347 1 IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF WYOMING 2 _ _ _ 3 TOBIN, et al, : NO. 00CV0025 4 Plaintiffs : : 5 vs. : : 6 SMITHKLINE BEECHAM, : Defendant : 7 _ _ _ 8 Continued Videotaped Deposition 9 of DAVID WHEADON, M.D., taken pursuant to 10 notice, at One Commerce Square, Suite 2600, 11 Philadelphia, Pennsylvania, on Thursday, 12 October 19, 2000, beginning at approximately 13 9:00 a.m., before Jeanne Hoyt_Christian, Court 14 Reporter_Notary Public, there being present. 15 _ _ _ 16 APPEARANCES: 17 VICKERY & WALDNER, LLP 18 BY: ANDY VICKERY, ESQUIRE 2929 Allen Parkway, Suite 2410 19 Houston, Texas 77019 Phone: (713) 526_1100 20 Representing the Plaintiffs 21 LAW OFFICE OF VINCE D. NGUYEN BY: DONALD J. FARBER, ESQUIRE 22 2858 Stevens Creek Boulevard San Jose, California 95128 23 Phone: (415) 491_0674 Representing the Plaintiffs 24 25 SPHERION DEPOSITION SERVICES (800) 880_1036 348 1 APPEARANCES CONTINUED: 2 PREUSS SHANAGHER ZVOLEFF & ZIMMER 3 BY: CHARLES F. PREUSS, ESQUIRE 4 AND THOMAS W. PULLIAM, JR., ESQUIRE 5 225 Bush Street, 15th Floor San Francisco, California 6 94104 Phone: (415) 397_1730 7 Representing SmithKline Beecham Company 8 STOEL, RIVES, LLP 9 BY: JOHN A. ANDERSON, ESQUIRE 201 S. Main Street, Suite 1100 10 Salt Lake City, Utah 84111 Phone: (801) 578_6930 11 Representing SmithKline Beecham Company 12 SMITHKLINE BEECHAM 13 BY: ANDREA L. PARRY, ESQUIRE Senior Counsel 14 One Franklin Plaza Philadelphia, Pennsylvania 15 19101 Phone: (215) 751_7022 16 Representing SmithKline Beecham Company 17 18 19 20 21 22 23 24 25 SPHERION DEPOSITION SERVICES (800) 880_1036 349 1 I N D E X 2 _ _ _ 3 WITNESS EXAMINATION 4 DAVID WHEADON, M.D. 5 BY MR. FARBER 350 6 BY MR. VICKERY 431 7 8 9 E X H I B I T S 10 _ _ _ 11 12 NUMBER DESCRIPTION PAGE MARKED 13 11 Letter. . . . . . . . . 351 14 12 Appendix V.1. . . . . . 363 15 13 Appendix V.1. . . . . . 363 16 14 Page 17 of Document. . 369 17 15 Excerpt of Transcript. 377 18 16 Table XI.21. . . . . . 387 19 17 3 Pages of a Document. 394 20 18 Conversation Record. . 424 21 19 Conversation Record. . 426 22 20 8/25/92 Memo. . . . . . 429 23 24 25 SPHERION DEPOSITION SERVICES (800) 880_1036 350 DAVID WHEADON, M.D. 1 THE VIDEO TAPE OPERATOR: 2 We're back on the video record. Today's date 3 is October 19, 2000. The time is 9:10. The 4 witness is still under oath. 5 _ _ _ 6 DAVID WHEADON, M.D., after 7 having been previously duly sworn, was 8 examined and testified as follows: 9 _ _ _ 10 EXAMINATION (CONTINUED) 11 _ _ _ 12 BY MR. FARBER: 13 Q. Doctor Wheadon, you recall, yesterday, 14 we were talking or I was talking at least, 15 considerably about akathisia? Do you recall 16 that? 17 A. Yes. 18 Q. Do you recall, in August or September of 19 1994, that you, at SmithKline, had received 20 notification from the FDA that certain 21 post_marketing labeling revisions must be made 22 because of certain reports on akathisia that 23 had come in from other parts of the world? 24 A. I do not recall that particular event, 25 no. SPHERION DEPOSITION SERVICES (800) 880_1036 351 DAVID WHEADON, M.D. 1 Q. I would like to mark Exhibit 11, a 2 letter from the Department of Health and Human 3 Services, FDA, actually, and if you would care 4 to look at that three_page exhibit when your 5 attorney gets through with it, please. 6 _ _ _ 7 (Whereupon the court 8 reporter marked document as Exhibit 11 for 9 identification.) 10 _ _ _ 11 MR. VICKERY: What is the 12 date of the letter? 13 MR. FARBER: The date of 14 the letter is September 13. 15 MR. VICKERY: '94? 16 MR. FARBER: '94. 17 BY MR. FARBER: 18 Q. My question is, Doctor, do you remember 19 when this letter came into SmithKline? 20 A. I do not recall exactly when this letter 21 came into SmithKline, no. 22 Q. Do you recall the contents of the letter 23 as you sit here today? 24 A. I reviewed the contents of the letter, 25 but I do not recall the contents of the SPHERION DEPOSITION SERVICES (800) 880_1036 352 DAVID WHEADON, M.D. 1 letter, yes. I have just reviewed it, now 2 that you handed it to me. I do not recall the 3 contents of this letter. 4 Q. Do you recall the issue at all of 5 labeling and akathisia in the 1994 or 6 thereabouts time frame? 7 A. Again, I can only respond to the letter 8 that you put in front of me. If you have a 9 question concerning this letter, I can respond 10 to it. 11 Q. My question is whether in 1994 or 5, 12 say, in that two_year period, you recall a 13 labeling requirement that was imposed on 14 SmithKline by FDA. That's the general 15 subject. Do you recall that? 16 A. Again, I do not recall a labeling 17 requirement in 1994 imposed upon SmithKline by 18 the FDA. If you have a question concerning 19 the letter you have just showed me, then I can 20 answer a question that you might have 21 concerning this letter. 22 Q. Well, if you don't have any recollection 23 on the subject, then I'm not going to ask you, 24 but based on your standard operating 25 managerial practices, do you think you would SPHERION DEPOSITION SERVICES (800) 880_1036 353 DAVID WHEADON, M.D. 1 have seen this letter when it arrived in '94? 2 A. I would not necessarily have seen this 3 letter. As you see, it is addressed to Doctor 4 Mike Brennan, who, at the time, was in 5 regulatory affairs. At that time, I was not 6 head of regulatory affairs. I was in a 7 different position. 8 Q. I understand that, but based on your 9 standard operating procedures and the 10 administrative routing of correspondence, 11 would this have been an interest item that you 12 think you would have received? 13 A. It may or may not, quite frankly, as I 14 pointed out, I do not recall seeing this 15 particular letter. 16 Q. At some point __ well, the question is, 17 do you recall at any point, after Paxil's 18 approval in December of '92, a labeling 19 requirement that dealt with akathisia that was 20 imposed on SmithKline by the FDA? 21 In other words, I'm opening 22 up the time frame to any time from '92 to the 23 present regarding __ let me finish __ 24 regarding akathisia? 25 A. Again, what you have put in front of me SPHERION DEPOSITION SERVICES (800) 880_1036 354 DAVID WHEADON, M.D. 1 is a request by the FDA to consider several 2 additions to the label to the post_marketing 3 report section. If that is what the question 4 is __ 5 Q. No, it is not the question. The 6 question is not the letter now. The question 7 is your recollection of the subject of 8 labeling, akathisia and a mandatory 9 requirement to that effect at any time between 10 '92 and the present regarding akathisia. 11 A. I do not recall, separate from this 12 exhibit that you put in front of me, any 13 discussion concerning a mandatory requirement 14 of putting akathisia into the label. 15 Q. So is it fair to say that prior to 16 today, prior to this instant, this hour, that 17 you were unaware that an akathisia labeling 18 requirement was placed on you by the FDA? 19 A. What I'm saying is, I do not recall a 20 specific labeling mandatory requirement, as 21 you have put it, concerning akathisia, placed 22 upon SmithKline by the FDA. 23 Q. Let's delete now the FDA and the 24 mandatory nature of the directive. 25 Do you recall the issue of SPHERION DEPOSITION SERVICES (800) 880_1036 355 DAVID WHEADON, M.D. 1 akathisia and labeling coming up at all in the 2 last six years? 3 A. Again, using the exhibit in front of me, 4 which I would like to use to try to be a bit 5 more concrete in attempting to answer your 6 question, I do recall issues around 7 neuroleptic malignant syndrome, extrapyramidal 8 syndrome being added to the label and in the 9 post_marketing report section pursuant to your 10 showing me this particular letter. 11 Q. I hear you. 12 Now, under this 13 extrapyramidal syndrome, there is the word 14 akathisia in parentheses. Did you 15 intentionally omit that or did you connect 16 akathisia with extrapyramidal syndrome, as the 17 letter here indicates? 18 A. If you are asking me to read what is in 19 here, the FDA has asked that the subsection, 20 meaning post_marketing reports subsection of 21 the labeling, be revised to read, voluntary 22 reports of adverse events which have occurred 23 in temporal relationship to Paxil, but which 24 may have no causal relationship with the drug 25 include, and among the long list of things the SPHERION DEPOSITION SERVICES (800) 880_1036 356 DAVID WHEADON, M.D. 1 FDA has put in here, extrapyramidal syndrome 2 (symptoms have included akathisia, 3 bradykinesia, cogwheel rigidly, hypertonia, 4 oculogyric crisis associated with concomitant 5 use one of pimozide in one case, tremor and 6 trismus). 7 Q. I don't want to interrupt. It is in the 8 record. I can read it. That was not my 9 question. 10 My question was, you read 11 and testified that you had recalled the word 12 extrapyramidal syndrome in regard to labeling 13 requirements, and my question concerned 14 akathisia, which was in parentheses after 15 that, whether you recalled that word being 16 attached to that word extrapyramidal 17 syndrome. That was the question. 18 A. As I pointed out, in terms of the letter 19 you put in front of me, I see that akathisia 20 is included as a symptom behind extrapyramidal 21 syndrome. 22 Q. Forget the letter, Doctor. That was not 23 my question. I can read the letter. My 24 question was whether you recalled akathisia 25 being tied to extrapyramidal syndrome on this SPHERION DEPOSITION SERVICES (800) 880_1036 357 DAVID WHEADON, M.D. 1 general subject. 2 A. And as I pointed out, pursuant to your 3 showing me the letter, I recall akathisia 4 being tied to extrapyramidal syndrome based on 5 seeing the letter. Prior to seeing the 6 letter, I did not recall a mandatory labeling 7 requirement placed upon SmithKline, as you 8 phrased it, concerning akathisia. 9 Q. Okay, thank you. 10 If you weren't __ I know 11 you are a very busy man. If you didn't 12 specifically see everything, I know you 13 delegate authority, and it is a large 14 organization at SmithKline. 15 Based on the standard 16 operating procedures at SmithKline in '94, 17 what senior officials would have been more 18 aware of the detailed nature of this labeling 19 requirement, besides yourself? 20 A. Quite frankly, I cannot give you any 21 definite answer to that. The letter is 22 addressed to Doctor Michael Brennan, who is 23 someone who is someone who was in regulatory 24 affairs at the time. I don't recall who in 25 1994 Doctor Brennan was reporting to in SPHERION DEPOSITION SERVICES (800) 880_1036 358 DAVID WHEADON, M.D. 1 regulatory affairs. In 1994, I was in the 2 clinical organization. I may or may not have 3 seen this letter. I quite frankly don't 4 recall seeing it specifically. I can't give 5 you more clarity than that. 6 Q. Which leads us into the next subject. I 7 guess you are double_hatted, at least now in 8 regulatory affairs. 9 When did you take over that 10 position in regulatory affairs? 11 A. I took my position in regulatory affairs 12 in 1997. 13 Q. Now, Thomas Klein was also a SmithKline 14 Beecham regulatory affairs officer, was he 15 not? 16 A. Tom Klein is a regulatory __ is a 17 SmithKline Beecham employee, who works in 18 regulatory affairs. 19 Q. He is still there? 20 A. He is still there, yes. 21 Q. So he is your subordinate in that 22 organization? 23 A. He reports to someone who reports to 24 me. 25 Q. Why did SmithKline __ just an open SPHERION DEPOSITION SERVICES (800) 880_1036 359 DAVID WHEADON, M.D. 1 question, not to imply anything __ why did 2 SmithKline appoint you double_hatted in this 3 position? 4 A. I'm not quite sure what you mean by 5 double_hatted. 6 Q. Well, you are also the medical director 7 in your technical medical position and 8 regulatory affairs, right? 9 A. That is not correct. 10 Q. Sorry. I forgot your exact title. But 11 you are now double_hatted, right? 12 A. That is not correct. 13 Q. Okay, what are you? 14 A. I am vice_president, regulatory affairs 15 and product professional services. 16 Q. Prior to 1997, that structure was not in 17 effect; correct? 18 A. That is not correct. 19 Q. I won't get into that. I guess it is 20 not that important. But after this letter 21 came in in September of '94, what actions 22 would have been taken by SmithKline Beecham to 23 effect these labeling changes? 24 A. Quite frankly, a review of the data 25 would have been undertaken and a discussion SPHERION DEPOSITION SERVICES (800) 880_1036 360 DAVID WHEADON, M.D. 1 with the FDA would follow concerning whether 2 or not these additions would be made or not. 3 Q. That raises an issue. I understood this 4 to be mandatory, and you said whether they 5 would be taken or not. I understand the 6 language could at some times by FDA be a 7 suggestion, but would you interpret this 8 letter as a directive by FDA? 9 A. I would not necessarily interpret this 10 letter as a directive, no. 11 Q. So is that because it says should? Are 12 we drawing distinctions __ and I, as a former 13 military guy, do draw distinctions on key 14 words, should, may, shall and so forth. And 15 you interpret this directive as a 16 non_mandatory suggestion? 17 A. If you look at Page 2, second paragraph, 18 end of that paragraph: We request that these 19 events be added to the post_marketing report 20 subsection of the labeling. 21 As with any request by the 22 FDA, the sponsor has an ability to go back and 23 discuss the requested change with the agency, 24 and ultimately, a decision is made, and an 25 agreement is reached on what the label change SPHERION DEPOSITION SERVICES (800) 880_1036 361 DAVID WHEADON, M.D. 1 will be, if any. 2 Q. Okay, I could go on for an hour at this, 3 but I won't for a minor point, but you 4 interpret the word request as simply a 5 suggestion? 6 A. As I pointed out, the FDA has made a 7 request, but within the regulations of 8 negotiating with the sponsor, the sponsor has 9 the ability to come back to the FDA with 10 additional requests around negotiating the 11 label, the language, provide additional data 12 that the FDA may not have had in front of him 13 in requesting this change. 