NO. 90-CI-6033 JEFFERSON CIRCUIT COURT DIVISION ONE (1) JOYCE FENTRESS, ET AL. ) ) Plaintiffs, ) ) vs. ) ) ) SHEA COMMUNICATIONS, ET AL. ) ) Defendants. ) _____________________________) The continued deposition upon oral examination of CHARLES M. BEASLEY, JR., M.D., a witness produced and sworn before me, Linda M. Bour, a Notary Public in and for the County of Marion, State of Indiana, taken at the offices of Baker & Daniels, 300 North Meridian Street, Suite 2700, Indianapolis, Marion County, Indiana, on the 30th day of August 1994, in accordance with the Applicable Rules of Civil Procedure. (VOLUME II) BOUR REPORTING P.O. Box 78261 Indianapolis, IN 46278-0261 (317) 875-3914 NO. 91-02496-A JACKIE LYNN BIFFLE, ET AL ) IN THE DISTRICT ) COURT OF ) DALLAS COUNTY, TEXAS V. ) ) ) ELI LILLY & COMPANY AND ) 14TH JUDICIAL DISTA PRODUCTS COMPANY ) DISTRICT The continued deposition upon oral examination of CHARLES M. BEASLEY, JR., M.D., a witness produced and sworn before me, Linda M. Bour, a Notary Public in and for the County of Marion, State of Indiana, taken at the offices of Baker & Daniels, 300 North Meridian Street, Suite 2700, Indianapolis, Marion County, Indiana, on the 30th day of August 1994, in accordance with the Applicable Rules of Civil Procedure. (VOLUME II) BOUR REPORTING P.O. Box 78261 Indianapolis, IN 46278-0261 (317) 875-3914 NO. 92-14775E RICHARD HAROLD CROSSETT, JR ) IN THE DISTRICT CHAD H. CROSSETT, AMY MICHELLE ) COURT OF CROSSETT AND KRISTEN ANN CROSSETT) DALLAS COUNTY, TEXAS INDIVIDUALLY AND AS SURVIVORS OF ) AND ON BEHALF OF THE ESTATE OF ) JOCQUETTA ANN CROSSETT, DECEASED ) ) V. ) ) ELI LILLY & COMPANY, DISTA ) 101st JUDICIAL PRODUCTS COMPANY, TEXAS ) DISTRICT PSYCHIATRIC COMPANY, INC. ) D/B/A HCA WILLOW PARK ) HOSPITAL, JAMES K. WITSCHY, M.D. ) The continued deposition upon oral examination of CHARLES M. BEASLEY, JR., M.D., a witness produced and sworn before me, Linda M. Bour, a Notary Public in and for the County of Marion, State of Indiana, taken at the offices of Baker & Daniels, 300 North Meridian Street, Suite 2700, Indianapolis, Marion County, Indiana, on the 30th day of August 1994, in accordance with the Applicable Rules of Civil Procedure. (VOLUME II) BOUR REPORTING P.O. Box 78261 Indianapolis, IN 46278-0261 (317) 875-3914 NO. A-921,405-C MARIA GUADALUPE REVES ) IN THE DISTRICT INDIVIDUALLY AND AS NEXT ) COURT OF FRIEND OF GRANT JULIAN REVES ) DALLAS COUNTY, TEXAS A MINOR CHILD, AND ON BEHALF ) OF THE ESTATE OF CHRISTIAN ) MARIE REVES, DECEASED ) ) V. ) ) ELI LILLY & COMPANY, DISTA ) ORANGE COUNTY, PRODUCTS COMPANY, RAVIKUMAR ) TEXAS KANNEGANTI, M.D., HOSPITAL ) CORPORATION OF AMERICA, A ) TENNESSEE CORPORATION, HEALTH ) SERVICES ACQUISITION CORP., ) A DELAWARE CORPORATION, ) HCA PSYCHIATRIC COMPANY, A ) DELAWARE CORPORATION, TEXAS ) PSYCHIATRIC CO., INC., A/K/A ) AND/OR D/B/A HCA BEAUMONT ) NEUROLOGICAL HOSPITAL, AND HCA ) HEALTH SERVICES OF TEXAS, INC. ) A/K/A AND/OR BEAUMONT ) 128th JUDICIAL NEUROLOGICAL HOSPITAL ) DISTRICT The continued deposition upon oral examination of CHARLES M. BEASLEY, JR., M.D., a witness produced and sworn before me, Linda M. Bour, a Notary Public in and for the County of Marion, State of Indiana, taken at the offices of Baker & Daniels, 300 North Meridian Street, Suite 2700, Indianapolis, Marion County, Indiana, on the 30th day of August 1994, in accordance with the Applicable Rules of Civil Procedure. (VOLUME II) BOUR REPORTING P.O. Box 78261 Indianapolis, IN 46278-0261 (317) 875-3914 IN THE CIRCUIT COURT OF COOK COUNTY, ILLINOIS COUNTY DEPARTMENT - LAW DIVISION RENATO DI SILVESTRO, Individually ) and as Special Administrator of ) the Estate of JOHN DI SILVESTRO, ) Deceased, ) ) Plaintiff, ) ) vs. ) No. 91 L 7881 ) ROBERT L. NELSON, et al., ) ) Defendants, ) ) GEORGE MELNICK, M.D. and PETER ) FINK, M.D., ) ) Defendants in Discovery. ) _____________________________________) The continued deposition upon oral examination of CHARLES M. BEASLEY, JR., M.D., a witness produced and sworn before me, Linda M. Bour, a Notary Public in and for the County of Marion, State of Indiana, taken at the offices of Baker & Daniels, 300 North Meridian Street, Suite 2700, Indianapolis, Marion County, Indiana, on the 30th day of August 1994, in accordance with the Applicable Rules of Civil Procedure. (VOLUME II) BOUR REPORTING P.O. Box 78261 Indianapolis, IN 46278-0261 (317) 875-3914 SUPERIOR COURT OF THE STATE OF CALIFORNIA FOR THE COUNTY OF LOS ANGELES DR. MARIUS SAINES, etc., et al., ) Case No: ) SC 008331 Plaintiffs, ) ) vs. ) ) ELI LILLY & COMPANY, a corporation; ) DISTA PRODUCTS COMPANY, a division ) of Eli Lilly & Company; and DOBS 1- ) 100, inclusive, ) ) Defendants. ) _____________________________________) The continued deposition upon oral examination of CHARLES M. BEASLEY, JR., M.D., a witness produced and sworn before me, Linda M. Bour, a Notary Public in and for the County of Marion, State of Indiana, taken at the offices of Baker & Daniels, 300 North Meridian Street, Suite 2700, Indianapolis, Marion County, Indiana, on the 30th day of August 1994, in accordance with the Applicable Rules of Civil Procedure. (VOLUME II) BOUR REPORTING P.O. Box 78261 Indianapolis, IN 46278-0261 (317) 875-3914 NO. 93-8792-D DAVID KUNG, DALE KUNG COHEN ) IN THE DISTRICT ROBERT KUNG, AND TIMOTHY KUNG, ) COURT OF INDIVIDUALLY AND AS SURVIVORS ) DALLAS COUNTY, TEXAS AND STATUTORY BENEFICIARIES ) OF MAY YUN KUNG, DECEASED ) ) vs. ) DALLAS, COUNTY ) TEXAS ) ELI LILLY AND COMPANY, DISTA ) PRODUCTS COMPANY, AND MONIQUE ) KUNKLE, Ph.D., ) The continued deposition upon oral examination of CHARLES M. BEASLEY, JR., M.D., a witness produced and sworn before me, Linda M. Bour, a Notary Public in and for the County of Marion, State of Indiana, taken at the offices of Baker & Daniels, 300 North Meridian Street, Suite 2700, Indianapolis, Marion County, Indiana, on the 30th day of August 1994, in accordance with the Applicable Rules of Civil Procedure. (VOLUME II) BOUR REPORTING P.O. Box 78261 Indianapolis, IN 46278-0261 (317) 875-3914 IN THE DISTRICT COURT OF JOHNSON COUNTY, KANSAS CIVIL COURT DEPARTMENT EUGENE HUSLIG, AS ADMINISTRATOR ) Case No: AND EXECUTOR AND ON BEHALF OF ) 94 C 192 THE ESTATE OF DEBORAH G. WEATHERS ) HUSLIG, DECEASED, AND AS SURVIVING ) HUSBAND AND HEIR AT LAW OF DEBORAH ) G. WEATHERS HUSLIG, DECEASED, ) AND IN HIS INDIVIDUAL CAPACITY AS ) HUSBAND OF DEBORAH G. WEATHERS ) HUSLIG, DECEASED, AND RONALD C. ) WEATHERS, SON OF DEBORAH G. ) WEATHERS HUSLIG, DECEASED, ) Plaintiffs,) VS. ) ) MARY L. BILLINGSLEY, EXECUTOR OF ) COURT NO. 7 THE ESTATE OF THAD BILLINGSLEY, ) CHAPTER 60 M.D., DECEASED D/B/A THE BENESSERE ) CENTER, SUSAN C. JOHNSON, PH.D., ) F/K/A THAD H. BILLINGSLEY, M.D. ) CHARTERED, D/B/A THE BENESSERE ) CENTER, ELI LILLY AND COMPANY, ) AND DISTA PRODUCTS COMPANY, ) Defendants.) The continued deposition upon oral examination of CHARLES M. BEASLEY, JR., M.D., a witness produced and sworn before me, Linda M. Bour, a Notary Public in and for the County of Marion, State of Indiana, taken at the offices of Baker & Daniels, 300 North Meridian Street, Suite 2700, Indianapolis, Marion County, Indiana, on the 30th day of August 1994, in accordance with the Applicable Rules of Civil Procedure. (VOLUME II) BOUR REPORTING P.O. Box 78261 Indianapolis, IN 46278-0261 (317) 875-3914 CAUSE NO. 93-04911-A LINDA JILL WELCH, CARLINDA ) WELCH REX, CONNAN ROSS WELCH ) AND CHAD MICHAEL WELCH, ) INDIVIDUALLY AND AS SURVIVORS ) AND STATUTORY BENEFICIARIES ) OF CARL EUGENE WELCH, DECEASED ) ) Plaintiffs, ) vs. ) ) ELI LILLY AND COMPANY, DISTA ) PRODUCTS COMPANY, NOE NEAVES, ) M.D., AND MINITH-MEIER ) CLINIC, P.A., ) ) Defendants. ) The continued deposition upon oral examination of CHARLES M. BEASLEY, JR., M.D., a witness produced and sworn before me, Linda M. Bour, a Notary Public in and for the County of Marion, State of Indiana, taken at the offices of Baker & Daniels, 300 North Meridian Street, Suite 2700, Indianapolis, Marion County, Indiana, on the 30th day of August 1994, in accordance with the Applicable Rules of Civil Procedure. (VOLUME II) BOUR REPORTING P.O. Box 78261 Indianapolis, IN 46278-0261 (317) 875-3914 A P P E A R A N C E S ----------------------------- CHARLES M. BEASLEY, JR., M.D. August 30, 1994 (Volume II) ----------------------------- PAUL SMITH COUNSEL FOR GROUP OF PLAINTIFFS 745 CAMPBELL CENTER 2 8115 NORTH CENTRAL EXPRESSWAY DALLAS, TX 75206 LAWRENCE J. MYERS STEVE LORE COUNSEL FOR ELI LILLY AND COMPANY FREEMAN & HAWKINS 4000 ONE PEACHTREE CENTER 303 PEACHTREE STREET, N.E. ATLANTA, GA 30308-3243 MARGARET M. HUFF ELI LILLY AND COMPANY LILLY CORPORATE CENTER 307 EAST McCARTY STREET INDIANAPOLIS, IN 46285 WILLIAM J. DOWNEY, III COUNSEL FOR PLAINTIFF SAINES KANANACK, MURGATROYD, BAUM & HEDLUND 12100 WILSHIRE BOULEVARD, SUITE 650 LOS ANGELES, CA 90025 I N D E X O F E X A M I N A T I O N PAGES DIRECT EXAMINATION (Continuing)............ 