say that in the foreign 4 countries they like to use comparator drugs. 5 Can you just kind of put that in lay terms 6 that the folks will understand? 7 A. Yeah. Let's say we have a drug for 8 diabetes, Avandia, it's a new drug, and the 9 traditional drug that's used in Europe, in 10 France is Medformin. This is an oral 11 antidiabetic as opposed to insulin which is an 12 injectable antidiabetic. 13 In order to get approval in 14 France we might actually have to show __ In 15 fact, the French authorities more or less said 16 that we would have to show that our drug was 17 better than Medformin. 18 Q. As good as or better? 19 A. We have to show that we're better. 20 Q. All right. 21 A. And this is in France. Now, this 22 happens to be one country in Europe. In other 23 countries in Europe the opinion might be a 24 little bit different. 25 In __ Generally, there is a SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 31 1 shift in the regulatory agencies driven 2 primarily by economics. Let's say if there 3 are established therapies that are cheaper, 4 you have to show that you're better. 5 In the U.S. there is still a 6 very strong concern that placebo control 7 studies are done to show efficacy except where 8 placebo would result in harm. 9 Q. Are the Americans more scientific than 10 the Europeans or vice versa either one? 11 A. I don't think so. 12 Q. Both are scientifically valid? 13 A. Both are scientifically valid. It's a 14 different viewpoint. 15 Q. So it is perfectly scientifically valid 16 when looking at the effects of a drug, whether 17 beneficial or adverse, to compare that drug in 18 a study of patients where some patients get 19 that drug and some people get another active 20 comparator drug? 21 A. Yes. 22 Q. To your knowledge has your company 23 sponsored any epidemiological research into 24 the question of whether or not your drug Paxil 25 or drugs of its class, the SSRI drugs, are SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 32 1 more likely to cause people to harm themselves 2 on purpose than other active comparator drugs 3 like the tricyclic antidepressants? 4 A. No. 5 Q. Let me show you a study which we're 6 going to mark as Yamada Exhibit_1. 7 _ _ _ 8 (Whereupon, a document was 9 marked Yamada_1 for purposes of 10 identification.) 11 _ _ _ 12 Q. I'll give you time to get your cheaters 13 on. 14 A. Sorry. 15 Q. No, that's okay. I'm at that age 16 myself. 17 Dr. Yamada, what I have handed 18 you is an article by Dr. Stuart Donovan and a 19 number of other colleagues entitled Deliberate 20 self_harm and antidepressant drugs, and it 21 comes from the British Journal of Psychiatry 22 in the year 2000. I believe it was published 23 late in the year. Volume 177 at pages 551 24 through 56. And if you will look __ Have you 25 ever seen this article before? SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 33 1 A. No. 2 Q. Look if you would back on __ under the 3 acknowledgments on the last page, page 556. 4 A. (Witness complies with request.) 5 Q. Do you see there the last sentence? 6 Would you just read the last sentence starting 7 S.D. is also appreciative? 8 A. "S.D. is also appreciative of the 9 unconditional contribution provided by Eli 10 Lilly, Knoll, and SmithKline Beecham 11 Pharmaceuticals to assist with the costs of 12 postage and data analysis associated with this 13 study." 14 Q. Now, were you aware that your company 15 SmithKline Beecham Pharmaceuticals made an 16 unconditional contribution for postage costs 17 and data analysis for this study? 18 A. I was not. 19 Q. What is Knoll? 20 A. It's a pharmaceutical company. 21 Q. And do they make a drug in the SSRI 22 class? 23 A. They do, and I don't know which one it 24 is. 25 Q. All right. And, of course, Eli Lilly SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 34 1 makes the Prozac, correct? 2 A. Yes. 3 Q. And your company makes Paxil? 4 A. Yes. 5 Q. And just so __ As we look at this 6 article and we keep our chemical names 7 straight, Paxil is Paroxetine? 8 A. Yes. 9 Q. Correct? 10 A. Yes. 11 Q. And Prozac is Fluoxetine? 12 A. Yes. 13 Q. Okay, sir. Look if you will at Table 3 14 on page 554. 15 A. Uh_huh. 16 Q. In the far right_hand column there is a 17 computation of relative risk of DSH, and DSH 18 is their shorthand for what this article is 19 about, deliberate self_harm. 20 A. Uh_huh. 21 Q. Do you know what a relative risk 22 calculation is? 23 A. In general terms, yes. 24 Q. What is it? 25 A. In general terms I understand it. SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 35 1 Q. Tell me your understanding of what a 2 relative risk calculation is? 3 A. It is the risk that someone would have 4 for an event compared against a standard which 5 would be nothing. 6 Q. All right. And is it usually __ When 7 you say a relative risk calculation, is it 8 relative to either the placebo or the 9 comparator drug that's involved in the study? 10 A. Yes, I believe so, but I'm not an expert 11 on epidemiology. 12 Q. All right. Now, you see there where it 13 reflects that the relative risk for deliberate 14 self_harm of your company's drug Paroxetine is 15 4.0. Does that number give you any cause for 16 concern or alarm? 17 MR. PREUSS: Well, I 18 object __ 19 A. Not really. 20 MR. PREUSS: I object to the 21 form. He hasn't had a chance to read the 22 document to analyze it. 23 A. I would have to read the full document 24 to understand what it meant here. 25 Q. Is there any relative risk number that SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 36 1 you consider a sort of watershed or blight 2 line, dividing line in terms of what is 3 significant to you as head of research for 4 SmithKline Beecham and what isn't? 5 A. It really depends on what you're trying 6 to establish. I mean I __ If you're trying to 7 establish an association between events and, 8 let's say, a single cause __ 9 Q. Okay. 10 A. __ perhaps you're one at risk of ten or 11 better. So the risk of a gene causing any 12 disease you would have to establish beyond any 13 doubt at all. For multifactorial events, it's 14 hard to know where to draw the line. 15 Q. Is there any significance to you, Dr. 16 Yamada, of a relative risk computation being 17 either greater than or less than 2.0? 18 A. I'm sorry. I didn't understand the 19 nature of the question. 20 Q. Is there anything significant to you as 21 head of research and development of SmithKline 22 Beecham of a relative risk computation for any 23 kind of adverse health event coming out at 24 either greater than or less than 2.0? 25 A. It would depend on the nature of the SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 37 1 data and exactly where it was obtained from. 2 I mean, you know, one could find associations 3 of 2.0 or better for many associations which 4 are not in any way causal related. 