14 Q. Of course. And did you, SmithKline, do 15 that in this case? 16 A. I do not recall what happened around 17 this particular case. 18 Q. But as you sit here today, you believe 19 or would assess that these changes were made 20 promptly after the issuance of this letter, 21 would you not? 22 A. I would not be able to give you an 23 opinion on that. I don't recall exactly what 24 happened around this particular case. 25 Q. Now, you recall, yesterday, I was SPHERION DEPOSITION SERVICES (800) 880_1036 362 DAVID WHEADON, M.D. 1 bringing up the subject of akathisia in the 2 non_US data base. Do you recall my 3 questioning in that area, we were talking 4 about that? 5 A. I recall, yes. 6 Q. And I made the __ well, I will stick 7 with the questions here. 8 Upon a receipt of that 9 letter, would it have been standard procedure 10 __ and as you can see from that letter, only 11 two incidents, two, precipitated the issuance 12 of this change, based on two reports of 13 akathisia. 14 Do you agree with that? 15 A. I do not agree with that. 16 Q. What would be the proper interpretation 17 of those two entries on akathisia then? Do 18 you think there was a hundred, and they only 19 mentioned two or what? What is your 20 explanation for that? 21 A. To bring you back to Page 2 of the 22 letter that you are now referring to again, 23 which was Exhibit 11, the term that was 24 actually added is extrapyramidal syndrome. 25 The adjective following that or the SPHERION DEPOSITION SERVICES (800) 880_1036 363 DAVID WHEADON, M.D. 1 explanatory sentence is, symptoms have 2 included akathisia, bradykinesia, cogwheel 3 rigidity, et cetera. 4 So if you look at the 5 number of extrapyramidal syndromes that were 6 reported in the table in the letter from the 7 FDA, there were more than simply two. So your 8 statement is not correct. 9 Q. Well, two out of three are correct. Two 10 of the three extrapyramidal syndromes had 11 akathisia examples attached; correct? 12 A. In terms of the table and this letter, 13 two of the three have akathisia and other 14 symptoms listed after extrapyramidal 15 syndrome. 16 Q. Okay, now, on akathisia in the non_US 17 data base, I have another exhibit. We are at 18 Exhibit 12. Actually, we will have two 19 exhibits. I have non_US, and I have two 20 categories here. We will do Exhibit 12 here, 21 and we will do Exhibit 13 for a second. 22 _ _ _ 23 (Whereupon the court 24 reporter marked documents as Exhibit 12 and 13 25 for identification.) SPHERION DEPOSITION SERVICES (800) 880_1036 364 DAVID WHEADON, M.D. 1 _ _ _ 2 MR. VICKERY: What's 3 Exhibit 12? 4 MR. FARBER: Actually, the 5 lower numbered pages, we will make Exhibit 12, 6 which are numbered 137, and then we have the 7 top one, which is numbered 157, which would be 8 Exhibit 13. 9 So Exhibit 12 is basically 10 a four_page exhibit, and Exhibit 13 is a 11 two_page exhibit. 12 BY MR. FARBER: 13 Q. Now, this is a large exhibit, Doctor, 14 but I only have a question or two. I just 15 wanted to get it on the record. And I could 16 be wrong, but I counted these quickly, and I 17 colored them. I counted, in these two 18 exhibits together, 28 akathisia incidents with 19 28 patients. 20 A. I cannot comment on that. 21 Q. Yes, I know. 22 My question is, there is 23 two, and you don't necessarily agree with me, 24 but I counted two incidents of akathisia that 25 precipitated this change of labeling, and I'm SPHERION DEPOSITION SERVICES (800) 880_1036 365 DAVID WHEADON, M.D. 1 counting 28 akathisia entries in the data 2 base, which would have been present at the 3 hearing or the approval process in 1992. 4 And my question is this. 5 With such a, what I would say is a concern by 6 FDA about akathisia, did that precipitate your 7 review of your data bases to see how many 8 other akathisia entries may have been present 9 during the NDA? 10 A. Well, again, the FDA did not express a 11 concern about akathisia in the letter that was 12 sent to us. 13 Q. We disagree on that, but okay, go 14 ahead. 15 A. So I wanted to be very clear about 16 that. So as a result, I really can't answer 17 your question any further than that. 18 Q. As far as you know, at least your 19 personal knowledge, there was no review 20 directed at this time to go back and count the 21 akathisia cases in the data base? That's a 22 fair statement on my part, isn't it? 23 A. I don't know what was done 24 specifically. I do not recall what was done 25 in relation to the letter that's marked as SPHERION DEPOSITION SERVICES (800) 880_1036 366 DAVID WHEADON, M.D. 1 Exhibit 11. 2 Q. Okay, now, let's just assume for 3 hypothetical purposes that there would have 4 been a review, let's say, an urgent symptom of 5 an urgent disease came to SmithKline's 6 attention in September of '94, and upon 7 review, it was determined at SmithKline that a 8 past historical review should be conducted 9 based upon this information. 10 Who would have conducted 11 that review? What office and what code or 12 what entity would have been responsible for 13 that at SmithKline? 14 A. Well, based on your hypothetical __ 15 Q. Based on the hypothetical that somehow, 16 a review must be __ 17 A. A review would have been carried out by 18 clinical safety, which I pointed out to you 19 yesterday is the individual group within 20 SmithKline that carries out safety analyses, 21 and there may have been an involvement with 22 clinical research in terms of looking at the 23 outcome of those analyses. 24 Q. And in September of 1994, if you know, 25 who was the head of clinical safety at SPHERION DEPOSITION SERVICES (800) 880_1036 367 DAVID WHEADON, M.D. 1 SmithKline at that time? 2 A. I quite frankly do not recall. 3 Q. Who is the head of clinical safety now? 4 A. As I mentioned to you yesterday, Doctor 5 Ian Hudson is the head of clinical safety. 6 Q. How long has Doctor Hudson been at 7 SmithKline? 8 A. I do not know. 9 Q. As we sit here today, based upon what 10 you now know and your experience, of course, 11 is it your testimony that you don't consider 12 akathisia a serious and urgent __ I will avoid 13 the compound question. 14 You don't consider 15 akathisia a serious adverse event in 16 determining the safety of Paxil? 17 A. I don't quite understand what you are 18 asking. 19 Q. Do you consider akathisia a serious 20 adverse event if it occurred on any Paxil 21 patient? 22 A. It quite frankly depends on the context 23 in which it occurs. 24 Q. But in the context of my question 25 yesterday about a red flag, do you consider SPHERION DEPOSITION SERVICES (800) 880_1036 368 DAVID WHEADON, M.D. 1 the word akathisia to send up a red flag on a 2 particular patient? 3 A. As I commented yesterday when you asked 4 that same question, akathisia occurring in the 5 context of a patient is not necessarily a red 6 flag, as you say. 7 Q. No, but I would like you to be more 8 precise. You said not necessarily. But as a 9 Board_eligible psychiatrist or even a general 10 physician, and a nurse subordinate told you 11 that this patient was suffering from 12 akathisia, would that send up an alerting 13 signal or red flag to you? 14 A. Not necessarily. 15 Q. It would depend on the situation; 16 correct? 17 A. Exactly. 18 Q. Now, you went to SmithKline in February 19 of '92, as I recall? 20 A. That's correct. 21 Q. And you presented the recommendation of 22 the company on either safety or efficacy at 23 the committee meeting in October of '92? 24 A. That is correct. 25 Q. Now, jumping ahead a little bit, after SPHERION DEPOSITION SERVICES (800) 880_1036 369 DAVID WHEADON, M.D. 1 Paxil was approved on December 29th, '92 __ 2 excuse me, after the board meeting on October 3 5th of '92, and before it was approved on 4 December 29th, SmithKline did have to work 5 through the labeling final instructions, if 6 you will, on labeling in that two_month 7 period; correct? 8 A. That is one of the things that happens 9 between the advisory committee and ultimate 10 approval, yes. 11 Q. Now, I have taken this __ there has been 12 labeling changes since '92, I understand, but 13 this was the initial __ I will represent that 14 as exhibit __ what are we at, Exhibit 14? 15 _ _ _ 16 (Whereupon the court 17 reporter marked document as Exhibit 14 for 18 identification.) 19 _ _ _ 20 BY MR. FARBER: 21 Q. Just a general question there. You 22 don't have to absorb every word of this, but 23 in regard to drug abuse and dependence entry, 24 there is a couple of subparagraphs, a 25 controlled substance, and I'm referring SPHERION DEPOSITION SERVICES (800) 880_1036 370 DAVID WHEADON, M.D. 1 specifically now to physical __ Number 2 2 there, physical and psychologic dependence. 3 MR. PREUSS: Excuse me, Mr. 4 Farber. Can you put some context into this? 5 This is Page 17 of some document that bears no 6 date at all. 7 MR. FARBER: Yes. I 8 represent to you that it is the approved 9 proposed labeling that was first approved when 10 Paxil was approved on December 29, 1992. And 11 this was part of the overall __ there is 12 probably 10 or 12 pages in this. Also, just 13 for information, this particular paragraph 14 hasn't changed. 15 BY MR. FARBER: 16 Q. Now, my question is, in regard to the 17 paragraph with bold print, physical and 18 psychologic dependence on the subject of drug 19 abuse. 20 Do you recall formulating 21 the labeling instructions on this paragraph? 22 A. Quite frankly, I have great difficulty 23 with dealing with this one sheet of paper 24 within which I can place no context. I don't 25 necessarily recall that this is, indeed, the SPHERION DEPOSITION SERVICES (800) 880_1036 371 DAVID WHEADON, M.D. 1 proposed label that was put forth for FDA 2 review at the time of the initial approval of 3 Paxil, so I am actually not __ 4 Q. You are taking my word for it, and I 5 don't want you to do that. 6 A. So I'm not very comfortable commenting 7 on all on what you put in front of me. 8 Q. I am representing it as a fact, and you 9 shouldn't have to accept my word on it. I 10 agree. 11 My question, though, is the 12 paragraph itself, do you agree that or do you 13 do you not agree that this paragraph was the 14 labeling instruction on physical and 15 psychologic dependence after Paxil was 16 approved? 17 A. I really would have to have the 18 labeling, the actual approved labeling in 19 front of me to compare what you have given me 20 to that. I don't recall that section well 21 enough to be able to comment any further that 22 than that. 23 Q. Well, forget what should or shouldn't 24 be. In regard to physical and psychologic 25 dependence, as we sit here today, do you think SPHERION DEPOSITION SERVICES (800) 880_1036 372 DAVID WHEADON, M.D. 1 this is an adequate warning or labeling 2 instruction in regard to Paxil's 3 characteristics in that area of dependency and 4 withdrawal? 5 A. I'm not quite sure what you are asking 6 me. 7 Q. I'm asking you to kind of elevate 8 yourself above this particular paper and go to 9 your general knowledge now on Paxil. You have 10 been now with the company eight years, and you 11 have studied and are aware, I presume, of 12 Paxil's traits in either causing or unrelated 13 to addiction and withdrawal, and based on that 14 general knowledge I think you probably have, 15 do you consider as a labeling instruction 16 today that this paragraph, physical and 17 psychological dependence, is a good labeling 18 instruction? 19 A. Well, quite frankly, it is an outdated 20 labeling instruction, because there have been 21 a number of systematic studies in humans 22 looking at the potential for Paxil for abuse, 23 tolerance and physical dependence. So 24 actually, there is data to date to negate the 25 statement that it has not been systematically SPHERION DEPOSITION SERVICES (800) 880_1036 373 DAVID WHEADON, M.D. 1 studied, because, in fact, it has been. 2 Q. That's in regard to the year 2000. Now, 3 I'm asking you to go back to 1992. 4 MR. PREUSS: Mr. Farber, 5 I'd like you to wrap this area up, because 6 dependence and withdrawal is not the subject 7 matter of the 30(b)(6). 8 MR. FARBER: I understand 9 your concern. 10 MR. PREUSS: And I thought 11 we made that clear at the start. 12 MR. FARBER: Well, I 13 connect it. Basically, we are talking now __ 14 you know, I have a fraud count in my 15 Complaint. You are aware of that? 16 MR. PREUSS: You have told 17 me that, yes. 18 MR. FARBER: Okay, and as 19 part of fraud, allegedly misleading statements 20 on any facet of Paxil to get Paxil approved by 21 the FDA in 1992 is certainly an element of 22 fraud, and it is certainly discoverable 23 information. Whether or not it is a suicide 24 or violence issue is not the issue. The issue 25 is misleading information of any type to get SPHERION DEPOSITION SERVICES (800) 880_1036 374 DAVID WHEADON, M.D. 1 Paxil approved. 2 MR. PREUSS: Let's just 3 wrap this up and move on to something else, 4 please. 5 MR. FARBER: Well, I'm 6 going as fast as I can. If your client would 7 be just a little more specific __ and I'm not 8 saying he shouldn't be evasive, but the more 9 evasive he is, the longer it takes. 10 MR. PREUSS: He is not 11 being evasive. You have given him Page 17 of 12 a document none of us have any idea, nor is 13 there any date to it. Hardly a fair inquiry. 14 MR. FARBER: My last 15 question disregards the relevance of any 16 data. I want to know if it is a good entry 17 for what he knew about Paxil in December of __ 18 or October of '92. That's the line of inquiry 19 right now. 20 MR. PREUSS: Ask your 21 question. 22 BY MR. FARBER: 23 Q. To repeat, do you think this paragraph, 24 physical and psychological dependence, is a 25 good entry for the withdrawal issue on Paxil SPHERION DEPOSITION SERVICES (800) 880_1036 375 DAVID WHEADON, M.D. 1 on what you knew in October, November and 2 December of 1992? 3 A. Quite honestly, Mr. Farber, I do not 4 recall what I knew in October, November and 5 December of 1992 that I could give you any 6 answer to that question. 