12 Questions by Mr. Paul Smith I N D E X O F E X H I B I T S (Continuing) ----------------------------- CHARLES M. BEASLEY, JR., M.D. August 30, 1994 (Volume II) ----------------------------- PAGES Plaintiffs' Deposition Exhibit No.: 19 - EXHIBIT............................... 24 20 - EXHIBIT............................... 81 21 - EXHIBIT............................... 111 22 - EXHIBIT............................... 126 23 - EXHIBIT............................... 133 24 - EXHIBIT............................... 142 25 - EXHIBIT............................... 154 26 - EXHIBIT............................... 168 27 - EXHIBIT............................... 224 PAGE 12 1 C H A R L E S M. B E A S L E Y, J. R., M. D., 2 having been first duly sworn to tell the 3 truth, the whole truth and nothing but the 4 truth relating to said matter, was examined 5 and testified as follows: 6 DIRECT EXAMINATION (CONTINUING) 7 QUESTIONS BY PAUL SMITH: 8 Q Dr. Beasley, your deposition is being summarized 9 at this time and I couldn't find it, and I need 10 to get from you just some things that will make 11 this go a little quicker. 12 A Yes. 13 Q Refresh my recollection of when you started with 14 Lilly. 15 A That would have been 7-7-87. 16 Q And you were a clinical research physician for 17 how long? 18 A Well, I began as an associate clinical research 19 physician; I think that was for approximately two 20 years. 21 Q And continued then -- 22 A Then was promoted to -- PAGE 13 1 Q Associate to clinical research physician? 2 A To research physician, that's correct. 3 Q And have you had any changes in job titles since? 4 A I was further promoted to senior. 5 Q When were you promoted to senior clinical 6 research physician, in '89? 7 A No, that would have been approximately March of 8 '91. 9 Q And you took your boards in Psychiatry, did you 10 not? 11 A That's correct. 12 Q And when did you take your boards? 13 A I took Part 1 in I believe it was April of 1987 14 and Part 2 I believe it was October or November. 15 I believe it was November of the same year, '87. 16 Q And received your certification shortly 17 thereafter? 18 A That's correct. I think it's about -- there's 19 actually I think about a gap of six months before 20 they notify people. 21 Q In your work as a research physician at Eli Lilly 22 and Company and in connection with your work on PAGE 14 1 Fluoxetine Hydrochloride, obviously you became 2 familiar with the clinical trial process involved 3 in the research and study of Prozac. 4 A That's correct. 5 Q And at the time you began with Lilly, Prozac was 6 in its final phases of approval; is that correct? 7 A That's correct. It was approved at the end of 8 that year that I joined. 9 Q And in your work at Lilly on Prozac, you have on 10 a number of occasions reviewed the clinical trial 11 data, have you not? 12 A Various components of that data I have reviewed, 13 yes, sir. 14 Q Especially in connection with the issue of Prozac 15 and suicide? 16 A That's correct. 17 Q And in connection with the issue of Prozac and 18 violent aggressive -- and aggressive behavior? 19 A Yes, although I would characterize that as, at 20 least on my part, a less extensive review than 21 the suicidality. 22 Q Your primary responsibility was the suicidality PAGE 15 1 review of the clinical trials? 2 A That's correct. 3 Q And you analyzed at least in part the data that 4 had been received post-marketing via the 5 Spontaneous Reporting System as well as the Drug 6 Experience Network at Lilly? 7 A The Drug Experience Network is the system for 8 spontaneous post-marketing results. 9 Q All right. So in your opinion the SRS and DEN is 10 one and the same? 11 MR. MYERS: Well, let me object to 12 the form of the question because now I think 13 you're talking about two different things, maybe 14 an FDA system and a Lilly system. 15 MR. SMITH: Okay. And that's what I 16 was trying to get to. 17 Q The DEN system is an in-house Lilly computer 18 database, is it not? 19 A That's correct for -- that's correct. 20 Q And the SRS, Spontaneous Reporting System, is 21 more of an FDA creature; is that right? 22 A The reports reside in the DEN system for PAGE 16 1 appropriate transmission to the Food and Drug 2 Administration. 3 Q All right. So once those reports are transmitted 4 to the Food and Drug Administration, does the FDA 5 keep their records in the terms of Spontaneous 6 Reporting System? 7 A I'm not sure. My knowledge is that what we 8 submit is a Federal Form 1639. 9 Q Correct. 10 A I'm not certain what the Food and Drug 11 Administration calls their database or the 12 computer system in which that data is kept. 13 Q Well, have you heard of the Spontaneous Reporting 14 System? 15 A Yes. 16 Q Have you heard the term SRS used as an 17 abbreviation for that system? 18 A No, this is the first time I've heard that term. 19 Q Okay. Let's then use Spontaneous Reporting 20 System. Is it your understanding just generally 21 that the Spontaneous Reporting System is 22 something that's maintained by the Food and Drug PAGE 17 1 Administration? 2 A That's correct. 3 Q And DEN is something that's maintained by Lilly? 4 A That's correct. 5 Q Now, Lilly in-house supplies information to the 6 Spontaneous Reporting System at the FDA through 7 their DEN system; is that right? 8 A That's correct by these Form 1639s. 9 Q Via a 1639? 10 A That's correct. 11 Q Will the Spontaneous Reporting System have more 12 data concerning post-marketing adverse events 13 than the DEN system? 14 A It well might. 15 Q Is the reason for that that the Spontaneous 16 Reporting System might pick up an adverse event 17 reported directly by, say, a physician to the 18 Food and Drug Administration as opposed to Lilly? 19 A That's correct. 20 Q But if that physician theoretically reported this 21 adverse event to Lilly, then Lilly would record 22 it in their DEN database and in addition if it is PAGE 18 1 required under the applicable rules and 2 regulations, report it via a 1639 to the FDA? 3 A That's correct. I believe that some events would 4 be reported in the annual report as well. 5 Q All right. So is it your understanding that 6 Spontaneous Reporting System data might also 7 include data that's reported to the FDA from 8 Lilly via the quarterly or annual safety updates 9 or reports? 10 A That's my understanding. 11 Q But there might well be more information in the 12 Spontaneous Reporting System because it might be 13 that a physician or health care provider or any 14 individual might have reported the adverse event 15 directly to the FDA instead of Lilly? 16 A That's correct, sir. Yes, sir. 17 Q Now, does Lilly do anything to seek out that 18 information from the Spontaneous Reporting System 19 to determine whether or not the Spontaneous 20 Reporting System contains instances of adverse 21 events in connection with Prozac that are not 22 contained within Lilly's DEN system? PAGE 19 1 A I don't believe that there is a regular routine 2 process for requesting that information. 3 Q All right. So in order to know the total number 4 of adverse events reported in connection with, 5 say Prozac in the United States, one would need 6 to look not only at the DEN data that Lilly had, 7 but also to the Spontaneous Reporting System at 8 the FDA to get a more inclusive number? 9 A That would be potentially correct, yes, sir. 10 Q Would there be any other sources that one would 11 examine to determine adverse events that had been 12 reported in different ways to different 13 governmental bodies? 14 MR. MYERS: Let me just object to 15 the form. When you say different governmental 16 bodies, it's unclear "different". Different than 17 what governmental body? 18 MR. SMITH: Different than those 19 reported to the Food and Drug Administration. 