5 Q. What I'm just trying to understand is, 6 is 2.0 in and of itself a magic or significant 7 number to SmithKline Beecham when we are 8 talking about relative risk computations? 9 A. There is no policy at SmithKline 10 Beecham. If you're asking what it means to 11 me, it would depend on the data. So 12 SmithKline doesn't have a policy that says 13 relative risk 2.0 that is important, relative 14 risk under 2.0 is not important. There is no 15 policy. 16 Q. How about you personally? And I realize 17 you told me you're not an epidemiologist, but 18 to you is the 2.0 line any kind of blight 19 line, dividing mark as to what's significant 20 or what is not? 21 A. Again, it would depend on the data. For 22 example __ I mean I could give you examples. 23 Let's say I want to find an association 24 between an event and cancer, and that might 25 be __ Let me go back to something I'm familiar SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 38 1 with which is the bacterium that causes an 2 ulcer, here we'll go back to pylori, is 3 associated with gastric cancer. 4 Q. Okay. 5 A. The relative risk for males may be 4 or 6 5. Now, that raises concern if people are 7 looking into this issue. It does not 8 necessarily mean there's a causal link. At 2 9 it would depend on the nature of the data and 10 how retrospective it was and it was 11 prospectively obtained or retrospectively 12 analyzed. 13 So I can't honestly say __ I 14 would draw the line here. It would depend on 15 the nature of the data itself. So, you know, 16 I haven't read this paper. I don't know 17 exactly the circumstances or the design of the 18 trial. So I don't know how to interpret out 19 of context the risk ratio of 4 or 5 or 10 or 20 2. 21 Q. Is it possible for a drug to cause an 22 event and yet have a relative risk of under 23 2.0? 24 A. If you read it __ 25 MR. PREUSS: I'm going to SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 39 1 object on foundation. 2 THE WITNESS: Should I answer 3 that? 4 MR. PREUSS: You should go 5 ahead. 6 THE WITNESS: Okay. 7 A. I would say that if you're talking __ It 8 depends on what you're saying about cause. If 9 you're saying cause, I doubt it. 10 Q. Okay. How about if we say contribute to 11 in a materially way? 12 A. It could be under 2. 13 Q. So if there is a phenomenon that is 14 multifactorial in nature and one of the things 15 it contributes to that drug or to that 16 phenomenon is a drug, it's a drug reaction, 17 are you saying that it's possible that that 18 drug would contribute in that way and yet 19 still the relative risk would be under 2.0? 20 A. It could be, yes. 21 Q. Okay. Well, I know you haven't had a 22 chance to read this, and I don't __ 23 A. No. 24 Q. __ want to ask you things out of context 25 about it. I would encourage you to read it SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 40 1 when you get a chance, because I think it's a 2 very good reporting paper. 3 Now, let me just go back and 4 talk about the funding. Oh, okay. That's the 5 very thing I wanted to talk to you about. 6 Tell me what you want to tell me about it? 7 A. I think there are studies that are 8 funded by R & D, research and development, and 9 certainly we spend a lot of money on clinical 10 trials and other research, but if money comes 11 from SmithKline Beecham for research, it does 12 not necessarily mean it comes from research 13 and development. And that's very important; 14 that is, to give somebody __ For example, 15 obtains money from, let's say, a marketing 16 group to explore a nuance of a compound, that 17 would not be a research and development 18 sponsored activity at all and I might not know 19 anything about it. 20 Q. And in all probability that's where this 21 funding came from for this study is the 22 marketing group; isn't it? 23 A. I don't know. 24 Q. Well, if this goal of the study was to 25 compare tricyclic antidepressants against SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 41 1 SSRIs as a class, doesn't it make sense that 2 your marketing people would want to fund a 3 study that they thought would show your drug 4 was better than or your class of drugs is 5 better than TCAs? 6 A. Not necessarily. They may actually 7 avoid that like the plague. I mean from the 8 standpoint of a marketeer I believe their 9 desire would be to avoid comparisons unless 10 they were absolutely certain that in a 11 comparative fashion they would rate. 12 Q. Well, that's frankly what strikes me 13 from this article. If you just look back on 14 Table 3 for a minute. 15 A. Uh_huh. 16 Q. And if you see that the relative risk of 17 deliberate self_harm on tricyclic 18 antidepressants is 1.9 and the relative risk 19 of deliberate self_harm on SSRIs combined is 20 5.5, that's a marketing disaster for the SSRI 21 drugs; isn't it? 22 A. Well, it has to do with the validity of 23 the study. I would not know how to interpret 24 the validity without having read the study. 25 The answer is there is a lot published about SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 42 1 every medication, and some of it is valid and 2 others not. 3 Q. Is it typical when people get funding 4 from the research and development section, 5 your section of SmithKline Beecham to get 6 unconditional funding as Dr. Donovan and 7 colleagues got in this instance? 8 A. No. 9 Q. What are the conditions that are usually 10 imposed on their funding? 11 A. A study design. 12 Q. It has to be designed as you want it? 13 A. It has to be designed with a __ the best 14 scientific input and with a specific gain. 15 It's usually associated with a regulatory 16 agency. 17 Q. And are there usually restrictions on 18 the confidentiality of the outcome? 19 A. Generally not. It's very difficult to 20 do that. Most universities would not allow 21 their faculty to be involved in a clinical 22 study in which the outcome could not be 23 published. 24 Q. Are you aware of any circumstance in 25 which SmithKline Beecham has had restrictions SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 43 1 going in where it in essence had the right to 2 decide after it saw the results of the study 3 whether those would be published or not? 4 A. Well, I'm not aware of any in the two 5 years that I've been involved in R & D. I 6 think all of us accept the fact that if we're 7 going to be involved in this study involving 8 legitimate scientists you just can't put a gag 9 order on the scientists. They have the right 10 to publish the results. 11 Q. Okay. Dr. Yamada, are you involved at 12 all with the question of whether and when to 13 put warnings on the labels of drugs made by 14 your company? 