7 Q. Now, I do have a question on the middle 8 of the paragraph. It says: While the 9 clinical trials did not reveal any tendency 10 for any drug_seeking behavior, these 11 observations were not systematic, and it is 12 not possible to predict on the basis of this 13 limited experience the extent to which a CNS 14 active drug will be misused. 15 I'm really, I guess, 16 ignorant and not aware of this. I want to 17 know what the scientific term or definitional 18 term of systematic is in this respect. 19 What is a systematic 20 observation for purposes of a warning? Is it 21 a formal study or is it some sort of 22 disciplined approach to a study? What does 23 systematic mean in this context? 24 A. It can mean a number of different 25 things, quite frankly. SPHERION DEPOSITION SERVICES (800) 880_1036 376 DAVID WHEADON, M.D. 1 Q. I assume that, but what would you assume 2 systematic to mean? A formal Par study 3 approved by FDA on this subject? 4 A. Not knowing where this comes from, not 5 knowing the author of this, in terms of what 6 you put in front of me, I really cannot give 7 you an opinion beyond that. 8 Q. Okay, fair enough. 9 Now, you appeared at the 10 October 5, '92 committee meeting, do you 11 remember that, in October 5th of 1992? 12 A. Yes. 13 Q. I'm sure you prepared a lot for that. 14 Now, what are we up to, Exhibit 15? Now, you 15 said you didn't recall exactly what you knew 16 about withdrawal or the addiction issue. 17 Did you speak to that, do 18 you recall, during that committee hearing in 19 October of '92, to the board members, who were 20 then going to vote on Paxil? 21 A. I spoke to the advisory committee to the 22 Food and Drug Administration that met on that 23 date, yes. 24 Q. Do you remember discussing the issue of 25 addiction, or my term, physical dependency, SPHERION DEPOSITION SERVICES (800) 880_1036 377 DAVID WHEADON, M.D. 1 that particular issue that I just showed you 2 in Exhibit 14, do you remember speaking to 3 that issue at that committee? 4 A. I remember speaking on a number of 5 safety issues, and that might have been one of 6 the topics, yes. 7 Q. Let's see if I can refresh your memory a 8 little better. Exhibit 15. 9 _ _ _ 10 (Whereupon the court 11 reporter marked document as Exhibit 15 for 12 identification.) 13 _ _ _ 14 BY MR. FARBER: 15 Q. I will let you review that for a 16 minute. 17 Do you recall a study __ 18 the number is P_A_R, Par __ by the way, does 19 that mean Paroxetine? 20 A. Yes. 21 Q. That's what I thought it meant. On 22 study Par 08_03 conducted in Yugoslavia from 23 late '89 to early '91, do you remember 24 reviewing that study in general? 25 A. I think the actual study is Par 08_3, SPHERION DEPOSITION SERVICES (800) 880_1036 378 DAVID WHEADON, M.D. 1 which was a long term depression study done in 2 Yugoslavia. 3 Q. By the way, maybe you don't know, but 4 who was the principal investigator in 5 Yugoslavia on that study? 6 A. I do not know. 7 Q. I'm sure that fact is in the records 8 somewhere at SmithKline, no doubt; correct? 9 A. I have no idea. 10 Q. You don't have any idea whether you keep 11 records of who principal investigators are? 12 A. I said, Mr. Farber, that I have no idea 13 who the investigator in Par 08_3 is or was. 14 Q. That wasn't my question. My question 15 was whether the records would reflect that, 16 and you said you had no idea. 17 A. I would imagine that records would 18 reflect that, yes. 19 MR. FARBER: That's what 20 I'm talking about. I don't want to be 21 contentious here, but the more evasion we get, 22 the longer it takes. 23 MR. PREUSS: He is 24 answering your questions, Mr. Farber, to the 25 best of his ability. SPHERION DEPOSITION SERVICES (800) 880_1036 379 DAVID WHEADON, M.D. 1 MR. FARBER: Well, he 2 didn't. I had to spend an extra two minutes 3 to get an admission here, which I thought was 4 fairly obvious. And just for the record, 5 that's why these things take so long. And I'm 6 going to take as long as I have to, no matter 7 how many days, to get the information. End of 8 speech. 9 BY MR. FARBER: 10 Q. Now, on Page 98, Doctor Wheadon, I'm 11 going to ask you to focus on discussion of 12 this Yugoslav study, Par 08_3, down through 13 Lines 17 through 22. 14 Now, I'm going to ask you 15 to read starting at the paragraph at Line 17 16 on Page 98 down through Line 22. Would you 17 read that, please? 18 A. "As you can see here, few numbers of 19 patients experienced any adverse event after 20 being randomized off Paroxetine into the 21 placebo group and the percentages are 22 certainly very small. These were the common 23 adverse events seen in that small population 24 in our attempt to systematically assess a 25 discontinuation syndrome. Yes, Tom." SPHERION DEPOSITION SERVICES (800) 880_1036 380 DAVID WHEADON, M.D. 1 Q. Okay, well, what did you mean there, if 2 you recall, when you said, in our attempt to 3 systematically assess a discontinuing 4 syndrome? 5 A. If I recall correctly, in this 6 particular study, patients were treated with 7 Paroxetine for a set period of time. I don't 8 remember exactly the length of time. They 9 were then randomized either to remain on 10 Paroxetine or to go on to placebo. 11 The question being asked in 12 that study was whether or not there would be a 13 greater rate of relapse of symptoms in those 14 patients who went off drug onto placebo, as 15 opposed to those patients who remained on drug 16 for up to one year of treatment. 17 The systematic assessment 18 of a discontinuation syndrome that I refer to 19 in Line 22 was looking at what, if any, 20 adverse effects were reported by those 21 patients who were randomized onto placebo off 22 of Paroxetine. 23 Q. And you concluded, did you not, that in 24 the placebo group, that the number of relapse 25 incidents were 18, as opposed to the SPHERION DEPOSITION SERVICES (800) 880_1036 381 DAVID WHEADON, M.D. 1 Paroxetine group that only had 4? I'm not 2 asking you to remember the exact numbers, but 3 do you recall a greater, much, much greater 4 number of placebo patients suffered, quote, 5 relapse than Paroxetine? 6 A. I don't recall the exact numbers. I 7 have not reviewed Par 08_3 in preparation for 8 this deposition. I do recall that more 9 patients on placebo had relapse, meaning 10 return to depressive symptoms, than those on 11 Paroxetine. 12 MR. FARBER: And just for 13 the record, counsel, this is on my notice on 14 Par 08_3, and I'm going to want a lot more 15 information on that, whether it is with Doctor 16 Wheadon or your other witness or later. 17 BY MR. FARBER: 18 Q. But I'm going back to the word 19 discontinuation. If you said to the board, on 20 their voting day, that you had an attempt in 21 Par 08_3 to systematically assess a 22 discontinuance syndrome, why would your 23 instructions issued two months later state to 24 the contrary, that there was no attempt to 25 systematically observe the discontinuation SPHERION DEPOSITION SERVICES (800) 880_1036 382 DAVID WHEADON, M.D. 1 syndrome? 2 A. I can only speak to the document that 3 you have put in front of me, which I can 4 identify, and the statement is that this was 5 our attempt to systematically assess a 6 discontinuation syndrome, meaning using the 7 Par 08_3 data. I cannot speak to what you 8 keep going back to, that being Exhibit 14, 9 which I have no ability to identify or to 10 verify. 11 Q. Well, I will take the time. Maybe we 12 can get this later at some point, but I do 13 want the contradiction explained at some 14 point. I understand what you are saying now. 15 But if what I put before 16 you is true, on Exhibit 14, if that's true, 17 can you explain the obvious discrepancy 18 between the systematic and the non_systematic 19 words in these two documents? 20 A. I cannot at this time, no. 21 Q. Now, on the issue of relapse, unquote, 22 versus withdrawal or discontinuation syndrome, 23 do you recall, at the October 5th meeting, 24 that the issue of relapse criteria that had 25 been established for Par 08_3 back in '88 or SPHERION DEPOSITION SERVICES (800) 880_1036 383 DAVID WHEADON, M.D. 1 when the protocol was written, do you recall 2 what the relapse __ in general, I'm not asking 3 you to quote it, but do you recall what the 4 relapse criteria was? 5 A. I do not recall exactly what that 6 criteria was. 7 Q. Do you remember the subject, though, of 8 the relapse criteria, whether it was too 9 stringent or about right? Do you recall the 10 criteria standard being discussed at the 11 committee meeting during discussions? 12 A. Quite frankly, I do not recall. 13 Q. Now, I'm going to ask you a more general 14 question based on your professional 15 background. 16 On the general issue of 17 relapse and withdrawal, I don't know if this 18 is true. Would you tell me if it is true that 19 if a person, a patient, who has been taking 20 Paxil __ and can we define basically the 21 withdrawal conditions as either being __ and I 22 think I have quoted this from your 23 publications __ either being a taper, a 24 gradual tapering down of Paxil use or an 25 abrupt quitting of Paxil altogether, so a SPHERION DEPOSITION SERVICES (800) 880_1036 384 DAVID WHEADON, M.D. 1 reduction of Paxil use by a patient. 2 When that occurs, and two 3 days later, let's assume, the patient was 4 taking Paxil regularly for three months under 5 my hypo. Two days later, after abruptly 6 quitting, the patient then suffers symptoms. 7 Now, my question is concerning symptoms. 8 Would you agree that the 9 symptoms upon review by the physician, that it 10 might be an open question whether the patient 11 were then suffering withdrawal or was 12 suffering a relapse into his prior depressive 13 state? 14 In other words, is that a 15 difficult situation or is it an important 16 situation to assess correctly from the 17 physician's point of view? 18 MR. PREUSS: Mr. Farber, 19 what does this have to do with the Lacuzong 20 case? 21 MR. FARBER: It goes back 22 to the issue of approval. If we could __ I 23 want to go off the record. 24 MR. PREUSS: I don't want 25 to go off the record. SPHERION DEPOSITION SERVICES (800) 880_1036 385 DAVID WHEADON, M.D. 1 MR. FARBER: Okay. It has 2 to do with fraud getting this approved. 3 MR. PREUSS: Mr. Farber, 4 the subject matter of today's deposition was 5 defined in the 30(b)(6), which, for whatever 6 reason, you apparently have not read, and you 7 are entitled to ask any questions you want 8 within that subject matter as it relates to 9 the Lacuzong case, which has nothing to do 10 with withdrawal at all. 11 So I think you are going to 12 have an opportunity to deal with that in 13 another context. The witness hasn't been 14 prepared on this. And I want to use the time 15 fruitfully for you inasmuch as the 30(b)(6) 16 defines the scope of this deposition, and we 17 are going to argue that you get no more 18 questioning in any of the areas in the 19 30(b)(6), so I would like to make the best use 20 of this time in covering that, because you 21 will have ample time to deal with your 22 withdrawal case, which has nothing to do with 23 Lacuzong. 24 MR. FARBER: I appreciate 25 that, counsel. I agree with what you just SPHERION DEPOSITION SERVICES (800) 880_1036 386 DAVID WHEADON, M.D. 1 said, but I'm talking now about Doctor 2 Wheadon's own presentation before this 3 committee in October of 1992 to get this drug 4 approved. 5 MR. PREUSS: But that 6 wasn't your last question. 7 MR. FARBER: That is the 8 general line of query here. I'm only dealing 9 with his representations and why he said what 10 he said at that committee hearing to get this 11 drug approved. That's very important. 12 Now, if you want to go on 13 the record now and say we will discuss that 14 entire subject at a later deposition in San 15 Jose or anywhere, that's fine with me. I will 16 take your commitment there. But whether it is 17 Doctor Wheadon or not, I'm discussing his 18 testimony now before this committee. 19 MR. PREUSS: Ask your 20 question as it relates to his appearance at 21 the hearing then. 22 BY MR. FARBER: 23 Q. On the issue of relapse, was the 24 standard of relapse discussed at that hearing 25 in your exchanges with committee hearing? Do SPHERION DEPOSITION SERVICES (800) 880_1036 387 DAVID WHEADON, M.D. 1 you remember that? 2 A. As I stated earlier, Mr. Farber, I do 3 not recall a discussion concerning the 4 definition of relapse in the Par 08_3 data. 5 Q. Okay, I'm done with that subject. Now, 6 let's get into suicide. 7 _ _ _ 8 (Whereupon the court 9 reporter marked document as Exhibit 16 for 10 identification.) 11 _ _ _ 12 BY MR. FARBER: 13 Q. Now, Doctor, Exhibit 16 is taken from 14 the NDA and the data base, as you can see, 15 from Bates Number 548 at the bottom, and it is 16 numbered __ actually, there is a 300 page 17 number on it, and the top is identified as 18 Table XI.21. It is Attempted Suicides and 19 Overdoses _ Worldwide Data. 20 Now, I just want to confirm 21 the format and the data on this sheet, and my 22 question concerns __ my question concerns the 23 suicides, attempted suicides percentage, and 24 we have here a number data base for Paroxetine 25 on the left of 1562, and the other active drug SPHERION DEPOSITION SERVICES (800) 880_1036 388 DAVID WHEADON, M.D. 1 is 464, the placebo was 497. 2 I would like to ask what __ 3 under suicides there, under N_1562, the figure 4 you see where it says 12 and then (0.7 5 percent)? 6 A. I see that, yes. 7 Q. And tell me what that means. What is 8 that figure, .7 or 12 suicides? What does 9 that depict? 10 A. 12 as the numerator, 1,562 as the 11 denominator, give you .07 percent. 12 Q. Doctor, I can read that. What do these 13 figures, what does .7 percent in plain 14 language mean? 15 A. Mr. Farber, I can't answer it any better 16 than I just did. It means that 12 of 1,562 17 patients on Paroxetine attempted suicide. The 18 percentage figure would be .07 percent. 19 Q. Okay, and you are right, that is 20 obvious. 