20 MR. MYERS: I'm sorry. Are you 21 talking about sources of information or 22 governmental bodies other than the FDA? That's PAGE 20 1 the problem I have with your question. 2 MR. SMITH: Other sources of 3 information. 4 MR. MYERS: All right. 5 A And we're talking about within the United States? 6 Q Or worldwide. You know, I'm not trying to -- 7 A Right. I'm just -- 8 Q -- to confuse you. It's my understanding that 9 there is international reporting systems that 10 collect adverse events to some extent and I'm 11 thinking of the CIOMS or CIOMS, C-I-O-M-S, 12 database. 13 A Right, which is a database that Lilly 14 participates in -- 15 Q Yes. 16 A -- and contributes to for international reporting 17 of adverse events. I'm unaware of other sources 18 by which CIOMS obtains information other than 19 from other manufacturers. There are clearly 20 regulatory bodies throughout the world that 21 receive information both via CIOMS but 22 potentially from local reporters as well. PAGE 21 1 Q All right. How then does Lilly determine 2 instances of adverse events that occur in foreign 3 countries? 4 A The Lilly affiliates are charged with the same 5 responsibility as Lilly U.S. to report any 6 spontaneous event reported to them or that they 7 learn of through essentially any mechanism into 8 the DEN system. 9 Q All right. So the DEN system will have some 10 international data? 11 A Yes, sir, that's correct. 12 Q But does that DEN system or does Lilly try to 13 track separate collections of adverse events 14 maintained in specific foreign countries? 15 MR. MYERS: Other than -- you mean 16 in any way other than what he's described? 17 MR. SMITH: Yes. 18 A I am unaware of what affiliates might or might 19 not do over and above what I have described. I 20 know that we do receive data from the British 21 collection system transmitted to us because I 22 have seen such reports. Now, the mechanism for PAGE 22 1 that I'm unaware of. 2 Q What's the name of the British collection system? 3 A I believe it's called the CSM. 4 Q Committee of Safety and Medicine? 5 A I believe that's correct. 6 Q All right. And so there is a collecting body in 7 England called the CSM similar to the FDA that 8 collects data on adverse events in connection 9 with drugs? 10 A That's my understanding. 11 Q Now, is it your understanding that Lilly requests 12 all data from England of adverse events reported 13 to the CSM? 14 A Again, I'm not familiar with the specifics of 15 what the affiliate does to obtain data from the 16 CSM. I have seen DEN reports where the source 17 has been indicated to be CSM. 18 Q All right. 19 A I'm not -- again, I'm not sure how that's made 20 available or obtained. 21 Q I guess my principal question is you said earlier 22 that Lilly doesn't do anything to track reports PAGE 23 1 that the FDA might have received that are in the 2 Spontaneous Reporting System at the FDA that 3 might not have been reported to Lilly; is that 4 correct? 5 A That's my understanding. 6 Q And I was wondering if that is the same procedure 7 worldwide; that is, there is no effort made by 8 Lilly to secure from a particular regulatory body 9 what reports had been made to them concerning an 10 adverse event? 11 A And, again, I don't know one way or the other 12 with regard to the affiliates. 13 Q All right. For instance in Mexico, a physician 14 in Mexico reported an adverse event directly to 15 some Mexican governmental body, and I don't 16 frankly know whether Mexico has a governmental 17 body that is required or regularly records 18 adverse events in connection with drugs, but if 19 that's such a situation where an event is 20 reported to the Mexican governmental body but is 21 not reported to the Lilly affiliate in Mexico, do 22 you know of any effort made to secure that PAGE 24 1 information directly from the Mexican regulatory 2 body? 3 A I don't. I don't know one way or the other. 4 Q I'm assuming that in your review of the Prozac 5 clinical trials in connection with the issue of 6 suicide and Prozac you reviewed the protocols or 7 some of the protocols of the various clinical 8 trials? 9 A Some of the protocols, yes, sir. 10 Q And these protocols are the guidelines or sort of 11 the rules and regulations under which the trial 12 is to be conducted? 13 A That's correct. 14 (Plaintiffs' Deposition Exhibit 19 was marked 15 for identification.) 16 Q Dr. Beasley, Exhibit 19 is IND Protocol 17 Number 27. You're of course free to read the 18 entire protocol, but I'm not going to ask you 19 in-depth questions about the entire one. If you 20 just want to make yourself familiar with it, I'll 21 point you to the specific areas that I'd like to 22 talk to you about, but of course you're free to PAGE 25 1 read it in its entirety if you would like. 2 A Thank you. 3 MR. MYERS: Thank you. 4 A I have not read the whole protocol, but I've 5 flipped through it, yes, sir. 6 Q Does this protocol appear to be in fact the 7 protocol for -- or the -- what is Protocol 8 Number 27? 9 A Yes, it does. I believe the protocol was later 10 amended and I do not see the amendments attached 11 here. 12 Q All right. We might have missed those. Do you 13 recall if there was any specific amendment to the 14 protocol that comes to mind? 15 A Well, what I do not see here are the provisions 16 for what I believe were extensions to the 17 protocol. 18 Q Extensions in what connection? 19 A In that patients who responded well could remain 20 on medication. Patients who discontinued because 21 of lack of efficacy were allowed the option of 22 going to open-label Fluoxetine. PAGE 26 1 Q Are there any other extensions or amendments -- 2 A Amendments. 3 Q -- to the protocol that you recall? 4 A That's the specific one that I believe I recall. 5 Q This is -- Protocol Number 27 was a multicenter 6 study comparing Prozac with Imipramine and 7 placebo, was it not? 8 A That's correct. 9 Q And this was considered by the Food and Drug 10 Administration as a pivotal study in examining 11 the safety and efficacy of Prozac, was it not? 12 A That's my understanding, yes, sir. 13 Q Imipramine is a tricyclic antidepressant, is it 14 not? 15 A That's correct. 16 Q And that tricyclic antidepressant was the 17 comparator drug in the study? 18 A Active comparator, yes, sir. 19 Q Yes. In addition the patients were given placebo 20 which is no drug, but they think -- they don't 21 know that it's no drug? 22 A Pharmacologically inactive, yes, sir. PAGE 27 1 Q All right. And the purpose of the study was to 2 compare Prozac with this existing tricyclic 3 antidepressant and a placebo; is that right? 4 A That's correct. 5 Q And is this protocol in fact sort of a guideline 6 as to how the study is to be conducted? 7 A That's correct. It's a description to the 8 investigators. 9 Q And it's kind of the rules and regulations as to 10 how this particular study is to be done? 11 A That's correct. 12 Q In other words, if you were designing a study 13 where you were only going to examine Prozac and 14 its effects on adolescents, for instance, it 15 would be designed in a little different way; 16 correct? 17 A The inclusion and exclusion criteria would 18 specify that you had to include adolescents and 19 that you couldn't include children or adults. 20 Q All right. And that's just a simple way to say 21 it gives guidelines as to who's going to be 22 included and who's not going to be included? PAGE 28 1 A That's correct. 2 Q Obviously this is set out in Part 5 on Page 2 of 3 the protocol, is it not? 4 A These would be what I have referred to, Part A as 5 Inclusion Criteria and Part B as Exclusion 6 Criteria. 7 Q And that continues through Page 4, does it not? 8 A That's correct. 9 Q Okay. And so Section 5, Parts A and B, are the 10 definition of the group of people that are going 11 to be studied; is that right? 12 A That's correct. 13 Q In other words, in order to properly design a 14 clinical trial you have to define who you're 15 looking at, don't you? 16 A That's correct. 17 Q And the first criteria for inclusion in this 18 particular study is that they not be 19 hospitalized, they be outpatients? 20 A That's correct. 21 Q Then you can include men and women? 22 A Uh-huh. (Affirmative nod). PAGE 29 1 Q Right? 