15 A. You know, I am not an expert on 16 regulatory affairs. I don't know the exact 17 procedure and probably better asked __ you're 18 better off asking David Reed about that. 19 Q. I'm not at all concern about regulatory 20 affairs. What I'm concern about is the 21 business decision made by your company. We're 22 going to put a warning on; we're not going to 23 put a warning on. Is that something that 24 you're involved in at all? 25 A. It's never a business decision. I think SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 44 1 you should know that. I'm a clinician. For 2 me it's a clinical decision. 3 Q. Whether the doctor needs that 4 information or not? 5 A. No. It's a matter of what is clinically 6 important, what is clinically valid, what is 7 clinically relevant to the use and abuse of a 8 medication. That's really what it comes down 9 to, and, you know, it is not regulatory at 10 all. 11 You're right in the sense that 12 if I felt or the people around me felt that 13 there was a significant problem, whether or 14 not the agency felt __ the agency meaning the 15 FDA felt it was a problem that we needed to 16 have a warning on, I personally would feel 17 that __ feel compel to put it on our label. 18 Q. Whether they thought you needed one or 19 not? 20 A. If I felt as a physician it was an issue 21 with a patient, I would absolutely insist on 22 it. 23 Q. And your company has the authority to 24 implement warnings without having to be told 25 by the FDA to do it; don't you? SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 45 1 A. I presume so, although we have not 2 tested that. 3 Q. To your knowledge does SmithKline 4 Beecham, we'll stay away from the Glaxo end of 5 it for a minute, but prior to the merger did 6 SmithKline Beecham market drugs in this 7 country with black box warnings? 8 A. I don't know. I have to check that. 9 Q. How about now that there is a merger, do 10 you know __ did the Glaxo side of the house 11 have any drugs that had black box warnings? 12 A. Glaxo withdrew a product that was going 13 to have a black box warning. 14 Q. Because of the black box warning? 15 A. No. 16 Q. Why did they withdraw it? 17 A. It was really a __ It's a sensitive 18 discussion with the FDA, and in fact we're 19 still working with the FDA on the issues, but 20 until the issues could be resolved we felt it 21 best to remove the product. 22 Q. Is there something about the warning 23 that went into the decision to remove the 24 product until it was all sorted out? 25 A. No. It was really __ It really had to SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 46 1 do with practicality __ the practicality of 2 the monitoring process. 3 Q. I don't want to get into it if it's 4 proprietary in nature. That's none of my 5 business. 6 A. It's actually a __ It's an ongoing 7 issue. That's why I'm a little hesitant to 8 discuss it. In fact, I was just at the FDA 9 yesterday discussing the issues with them. 10 Q. What's been your experience in your 11 interaction with the folks at the FDA insofar 12 as, you know, regulatory decisions like do we 13 put a warning, don't we put a warning, do we 14 take it off the market for awhile, don't we? 15 I mean is there a reasonable dialogue and 16 working relationship between the FDA and the 17 pharmaceutical industry? 18 A. Absolutely. I'm impressed with sort of 19 collegiality of the relationship between the 20 pharmaceutical company and the FDA. I believe 21 that in most instances the discussions are a 22 physician to physician and they're really 23 worried about what's going to happen to the 24 patient, and the FDA is really in a difficult 25 position because they have to try to find new SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 47 1 medications and get them to patients as 2 quickly as possible. 3 And they also feel that 4 they're guardians of the patients' safety. I 5 have to say that as a pharmaceutical company 6 we have the same pressures. We have the real 7 pressure to try to get new medications to the 8 patients as quickly as we can. We also have 9 the pressure to understand that our drugs 10 aren't safe and that every drug __ although 11 every drug __ every drug has potential 12 complications but the benefits outweigh the 13 risks. 14 Q. And in that context, what is the 15 importance of proper labeling as a means to 16 accommodate these two competing interests? We 17 need to get this drug out there on the one 18 hand to people but the drug might hurt some 19 people. Can that be ameliorated in some 20 degree by proper labeling? 21 A. That is the hope. That is the hope. 22 It's not __ It's not always been borne out, 23 and so the FDA is rethinking about what they 24 want to do, how they actually control the 25 physician. I mean one of the problems is SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 48 1 that __ Maybe I'm saying too much here, 2 Chuck. 3 Q. I can't ask you what he said yesterday, 4 but I bet one of them was just answer his 5 questions. But I appreciate your 6 helpfulness. 7 A. It's like a pack of cigarettes. You see 8 on there Surgeon General's warning. 9 Q. Right. 10 A. Nobody pays any attention to it. 11 Q. Right. 12 A. I mean I don't know. Maybe at some 13 point some person for the first time taking a 14 cigarette might look at that pack and say, you 15 know, this might be harmful to me. 16 And I think that my concern 17 and the FDA's concern would be that there's so 18 much on these labels now. Every known __ 19 practically every known association is 20 included in the label, so that there's a 21 signal to noise problems. You know, the real 22 issues might get lost and this compendium of 23 potential issues associated with the product. 24 And the FDA is concern about 25 this and so am I. SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 49 1 Q. Let's see if we can find some common 2 ground. Would you agree with me that if the 3 adverse health outcome is one that is life 4 threatening that it becomes more important to 5 have adequate information on the label? 6 A. If there is validity to that 7 association. If there is real scientific 8 validity, absolutely. 9 Q. Okay. Would you agree with me that if 10 the __ if the information on the label appears 11 in the warnings section, it is more likely 12 that physicians will look at it and heed it 13 than if it appears in other sections of the 14 label? 15 A. I can't say for all physicians, but 16 from __ you know, for myself and for others 17 the decision is always a clinical one and of 18 well __ We understood what the issues were. 19 We always looked at it in the context of what 20 the patient's need was. 21 So in treating a patient I 22 would make a decision. This drug has these 23 side effects but the condition is sufficiently 24 bad that it warrants medication. 25 I remember some of the most SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 50 1 effective antibiotics, for example, for 2 certain types of infections caused damage to 3 the kidney. We knew that. 4 Q. Quinolones? 