21 Now, on the percentages, 22 you had mentioned yesterday, I believe, that a 23 percentage of 1 percent was considered 24 frequent; correct? An FDA lexicon of numbers, 25 an occurrence occurring at the rate of 1 SPHERION DEPOSITION SERVICES (800) 880_1036 389 DAVID WHEADON, M.D. 1 percent or greater is considered frequent? 2 A. In terms of the listing of adverse 3 effects in the prescribing information, that 4 is correct. 5 Q. Now, shifting to your right, if you 6 would, under Paroxetine, under non_US data, 7 the figure 30, I just want to verify again 8 what this means. I can read it, but I want to 9 know if the figure 2 percent means that 2 10 percent of all the non_US patients in this 11 data base attempted suicide. 12 Is that what that means? 13 A. It means that 30 out of 1,401 patients 14 on Paroxetine in the non_US data base 15 attempted suicide. 16 Q. Which, at 2 percent, would be twice the 17 rate of nearly frequent; correct? 18 A. Mr. Farber, you are mixing apples and 19 oranges. This is looking at the safety data 20 base of the NDA. The frequency rate refers to 21 how the FDA collates frequent, infrequent and 22 rare in prescribing information. So they are 23 two different scenarios. 24 Q. Would 2 percent be considered frequent? 25 A. In the lexicon, as you say, of frequent, SPHERION DEPOSITION SERVICES (800) 880_1036 390 DAVID WHEADON, M.D. 1 infrequent and rare, 2 percent would be 2 considered frequent, yes. 3 Q. So just to clarify, I'm not trying to 4 repeat myself, but on the non_US data base, 5 the attempted suicides considering 1 percent 6 being frequent were actually twice a rate that 7 could have qualified for frequent; isn't that 8 correct? 9 A. The figure is 2 percent, and if you 10 multiply 2 times 1 percent, yes, it is twice. 11 Q. Thank you. We agree on the math, okay. 12 Now, these are real 13 numbers, aren't they? And I'm contrasting 14 that now with the phrase patient years or 15 patient exposure years. 16 A. I'm not quite sure what your question 17 is. 18 Q. Well, let's start by asking, this data 19 that I have just showed you in Exhibit 16 is 20 not listed in patient years or patient 21 exposure years; isn't that correct? 22 A. This table is not expressed in terms of 23 patient exposure years, that is correct. 24 Q. Now, let's get into that subject. 25 Did your suicide data SPHERION DEPOSITION SERVICES (800) 880_1036 391 DAVID WHEADON, M.D. 1 ultimately presented before the committee 2 change its measuring standard from real data 3 in Exhibit 16, ultimately change into a 4 patient years criteria? 5 A. If I recall correctly, real data, 6 regardless of how you express it, was 7 presented to the advisory committee. 8 Q. Okay, was this data that I have showed 9 you in Exhibit 16 ultimately transferred to a 10 patient years or patient exposure years 11 measuring standard? 12 A. I don't recall exactly how the data was 13 presented at the committee, but either way of 14 presenting it is a real presentation of data. 15 Q. Yes, but I'm trying to get here to why 16 we changed __ if we changed. I guess you 17 acknowledge we changed from real data, real 18 numbers, to patient years and patient exposure 19 years at some point after the publication of 20 Exhibit 16; isn't that correct? 21 A. No, I do not say that at all. 22 Q. Well, that's my question. Did we change 23 from data here into a different data system 24 for measuring? 25 A. No, we did not. SPHERION DEPOSITION SERVICES (800) 880_1036 392 DAVID WHEADON, M.D. 1 Q. Now, you went to SmithKline in February 2 of '92, but did you become aware that before 3 the committee hearing and the approval 4 process, that there was a suicide ideation 5 paper that was prepared by SmithKline and 6 forwarded to FDA on April 29, 1991 that was 7 substantial in length? Are you aware of that 8 fact? 9 A. I am aware of that paper, yes. 10 Q. Now, do you know how long __ and I know 11 you weren't there until February of '92, but 12 because you presented before the committee, 13 did you ever hear of how long this particular 14 suicide ideation paper took in preparation? 15 A. I do not. 16 MR. FARBER: Now, if I 17 might ask a question on your other witness, it 18 talks about clinical trials preceding Doctor 19 Wheadon's arrival. You have a witness for 20 that; correct? 21 MR. PREUSS: That's 22 correct. 23 MR. FARBER: Okay, so I 24 will save most of these questions for her. Is 25 it her? SPHERION DEPOSITION SERVICES (800) 880_1036 393 DAVID WHEADON, M.D. 1 MR. PREUSS: It is her. 2 BY MR. FARBER: 3 Q. Now, at some point after arriving at 4 SmithKline, you did review the suicide 5 ideation paper; correct? 6 A. That is correct. 7 MR. FARBER: Counsel, if 8 you have any questions, I have taken three 9 pages from this suicide ideation paper, if 10 there is any questions about that, so the 11 whole document can be reviewed, but the 12 exhibit that I am passing out, Exhibit 17, has 13 only three pages from this document. You are 14 free to look at this entire document, if you 15 want, during questioning, but __ 16 MR. VICKERY: May I ask if 17 those things have Bates numbers? And are they 18 the same Bates numbers that Mr. Farber got 19 that I have? 20 MR. FARBER: We have an SB 21 number. 22 MR. PULLIAM: I believe the 23 SB number on Mr. Farber's documents would also 24 appear on yours. They are not the PAR number 25 that was put on all of the documents SPHERION DEPOSITION SERVICES (800) 880_1036 394 DAVID WHEADON, M.D. 1 sequentially in your production. 2 MR. VICKERY: As long as 3 his page numbers correlate to mine, then I 4 don't have any objection to this, because we 5 can just look at the Bates number, but if, for 6 some reason, you all produced different 7 numbered sets to Mr. Farber and me, then that 8 would create __ 9 MR. FARBER: I would add 10 that this document was a quite popular 11 document, for obvious reasons, and it was 12 distributed in many different forms. I don't 13 think there was any attempt to confuse 14 anybody, but this is the basic document that 15 we are talking about. 16 MR. PULLIAM: The main 17 numbers used in your production were different 18 numbers, but I'm 90 percent certain that this 19 SB number that's stamped on his also would 20 appear on yours as an additional number, but I 21 would have to doublecheck. 22 _ _ _ 23 (Whereupon the court 24 reporter marked document as Exhibit 17 for 25 identification.) SPHERION DEPOSITION SERVICES (800) 880_1036 395 DAVID WHEADON, M.D. 1 _ _ _ 2 BY MR. FARBER: 3 Q. Now, I have, Doctor Wheadon, out of this 4 suicide ideation report, Exhibit 17 is three 5 pages in that report, and I call your 6 attention to Table 1 at the bottom of the 7 first page, where we have suicides, we have 8 five and we have two and we have three 9 respectively, Paroxetine, placebo and active 10 controls, and you will notice here we have a 11 P.E.Y. fixed in here below. I assume that 12 means patient exposure years? 13 A. That is correct. 14 Q. You would agree, would you not, that the 15 previous data I showed you from November of 16 '89 did not have the data in patient exposure 17 years? 18 A. That is correct. 19 Q. Do you know why the standard of 20 measuring was changed to patient exposure 21 years for purposes of this suicide ideation 22 report? 23 A. The standard of measure did not change 24 between what you put in front of me in terms 25 of Exhibit 16 and what you have given me now SPHERION DEPOSITION SERVICES (800) 880_1036 396 DAVID WHEADON, M.D. 1 in terms of Exhibit 17. 2 If you will look, Exhibit 3 16 has __ actually, Exhibit 16 is only 4 attempted suicides, not completed. The table 5 you are referring to __ 6 Q. That's right. 7 A. __ are completed suicides. So it is not 8 an apples to apples comparison again. 9 Q. I will get there. 10 A. Okay. So your question is? 11 Q. Well, my question is, you don't deny 12 that they changed the standard from '89 to '91 13 from real data to patient exposure years on 14 the subject of suicide, do you? 15 A. I do deny that. 16 Q. You do deny it? 17 A. Yes. 18 Q. You don't deny that there is no patient 19 exposure years in Exhibit 16, do you? There 20 is no data here on patient exposure years? 21 A. Again, Table 16 is attempted suicides 22 and overdoses worldwide data. Table 1 is 23 suicides. If you want to compare apples and 24 apples, we can do that, but you need to be 25 clear. SPHERION DEPOSITION SERVICES (800) 880_1036 397 DAVID WHEADON, M.D. 1 Q. You are technically correct, but we are 2 again here __ let's go to the next page. Go 3 to attempted suicides on Page 2 of Exhibit 4 17. Now, we are into attempted suicides. 5 Now, the same question applies. 6 A. Table 2 has a number of attempted 7 suicides, the percent that number represents 8 similar to the Table 11.21 of Exhibit 16, and 9 Table 2 also expresses the number per patient 10 exposure year. 11 Q. Okay, and my question is, why do we have 12 patient exposure years on the latter document 13 on attempted suicides, but not on the 1989 14 document? 15 A. The reason for that is the following. 16 This particular paper, as you well know, was 17 prepared at the request of the FDA as a 18 contribution to the advisory committee 19 concerning the issue of suicide attempts 20 behavior, what have you, on SSRI's. That was 21 an advisory committee that the FDA called 22 primarily around the issue of Prozac and 23 suicides that occurred on it. 24 One of the issues there is, 25 what would one expect in terms of the rate of SPHERION DEPOSITION SERVICES (800) 880_1036 398 DAVID WHEADON, M.D. 1 occurrence of these events in the broader 2 population. 3 If you recall, at the time 4 of the advisory committee, Prozac was already 5 on the market. So one of the questions very 6 important for the committee to consider is 7 what would the rate be that one might expect 8 based on what was seen in the clinical 9 trials? 10 The way you answer that 11 question is to calculate based on your 12 clinical trial data, based on your, as you 13 call, real data of the percent occurrence of 14 events, in this case, suicide attempts, what 15 would you expect that translation to be as you 16 go out into the broader population for which 17 these drugs may be prescribed? 18 And the way you do that is 19 by estimating the number of expected suicide 20 attempts per patient exposure year. It is a 21 very accepted, very credible way of expressing 22 such data. 23 Q. Well, that's my question. Why is it 24 more credible? 25 A. I did not say more credible. I said it SPHERION DEPOSITION SERVICES (800) 880_1036 399 DAVID WHEADON, M.D. 1 is very accepted, very credible way of 2 expressing the data. 3 Q. Okay, why is it more credible than the 4 real data in the 1989 report? 5 A. Mr. Farber, I did not say more 6 credible. I will repeat it one more time. It 7 is a very accepted, very credible way of 8 expressing the data. 9 Q. Okay, is it a more accurate way of 10 expressing the data than the real terms, the 11 real data, in the 1989 exhibit? 12 A. It is an acceptable way of expressing 13 the data. If you will look at Table 2, both 14 ways of expressing it, both percent 15 occurrence, as well as the patient exposure 16 year are both expressed in the '91 paper. 17 Q. But the percentage is not. The 18 percentage is based on patient exposure years, 19 isn't it? 20 A. That is not correct. 21 Q. Look at there. It says .040 under 22 Paroxetine, .083 under placebo, .055, and then 23 it says number, patient exposure years. 24 Am I missing something? 25 A. Okay, what you are reading in Table 2 of SPHERION DEPOSITION SERVICES (800) 880_1036 400 DAVID WHEADON, M.D. 1 Exhibit 17, the bottom section of that table 2 is the expression of the rate per patient 3 exposure year. So that is not a percentage. 4 The 0.04 for Paroxetine is not a percentage. 5 That is the rate of the event per patient 6 exposure year. 7 Q. That's my question. Now, you can talk, 8 if you want to, about that. You can make your 9 speeches, but that's my question. Why is 10 patient exposure years more credible for this 11 report than the real data in this 1989 12 exhibit? 13 You chose, apparently, at 14 SmithKline, to use this in patient exposure 15 years. Why did SmithKline choose to measure 16 it that way? 17 A. I'm going to try one more time. 18 Q. Well, be more specific, or we are going 19 to be here for __ 20 A. If you will look at Table 2. 21 Q. I have looked at it many times now. 22 A. Please look at it again. 23 Q. Sure. 24 A. The top of the table has the number of 25 attempted suicides, and in parentheses, there SPHERION DEPOSITION SERVICES (800) 880_1036 401 DAVID WHEADON, M.D. 1 is a percentage that that number represents 2 for Paroxetine, placebo and active controls. 3 The bottom of Table 2 has a number per patient 4 exposure year. That's taking the number of 5 attempted suicides and dividing that by the 6 total patient exposure year, which, in the 7 case of Paroxetine, is 1,008. That gives you 8 a rate per patient exposure year. So the rate 9 of attempted suicides is .04 per patient 10 exposure year. 11 So there is no data that's 12 been left out, as you say. It is a different 13 way of expressing the same data, and both ways 14 of expressing the data are listed in Table 2. 15 Q. Do you consider patient exposure years a 16 reliable index of the suicide data in this 17 data bank? Patient exposure years, is that a 18 reliable measuring standard? 19 A. As I said, that's a credible way of 20 looking at the data concerning attempted 21 suicides, yes. 22 Q. Now, you weren't there, and I will ask 23 this afternoon. Was the shift to patient 24 exposure years a tactic to make the statistics 25 look lower? SPHERION DEPOSITION SERVICES (800) 880_1036 402 DAVID WHEADON, M.D. 1 A. Absolutely not. 2 Q. Not a tactic at all? 3 A. Absolutely not. 4 Q. Now, let's get into the hard data 5 itself. Under Table 2, under Paroxetine at 6 the top there on the left, we have 40 7 attempted suicides. If you would follow me, 8 it is up on Page 2 there, under attempted 9 suicides, Paroxetine, 108, number percentage, 10 it has 40; correct? 11 A. That's correct. 