2 A That's correct. 3 Q And you were going to include a pretty broad 4 range of years from age 21 to 70; is that right? 5 A Depending upon the state, the majority 18 or 21 6 up to age 70. 7 Q So since you're including that group, you 8 probably couldn't draw any specific conclusions 9 from this study concerning how Prozac would act 10 in children based on this study? 11 A No, this study would not provide empirical data 12 regarding children. 13 Q Because it didn't study children? 14 A That's correct. 15 Q In fact children were excluded from the study by 16 virtue -- by implication of the inclusion 17 criteria? 18 A That's correct. 19 Q And the people who were going to be participating 20 in the study were people that agreed to 21 participate in the study; right? 22 A Yes, participation is always voluntary. PAGE 30 1 Q Were there any studies that Lilly did in 2 connection with Prozac where the people who were 3 the subject of the study were being studied 4 against their will? 5 A Certainly none that I'm aware of. 6 Q The next section there has to do with the 7 diagnostic criteria; right? 8 A That's correct. 9 Q It says that DSM-III criteria will be used. What 10 is the DSM-III? 11 A DSM-III is the third edition of the Diagnostic 12 and Statistical Manual published by the 13 American -- drawn up and published by the 14 American Psychiatric Association. 15 Q What basically is that document? 16 A It is a document which lists the total range of 17 official diagnostic labels recognized by the 18 developing body, the American Psychiatric 19 Association. And then on top of that the first 20 thing it does is lay out diagnostic criteria 21 referred to as operational criteria, things that 22 have to be observed and be present and be absent PAGE 31 1 both in what we call cross-sectional time, 2 meaning at the point of observation, but then in 3 some cases also historically over a longer time 4 course in order to label a given individual, 5 potentially a patient, with that diagnostic label 6 or diagnosis. It has other components. The full 7 manual has other components as well. It talks 8 about associated features, epidemiology, 9 et cetera. 10 Q I've seen terms like the DSM-III-R. Is there 11 such -- is that correct, there is a -- there was 12 at least a DSM-III-R? 13 A Yes, sir, that's correct. 14 Q Does the "R" stand for Revised? 15 A Yes, it does. 16 Q It's just a refinement of the original DSM-III, 17 isn't it? 18 A That's correct. 19 Q Now, is there a DSM-IV? 20 A Yes, there is. 21 Q When did the DSM-IV come out? 22 A The DSM-IV I believe had its unveiling at about PAGE 32 1 the time of this year's APA meeting which would 2 have been in May. 3 Q Does this DSM -- what's that stand for, 4 Diagnostic -- 5 A Diagnostic and Statistical Manual. 6 Q Does this have to do with only psychiatric 7 illnesses and disorders? 8 A Yes, except that it specifies for the 9 psychiatrist how to list within a global 10 assessment of the patient medical sort of 11 nonpsychiatric conditions as well so that when 12 one prepares a report on a patient, it would be 13 appropriate to list and describe the 14 nonpsychiatric conditions that the patient might 15 suffer from. It lays out the ways that that's 16 supposed to be done. 17 Q But it's in relation to mental disorders and 18 illnesses, is it not? 19 A That's the overwhelming focus of the -- 20 Q In other words, you're not going to look at 21 DSM-III to diagnose or to find a diagnostic 22 criteria for heart attack? PAGE 33 1 A No. 2 Q Or a stroke? 3 A No. 4 Q Or some orthopaedic complaint? 5 A No. 6 Q It has to do with something done by 7 psychiatrists, for psychiatrists and I suppose 8 psychologists and other health care professionals 9 involved in psychological and psychiatric care 10 and treatment? 11 A Yes, sir, that's correct. 12 Q So back to the protocol, it says that the DSM-III 13 criteria for Major Depressive Disorder is going 14 to be a requirement for inclusion; is that right? 15 A That's correct. 16 Q In other words, an individual has to be depressed 17 in order to be a participant or a member of the 18 group that's going to be studied in this 19 protocol? 20 A Yes. Even more specifically meet specifically 21 the criteria for Major Depressive Disorder. 22 Q All right. And is there a difference between PAGE 34 1 Major, Moderate and Minor Depressive Disorder? 2 A Well, within the -- the latter two terms that you 3 just mentioned are not recognized within DSM-III, 4 III-R, IV, but there is a condition called 5 Dysthymia which is a more -- which is a less 6 severe but more chronic form. And then, at least 7 in DSM-III-R, there was a diagnosis called 8 depression and not otherwise specified which 9 could be a more minor and less chronic form. 10 Q All right. So they have to have -- under this 11 protocol they have to be diagnosed under the 12 DSM-III criteria as having Major Depressive 13 Disorder; correct? 14 A With one slight exception to that that's 15 indicated in the parenthetical; the DSM-III 16 required two weeks of symptoms to meet criteria. 17 You'll note that this was extended to at least 18 one month's symptoms, but other than that, that's 19 correct. 20 Q Okay. It says next that they will be unipolar 21 depressed patients with either a single or a 22 recurrent episode; correct? PAGE 35 1 A That's correct. 2 Q Well, let's define unipolar depressed patients. 3 A Okay. Unipolar is depression and -- what I want 4 to call mood disorders in general -- have cyclic 5 phases; they're chronic episodic illnesses so 6 that there are periods of symptoms and then 7 symptom-free periods for the most part. A high 8 percentage of patients, probably 50 or 70 percent 9 of patients will have, if you follow them across 10 their life, will have recurrent episodes. The 11 unipolar refers to the nature of the mood 12 episodes as being only depressive in nature and 13 not alternating between depression and manic 14 episodes which is roughly the opposite of what we 15 refer to as a mood or an affective continuum. 16 Q So we've heard the term manic depressive in 17 bipolar individuals. What this study is looking 18 at is not those people, but the people you've 19 earlier described that in their particular 20 illness just have the depressive aspect of the 21 illness? 22 A That's -- that's correct. PAGE 36 1 Q Now, it says that these individuals have been 2 depressed or had this Major Depressive Disorder 3 for at least one month; is that right? 4 A Their current episode must have been of one 5 month's duration. 6 Q Well, then it says it could be either a single or 7 a recurrent episode. 8 A That's correct. This is referring to the current 9 episode. Remember I said that the depression or 10 mood disorders are chronic but cyclic illnesses 11 so that patients have -- at least 50 to probably 12 70, 80 percent of patients -- will get 13 symptomatic and then if you follow them, they'll 14 remit and be normal, and then they will have 15 another episode. What this is referring to is 16 that patients can be in their first episode or 17 they can be in a later episode in a natural 18 course of a recurring illness, but the current 19 episode must have been at least a month's 20 duration. 21 Q So does that mean, Dr. Beasley, that in this 22 study that you would have people that might have PAGE 37 1 been depressed for one month and one day or might 2 have been depressed for their entire lifetime? 3 A That would be theoretically possible from the 4 description. 5 Q Well, I guess it could be practically possible, 6 too, couldn't it? 7 A There are some people that describe themselves as 8 having been depressed for their entire lifetime. 9 There is debate about the reality of that 10 clinical entity. 11 Q Okay. Let's make it simpler then. You could 12 have an individual practically and theoretically 13 in Protocol Number 27 who had been depressed off 14 and on over the last 20 years for instance or you 15 could have an individual who had only just 16 recently had these symptoms and had only had 17 depressive symptoms for one month and one day? 18 A That's correct. 19 Q So some people, some of these people in this 20 study could have been suffering from these signs 21 and symptoms for a long time; correct? 