5 A. No, this is gentamicin. 6 Q. Dr. Yamada, as a physician, clinician, 7 academician who not only practiced medicine 8 but taught other doctors how to practice 9 medicine for many years, would you agree that 10 as a general proposition that if language 11 appears in the warnings section in boldface 12 that it is more likely that doctors will take 13 heed of that information than if it's put back 14 in the postmarketing surveillance section and 15 it's not in boldface? 16 A. Well, my experience would be that 17 doctors just don't look at the label, period. 18 Now, it could be because I was in an academic 19 institution and that's what we did. Maybe we 20 felt that we were more up_to_date and 21 therefore we didn't need no label. I don't 22 know, but my experience is that most 23 physicians don't look at the label very 24 carefully. 25 And I'm not certain __ I SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 51 1 personally am not certain whether it would 2 make a difference whether something was in a 3 black box or in a warning section or in a 4 precaution section, and if you would ask 20 5 young physicians, I'm not sure they could tell 6 you the difference between those three. 7 Q. Do you know that in the information 8 disseminating process one of the truly 9 important ways that your company communicates 10 both the indications and the side effects of 11 your medications to doctors is through the __ 12 I forget what title we were using about the 13 detail men, as I call them, the people that 14 call on doctors? 15 A. Yes. 16 Q. That's a very important conduit for 17 information; isn't it? 18 A. I believe it is, yes. 19 Q. And do you know that your people are 20 trained, your salespeople that call on doctors 21 are trained to emphasize and reemphasize 22 information that is in the warning section of 23 the labels to doctors for the very reasons 24 that you talk about? 25 A. I believe so, but I don't know for a SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 52 1 fact. 2 Q. Okay, sir. How are you doing comfort 3 wise? 4 A. I'm fine. I'm fine. 5 Q. Any time you want to take a break __ 6 MR. PREUSS: Why don't we take 7 a break. 8 THE VIDEOTAPE OPERATOR: Off 9 the record. The time is 1:54. 10 _ _ _ 11 (Short break.) 12 _ _ _ 13 THE VIDEOTAPE OPERATOR: Back 14 on the record. The time is 2:05. 15 BY MR. VICKERY: 16 Q. Dr. Yamada, tell me if you would just 17 sort of in lay terms the process through 18 research and development of a new drug or the 19 approval for a new indication for an existing 20 drug? How does that process work? 21 MR. PREUSS: You're talking 22 about at the current time? 23 Q. Well, throughout your tenure. I mean I 24 understand it's the last two, three years. 25 A. Yeah. Well, we have a discovery SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 53 1 process. Generally now we start out with a 2 molecule, a target we call it. It's like a 3 lock. Then we find a chemical for that 4 target. So the target might be a histamine 5 receptor, and then we would screen the 6 histamine receptor with our bank of library of 7 a million compounds and see if we can get a 8 key that fits this lock. 9 Then we would have to do some 10 biology. I know it sounds kind of backwards 11 because it's different from the old days, but 12 we would then have to do some biology to see 13 what door this lock was opening. So the door 14 might be, let's say, cold symptoms. Another 15 door might be peptic ulcer. A third door 16 might be something else. 17 And so effectively we would 18 have a lock and a key, and we would find out 19 the most appropriate door for which this lock 20 and key fits and we would do a lot of biology 21 behind it. 22 Once we got the biology worked 23 out we would reoptimize the chemistry so that 24 we would have the best key possible for this 25 lock. SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 54 1 Then once we had a compound 2 that was the best fit and had the best 3 biological effects that we look at, then we 4 would do the safety studies to see whether 5 this in fact was a safe compound. 6 Once the __ sort of the safety 7 studies have been done, the biology has been 8 worked out, and the best chemistry has been 9 worked out, then we would go to a decision 10 that it is probably safe now to take this to 11 man. 12 So we do a __ And this would 13 be in discussions with the FDA about the kinds 14 of studies we wanted to do. They would look 15 at the data and they would look at the 16 chemistry and they would look at all of that, 17 and then we would do our initial studies first 18 to demonstrate safety intolerability, if the 19 drug didn't cause big problems and that the 20 patients didn't get immediately sick when they 21 took the medicine. 22 After that, then we would do 23 our initial proof of concept studies. We 24 would call that Phase II. Phase I being the 25 safety intolerability, and Phase II studies SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 55 1 would be studies to demonstrate that in fact 2 this chemical would treat the symptoms of a 3 cold, for example. And we would set up a 4 study that had a design that would allow us to 5 answer the question in a positive or negative, 6 and that would demonstrate a proof of 7 concept. 8 And then we might do some 9 other studies to sort of fully characterize, 10 you know, exactly does it work better in flu 11 than in, you know, a standard common cold. 12 Does it work in other symptoms of asthma for 13 example. Like we might do those kinds of 14 studies. Those would be what we would call 15 Phase II B studies. Filling out the 16 characterization of a drug. 17 Then we would embark on what's 18 called Phase III which would be the big 19 studies to demonstrate efficacy for a specific 20 clinical condition. These are generally two 21 randomize double blind controlled trials 22 called pivotal studies that we would have to 23 be able to demonstrate positive efficacy on 24 and within the boundaries of safety to be able 25 to demonstrate a risk benefit equation or that SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 56 1 the drug had an effect that was of sufficient 2 benefit, that it overcame the blemishes of the 3 drug as every drug has in terms of its 4 usefulness for a patient with a given clinical 5 condition. 6 We would then gather up the 7 data, write it up, submit an application to 8 the FDA for registration of the compound. 9 Q. What is the role of animal studies? Is 10 that part of the Phase I process? 11 A. No. Animal studies occur before we ever 12 go into man. 13 Q. So preclinical? 14 A. Preclinical. 15 Q. And what is the significance of results 16 achieved in the animal studies? 