12 Q. Now, if you look back at Exhibit 16 __ 13 have you got that in front of you? 14 A. Yes, I do. 15 Q. Under Exhibit 16, under Paroxetine 16 worldwide, we have 42 suicides; correct? 17 A. If you add the two together, yes, it 18 comes to 42, that is correct. 19 Q. Why do we have 40 on the latter document 20 and 42 on the earlier document? 21 A. I cannot give you any clarity around why 22 that number changed between 1989 and 1991. My 23 speculation is that further information became 24 available to the company, such that 2 was 25 presumed attempted suicides were clarified not SPHERION DEPOSITION SERVICES (800) 880_1036 403 DAVID WHEADON, M.D. 1 to be such, but I cannot give you any further 2 information on that. 3 Q. I agree with you, that's what happened. 4 And I'm sure if we checked into the data bank, 5 we could find out what patients were involved 6 here, the two patients. I'm sure of that. 7 Now, let's talk about 8 measuring data in particular with a particular 9 clinical trial at a baseline. We have a start 10 of a baseline, and then a four or six_week 11 trial. Talk to me about a wash_out or a 12 lead_in period and the issue of both placebo 13 and active drug patients having a wash_out 14 period before a baseline. Would you explain 15 how this procedure works leading up to the 16 baseline? 17 A. In certain clinical trials, 18 particularly, in depression, you have what's 19 called a placebo lead_in. And the reason for 20 that is because depression and its symptoms 21 can be fluctuating, you use a placebo lead_in 22 to establish the stability of the level of 23 depression. So those patients that seem to be 24 appropriate per the inclusion criteria in 25 terms of their HAM_D score are treated with SPHERION DEPOSITION SERVICES (800) 880_1036 404 DAVID WHEADON, M.D. 1 placebo, all patients, for a period of a week, 2 two weeks, to see that stability of their 3 level of depression before they are randomized 4 to either drug or placebo, whatever may be the 5 randomization groups in the particular study. 6 Q. And the patients themselves, because it 7 is a blinded study, don't know what they are 8 getting? 9 A. They do not know what they are getting, 10 that's correct. 11 Q. Now, if you look under __ back to the 12 actual suicides now, on Number 17? 13 A. Exhibit 17? 14 Q. Yes, in the middle category, front page, 15 it says, placebo, 2 suicides? 16 A. Yes, I see that. 17 Q. So in this whole period, we only have 2 18 placebo suicides; correct? 19 A. That is correct. 20 Q. Now, go back to the final page, which is 21 Appendix 1, we haven't looked at that page 22 before, it has got a number of SBO20 at the 23 back. And at the bottom, we have an asterisk, 24 and it says both __ I will read it. "Suicides 25 were committed during the placebo wash_out SPHERION DEPOSITION SERVICES (800) 880_1036 405 DAVID WHEADON, M.D. 1 phase of an active control study. These acts 2 were committed two days and seven days prior 3 to the baseline evaluation." 4 What does that mean? 5 A. That means that the suicides were 6 committed while the patients were on placebo 7 in the placebo run_in or wash_out phase, 8 whichever way you want to describe it. 9 Q. That was my question. Is wash_out and 10 run_in the same? 11 A. Yes. 12 Q. Why were they counted? If it didn't 13 occur during the baseline period, why were 14 they counted at all? 15 A. Because it happened during the control 16 phase of the trial. 17 Q. Was that consistent with protocol, that 18 these __ maybe I'm operating under a mistaken 19 assumption. I thought data that occurred 20 during these wash_out, lead_in phases were not 21 counted in the data. 22 A. That is not correct. The way this data 23 was collected __ and I need to correct 24 myself. It wasn't because they happened 25 during the control phase of the trial. The SPHERION DEPOSITION SERVICES (800) 880_1036 406 DAVID WHEADON, M.D. 1 way these data were collected, any suicide 2 that occurred during the course of observation 3 of a clinical trial was included in this data 4 base. 5 So __ just a minute. 6 Placebo run_ins were counted as placebo, 7 because they were on placebo. There were also 8 suicides that occurred in patients that were 9 on Paxil, for example, in long term extension, 10 where there was no placebo, there was no 11 active comparator, so the full breadth of the 12 experience was accommodated in this particular 13 analyses. 14 Q. I agree, that's what happened, that's 15 exactly what the data represents, but my 16 question is whether that is a valid scientific 17 measuring device for conducting clinical 18 trials. 19 A. Absolutely. 20 Q. Now, would the protocol or rules for 21 this study have stated that at the beginning? 22 A. When you say a protocol or rules, what 23 do you mean? 24 Q. Well, you have rules for collecting 25 data, right? You had rules for establishing a SPHERION DEPOSITION SERVICES (800) 880_1036 407 DAVID WHEADON, M.D. 1 wash_out phase. I mean that concept __ 2 A. You have to recall, Mr. Farber, the 3 protocol for these studies were for different 4 purposes. They were for treating depression. 5 The protocol for establishing an answer to the 6 question of the occurrence of suicides on 7 placebo or drug or active comparator did 8 include that as I described, and that is 9 collecting all suicides that occurred during 10 observation in a clinical trial, regardless of 11 whether it happened in placebo run_in, during 12 randomization or during extension, open label 13 extension, where people were on Paxil, and 14 they, in some cases, knew they were on Paxil. 15 Q. And you consider this a valid scientific 16 practice? 17 A. Absolutely. 18 MR. FARBER: What I'm going 19 to do, counsel, I'm not going to finish in 20 time, but I will try to honor __ Mr. Vickery 21 has questions. I will try to hasten, but I 22 just want to go on the record as saying I 23 won't complete with all my issues, but I will 24 hurry up to the best I can now and turn it 25 over to you, Mr. Vickery, as soon as I can. SPHERION DEPOSITION SERVICES (800) 880_1036 408 DAVID WHEADON, M.D. 1 MR. VICKERY: Try to give 2 me 30 minutes before noon. 3 MR. FARBER: I try to keep 4 it to 10:45. I will finish by 10:45. 5 BY MR. FARBER: 6 Q. Principal investigators, what type of 7 compensation package do they have or do they 8 have a fixed salary for a fixed period of time 9 or are they paid by the hour or generally what 10 is their compensation package? How does it 11 consist? 12 A. Investigators are not compensated for 13 participating in clinical trials in the way 14 that you are describing. 15 Q. Well, how are they compensated at all? 16 A. Investigators are paid for the work that 17 they do and from the standpoint of the cost of 18 carrying out the trial. 19 So, for example, if a 20 protocol calls for an EKG to be done, the 21 investigator is reimbursed for the cost of 22 that EKG. If the protocol calls for a 23 Hamilton Depression Scale to be done by a 24 trained rater, the investigator is compensated 25 for the cost of administering that Hamilton SPHERION DEPOSITION SERVICES (800) 880_1036 409 DAVID WHEADON, M.D. 1 Depression Scale. 2 Investigators are not on 3 salary. They are not paid per hour, as you 4 described. They are only compensated for the 5 carrying out of the protocol, for doing the 6 investigative procedures, laboratories, EKG's, 7 assessment tools that are required by the 8 protocol. 9 Q. As an attorney, I know that costs. So 10 costs are reimbursed to them; correct? 11 A. That is correct. 12 Q. But they get no fee or salary at all? 13 Is that what you are saying? 14 A. That is correct. 15 Q. How about their organizations or 16 entities that they work with? Does the same 17 principle apply? If a PI works for the San 18 Jose Medical Group, does the same principal 19 apply to the employer; i.e., the San Jose 20 Medical Group? 21 A. That is correct. 22 Q. So they work for free, essentially? 23 A. Essentially, from a standpoint of 24 salary, that is correct, yes. 25 Q. Now, how about the patients, the SPHERION DEPOSITION SERVICES (800) 880_1036 410 DAVID WHEADON, M.D. 1 volunteers, if you will, the patients? In the 2 Par 02 series and the Par 03 series, what were 3 the patients given or what consideration were 4 they given to participate in these studies? 5 A. I quite frankly have no knowledge of 6 that. 7 Q. Today, the year 2000, on the studies you 8 are conducting in psychoactive drugs, I will 9 use, are you doing clinical trials today on 10 Paxil? 11 A. Yes. 12 Q. And take a patient today, in the year 13 2000, that is enrolled in this study. What 14 consideration are they given to participate? 15 A. Quite frankly, that varies from one 16 study to another, but as far as I recollect, 17 and again, I'm not involved day to day in 18 that, the patients are reimbursed for things 19 like parking fees, that sort of thing, the 20 time and effort to come into the clinical 21 trial site, but they are not paid for 22 participating. 23 Q. Would they be or are they given 24 consideration, such as, if you complete this 25 study for the full six weeks, you will receive SPHERION DEPOSITION SERVICES (800) 880_1036 411 DAVID WHEADON, M.D. 1 eight months of free mental health treatment? 2 A. No. 3 Q. Do you have any guidelines on this __ 4 written for principal investigators on this 5 subject? 6 A. I'm sure we do, but I can't tell you 7 specifically where it is. 8 Q. Let me talk about suicidality in the 9 Hamilton and the MADRS and the general 10 subject. You had much data on your efficacy 11 trials on suicidality under these standards, 12 did you not? 13 A. The Hamilton and the MADRS have suicide 14 items as a part of the assessment, yes. 15 Q. What is the definition under FDA of a 16 positive trial or a positive study in regards 17 to suicidality and these subjective 18 standards? 19 A. There is no frank definition in terms of 20 a positive study, as you say, in terms of 21 suicidality. 22 Q. How about a supportive study? Do you 23 know the difference between a supportive and a 24 positive study result? 25 A. I'm not sure how you are using the SPHERION DEPOSITION SERVICES (800) 880_1036 412 DAVID WHEADON, M.D. 1 terms, no. 2 Q. I'm using it the way the FDA did on that 3 October day. They had a certain category of 4 supportive trials, and they also had a 5 category of positive trials. 6 A. If you are referring to the advisory 7 committee in 1992, that was concerning 8 positive and supportive trials for the 9 treatment of depression, not around 10 suicidality. 11 Q. But under efficacy, the issue of 12 suicidality week by week was computed to show 13 that Paxil improved the patient over a course 14 of four, five or six weeks, didn't it? 15 A. I'm not sure what you are asking, Mr. 16 Farber. 17 Q. Well, you said they didn't cover 18 suicidality, but they, in fact, did over all 19 of these tests, the CGI and the HAM_D, give a 20 week by week analysis that indicated that 21 Paxil, with use over six weeks, did improve, 22 if you will, the suicidality became less; 23 isn't that correct? 24 A. The week by week analysis that was 25 presented at the advisory committee in October SPHERION DEPOSITION SERVICES (800) 880_1036 413 DAVID WHEADON, M.D. 1 of 1992 was a week by week analyses of the 2 change on the Hamilton total score. So that's 3 a collection of all of the various assessments 4 involved in the Hamilton, or in some cases, 5 the MADRS. 6 So what you are recalling 7 is a week by week analyses of the total score 8 of the Hamilton, indicating improvement over 9 the course of the six_week trial. 10 Q. And Paxil did pretty well, didn't they? 11 A. Paxil did very well compared to placebo, 12 yes. 13 Q. And that's why it got approved for 14 efficacy; isn't that correct? 15 A. That is correct. 16 Q. Now, my question is, the underlying 17 basis for the HAM_D, and indeed, all of them, 18 the MADRS and the others __ let's talk about 19 how this data was gathered. Let's take a 20 visit of a patient on one of these studies 21 that came in for the six_week trial. 22 When that patient __ first 23 of all, recruiting him, I won't get into the 24 recruiting, but when that patient was screened 25 for the criteria of the study, the patient SPHERION DEPOSITION SERVICES (800) 880_1036 414 DAVID WHEADON, M.D. 1 then came in, did he or she not, week by week 2 for the protocol to be examined by the 3 principal investigator or the physician? 4 A. I don't recall the actual defined 5 protocol visits for each of the protocols 6 involved in the NDA for Paxil, but in general, 7 you are correct, that the patients would come 8 in on average on a weekly basis to be assessed 9 by the investigator and his clinical staff. 10 Q. And in the records, would it state each 11 __ I'm sure, if I checked the records, would 12 it not, that each week's visit would have a 13 little score card made out on each of these 14 testing methods, whether it be HAM_D or MADRS 15 or CGI or whatever; correct? 16 A. If the protocol defined that the 17 Hamilton or the MADRS or the CGI would be done 18 at each weekly visit, there would be a record 19 of that, yes. 20 Q. How long __ I know it depends. How long 21 for all these forms on a weekly visit, how 22 long must the patient be in the office to get 23 this data properly recorded by the physician? 24 A. I have no ability to answer that, Mr. 25 Farber. SPHERION DEPOSITION SERVICES (800) 880_1036 415 DAVID WHEADON, M.D. 1 Q. Are you aware that Doctor Hamilton in 2 1960, when he first issued his article, gave 3 standards for how to collect his data? 4 A. I'm aware that Doctor Hamilton gave a 5 methodology for how his scale was to be 6 utilized in assessing depression, yes. 7 Q. Are you also aware that in his article, 8 he indicated that the techniques and the 9 procedures to be used in gathering the data? 10 A. Again, I am aware that Doctor Hamilton 11 discussed the methodology for how the scale is 12 to be utilized. 13 Q. And are you __ let's put it this way. 14 Strike that. 15 Are you aware that he gave 16 a time standard at which a minimum time must 17 be utilized to gather his check_off sheet 18 data? 19 A. I'm not aware of a time standard. 