22 A That's correct. PAGE 38 1 Q And some of them could have been suffering from 2 these signs and symptoms for only a short period 3 of time? 4 A That's correct. 5 Q Some of these people could have been seeing a 6 number of psychiatrists for a number of years 7 receiving a number of different kinds of 8 treatment; correct? 9 A I would need to check and see whether there was 10 an exclusion for some degree of what we would 11 call refractoriness. I don't believe that 12 that's -- 13 Q Check that before you finish that so we can get 14 an accurate answer. 15 A I don't believe that that's an exclusion. No, I 16 do not see an exclusion for any type of -- any 17 definition of refractoriness. 18 Q So I'll ask you my question again. A number of 19 these people could have been seeing a number of 20 psychiatrists for a long period of time 21 undergoing a number of different types of 22 treatment; correct? PAGE 39 1 A That's correct. 2 Q And be in the same group being studied who were 3 only depressed for one month and one day who had 4 never seen another psychiatrist, who had never 5 received any type of treatment for that 6 depression? 7 A That's correct. 8 Q There is not any distinction between those people 9 according to the protocol? 10 A That's correct. 11 Q Was there ever any effort made by anybody at 12 Lilly to make any determination as to how these 13 particular aspects of the treatment group 14 actually broke down in the clinical trials, 15 Dr. Beasley? 16 A I am not aware of whether or not analysis looking 17 at differences in the length of illness were or 18 were not conducted. 19 Q Or different types of treatment? 20 A Or past medication history, that's correct. 21 Q Or past psychiatric history? 22 A That's correct. PAGE 40 1 Q It appears to me under this diagnostic criteria 2 under the people that you're going to include, 3 you're going to get a lot of different types of 4 depressed individuals, are you not? 5 A They will be similar in terms of the principal 6 psychiatric diagnosis. Their additional history 7 in terms of length of illness, past medication 8 history, could be substantially different. 9 Q The only thing they've got in common is this 10 particular diagnosis of Unipolar Major Depressive 11 Disorder; correct? 12 A That's correct of at least one month's duration. 13 Q They don't have anything in common concerning 14 age? 15 A They are -- 16 Q -- between the ages of 18 and 70 so there's, you 17 know, 50 years difference in ages, correct, 18 theoretically possible? 19 A Yes. 20 Q And practically possible? 21 A Yes. 22 Q They're going to have all kinds of differences in PAGE 41 1 past psychiatric treatment, are they not? 2 A They may well. 3 Q They're going to have all kinds of different 4 instances of past psychiatric medications, also, 5 are they not? 6 A Excuse me. They might. 7 Q Some may have been hospitalized for their 8 depression -- 9 A They might. 10 Q -- under this inclusion criteria; right? 11 A In the past, yes. 12 Q Yes. And some may never have even driven by a 13 psychiatric hospital? 14 A That's possible. 15 Q Some may have seen eight psychiatrists and some 16 this may be the -- and then others this may be 17 the first psychiatrist they've seen? 18 A That's possible. 19 Q Is it not correct, Dr. Beasley, that Unipolar 20 Major Depressive Disorder encompasses a 21 relatively wide degree of severity also in 22 connection with this particular illness? PAGE 42 1 A Within this protocol or in general? 2 Q Well, let's say within this protocol, number one. 3 A Okay. I believe that in addition to the 4 diagnostic criteria, there are minimal severity 5 scores specified on the Hamilton. 6 Q All right. What is the minimum severity score, 7 20? 8 A I believe that's correct. Hamilton Psychiatric 9 Depression scale score of at least 20 and a 10 Raskin scale score of at least 8. 11 Q Okay. So above 8 and above 20, you can go way on 12 up on the scale, can't you? 13 A That's correct. 14 Q How far up could you go on the Hamilton 15 Depression scale? 16 A Sir, I believe that on the 21 item the 17 approximate upper limit is 64. I would really 18 need to confirm that, but I think I'm plus or 19 minus a point or two. 20 Q How far up can you go on the Raskin scale? 21 A I don't recall on the Raskin how far one can go 22 up. PAGE 43 1 Q Can you go up two-thirds like you can on the 2 Hamilton Depression scale? 3 A It's a much more restricted scale and I do not 4 believe that that's the case. 5 Q Was there ever any analysis made of what the 6 baseline HAMD scores were of these patients that 7 were admitted under Protocol Number 27 by Lilly? 8 A I have reviewed the article that describes the 9 outcome of a component of this study. On 10 occasion I have looked at components of the NDA 11 that refer to the report on this study. In an 12 analysis of change, a sort of principal outcome 13 that's measured, one has to take into account the 14 beginning baseline of those patients. One is 15 interested in change from whatever that baseline 16 is. 17 Q Yes, I understand that. But my question is: If 18 the patients could be either a 20 or all the way 19 up to a 60 under this protocol, was there ever 20 any analysis made to say "We've got X percentage 21 of patients at baseline that were 25; we've got X 22 percentage of patients that were 45; and we've PAGE 44 1 got X percentage of patients at 55" to make some 2 kind of distinction as to how severely depressed 3 these individuals were? 4 A I'm not aware -- I'm simply -- I'm not aware of 5 such an analysis. 6 Q Would that be a reasonable analysis to make, 7 Dr. Beasley, concerning the safety and efficacy 8 of this drug under this protocol? 9 A My personal opinion is that I would not find it 10 an extremely interesting or important analysis. 11 It if were done, it would be something that I 12 would look at. It is generally something that we 13 do -- you just jogged my memory. 14 Q Okay. 15 A Terribly sorry. There has been a retrospective 16 analysis done I believe by Dr. -- either 17 Dr. Pande or Dr. Tollefson looking, and again 18 this is across studies, but looking at 19 distinctions between various severities of 20 depression based on the Hamilton score, and this 21 study would have been included in that. 22 Q Can you give me the name of that article or where PAGE 45 1 that -- well, number one, was that article 2 published? 3 A Okay. Not being an author, I'm not intimately 4 familiar with the history. I believe it has been 5 presented as a poster. I believe that it has 6 been developed as a paper, but I'm not sure of 7 the publication status; it may well have been 8 published or in press. I'm sorry, I don't know. 9 Q Pande and Tollefson are fairly recent vintage 10 within the Lilly group, are they not? 11 A I guess Dr. Tollefson has been with us about a 12 little over three years. 13 Q All right. So this analysis would have been done 14 within the last three years? 15 A That's correct. 16 Q Okay. Do you remember the results of that 17 analysis concerning how these particular patients 18 fit within this broad range of severity of their 19 depression scores? 20 A I don't remember the specific cut points for 21 grouping patients as mild or more moderate or 22 more severe nor the distribution of patients PAGE 46 1 within those, within those categories. I believe 2 it was done in that fashion. 3 Q Well, now, you said mild, moderate, and severe. 4 Are you saying that there are categories of mild, 5 moderate, and severe under Major Depression? 6 A Yes, there are. If one looks in DSM-III-R or IV, 7 there is a whole list of qualifiers that are 8 added, potentially added to the diagnosis. These 9 are not specified in a specific way. It's sort 10 of physician's intuitive judgment; in other 11 words, as opposed to the diagnosis, there are no 12 operational criteria. 13 Q A very subjective analysis or somewhat subjective 14 analysis by the psychiatrist himself? 15 A Based on his clinical experience. 16 Q Yes, as opposed to saying "Okay, from 20 to 30 17 it's going to be mild, and from 30 to 40 it's 18 going to be moderate, and from 40 to 60 it's 19 going to be severe"? 20 A That's correct. 21 Q But none of those distinctions were made in 22 making the selection of patients that were going PAGE 47 1 to participate in Protocol Number 27? 2 A That's correct. 3 Q This large multicenter study that was done? 4 A That's correct. 