17 A. The animal studies are very important 18 because they provide clues as to what may or 19 may not happen when it goes into man. 20 Q. For example, the one you used earlier 21 on, if you knew a drug caused liver damage in 22 animals and then you started seeing people 23 that had liver damage that were taking the 24 drug, there would be a cause for real concern 25 that the drug was causing it? SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 57 1 A. Absolutely, yeah. 2 Q. Do you know what serotonin is? 3 A. Yes. 4 Q. Do you know what it's frequently called 5 in the scientific community, 5_HT? 6 A. 5_hydroxytryptamine, yes. 7 Q. Do you know what it metabolizes into 8 once the body processes it? 9 A. No. 10 Q. Something called 5_HIAA? 11 A. Uh_huh. 12 Q. And do you know whether or __ 13 A. That is __ 5_hydroxyindoleacetic acid is 14 the way it comes out in the urine. I'm not 15 sure what other potential products or 16 intermediates there might be. 17 Q. All right. Do you know, for example, 18 that the whole hypothesis of selective 19 serotonin reuptake inhibitors working for 20 depression began out of some studies that 21 indicated that people who had killed 22 themselves had low levels of 5_HIAA, the 23 serotonin metabolite in their cerebral spinal 24 fluid when they were autopsied? Did you know 25 that? Have you heard of it? SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 58 1 A. No, I didn't know that. 2 Q. If that's the case and if Paroxetine or 3 Paxil replicates that biological phenomenon in 4 animals, would that cause you to fear that it 5 might cause suicidal behavior in humans? 6 A. No. 7 Q. So even though the same biological 8 condition that was found in people who killed 9 themselves was caused by Paxil, that's not a 10 cause for a concern or alarm? 11 MR. PREUSS: Well, I object. 12 No foundation. 13 A. Yeah, I think __ Yeah. Yeah, I mean I 14 think you're really stretching it quite a 15 ways. I think if __ I don't know the 16 circumstances by which the theory or realms 17 about using SSRIs for depression and I don't 18 know the data on what happens in the reports 19 that you're talking about associated with low 20 spinal fluid 5_HT levels in patients who 21 committed suicide, but by no means would I 22 extrapolate that to anything that happened in 23 animals. 24 And, you know, I'm not certain 25 that __ Unless you could reproduce a suicidal SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 59 1 animal in some way that you could actually 2 reproduce the phenomenon in man. The fact 3 that you can influence CSF 5_hydroxytryptamine 4 levels with a drug does not imply that when 5 it's actually happening at the site of action 6 it is the same mechanism. 7 Q. I think I've done a poor job with my 8 question. It's obvious that if you think I'm 9 stretching it and it's obvious to me from your 10 answer that I haven't done a good job with my 11 question. Let me try again. 12 If there is a biological 13 condition that is associated with completed 14 suicides and your drug replicates that 15 biological condition, is that a cause for 16 concern which would manifest itself in either 17 further testing or specific warnings? 18 MR. PREUSS: I object to 19 form. 20 A. No, no. 21 Q. Okay. Back to the process you described 22 for us. What are the Phase II studies? Are 23 those the healthy volunteer studies? 24 A. No. The Phase I studies are the healthy 25 volunteer studies. SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 60 1 Q. Why is it important to use healthy 2 individuals in doing those studies? 3 A. Well, I think essentially there are 4 several reasons. I'm not sure how the 5 practice evolved, but let me try to 6 reconstruct why I might do studies in healthy 7 volunteers. And, by the way, not all Phase I 8 studies are done in healthy volunteers. 9 For example, cancer 10 medications are sufficiently dangerous to 11 healthy volunteers that you usually use 12 patients for the Phase I studies. 13 So if the drugs are deemed to 14 be safe or through the animal studies and 15 through the safety analysis in animals, then 16 you can do studies in healthy volunteers. 17 The point of doing the healthy 18 volunteers I presume is to look at immediate 19 safety in man and people who are not 20 compromised by illness, No. 1, and No. 2, who 21 are most likely to be in a position to 22 tolerate the medications. 23 Q. If an adverse event occurs with a 24 healthy individual, then is it more suspicious 25 that the drug was involved than if it occurs SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 61 1 in someone who has a disease which could also 2 cause or contribute to that adverse event? 3 MR. PREUSS: I object to 4 form. 5 MR. VICKERY: Let me rephrase 6 it. That's undoubtedly a good objection. 7 BY MR. VICKERY: 8 Q. Suicide is a risk of depression, 9 correct? 10 A. That's correct. 11 Q. Now, if a patient is on an 12 antidepressant such as Paxil and they become 13 suicidal or more suicidal or actually kill 14 themselves or attempt to do so, then the 15 question that confronts us as we examine that 16 situation is well what caused it or contribute 17 to it. Was it the depression, was it the 18 drug, was it a combination of both, were there 19 other factors. Would you agree with me that 20 that's the case? 21 A. Uh_huh. Yes. 22 Q. But if the patient was not depressed and 23 had no other physical condition that we know 24 about that would cause them to become suicidal 25 and yet they became suicidal on the drug, SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 62 1 that's the kind of thing that would sort of 2 make us __ make our antenna go up, make red 3 flags go off or bells go off? In other words, 4 concern us; wouldn't it? 5 MR. PREUSS: I object to 6 form. 7 Q. Would it concern us if people who 8 were __ who did not have a disease to put them 9 at risk for suicide became suicidal on Paxil? 10 MR. PREUSS: Same objection. 11 Q. You may answer that one. 12 A. Do you want to ask the question again so 13 I understand it. 14 Q. Yes, sir. If people from a healthy 15 study which __ which means that they 16 didn't __ did not have any underlying disease 17 process that put them at risk for suicide 18 became suicidal on taking Paxil or any other 19 SSRI drug, would that be a cause for concern 20 that the drug may be causing or contributing 21 to this suicidality? 22 MR. PREUSS: I object to 23 form. 24 A. We would look at all of the data 25 obtained in our healthy volunteers and try to SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 63 1 examine in the proper context. I can give you 2 an example, examples of drugs that caused 3 people to faint in Phase I studies that we 4 took forward in the clinical studies, because 5 viewed in the proper context the fainting 6 episode was not relevant to the effect of the 7 drug. 8 We have had other 9 circumstances when people would have altered 10 rhythms of the heart during the course of a 11 Phase I study. That would not necessarily 12 prevent us nor would it the FDA prevent us 13 from continuing on those clinical studies, 14 because bad things happen to people all the 15 time and the temporal relationship does not 16 necessarily imply causation. 