20 Q. Do you know if time standards for the 21 Hamilton tests were promulgated in the 22 protocol or in the rules for each study that 23 used the HAM_D? 24 A. I'm not aware that a time standard was 25 applied, no. SPHERION DEPOSITION SERVICES (800) 880_1036 416 DAVID WHEADON, M.D. 1 Q. And you are not aware that Doctor 2 Hamilton said a minimum of 30 minutes was 3 required for his check_off sheet? 4 A. I'm not aware of that, no. 5 Q. Are you aware that he also said a 6 minimum two raters are required for each 7 check_off sheet in each session? Are you 8 aware of that? 9 A. I'm not aware that he specified that, 10 no. 11 Q. Are you aware whether those standards, 12 whatever they were, were promulgated to the 13 principal investigators to collect all that 14 data? 15 A. I'm not aware that that was stated in 16 the protocol, no. 17 Q. Now, are you aware that all of these 18 sheets that are filled out __ strike that. 19 In collecting the data and 20 recording it on the printed sheets, filling in 21 all the blocks, are you aware that Doctor 22 Hamilton specified the qualifications of the 23 personnel to do that? 24 A. I'm not aware of that, no. 25 Q. Based on what you know today and your SPHERION DEPOSITION SERVICES (800) 880_1036 417 DAVID WHEADON, M.D. 1 general experience, and if you were to give 2 guidance today, what guidance would you give 3 to principal investigators on the 4 qualifications of the rater who is filling out 5 these HAM_D tests? 6 A. Our standard guidance is a rater should 7 be experienced in the use of the Hamilton, 8 should also have had experience in terms of 9 going through what we call interrater 10 reliability training. That is something we do 11 at all of our start_up meetings to insure that 12 our clinicians that are doing the rating have 13 good interrater reliability. 14 Q. Let's be more specific now. Let's take 15 an office, a clinic that's participating, and 16 obviously, a psychiatrist is qualified to do 17 this. Is a general physician without a 18 specialty qualified to collect this data? 19 A. If he is trained appropriately, yes. 20 Q. How about a nurse? 21 A. If she is trained appropriately, yes. 22 Q. Psychiatric nurse would certainly fit 23 into that category? 24 A. That's correct. 25 Q. How about a physician's assistant? SPHERION DEPOSITION SERVICES (800) 880_1036 418 DAVID WHEADON, M.D. 1 A. If he or she is trained correctly, yes. 2 Q. Do you know whether the criteria for 3 qualifications of the rater, whatever they 4 are, were specified in the protocol? 5 A. I'm not aware if there was a specific 6 criteria specified or not. I'm not familiar 7 with those protocols. 8 Q. What if you learned later that the 9 person filling out the sheet with the patient 10 was a nurse's assistant, unqualified, and that 11 the doctor who signed the sheet didn't even 12 see the patient that day? Would that affect 13 your opinion of the reliability of the data? 14 A. Of what data? 15 Q. Of a patient session on Week 2? 16 A. Again, it depends on the specifics, Mr. 17 Farber. I can't give you any clarity beyond 18 that. I have to have more specifics. 19 Q. Well, that's the specifics I'm giving 20 you. I'm telling you that a patient is coming 21 in in my hypo and was seen by a nurse's 22 assistant, sat down with the patient for 30 23 minutes, asking the question to her, filled it 24 out, and the physician never saw the doctor 25 that day. That is my hypo. SPHERION DEPOSITION SERVICES (800) 880_1036 419 DAVID WHEADON, M.D. 1 A. The physician never saw the doctor? 2 Q. The physician didn't see the patient 3 that day, but just passing to sign off the 4 sheet. 5 A. Well, that is not __ 6 Q. That's my hypo. 7 A. That is not per the requirements that we 8 state in our protocols or in our practice of 9 procedures for carrying out a clinical trial. 10 A principal investigator is responsible to see 11 the patient and to sign off on the procedures 12 that have been carried out on the patient. 13 Q. I understand that, but if that didn't 14 happen, a substantial period of the time, 15 let's say on a six_week visit, let's say that 16 didn't happen but two times, and the other 17 four times, the nurse's assistant saw the 18 patient, filled out the form, and then had the 19 doctor sign it. 20 Would you consider those 21 four visits that were improper, but with two 22 visits that were proper, would you consider 23 that patient's data to be valid for purposes 24 of clinical trials? 25 A. If two of the visits were done per SPHERION DEPOSITION SERVICES (800) 880_1036 420 DAVID WHEADON, M.D. 1 protocol, then those two visits would be 2 appropriate. If four visits were not done per 3 protocol, those four visits may be excluded. 4 Q. Should they be excluded? That's my 5 question. 6 A. I'm saying they may be excluded. I have 7 to have more specifics. I cannot give you 8 more clarity than that. 9 Q. You don't want to express an opinion on 10 the fact if the data was collected by a 11 nurse's assistant? You need more data than 12 that? 13 A. Yes, I do. 14 Q. Was the protocol specified for the 15 collection of data or did it require the 16 session to be conducted without access to the 17 previous screening sheets for that test? 18 In other words, if the test 19 came in last week as usual, but he came in 20 again this week, did the protocol permit the 21 rater for the latter week to have access to 22 the earlier sheet? 23 A. I don't recall those specifics. 24 Q. And you don't know whether the protocol 25 specified that or not? SPHERION DEPOSITION SERVICES (800) 880_1036 421 DAVID WHEADON, M.D. 1 A. I do not recall. 2 Q. And you don't know whether Doctor 3 Hamilton promulgated that requirement or his 4 requirement? 5 A. I don't recall. 6 Q. Now, on Par 08_1, are you aware that 7 there was on this Par approximately 8 or 8 8 plus percentage of patients who reported 9 withdrawal symptoms? 10 A. I'm not familiar with Par 08_01, Mr. 11 Farber. I did not review that in preparation 12 for this deposition. 13 Q. That's unfair, I know, but let us 14 assume, and I will represent as a hypo, if in 15 one Par, that 8 plus percent of patients 16 reported that they were suffering withdrawal 17 symptoms, and that data came into SmithKline. 18 Would SmithKline accept 19 that as clinical data that 8 percent of 20 withdrawal patients had, in fact, experienced 21 that? 22 A. I really can't comment specifically on 23 that, Mr. Farber, in terms of the hypothetical 24 situation. I need more information. 25 Q. Are you aware, in Doctor Brecher's SPHERION DEPOSITION SERVICES (800) 880_1036 422 DAVID WHEADON, M.D. 1 report in 1991, that he reported that incident 2 of 8.2, whatever it is, 8.2 percent of the 3 patients had reported suffering withdrawal 4 symptoms, and that upon review of the data by 5 FDA and SmithKline, it was determined that 6 they were not, in fact, suffering withdrawal, 7 because they had been dosed all the way up to 8 the report, suggesting that the patients were 9 indeed suffering relapse, rather than 10 withdrawal, in other words, akin to the 11 Yugoslav situation? Are you aware of that 12 general report by Doctor Brecher? 13 A. I did not review Doctor Brecher's report 14 in preparation for this deposition, so I 15 cannot comment. 16 Q. I got seven minutes here. I will finish 17 one way or the other. 18 New subject, suicide and 19 the suicide issue in total, what Mr. Vickery 20 was talking about and this whole issue of 21 Prozac and so forth, is that a public 22 relations problem for your company? Do you 23 consider that __ I know it doesn't have a 24 precise answer. I'm just asking for your 25 opinion. Does this present a public relations SPHERION DEPOSITION SERVICES (800) 880_1036 423 DAVID WHEADON, M.D. 1 problem for SmithKline Beecham? 2 A. Frankly, it presents a problem for the 3 psychiatric field and for the cause of 4 insuring that people are willing to seek 5 mental health care. 6 One of the issues in this 7 country has always been that there is a 8 closeted notion about people with psychiatric 9 illness. And this serves a great disservice 10 to people that really need to be willing to 11 come forward and get care. 12 So from that standpoint, 13 SmithKline and I, as a psychiatrist, are very 14 concerned about this issue. 15 Q. I agree with that. I totally agree with 16 that. And my question is, if, therefore, it 17 were deemed to be studied as an issue, as a 18 valid scientific inquiry, is it not proper for 19 the authorities, such as FDA and SmithKline, 20 to, in fact, treat it as a clinical serious 21 problem for studying, rather than themselves 22 treating it as a PR problem? Do you agree 23 with that proposition? 24 A. I don't understand your question. 25 Q. Well, if it is a serious problem, and I SPHERION DEPOSITION SERVICES (800) 880_1036 424 DAVID WHEADON, M.D. 1 agree, it is a very serious problem, and it 2 were deemed to be important enough to be held 3 at an FDA hearing to determine that, isn't it 4 an important enough subject to be studied 5 scientifically? 6 A. And it has been studied scientifically. 7 Q. Are you aware that Doctor Brecher called 8 SmithKline __ I know this happened before your 9 watch, and if you don't know anything about 10 it, you can tell me, but are you aware or did 11 somebody tell you that Doctor Brecher called 12 SmithKline on October 3rd, 1990, and basically 13 said, this whole suicide issue is just a PR 14 problem, don't worry about it? That's my 15 words. 16 A. I'm not aware of that. 17 Q. Let's go to Exhibit 18. 18 _ _ _ 19 (Whereupon the court 20 reporter marked document as Exhibit 18 for 21 identification.) 22 _ _ _ 23 MR. PREUSS: Mr. Farber, 24 whose writing is this on the margin? 25 MR. FARBER: Preconceived? SPHERION DEPOSITION SERVICES (800) 880_1036 425 DAVID WHEADON, M.D. 1 MR. PREUSS: Right, and PR. 2 MR. FARBER: It is my 3 writing. I will specify that for the record. 4 MR. PREUSS: I would like a 5 copy that goes in that is free of this for the 6 exhibit. 7 MR. FARBER: That's fine. 8 I have no problem with that. We will get a 9 corrected copy for the thing, okay? So the 10 original exhibit will have this deleted. 11 BY MR. FARBER: 12 Q. Now, this general subject reported in 13 the summary of conversation __ I know you 14 weren't there at the time, and you may not 15 have seen this, but are you aware of this 16 general subject that an FDA official called 17 SmithKline at some point before your arrival 18 and indicated that the suicide issue was 19 merely a PR problem? 20 A. No, I was not aware. 21 Q. Exhibit 19, same thing, if you don't 22 like my funny face, I will delete that. There 23 is a funny face on this. 24 MR. PREUSS: I think we 25 should delete it. SPHERION DEPOSITION SERVICES (800) 880_1036 426 DAVID WHEADON, M.D. 1 MR. FARBER: We will. I 2 have no problem deleting it. 3 _ _ _ 4 (Whereupon the court 5 reporter marked document as Exhibit 19 for 6 identification.) 7 _ _ _ 8 BY MR. FARBER: 9 Q. Exhibit 19 is a FDA conversation record, 10 July 19th, from a conversation with Tom 11 Laughren, M.D., at FDA, calling Thomas 12 Donnelly, the regulatory affairs officer. And 13 basically, I will summarize. I don't think 14 you will have a problem with this. 15 There is a call, where 16 Doctor Laughren called SmithKline and wanted 17 assistance for a ten_year data base and asked 18 the company for a large data base, so he could 19 go out and give a presentation on it 20 personally, out of official business. That's 21 what this says. That's my summary. 22 And my question to you is 23 this: Is it standard operating procedure at 24 SmithKline to do personal favors for FDA 25 officials? SPHERION DEPOSITION SERVICES (800) 880_1036 427 DAVID WHEADON, M.D. 1 A. No. 2 Q. Has SmithKline under your watch, at 3 least as far as you know, ever met socially 4 with __ let me go back. 5 In 1992, from the time you 6 arrived in February, up until the committee 7 meeting in October of '92, did any SmithKline 8 official have contact with any of the six 9 members who sat on that committee meeting on 10 October 5th? 11 A. That is such a broad question, Mr. 12 Farber, I quite frankly have no ability to 13 answer that. 14 Q. No, if you don't know, I would 15 understand that. But you don't know; correct? 16 A. I have no idea. 17 Q. Would it be contrary to company policy 18 to make personal contact with any committee 19 member who was assigned to sit on an impending 20 committee to consider a SmithKline product in 21 the approval process? 22 A. You have to be far more specific. It 23 would not be unusual for a scientist and a 24 member of an FDA committee to be present at 25 the same meeting. They may have a SPHERION DEPOSITION SERVICES (800) 880_1036 428 DAVID WHEADON, M.D. 1 conversation on the scientific issue that may 2 be discussed at that meeting. 3 So simply having contact, 4 meaning running into one another at a meeting 5 and having a friendly discussion is certainly 6 not outside of company policy, no. 7 Q. I'm not talking about the day of the 8 meeting. Let's eliminate the day of the 9 meeting and coffee breaks and all that 10 nature. 11 I'm talking about the 12 lead_up to the meeting, when the members have 13 been identified, and a drug of your company 14 will be under consideration by that 15 committee. 16 Is there a company policy 17 preventing, call it a conflict of interest 18 policy or whatever you want to call it, such a 19 policy in effect to preclude social or any 20 personal contacts with any of the committee 21 members? 22 A. As I answered previously, and I think 23 you may have misunderstood my answer, it is 24 not outside the realm of possibility, and it 25 is perfectly acceptable if a member of the SPHERION DEPOSITION SERVICES (800) 880_1036 429 DAVID WHEADON, M.D. 1 company and a member of an advisory committee 2 happened to run into one another at a 3 scientific meeting, not the advisory committee 4 meeting, and exchanged pleasantries and maybe 5 have a brief discussion, that is acceptable. 