5 Q This protocol additionally says that "they", 6 meaning these individuals we've already 7 discussed. I'm at the bottom of Page 2 of the 8 protocol. 9 A Uh-huh. 10 Q "They will be further classified according to one 11 or more of the following subtypes:" Then it 12 gives six subtypes. Primary Major Depressive 13 Disorder; Single Episode Unipolar Major 14 Depressive Disorder; Recurrent Unipolar Major 15 Depressive Disorder; Endogenous Major Depressive 16 Disorder; Agitated Major Depressive Disorder; or 17 Retarded Major Depressive Disorder; correct? 18 A Correct. 19 Q Who was going to be making the classifications of 20 these patients into one of these six groups? 21 A That would have been the investigator working 22 with the patient. PAGE 48 1 Q All right. And how would he have done that? 2 A These six categories are nonmutually -- 3 nonmutually exclusive categories. They're 4 actually part of a diagnostic system that 5 preceded DSM-III-R called the Research Diagnostic 6 Criteria. 7 Q Well, I thought we were talking about the DSM-III 8 in connection with Protocol 27. 9 A We were, but they then -- it's actually quite 10 comparable to the RDC criteria. RDC has this 11 one-month duration. For example, that's 12 something that's been pulled from RDC. These are 13 subtypes of depression from amongst those. 14 Obviously we're not making reference -- explicit 15 reference is not made to RDC. I don't believe 16 that the criteria were specified on the Case 17 Report Form. One would presume that the 18 investigators were expected to be familiar with 19 these concepts and make the appropriate diagnoses 20 given their training. 21 Q Well, I don't understand. The protocol says 22 "they", meaning the patients "will be further PAGE 49 1 classified according to one or more of the 2 following subtypes:" Then it lists the specific 3 six subtypes. 4 A Right. 5 Q Now, are you saying that this wasn't done? 6 A No, I believe that it was done. 7 Q All right. And where would I see wherever that 8 was done? 9 A Okay. On the Case Report Form -- 10 Q Yes. 11 A -- there would be boxes to check or numbers to 12 fill in, some such, to indicate whether the 13 patient was a Primary Major Depressive Disorder, 14 a Single Episode or Recurrent Episode. 15 Categories 2 and 3 are mutually exclusive. 16 Q Obviously. 17 A But the others really aren't. Endogenous is a 18 particular -- I'd be happy to tell you more about 19 what these are. And then Agitated and Retarded. 20 And in fact those aren't absolutely mutually 21 exclusive because you can have a mixed picture. 22 Q Okay. So is there six different blocks? PAGE 50 1 A That would -- 2 Q Or four different blocks on the Case Report 3 Forms? 4 A There would be -- I'm not -- I didn't design the 5 Case Report Form for this study, but presumably 6 there are boxes to be checked as to whether the 7 patient was a "1", a "2", a "3", a "4", a "5" or 8 "6", all that apply. 9 Q All right. Now, have you seen Case Report Forms 10 done in the clinical trials on Prozac? 11 A Yes. 12 Q Do you have any recollection of seeing this 13 categorization on the Case Report Forms? 14 A I can't recall specifically seeing this, but 15 since I've used a component of this in an 16 analysis that I've performed, I know that it was 17 checked. 18 Q What component did you use? 19 A I was interested in the agitated/retarded 20 distinction. 21 Q All right. In connection with your suicide 22 analysis? PAGE 51 1 A No, in connection with assessment of clusterings 2 of adverse events. 3 Q All right. So was there some kind of database 4 that you could punch up where you could look at 5 Protocol Number 27 and determine how many 6 patients were agitated, put them in a pot, 7 determine how many patients were retarded, put 8 them in a pot, and then examine separate and 9 distinct adverse events in connection with each 10 group? 11 A Not personally, but that could be done by the 12 computer analysts and statisticians. 13 Q Well, did somebody give you such a printout of 14 that for your study? 15 A Yes, sir. 16 Q But is it correct that the investigator was 17 charged with the responsibility of classifying 18 each patient in the clinical trials as falling in 19 one or more of these six categories listed on 20 Page 3 of this protocol? 21 A That would be correct, yes, sir. 22 Q And you think it's probably on the Case Report PAGE 52 1 Form? 2 A Yes, sir. 3 Q I mean, I don't know of any other way that 4 information could be transmitted to Lilly, do 5 you? 6 A No, I mean I can't think of any other way that 7 the data would have gotten into the computer but, 8 again, I can't recall specifically me looking at 9 the Case Report Forms to see the boxes. 10 Q Did you look at any Case Report Forms in your 11 work in reviewing the side effects that occurred 12 on Prozac? 13 A I have looked at Case Report Forms, yes, sir. 14 Q No, that's not what I asked you. Did you ever -- 15 do you recall looking at any Case Report Forms in 16 your analysis of the side effects that occurred 17 on Prozac during the clinical trials? 18 A With regard to the suicidality issue, yes. 19 Q All right. Now, back to this categorizing these 20 patients in another way. Since the protocol is 21 specifying that these patients be categorized, 22 I'm assuming that these six categories reflect a PAGE 53 1 variety of other different types of depression 2 within major: Unipolar Major Depression, Major 3 Unipolar Depressive Diagnosis under DSM-III? 4 A DSM recognizes clearly the distinction between 5 single episode and recurrent. It recognizes a 6 subtype. Although the word -- although 7 endogenous is not used, a comparable word 8 "melancholic" is recognized. It does not clearly 9 recognize the concept of primary major 10 depression, although that's to some extent built 11 into the way that the diagnostic criteria are 12 written. What it clearly does not recognize is a 13 distinction between retarded and agitated. 14 Q All right. 15 A So in that sense there was some differences 16 between Research Diagnostic Criteria and DSM. 17 Q Is what you're saying that retarded and agitated 18 major depressive disorders include some common 19 features in connection with these depressed 20 symptoms, but some features that are distinctly 21 different? 22 A There would be -- to meet the criteria for PAGE 54 1 depression in the first place, there would have 2 to be at least five symptoms. There would be 3 potentially a lot of commonality, so only in one 4 aspect of a symptom that could contribute to that 5 diagnosis is there a difference. 6 Q No, but I'm talking about the difference between 7 retarded and agitated depressed patients; they 8 have separate and distinct symptomatology, do 9 they not? 10 A A number of their symptoms could be very similar 11 with regard to one symptom which is where they 12 fall on a psychomotor activity status continuum. 13 They are distinctly different. 14 Q Yes. Agitated includes pacing, hand wringing, 15 unable to sit still, pulling or rubbing on hair, 16 skin, clothing or other objects, outbursts of 17 complaining or shouting and talks only on own and 18 can't seem to stop talking; right? 19 A Right. 20 Q Where retarded is something -- 21 A Yeah. 22 Q -- is totally different? PAGE 55 1 A Yeah, the opposite. 2 Q Slowed speech, specifically slowed speech, 3 increased pauses before answering, low or 4 monotonous speech, mute or markedly decreased 5 amount of speech or slowed body movements. 6 A Correct. Those sound like to me the RDC criteria 7 for the two subtypes, yeah. 8 Q We'll get to that, but I just at this point 9 wanted you to explain for us the vast difference 10 in those two groups of depressed individuals as 11 I've just described. 12 MR. MYERS: Are you asking if "are 13 those the differences", or do you want him to 14 describe these? He's told you what the 15 commonality and the differences are a couple of 16 times. I guess what's the question at this 17 point? 18 Q The question is there are vast differences 19 between retarded and agitated depressed patients, 20 aren't there? 21 A I'm not sure that I personally would characterize 22 those as vast. There is clearly differences on PAGE 56 1 this particular spectrum that are -- 2 Q And those differences are distinct, are they not? 3 A Absolutely. They're diametrically opposed to one 4 another. 