17 Q. We can certainly agree on that. 18 Can we also agree that if the 19 bad thing happens to a person on a drug and 20 that person is a healthy volunteer that at 21 least we can take some underlying disease 22 process out of the equation in trying to 23 figure out what caused Mr. Jones to have this 24 bad result? 25 A. No. I think the reason why I answered SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 64 1 your question originally the way that I did 2 was because nobody's healthy. See, 3 healthy __ I mean you're not healthy and I'm 4 not healthy. We all tomorrow could have some 5 event that we didn't know about, and that 6 event might be temporally associated with 7 drinking a cup of coffee or signing your 8 name. You know, one can develop a lot of 9 superstitions about what may or may not be 10 associated between an illness and supposed 11 causation that was association __ associated 12 in the events starting that illness. 13 So, you know, some people may 14 feel a cold coming on. They'll do certain 15 things because they think it makes them __ it 16 will prevent the cold. It doesn't mean that 17 whatever they're doing will either prevent the 18 cold or one fact have any bearing on the 19 evolution of that cold. This is the reason 20 why the FDA and also pharmaceutical companies 21 always take any event that occurs in healthy 22 volunteers in the context of the overall phase 23 of our program to make a decision about 24 whether a Phase __ further patients should be 25 exposed to the medication. SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 65 1 Q. Are you done? I didn't want __ 2 A. Yeah. 3 Q. __ to interrupt you. 4 A. No, I'm just __ I just want to indicate 5 to you it happens all the time. 6 Q. Well, I don't for a moment doubt that 7 there may be some patient who appears to be 8 healthy, who has some undiagnosed health 9 condition that really could be the culprit 10 here. I will concede that to you readily, but 11 will you not, sir, concede that when you use 12 healthy volunteers the goal in using them is 13 to try to eliminate some underlying disease 14 process that could be a confounding factor in 15 whatever it is you're trying to measure? 16 A. I think that's true absolutely but never 17 in a single patient. So that's why we study 18 20 patients or 30 patients in a Phase I study 19 so that we don't extrapolate from one the 20 event to all. 21 Q. All right. I appreciate that. 22 Do you know whether or not in 23 the healthy patient population that was used 24 for healthy volunteer studies on Paxil that 25 there was any treatment emergent suicidality? SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 66 1 A. I'm not familiar with what happened in 2 the Phase I at all. 3 Q. Okay. I want to get back to your key 4 and lock metaphor, because I think it is a 5 helpful one for us. 6 Is your company's drug Paxil 7 marketed as a selective serotonin reuptake 8 inhibitor? 9 A. That is the class of compounds. 10 Q. What is selective about them? 11 A. Are you asking me a scientific question? 12 because I don't know __ 13 Q. Okay. 14 A. __ the answer. 15 Q. Tell me this. Do you know how many 16 different doors to different maladies this 17 selected key opens? 18 A. I don't know. 19 Q. Do you know how many different 20 indications your company currently has for 21 Paxil in this country? 22 A. We have quite a few indications. 23 Q. Can you explain for me why it is that a 24 single selective psychoactive drug like Paxil 25 would be beneficial in treating a whole SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 67 1 handful of different maladies? 2 A. It could be the same mechanism as behind 3 the maladies, and it may be the side of the 4 brain where those neurons are. At one side __ 5 one place in the brain it may cause one 6 condition. The other side of the brain 7 another. 8 Q. One of your company's indication for 9 Paxil is __ What's it technically called? I 10 call it shyness, but it's really social phobia 11 or something like that? 12 A. That's correct. That is __ There's a 13 big difference between social phobia and 14 shyness. 15 Q. You all spend a lot of money on 16 television advertising for Paxil in that 17 indication; do you not? 18 A. For Paxil in general I've certainly seen 19 ads for that indication. 20 Q. And you would not be able to do that 21 television advertising directly to consumers 22 if you had a black box warning on Paxil's 23 label, would you? 24 A. I don't think so. 25 Q. Would __ Other than the inability to SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 68 1 conduct direct to consumer advertising, do you 2 believe that a black box warning or indeed any 3 bold_faced warning about suicide would hurt 4 sales of Paxil? 5 A. I believe that a black box warning would 6 have an impact on the sales of Paxil, yes. 7 Q. Now, the sales __ 8 A. Sales of __ Let me just talk about 9 social phobia which is a slightly different 10 indication. Personally I'm not certain that 11 the ads have much impact on social phobia only 12 because an interesting observation that we've 13 made is we have a web site for social phobia, 14 and the number of hits on that site are 15 unbelievable. There are many people. I mean 16 maybe because they have social phobia they 17 spend time on the computer. I don't know, but 18 I do believe __ 19 Q. Yeah, because they're shy they're on the 20 computer. They're serving the net. 21 A. No, no, no. Social phobia is different 22 from shyness. 23 Q. Okay. 24 A. Shy people go out and enjoy themselves 25 and do a lot of wonderful things. Social SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 69 1 phobia is a real pathological condition which 2 prevents people from living happy, enjoyable 3 lives, and that's a very big distinction that 4 we certainly make in the application of 5 Paxil. 6 But all I'm pointing out is 7 that you're absolutely right. If we had a 8 black box, chances of us being able to do a 9 direct to consumer campaign would be very 10 limited, and would that have an impact on the 11 sales of Paxil? Probably. Would that 12 result __ that impact result from social 13 phobia patients not being exposed to the 14 drug? I don't think so. 15 Q. Okay. I appreciate the clarification. 16 Before the merger, how 17 important was Paxil in the overall drug 18 portfolio that your company was actively 19 marketing at that time? 20 A. Very important. 21 Q. Can you give me some barometer? I know 22 you all sell about 2 billion dollars' worth a 23 year, right? 24 A. Probably something in that range. 