6 Q. How about a concentrated attempt to 7 contact one of these officials specifically 8 for the purpose of discussing the issue? 9 A. That is contrary to company policy. 10 Q. I'm not done, but I will quit here in 11 one minute. 12 _ _ _ 13 (Whereupon the court 14 reporter marked document as Exhibit 20 for 15 identification.) 16 _ _ _ 17 BY MR. FARBER: 18 Q. I guess I'm cut off here. Just for the 19 record, I'm not done, counsel, but for today, 20 I will quit here in one minute. 21 My Exhibit Number 20 is a 22 memorandum and a fax, really, from Doctor 23 Laughren to Tom Donnelly, and you will see it 24 is dated August 25, 1992, after your arrival 25 at SmithKline, and it is a two_page letter, SPHERION DEPOSITION SERVICES (800) 880_1036 430 DAVID WHEADON, M.D. 1 and he talks __ I'm specifically focusing on 2 Page 2. 3 My question concerns Page 2 4 in the second paragraph under discontinuation 5 for adverse events. And you can see it is a 6 dialogue. I will read it. It says, quote, I 7 find that a number of events occurring at an 8 incidence of 1 percent or greater for 9 Paroxetine in Appendix 4_B are not in this 10 section; e.g., vomiting, confusion, manic 11 reaction, abdominal pain, hypertension, 12 palpitation, paresthesia, constipation, 13 decreased appetite, weight gain, CNS 14 stimulation. This discovery erodes my 15 confidence somewhat, and I would like an 16 explanation for this fairly obvious 17 discrepancy, unquote. 18 Does this general subject 19 ring a bell with you as to what Mr. Laughren 20 was talking about, Doctor Laughren was talking 21 about? 22 A. I'm quite frankly not familiar with this 23 particular item, nor this particular topic. 24 Q. So nothing that I have just read rings a 25 bell at all? SPHERION DEPOSITION SERVICES (800) 880_1036 431 DAVID WHEADON, M.D. 1 A. No. 2 MR. FARBER: Okay, counsel, 3 I will turn it over to Mr. Vickery. 4 MR. PREUSS: Is that your 5 writing on Page 2 of this exhibit? 6 MR. FARBER: Yes. 7 MR. VICKERY: Why don't we 8 take a break? 9 THE VIDEO TAPE OPERATOR: 10 Going off the video record. The time is 11 10:48. 12 THE VIDEO TAPE OPERATOR: 13 We're back on the video record. The time is 14 11:02, the beginning of Tape Number 2. 15 _ _ _ 16 EXAMINATION 17 _ _ _ 18 BY MR. VICKERY: 19 Q. Doctor Wheadon, I want to make sure I 20 understand your testimony and your company's 21 position on this akathisia business. 22 Is there or is there not 23 something now in the adverse reaction section 24 of the Paxil label about akathisia? 25 A. If I recall correctly __ and I would SPHERION DEPOSITION SERVICES (800) 880_1036 432 DAVID WHEADON, M.D. 1 actually like to read exactly what is in the 2 label to you, so if we can produce a copy of 3 the present label, I would be happy to answer 4 that correctly. 5 Q. Well, I don't have one right now with 6 me, and I presume you don't, either? 7 A. I guess we do not, so quite frankly, I 8 did not come prepared to discuss in detail 9 akathisia, so I can't tell you exactly the 10 wording in the label, but I would like to give 11 you that exactly. 12 Q. Well, I would like it, if you could, 13 too, but since neither of us happen to have 14 one right now, in the interest of time, will 15 you just tell me what you believe to be 16 there? I won't hold you to the precise 17 wording, but do you believe that there is 18 something in the adverse reaction section of 19 the label about extrapyramidal reactions, 20 including akathisia? 21 A. I think that is the term that is stated 22 in the post_marketing report section, but I'm 23 not absolutely sure concerning that, and I 24 would like to have the label to refer to to 25 give you an exactly correct answer. SPHERION DEPOSITION SERVICES (800) 880_1036 433 DAVID WHEADON, M.D. 1 Q. Post_marketing reports is a subsequent 2 section that comes in later after the adverse 3 reaction section, right? 4 A. It refers to the receipt of 5 post_marketing reports after the approval of 6 the drug, yes. 7 Q. The standard for including information 8 in the adverse reaction section is the same as 9 in the warnings section and the same as in the 10 precaution section; in other words, that the 11 federal regulations use that same standard we 12 are talking about yesterday, reasonable 13 evidence of a possible association, that's the 14 standard before something is included in any 15 of those sections, isn't it? 16 A. That's not correct. 17 Q. No? 18 A. No. 19 Q. All right. 20 Well, is that standard used 21 for anything other than the warnings section, 22 as best you can recall? 23 A. Warnings and precaution, that standard 24 is applied. That does not necessarily apply 25 to the long list of adverse events that were SPHERION DEPOSITION SERVICES (800) 880_1036 434 DAVID WHEADON, M.D. 1 reported in clinical trials, that follows in 2 the adverse events observed during clinical 3 trials section. 4 Q. Only on the warnings and precautions? 5 A. That is correct. 6 Q. I think you may be right. All right. 7 Does Paxil cause 8 extrapyramidal reactions? 9 A. Extrapyramidal reactions or syndrome has 10 been reported rarely in patients who are 11 receiving Paxil. No causality has been 12 established around that. 13 Q. Do you believe that it causes 14 extrapyramidal reactions? 15 A. I do not believe, based on the data that 16 I have seen, that Paxil causes extrapyramidal 17 reactions, no. 18 Q. So then you do not believe that it 19 causes akathisia? 20 A. I do not believe, again, based on the 21 data that I have seen, that a causation has 22 been established for Paxil and akathisia. 23 Q. I am confused about one thing, and it is 24 because the papers that I have have two 25 different dates on them. SPHERION DEPOSITION SERVICES (800) 880_1036 435 DAVID WHEADON, M.D. 1 Were you deposed in the 2 Fentress case in June of '92 or '94? 3 A. I am quite frankly not completely sure, 4 but I'm pretty sure it was in '92. It was 5 shortly after I joined SmithKline. 6 Q. It was? 7 A. But I may be wrong on that. 8 Q. Well, the copy I have, I will show it to 9 you, one of them says June 9th and 10th, '94, 10 but then, at the top of the transcript, it 11 says June 9th and 10th, '92, so I just didn't 12 know, but if it was shortly after you joined 13 __ 14 A. I am pretty sure it was shortly after I 15 joined SmithKline, so I am almost positive it 16 was '92, but again, I may be wrong. 17 Q. In that deposition, when you were asked 18 about this trip you made to Europe, where the 19 seven people said, well, the most definitive 20 way to resolve this would be a prospective 21 test, you agreed, didn't you? 22 A. I don't recall that I agreed with that, 23 no. 24 Q. I will show you Page 125, and the 25 question was asked of you: All right, do you SPHERION DEPOSITION SERVICES (800) 880_1036 436 DAVID WHEADON, M.D. 1 agree that the best way or that the most 2 definitive assessment of this issue of a 3 potential relationship between Fluoxetine 4 treatment and suicidal ideation and/or 5 behavior would be an assessment of the 6 potential relationship by some sort of 7 prospective study? 8 Would you read, please, 9 your answer, beginning on Line 22? 10 A. Are we marking this as an exhibit? 11 Q. No, I'm just asking you to read it. It 12 is Page 125, Line 22. 13 MR. PREUSS: You can read 14 it a little forward, a little back, to get it 15 in context, if you want. 16 THE WITNESS: I quite 17 frankly am not seeing the Line 22 you are 18 referring to. The 22 that I see is: I don't 19 see where there is a difference in opinion 20 there. 21 BY MR. VICKERY: 22 Q. This has six pages on a page. This is 23 Page 125, and that's Line 22 right there, your 24 answer. So let me read the question again: 25 All right, do you agree that the best way or SPHERION DEPOSITION SERVICES (800) 880_1036 437 DAVID WHEADON, M.D. 1 that the most definitive assessment of this 2 issue of a potential relationship between 3 Fluoxetine treatment and suicidal ideation 4 and/or behavior would be on assessment of the 5 potential relationship by some sort of 6 prospective study? 7 Would you read the answer 8 you gave there, please? 9 A. "I agree that the most definitive 10 assessment of the question is a prospective 11 study." 12 Q. Was that testimony truthful when you 13 gave it? 14 A. At the time I gave it, that is correct. 15 Q. And is it truthful today? 16 A. The most definitive assessment is a 17 prospective study. 18 Q. Which SmithKline Beecham has never done? 19 A. We have not done a prospective study, 20 that is correct. 21 Q. Now, I take it that one of the things 22 that made you attractive to SmithKline 23 Beecham, when you were recruited in '92, was 24 that you had considerable experience at Lilly 25 in working on Prozac, and particularly, at the SPHERION DEPOSITION SERVICES (800) 880_1036 438 DAVID WHEADON, M.D. 1 time of the launch; is that true? 2 A. I have no idea what made me attractive 3 to SmithKline Beecham. 4 Q. You mean, in the interview process, they 5 didn't seem excited about the fact that you 6 had that experience? 7 A. Well, certainly, they were interested in 8 my experience as a psychiatrist, and 9 certainly, my experience at Lilly was a part 10 of that. But again, I can't say what made me 11 particularly attractive to them. 12 Q. Well, your experience as a psychiatrist 13 in terms of practicing was as a psychiatrist 14 in the context of working for a big 15 pharmaceutical company, rather than a 16 psychiatrist in a private clinical practice; 17 isn't that true? 18 A. Additionally having been trained as a 19 psychiatrist, yes. 20 Q. Incidentally, having been trained as a 21 psychiatrist, what do you think about the fact 22 that 70 percent of your company's market for 23 Paxil is people who did not have that kind of 24 training? 25 A. I'm not sure what you are asking. SPHERION DEPOSITION SERVICES (800) 880_1036 439 DAVID WHEADON, M.D. 1 Q. Do you endorse the idea of non_mental 2 health care professionals diagnosing 3 depression and treating it with psychoactive 4 drugs like Paxil? 5 A. Yes, I do. 6 Q. And isn't that about 70 percent of 7 Paxil's market, non_mental health care 8 professionals? 9 A. If I recall correctly, 70 percent of the 10 scripts are written by non_psychiatrists. 11 Q. Okay, so that's non_mental health 12 people, right? Is there some kind of mental 13 health person that's not a psychiatrist that 14 can write prescriptions? 15 A. There are a number of general 16 practitioners that do have a specific ability 17 to take care of psychiatric patients. So the 18 schism, if you will, is not quite as distinct 19 as you are trying to propose. 20 Q. Well, how many years of study and 21 training did you undertake to become a 22 psychiatrist? 23 A. Four. 24 Q. Four years __ 25 A. In terms of residency training. SPHERION DEPOSITION SERVICES (800) 880_1036 440 DAVID WHEADON, M.D. 1 Q. And so do you really, honestly, in your 2 heart, believe that someone who did not go 3 through that four years of rigorous training 4 is as capable of diagnosing and treating a 5 condition as serious as depression as you or 6 someone similarly trained as you? 7 A. Well, again, in terms of diagnosing and 8 treating depression, yes, a well_trained 9 internist, a general practitioner or other 10 physician can adequately diagnose and treat 11 depression. 12 Q. Why? Is there something about 13 depression that makes it a not so big deal in 14 the field of psychiatry? 15 MR. PREUSS: Objection, 16 argumentative. 17 THE WITNESS: I wouldn't 18 say it is something that makes it not such a 19 big deal. It is a matter of having the 20 appropriate diagnostic tools, the appropriate 21 understanding of depression and being able to 22 discern how it is distinguished from other 23 medical illnesses, for example, that may cause 24 depressive symptoms. 25 So general practitioners, SPHERION DEPOSITION SERVICES (800) 880_1036 441 DAVID WHEADON, M.D. 1 internal medicine physicians, other medical 2 care professionals are very able to adequately 3 diagnose and treat depression, yes. 4 BY MR. VICKERY: 5 Q. Well, in any event, your company 6 certainly directs a lot of its marketing 7 efforts towards non_psychiatrists, don't you? 8 A. I cannot comment on that particularly. 9 Q. Now, from your familiarity with the 10 various literature regarding SSRI's and 11 suicide, you do know that akathisia has been 12 postulated by many as the likely biologically 13 plausible means by which an SSRI drug can 14 precipitate suicide, don't you? 15 A. I am aware that there are some that have 16 postulated that akathisia may be a promoting 17 effect in some people that attempt suicide, 18 yes. 19 Q. Did SKB use the HAM_D and the MADRS on 20 all of the clinical trials or did it use one 21 in some instances and one in the other or can 22 you tell me? 23 A. Primarily, it was one or the other that 24 was used in the clinical trials. 25 Q. And would it be the HAM_D for most of SPHERION DEPOSITION SERVICES (800) 880_1036 442 DAVID WHEADON, M.D. 1 the time, and then the MADRS for a smaller 2 percent? 3 A. I don't know what the actual breakdown 4 is, but the Hamilton was the predominant scale 5 that was used. 6 Q. Did they ever use the MSSI_R scale that 7 we saw in that memo, that May '91 memo, about 8 the meeting with the FDA? 9 A. Not that I am aware of. 10 Q. Ever use the Beck's scale? 11 A. That, I'm not at all sure about. 12 Q. Ever, to your knowledge, use any other 13 scale, other than the HAM_D or the MADRS with 14 respect to suicidal ideation? 15 A. Not that I am aware of. 16 Q. Ever use any scale whatsoever to measure 17 treatment_emergent akathisia? 18 A. Not that I am aware of. 19 Q. Yesterday afternoon, Mr. Farber was 20 quizzing you some on coding of terms to World 21 Health Organization terms and all. 22 With respect to the way 23 that your company, SmithKline Beecham, handles 24 the receipt of information about adverse 25 events and codes it and reports it to the FDA, SPHERION DEPOSITION SERVICES (800) 880_1036 443 DAVID WHEADON, M.D. 1 has your experience there been pretty much the 2 same as it was at Lilly? 