5 Q That's all I was trying to point out. And both 6 of those two types of individuals are going to be 7 included in Protocol Number 27? 8 A That's correct, because they suffer from Major 9 Depressive Disorder. 10 Q Right, and were indeed included in Protocol 11 Number 27? 12 A That's correct. 13 Q Now, did I understand you to say earlier that 50 14 to 70 percent of individuals suffering from Major 15 Depressive Disorder will get remission of their 16 symptoms over a period of time? 17 A I believe what you heard me to say was that 50 to 18 70 percent of individuals will have recurrences 19 of their depression. 20 Q That says to me that if they're going to have 21 recurrences of their depression that there must 22 be in between a period of time where those PAGE 57 1 depressive conditions do not exist. 2 A Improve for some reason, yes, sir. 3 Q And they wouldn't meet that criteria of Major 4 Depressive Disorder? 5 MR. MYERS: Object to the form. At 6 what point in time? 7 MR. SMITH: At the time they're 8 being evaluated. Listen to the question. 9 A Okay. Actually -- 10 MR. MYERS: I heard it. 11 MR. SMITH: No, you didn't or you 12 wouldn't make that objection. 13 MR. MYERS: I still object to the 14 form. 15 A Actually they would meet the criteria for Major 16 Depressive Disorder since that's a longitudinal 17 lifetime diagnosis. They would not be in a 18 current episode. 19 Q All right. But if they were not in a current 20 episode, their HAMD -- and what is the other -- 21 and the other scales would not put them in that 22 category that they would be suitable for this PAGE 58 1 study; is that correct? 2 A That's correct, sir. 3 Q Their symptoms even though they might have a 4 lifetime diagnosis of Major Depressive Disorder, 5 their symptoms might be such that they're feeling 6 fine? 7 A Yes, sir, the symptoms would be absent. 8 Q Right. And by virtue of the absence of their 9 symptoms, they're not feeling depressed? 10 A Yes, sir. 11 Q Probably not seeking psychiatric care -- 12 A Some -- 13 Q -- for their Major Depressive Disorder at that 14 time? 15 A There I would beg to differ with you because 16 particularly with patients who have had 17 recurrences, a common practice is to treat 18 patients chronically long term to try to prevent 19 the emergence of the symptoms in later 20 hypothetical episodes so that -- 21 Q Psychopharmacologically? 22 A Yes, sir. PAGE 59 1 Q Does that mean, Dr. Beasley, that an individual 2 that has Major Depressive Disorder should, since 3 it's a lifetime diagnosis, have lifetime 4 psychopharmacological treatment? 5 A Not under all circumstances, sir. 6 Q Under most circumstances? 7 A The criteria -- that's really a clinical issue to 8 be decided between the treating physician and the 9 patient. 10 Q But isn't that a clinical issue -- 11 MR. MYERS: Let him finish, Paul. 12 Q -- that needs to be analyzed by you as a clinical 13 research physician researching a pharmacological 14 treatment for depression? 15 MR. MYERS: Excuse me. Before you 16 answer that question, if you were not finished 17 with your earlier answer, finish it and then 18 answer that question. 19 Q That's correct, I did interrupt you, but I had to 20 finish my train of thought and I apologize. 21 MR. MYERS: That's fine. 22 A I'll ask you your second question again in a PAGE 60 1 couple minutes. What I was going to say is that 2 one of the areas that's I think I'd say pretty 3 hotly debated within the psychiatric scientific 4 academic community is what are the appropriate 5 criteria in which to use to encourage a patient 6 to go on what's called maintenance 7 pharmacotherapy. Most people think it's 8 appropriate, the sort of criteria that are 9 usually talked about are frequency of episodes, 10 multiple -- clear multiple episodes, episodes 11 that have had major adverse psychosocial impact: 12 Divorce, job loss, things like that or suicide 13 attempts associated with the depressive episodes, 14 so these are considered some of the grounds on 15 which to consider long-term maintenance therapy. 16 Q Well, do you know whether or not Lilly has a 17 position on whether or not there should be 18 long-term maintenance antidepressive therapy in 19 connection with Major Depressive Disorders? 20 A I don't think Lilly has any official policies. 21 My sense would be that that's something to be 22 decided upon between a physician and patient with PAGE 61 1 any given form of therapy, be it pharmacotherapy 2 or psychotherapy. 3 Q Well, do you know there's a consensus among the 4 Lilly psychiatric advisory panel on this issue? 5 A I -- I've never asked them explicitly what their 6 group opinion is. I've sort of talked about 7 psychiatry in general in the debate, but it would 8 be speculation for me to comment on that specific 9 group's feelings. 10 Q Did you say the debate? 11 A I said -- I referred to a debate within 12 psychiatry about the appropriate grounds for 13 instituting it. 14 Q Okay. I thought you might have attended some 15 particular debate. 16 A No, sir. I'm sorry. 17 Q Do you have an opinion concerning whether or not 18 individuals who have major depressive diagnosis 19 should be on lifetime pharmacological 20 antidepressive therapy? 21 A Yes, I do. 22 Q And what is that opinion? PAGE 62 1 A I come back to the criteria that I mentioned. If 2 a patient has had multiple frequent episodes that 3 would lead me to treating a patient to discuss a 4 potential need for that. Clearly if the patient 5 had had major problems during one or more 6 episodes, and clearly the more problems, the more 7 that I would be inclined toward recommending 8 that, and the examples that I've used were 9 divorce, job loss, suicide attempt. 10 Q Okay. But back to your percentage of 50 to 11 75 percent of individuals with Major Depressive 12 Disorder have periods of recurrence and periods 13 where it subsides, for those individuals their 14 HAMD scores if they were given HAMD tests would 15 go up and down, would they not, because of the 16 recurrent nature of this? 17 A That's correct, sir. 18 Q And one particular month they might meet the HAMD 19 criteria or the criteria under this diagnosis or 20 under this protocol for Major Depressive Disorder 21 and that the next month might not meet it? 22 A That is possible, yes, sir. PAGE 63 1 Q Practical, too? 2 A Yes. My concern is with picking a month. 3 Q Okay. Can we say a quarter for instance? 4 A This has been studied in both the U.S. and Europe 5 with slightly different views. First of all, 6 about 20 percent of patients go on coming out of 7 any individual episode to a chronic course; they 8 go in and they don't come out, but that's 9 decreasing over time. Obviously you start with a 10 particular number of patients. Each time an 11 individual goes into a depression, there is about 12 a 20 percent potential for that patient to go in 13 and become a basically chronic patient. The 14 episode length for first episodes is probably 15 something on the order of -- depending upon the 16 study -- six to nine months particularly early in 17 the illness process. There has been a debate 18 about whether that potentially lengthens over the 19 course of illness or not. Again I use debate 20 metaphorically. 21 Q I understand. Well, how long generally is the 22 second episode? PAGE 64 1 A We can again characterize things and we're 2 talking here about group data because there is 3 variation around this obviously as that six to 4 nine months. 5 Q How about the third episode? 6 A Again, I would put them all in the sort of six to 7 nine-month range recognizing that there is 8 individual variation, that there are some 9 patients who will become chronic. 10 Q And you say 20 percent -- 11 A That's a figure that changes. 12 Q -- stand a chance that once they go into one 13 episode of having a recurrence or becoming 14 chronic? 15 A Becoming chronic. 16 Q All right. And, again, in Protocol Number 27 17 there was no distinction made between whether or 18 not this was the first, second or third episode 19 of depression as long as it met the diagnosis of 20 major depression? 21 A That's correct, sir. 22 Q And there's no distinction concerning whether or PAGE 65 1 not this is chronic? 2 A No, sir. 3 Q And you might catch somebody in the middle of 4 this six to nine-month period; correct? 