25 Q. And is there any other single drug that SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 70 1 was sold by SmithKline that sells that volume 2 of drugs? 3 A. No. Augmentin, an antibiotic we have 4 comes close, but it's not the same. 5 Q. And approximately what percentage of the 6 SmithKline gross revenues were represented by 7 Paxil sales? 8 A. I'm not certain. I have to check. 9 Q. Did the Glaxo side of the house have any 10 kind of antidepressant? 11 A. Yes, they do. 12 Q. What? 13 A. Wellbutrin. 14 Q. Okay. After the merger, are either of 15 those going to be emphasized or deemphasized 16 more than the other or are they still going to 17 be both actively marketed? 18 A. They're both very actively marketed. 19 Q. Bear with me a minute. I'm going down 20 my checklist. That's a good sign. 21 A. Okay. 22 Q. I know you have told me that you are not 23 an epidemiologist, but do you have a general 24 understanding as a physician and particularly 25 as an academician about the concepts of SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 71 1 statistical significance? 2 A. Yes. 3 Q. Tell us sort of in lay terms what it is 4 and what its significance is when we're 5 talking about a drug study? 6 A. Significance deals with the likelihood 7 that an event does not occur by chance alone. 8 Q. And is that a __ Is that something that 9 typically in scientific literature is 10 published whether it's statistically 11 significant results or not? 12 A. Yes. 13 Q. Is there also a concept known as a 14 confidence interval? 15 A. Yes. 16 Q. What's the significance of that concept? 17 A. I would only be able to tell you in the 18 most general terms. 19 Q. Okay. 20 A. But essentially it is the range of 21 results around which you can have confidence 22 that the results did not occur by chance 23 alone. 24 Q. Is that really what's called a P value, 25 if you know? SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 72 1 A. Well, P is __ P value is the likelihood 2 that an event did not occur by chance at all. 3 Q. So if you are sitting down to read a 4 paper to determine what scientific weight you 5 are to give that paper, are both the 6 statistical significance or not and the 7 confidence interval things that are important 8 to you in determining am I going to put any 9 weight on this or not? 10 A. Yes. The most important would probably 11 be the P value. 12 Q. Okay. So when you see, for example, in 13 Exhibit No. 1 to your deposition that the P 14 value is .001, does that indicate a very high 15 level of confidece in the results? 16 A. That indicates __ 17 MR. PREUSS: I object to 18 form. 19 A. I don't know the nature of the study and 20 I would have to read the study, but a P value 21 would suggest that if it were .05, you have a 22 5 in 100 chance that it would have occurred by 23 chance alone. 24 Q. So to extrapolate from that, if the P 25 value is .001, that indicates that there's a 1 SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 73 1 in 1,000 chance that it would happen by chance 2 alone, correct? 3 A. I'm not sure what you're referring to. 4 Q. I'm referring to __ 5 A. I'm not commenting on the study. If you 6 were to say in any study if somebody showed 7 that event A and event B differed by a P value 8 of .001, that would suggest that there's a 1 9 in 1,000 chance that this difference is 10 attributable to chance. 11 Q. Okay. Is there any rule of thumb, Dr. 12 Yamada, as to the economic value to __ 13 A. I'm sorry. There is one thing, though. 14 Q. Sure. 15 A. And this is very important to look at, 16 the statistical methodology that's used in any 17 of those analyses. For example, P values have 18 to have corrections for multiple comparisons 19 against the single control, and so you might 20 see a P value .001 and then you might have to 21 correct for the fact that you made ten 22 comparisons, because each time you do a 23 comparison, the likelihood that a chance event 24 has occurred increases. 25 Q. Okay. Is that something that in your SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 74 1 experience the peer review process insures 2 that it's done? 3 A. No, no. 4 Q. You don't think that the peer review 5 process insures the scientific integrity of 6 the ultimate published document? 7 A. I wouldn't comment on the integrity of 8 the document, but reviewers are limited by 9 what their knowledge base is. So if somebody 10 doesn't know statistics and they were doing a 11 paper on statistics, they may not comment on 12 something that is statistically invalid. 13 Q. Do you know what the peer review process 14 is? 15 A. Absolutely. 16 Q. And is it a process that is designed to 17 sort of serve as a check on the scientific 18 appropriateness of the methodology and the 19 conclusions and the analysis in published 20 scientific literature? 21 A. That is what it's meant to be, but 22 that's not always what happens. I'm certainly 23 aware of many papers that have invalid 24 methodology when sometimes wonders who 25 reviewed those papers, but it's not an SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 75 1 infrequent event. 2 Q. Sure. 3 A. I believe that academic physicians are 4 flawed by their lack of knowledge just like 5 everybody else. 6 Q. Do you take the New England Journal of 7 Medicine? 8 A. I do. 9 Q. Do you read the editorials? 10 A. I do. 11 Q. Did you read Dr. Marshall Angel's 12 editorial in last May's edition, Is Academic 13 Medicine For Sale? 14 A. I did. 15 Q. What's your impression of it? 16 A. I thought it was very unfortunate. I've 17 been on both sides of the fence and __ only 18 because I've been in academia for most of my 19 life and I've been in the industry for a 20 number of years. 21 I believe that the best people 22 to do clinical trials are people in academic 23 medical centers. I think they're people that 24 are __ hold themselves to the highest 25 standards. SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 76 1 There are many checks and 2 balances in an academic institution. Things 3 are not likely to go bad or wrong where 4 erroneous results are reported also to say the 5 least. 6 So the industry needs 7 academicians to be able to do their studies 8 well. You know, I much rather go to an 9 academic institution than say a group of 10 people. The only reason why they're 11 interested in the study is so they can make 12 money. Whereas, an academic might be 13 interested in the science. 14 Now, in that context it's very 15 difficult if by doing a clinical trial an 16 academician becomes painted as somehow bought 17 by the drug industry, and I thought that 18 that's what Marshall Angel's editorial kind of 19 pointed to. 20 I was __ It was unfortunate. 