3 A. That is correct. 4 Q. So they are sort of standard norms that 5 both companies followed, and SmithKline is 6 neither any better nor any worse than Lilly in 7 that regard? 8 A. That is correct. 9 Q. Now, are you aware of the fact that 10 within Lilly, there was considerable 11 dissension about the coding of suicides and 12 suicide attempts as overdoses? 13 A. There were some situations, as far as I 14 can recall, that there were suicide attempts 15 that involved overdoses, but there were other 16 situations where an overdose was listed that 17 was actually not a suicide attempt. In those 18 cases, the patients actually took more than 19 the prescribed number of capsules in that 20 particular __ let's say, two rather than one, 21 and it was coded as an overdose. 22 Q. No, I'm not talking about that. I'm 23 talking about, are you aware of a guy that was 24 the head of the Lilly office in Germany really 25 kind of racing heck with the people in SPHERION DEPOSITION SERVICES (800) 880_1036 444 DAVID WHEADON, M.D. 1 Indianapolis, because they were requiring them 2 to code everything as overdose, so that even 3 if somebody attempted suicide, say, with a gun 4 or a knife, it would be coded as overdose? 5 A. That, I'm not aware of, no. 6 Q. Well, would you agree to use the 7 metaphor that Mr. Farber was using, that if 8 that were done, that that's one of those 9 garbage in, garbage out situations? 10 A. Well, certainly, if overdose was not 11 involved, and it was coded as an overdose, 12 that would be an incorrect listing. 13 Q. And that's what we mean by garbage. 14 That's garbage, isn't it? 15 A. That's an incorrect listing, yes. 16 Q. Now, help me out on understanding this 17 patient years business. If it is true __ and 18 I want to tell you what my source of confusion 19 is. If it is true that the risk of a 20 drug_induced suicide is most acute in the 21 early period, in the first couple of weeks, 22 maybe 30 days, at most, then doesn't the use 23 of patient years as the barometer for sort of 24 global statistical massaging of the data 25 really skew the data in the company's favor? SPHERION DEPOSITION SERVICES (800) 880_1036 445 DAVID WHEADON, M.D. 1 A. No. 2 Q. Well, can you explain why not? Let me 3 use the hypothetical. 4 A. Again, given your postulate that the 5 risk is most acute in the first few days to 6 weeks of treatment, if that is true, even with 7 expressing it in terms of patient exposure 8 years, you would still have a greater 9 occurrence in the larger data base of Paxil 10 than you would in the placebo data base, which 11 is in terms of patient exposure years, 12 smaller, because patients were maintained on 13 placebo for a shorter period of time, smaller 14 number of patients, shorter period of time. 15 However, there were a 16 number of Paxil patients that were coming onto 17 trials, many different trials. So even if it 18 happens in the early phase of treatment, you 19 would still see that signal, if it exists, in 20 the patient exposure year expression. 21 So you are not waiting in 22 favor of your drug by doing the patient 23 exposure year calculation. It is just a 24 different way of expressing the data. 25 Q. Maybe an example will illustrate it and SPHERION DEPOSITION SERVICES (800) 880_1036 446 DAVID WHEADON, M.D. 1 get it through my thick head. If you and I 2 were both on Paxil, and you took it for 51 3 weeks without any problem at all, and I took 4 it for a week and killed myself, then how do 5 you express the incidence rate of suicide in 6 terms of patient years, if we are the whole 7 body, we are the whole study, just the two of 8 us? 9 A. You have to give me that again. 10 Q. There is one year of patient years, 11 okay? You are on it 51 weeks, and you do just 12 fine. I'm on it for a week, and I kill 13 myself. 14 Now, when we do a 15 statistical analysis on this tiny, little 16 study protocol, how does that get expressed? 17 How does the incidence rate __ you know what 18 an incidence rate is, don't you? 19 A. Right. 20 Q. How does the incidence rate of suicide 21 get expressed in terms of patient years? 22 A. Well, in your example __ again, I'm not 23 familiar with the overall calculation. In 24 your example, the actual rate of occurrence, 25 meaning percent, would be factored. You would SPHERION DEPOSITION SERVICES (800) 880_1036 447 DAVID WHEADON, M.D. 1 see that. 2 So in your example, of the 3 two patients on Paxil, right, 50 percent 4 committed suicide; correct? Is that correct? 5 Q. That's correct. 6 A. So that would be there. If you express 7 it then in terms of patient exposure year, I 8 don't know exactly all the calculations that 9 go in, but if there were none on placebo __ 10 let's say, there were two on placebo that were 11 on for the same period of time that you were 12 or on as long as I was, okay? None committed 13 suicide on placebo. So that would be 50 14 percent versus 0 percent on placebo; correct? 15 So you have a signal. 16 Q. That's a big signal, isn't it? 17 A. It is a big signal. You then translate 18 down to the patient exposure year, and I don't 19 know the calculation, but for the sake of 20 argument, let's say it would be .2 per patient 21 exposure year for Paxil, and it would still be 22 0 for placebo. So the difference would be 23 carried out. Do you see what I'm saying? 24 Q. I see what you are saying, but I don't 25 think you addressed my concern. And the SPHERION DEPOSITION SERVICES (800) 880_1036 448 DAVID WHEADON, M.D. 1 concern is that the incidence of suicide, once 2 it is converted to patient years, it gets 3 hidden in the fact that this is a phenomenon 4 that occurs early on, and that people who do 5 well on it are likely to say on it for a year, 6 two years, three years, so that that, in 7 effect, unfairly waits __ it gives your 8 experience 51 times more credence than my 9 experience in the example I gave you? 10 A. I don't think that's correct. Again, 11 I'm not a statistician. I'm not able to be 12 as, perhaps, erudite as I should be in walking 13 you through it, but it does not hide that. 14 That is not a way of hiding the fact that 15 these events may occur early versus later. 16 Q. Well, let me ask you this. When Pfizer 17 __ I'm sorry, SmithKline Beecham. That's 18 twice I have done that to you all. I can 19 think of no worse thing to do to a 20 pharmaceutical company than to call them 21 Pfizer. 22 When SmithKline Beecham did 23 the meta analysis of your depression clinical 24 trials and your OCD clinical trials, did you 25 include in that analysis every patient who SPHERION DEPOSITION SERVICES (800) 880_1036 449 DAVID WHEADON, M.D. 1 ever took the drug or did you include only 2 those who completed the study? 3 A. Every patient who ever took the drug. 4 So those were what we call intent to treat 5 analyses. So no matter when they may have 6 exited the study, they were counted. 7 Q. So the roughly 20 percent of patient 8 drop_outs you had from the clinical trials 9 were factored into that analysis? 10 A. Exactly. 11 Q. Now, how do you factor into that 12 analysis whether a person who dropped out 13 really dropped out because they were 14 suicidal? You are familiar with a term called 15 lost to follow_up, aren't you? 16 A. Yes. 17 Q. And what is that? 18 A. Lost to follow_up is a patient that does 19 not come back for a subsequent visit, and they 20 are not able to collect what happened, why, 21 and that sort of thing. 22 Q. So if I'm a patient in a clinical trial, 23 and after one week on this stuff, I just 24 become intensely suicidal, and I say, I'm not 25 going back, this drug is driving me crazy, SPHERION DEPOSITION SERVICES (800) 880_1036 450 DAVID WHEADON, M.D. 1 then nobody ever knows if I had a change in my 2 HAM_D score, because I just don't go back, 3 right? 4 A. The same thing would be true for placebo 5 patients, however. The same thing could be 6 exactly true for a placebo patient, that they 7 decide, for whatever reason, that they are not 8 going back, because they don't know what they 9 are taking, they are feeling worse, they are 10 not being helped, so __ 11 Q. So what's your point? 12 A. The deck is stacked equally in both 13 directions, for drug versus placebo. So your 14 argument is well taken, but it is stacked 15 equally for placebo or for Paxil. 16 Q. Was the drop_out rate equal for placebo? 17 A. I don't recall exactly what the placebo 18 drop_out rate was. 19 Q. It wasn't nearly as high as the 20 20 percent for Paxil, was it? 21 A. But those were not people lost to 22 follow_up. There was a 20 percent early 23 discontinuation rate due to adverse events. 24 We know about what happened to those people. 25 Q. To every one of them? SPHERION DEPOSITION SERVICES (800) 880_1036 451 DAVID WHEADON, M.D. 1 A. Yes. 2 Q. And so we know if they __ if each and 3 every one of those people dropped out because 4 they developed intense suicidal thoughts? 5 A. That would be captured. I don't know 6 exactly the lost to follow_up rate, but it is 7 not 20 percent. But the 20 percent that you 8 are quoting, discontinued early due to adverse 9 effect, we know what they discontinued for. 10 Q. What's a differential diagnosis? 11 A. Differential diagnosis refers to a list 12 of possibilities that might explain the 13 symptoms that a patient is describing to you. 14 Q. Now, in the example you and I discussed 15 yesterday of a person who commits suicide and 16 __ 17 THE VIDEO TAPE OPERATOR: 18 Going off the video record. The time is 19 11:25. 20 THE VIDEO TAPE OPERATOR: 21 Back on the video record. The time is 11:27. 22 BY MR. VICKERY: 23 Q. Now, I apologize for the interruption. 24 We were discussing differential diagnoses, and 25 particularly, with regard to the hypothet that SPHERION DEPOSITION SERVICES (800) 880_1036 452 DAVID WHEADON, M.D. 1 you and I discussed yesterday, a man dies, and 2 we know two things about him, we know he was 3 depressed, and we know that he was drunk. And 4 so our differential diagnoses for the things 5 that may have caused or contributed to his 6 suicide would include what? 7 A. Depression, number one. 8 Q. Right. 9 A. Exacerbation by the depressant effect of 10 alcohol. 11 Q. Right. Now, there could be other things 12 that one would put on the list as well? 13 A. Yes. 14 Q. Like what? 15 A. It could be a nascent psychosis that no 16 one noticed. Sometimes, people who drink 17 significant amounts of alcohol can have 18 essentially a psychotic reaction. So that's 19 another low on the list possibility, but not 20 impossible. 21 Q. Can a psychoactive drug like Paxil cause 22 a psychotic reaction? 23 A. Not that I am aware of, no. 24 Q. Now, what if the man died, and we knew 25 two things about him; one was that he was SPHERION DEPOSITION SERVICES (800) 880_1036 453 DAVID WHEADON, M.D. 1 depressed, but two was that he shot three 2 other people first? 3 Now, depression wouldn't be 4 on our differential diagnosis in that 5 instance, would it? 6 A. I'm not sure what you are asking. 7 Q. Yesterday, you testified that aggression 8 towards others is really not a facet of 9 depression. The suicide is, but homicide is 10 not, right? 11 A. That's correct. 12 Q. So if we know that this person killed 13 three other people immediately before he 14 killed himself, then our differential 15 diagnosis does not include depression, does 16 it? 17 A. That is not necessarily true, no. 18 Q. You are telling me it would include 19 depression? 20 A. It could include depression, yes. 21 Q. To account for the suicide? 22 A. To account for the suicide, but it could 23 also account for the homicide from the 24 standpoint of depressed suicidal individuals 25 sometimes take the lives of others because SPHERION DEPOSITION SERVICES (800) 880_1036 454 DAVID WHEADON, M.D. 1 they cannot deal with the guilt of leaving 2 behind a child, of leaving behind a loved one, 3 so to their idea, the way of relieving that 4 guilt in the final moments before taking their 5 own lives is to make sure that that loved one 6 is not left suffering. 7 Q. So you are saying now that depression 8 does have a component of violence towards 9 others? 10 A. No, that is not what I'm saying. I'm 11 giving you, if you will, a sort of psychiatric 12 explanation for why sometimes there are 13 murder_suicides. But homicide is not a core 14 component of depression, like suicide is. 15 MR. VICKERY: Those were 16 all of the notes that I made. Thank you. 17 THE VIDEO TAPE OPERATOR: 18 Going off the video record. The time is 19 11:31. 20 21 22 23 24 25 SPHERION DEPOSITION SERVICES (800) 880_1036 455 1 C E R T I F I C A T E 2 _ _ _ 3 STATE OF NEW JERSEY : 4 : SS 5 COUNTY OF BURLINGTON : 6 7 I, Jeanne Christian, 8 Court Reporter_Notary Public within and for 9 Burlington County, Commonwealth of New Jersey, 10 do hereby certify that the foregoing testimony 11 of David Wheadon, M.D. was taken before me at 12 2600 One Commerce Square, Philadelphia, 13 Pennsylvania on Thursday, October 19, 2000; 14 that the foregoing testimony was taken in 15 shorthand by myself and reduced to typing 16 under my direction and control, that the 17 foregoing pages contain a true and correct 18 transcription of all of the testimony of said 19 witness. 20 21 22 ..................... JEANNE CHRISTIAN 23 Notary Public 24 My Commission expires 25 May 21, 2003 SPHERION DEPOSITION SERVICES (800) 880_1036 456 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. SPHERION DEPOSITION SERVICES (800) 880_1036 457 1 I have read the foregoing 2 deposition and the answers given by me are 3 true and correct, to the best of my 4 knowledge and belief. 5 6 7 8 ...................... DAVID WHEADON, M.D. 9 10 ....................... Witness to signature 11 ....................... 12 Address 13 My Commission expires 14 ...................... 15 16 17 18 19 20 21 22 23 24 25 SPHERION DEPOSITION SERVICES (800) 880_1036 458 1 ERRATA SHEET 2 PAGE LINE # CHANGE REASON THEREFOR 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 (800) 880_1036