21 I was personally thinking about writing her a 22 letter myself because I think it reflected a 23 lack of understanding of what the industry's 24 goals are. I believe most of us in the 25 industry __ I mean why did I join industry for SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 77 1 academia? Because my ultimate goal has always 2 been to bring treatments to people, and so 3 science was the way I did it before. But I 4 realize the application of that science really 5 required, you know, something like a 6 pharmaceutical company. That's their 7 practice. That's what most of us want, and 8 Marshall Angel I thought implied that her 9 goals were not the same. 10 Q. If it's any solace, she takes equal joy 11 at taking potshots at guys like me, so. 12 Dr. Yamada, what is the 13 economic value or consequence to a company 14 such as SmithKline Beecham getting regulatory 15 approval for an additional indication for a 16 medicine? 17 A. Well, it depends on the medicine. It is 18 a way of expanding the value of the enormous 19 amount of research we put into a compound that 20 turns out to be safe. You know, the hard part 21 is actually creating the compound that is not 22 only efficacious but safe. Once we have that 23 combination, then it is really incumbent upon 24 us to find out every condition for which this 25 medicine could potentially be used. SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 78 1 And, you know, so in the case 2 of Paxil, it was indicated for depression, but 3 it turned out that it's useful in a wide 4 variety of clinical conditions which are not 5 necessarily related to depression. 6 Q. And is each of those new indications 7 something that increases the market or sales 8 potential of the drug dramatically? 9 MR. PREUSS: I object to 10 form. 11 A. Yes. Sometimes yes, sometimes no. 12 Q. Well, with regard to Paxil, has each of 13 the newly approved indications increased the 14 market potential or sales of that drug? 15 A. Every year the sales of Paxil, Paxil has 16 been growing. It's not always easy to 17 attribute why. 18 Q. You all do know the indications for 19 which the drug is prescribed in terms of we 20 sell roughly this much for this indication and 21 this much for this indication, et cetera; 22 don't you? 23 A. Yes __ No, we don't. I mean that's one 24 of the __ The difference between a 25 prescription and a lab test you have to SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 79 1 actually put a diagnosis on a lab test to get 2 paid. On a prescription you don't have to 3 write the diagnosis. So you can not 4 necessarily link a prescription to a specific 5 diagnosis. 6 Q. I see. So you just have to look at it 7 globally and see sales went up and think that 8 maybe it's because of a new indication and 9 maybe because of other things? 10 A. Yeah. A lot of effort is trying to put 11 in to figure out what caused what, but looking 12 at it from a distance, I would say it's 13 probably very difficult to do. 14 Q. When a drug is launched after the Phase 15 III studies and you get your first approval 16 for your first indication for a drug, does the 17 drug company know all of the adverse side 18 effects at that point in time or does it 19 continue to learn things in the process? 20 A. We do have a postmarketing surveillance 21 process. 22 Q. And do you all learn things about what 23 your drug causes or doesn't cause in the 24 postmarketing surveillance __ 25 A. Absolutely. SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 80 1 Q. I'm going to break your heart. I have 2 no more questions here. Is there something 3 else that you would like to tell me about your 4 company or your drug before I leave? 5 A. No, I __ I think I've had a long day. 6 I'm perfectly happy to stand here. 7 MR. VICKERY: Okay. Thank 8 you. 9 THE WITNESS: Thank you very 10 much. 11 MR. VICKERY: I appreciate 12 your time. 13 MR. PREUSS: I have no 14 questions at this time. 15 MR. ANDERSON: Andy, for the 16 record, this deposition has also been taken in 17 the remaining cases you have against 18 SmithKline Beecham? 19 MR. VICKERY: I don't intend 20 to __ Yeah, I'll say that for the record. I 21 do not intend to take this man's valuable time 22 more than once unless there's some compelling 23 reason to do that, and I do not perceive 24 that. 25 THE VIDEOTAPE OPERATOR: That SPHERION DEPOSITION SERVICES 1_713_650_3500 TADATAKA YAMADA, M.D. 81 1 completes the videotape deposition. The time 2 is 2:42. 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 SPHERION DEPOSITION SERVICES 1_713_650_3500 82 1 C E R T I F I C A T E 2 _ _ _ 3 COMMONWEALTH OF PENNSYLVANIA: 4 : SS 5 COUNTY OF PHILADELPHIA 6 7 I, Frances P. Survilo, 8 Registered Professional Reporter_Notary Public 9 within and for Philadelphia County, 10 Commonwealth of Pennsylvania, do hereby 11 certify that the foregoing testimony of 12 Tadataka Yamada, M.D., was taken before me at 13 2400 One Commerce Plaza, 2005 Market Street, 14 Philadelphia, Pennsylvania on Wednesday, 15 January 24, 2001; that the foregoing testimony 16 was taken by me in shorthand by myself and 17 reduced to typing under my direction and 18 control, that the foregoing pages 1 to 81 19 contain a true and correct transcription of 20 all of the testimony of said witness. 21 22 .................. FRANCES P. SURVILO 23 Notary Public 24 My Commission expires 25 April 25, 2004 SPHERION DEPOSITION SERVICES 1_713_650_3500 83 1 I have read the foregoing 2 deposition and the answers given by me are 3 true and correct, to the best of my knowledge 4 and belief. 5 6 7 8 .......................... 9 TADATAKA YAMADA, M.D. 10 11 12 ........................ 13 Witness to signature 14 15 16 ........................ 17 Address 18 19 20 My Commission expires ................... 21 22 23 24 25 SPHERION DEPOSITION SERVICES 1_713_650_3500 84 1 INSTRUCTIONS TO WITNESSES 2 Read your deposition over carefully. It 3 is your right to read your deposition and make 4 changes in form or substance. You should 5 assign a reason in the appropriate column on 6 the errata sheet for any change made. 7 After making any change in form or 8 substance which has been noted on the 9 following errata sheet along with the reason 10 for any change, sign your name on the errata 11 sheet and date it. 12 Then sign your deposition at the end of 13 your testimony in the space provided. You are 14 signing it subject to the changes you have 15 made in the errata sheet, which will be 16 attached to the deposition before filing. You 17 must sign it in front of a witness. Have the 18 witness sign in the space provided. The 19 witness need not be a notary public. Any 20 competent adult may witness your signature. 21 Return the original errata sheet & 22 transcript to deposing attorney, (attorney 23 asking questions) promptly! Court rules 24 require filing within 30 days after you 25 receive the deposition. Thank you. 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