5 A That's correct, sir. 6 Q Or you might catch somebody in the last week of 7 this six to nine-month period? 8 A That's correct, sir. 9 MR. SMITH: Let's take a quick 10 break. 11 MR. MYERS: Okay. 12 (A brief recess was taken.) 13 Q In connection with the clinical trials under 14 Protocol Number 27 was there any effort made to 15 categorize whether or not patients were at the 16 beginning or ending period of these periods of 17 remission and recurrence, that is, that we've 18 been discussing? 19 A For an individual patient given that they have -- 20 they may have had treatments in the past and that 21 some percentage become chronic, I don't believe 22 that it is possible to know where a patient, an PAGE 66 1 individual patient, sits in his or her particular 2 nth episode. The data which might be captured, 3 and I don't know if it was or was not, was the 4 length of the current episode and the total 5 amount of time since the person first became 6 depressed. 7 Q There is no provision for that in the protocol, 8 is there? 9 A That's correct, but frequently Case Report Forms 10 will request more information than is specified 11 explicitly in the protocol. 12 Q Did you see any Case Report Forms that requested 13 that specific information, "Was this chronic" or 14 "How long had the patient been depressed?" 15 A I am familiar with some protocols which have 16 requested that information. 17 Q I'm talking about Protocol Number 27. 18 A No. And, again, I have -- I cannot recall seeing 19 that information being requested on the Case 20 Report Form for this protocol. 21 Q And have you ever seen any analysis under 22 Protocol Number 27 concerning whether or not PAGE 67 1 there was any distinction in the efficacy or 2 safety of Prozac versus comparator versus placebo 3 in chronic patients under this protocol versus 4 recurrent or single episode patients? 5 A You ask about the distinction between chronic and 6 single versus recurrent chronic patient. 7 Q Well, maybe a chronic might fall into the 8 recurrent patient. 9 A Could be either. 10 Q All right. 11 A I'm unaware of any analyses -- may or may not 12 have been done -- that have looked at potential 13 differential in efficacy across either length, 14 length of illness or length of current episode. 15 Q All right. Is there any analysis that you've 16 seen in connection with any of the Prozac 17 clinical trials that examined frequency of side 18 effects in relation to whether or not the patient 19 was a single episode depressed patient or a 20 recurrent episode depressed patient? 21 A No. 22 Q Do you follow what I'm saying when I'm talking PAGE 68 1 about that? Is it more likely for a patient to 2 have side effects from the study drug or the 3 comparator drug, either single episode or 4 recurrent episode patients? 5 A If I may, let me restate what I think you asked 6 and what I believe I answered to. 7 Q Okay. 8 A Has Lilly performed an analysis to look at 9 differential rates of adverse events in patients 10 in single episode versus a recurrent episode? 11 Q Right. 12 A My answer to that is I am unaware of such an 13 analysis. 14 Q Has there been any analysis in any of the 15 clinical trials of either the safety or efficacy 16 of Prozac in single versus recurrent episodes of 17 depression in patients? 18 A Let me make sure I understand the question by 19 restating it, please. You're asking if what 20 we've just talked about has been done in any 21 protocol over and above Protocol 27 that I'm 22 aware of? PAGE 69 1 Q We know about 27. 2 A Right. No. 3 Q In this inclusion group would the diagnosis of 4 psychotic depression be included in individuals 5 who are included in Protocol Number 27's study 6 group? 7 A Let me look at the exclusionary criteria if I 8 might. Exclusionary criteria B9. 9 Q All right. That has to do with schizophrenia and 10 other psychotic states likely to be aggravated by 11 Imipramine. 12 A And I am not certain -- again, I did not write 13 this protocol. 14 Q I understand. 15 A I did not administer this protocol. I was not at 16 the start-up meeting or any meetings with 17 investigators where any of these inclusion or 18 exclusion criteria were elaborated on. B9 may 19 well have excluded patients with psychotic 20 features. I don't know that it did or did not. 21 Q You just can't tell from looking at that 22 exclusion criteria? PAGE 70 1 A From looking at that, I would raise that as a 2 question. It would be speculative for me to 3 answer the question I posed. 4 Q All right. If you look at the inclusion 5 criteria, Dr. Beasley, would individual -- could 6 individuals who were suffering from psychotic 7 depression if they met the other inclusion 8 criteria, could they be included in those 9 individuals studied in Protocol Number 27? 10 A Psychotic -- with psychotic features is a 11 qualifier on the DSM diagnosis of Major 12 Depressive Disorder. It's not a distinct 13 stand-alone diagnosis. I would -- again, my 14 reading this, my interpretation of this, is -- 15 Q As a board certified psychiatrist -- 16 A -- is -- 17 Q -- and as a senior clinical research physician 18 for Eli Lilly and Company, I want your 19 interpretation. 20 A -- is that they could be included. I guess 21 probably the best way for me to answer the 22 question is if I was going to be a potential PAGE 71 1 investigator and I was given this protocol, I'd 2 see that they -- my interpretation would be that 3 they weren't excluded under 5a. I'd get over 4 here to 5b and I'd read down and I'd read 9 and 5 I'd probably ask the sponsor what that meant. 6 Q All right. So you'd call the medical monitor. 7 If you called the medical monitor at Lilly 8 responsible for the clinical trials and he said, 9 "Yeah, we're not excluding individuals with 10 psychotic features as long as they meet the other 11 inclusion criteria", then you would as the 12 investigator admit them to the clinical trial 13 even though they were -- if they had Unipolar 14 Major Depressive Disorder with psychotic 15 features? 16 A Dependent upon my view of the relationship, the 17 appropriateness of treating a psychotic, mood 18 congruent psychotic depressed patient with 19 potentially Imiprimine only. 20 Q I don't understand. 21 A Well, you know, there would be debate within the 22 medical field in psychiatry about whether or not PAGE 72 1 to treat a patient with major depression with 2 psychotic features with an antidepressant -- 3 Q Why? 4 A -- only. 5 Q Why? 6 A The feeling is that those patients may benefit 7 more from a combination of medications. We 8 talked about -- 9 Q What combinations? 10 A With an -- an antidepressant with an 11 antipsychotic medication or other forms of 12 therapy. 13 Q What other forms of therapy? 14 A Electroconvulsive therapy. 15 Q Okay. Any other forms of therapy? 16 A Those would be the most commonly used. Another 17 issue would be whether or not a psychotic patient 18 should in fact be hospitalized. 19 Q All right. 20 A Some would feel that that's an indication for 21 hospitalization. This was supposed to be an 22 outpatient study. Sort of what I'm getting at is PAGE 73 1 these are sort of secondary issues. It doesn't 2 explicitly say psychotic depression excluded, but 3 because of some of these issues over and above 4 what's explicitly written here, one would wonder 5 about the appropriateness. You know, I'm now 6 taking the position of an investigator dealing 7 with patients coming into my door, whether or not 8 a psychotic depressed patient would be 9 appropriate for inclusion in the protocol. 10 Q All right. Now, let me ask you: Based on your 11 review of the Prozac clinical trials, were 12 individuals who were suffering from depressive 13 disorders with psychotic features, or as 14 sometimes referred to psychotic depressive 15 individuals, were they included in the Prozac 16 clinical trials? 17 A Okay. I do not know about the clinical trials. 18 I don't know absolutely. I don't know about the 19 clinical trials before I arrived. The exclusion 20 language over time in depression trials I can 21 tell you has evolved. At this point it's pretty 22 explicit that patients with psychotic features PAGE 74 1 should not be included. 2 Q In Protocol 27? 3 A Oh, no. No. 4 Q Oh, you mean now? 5 A What I'm saying is that in looking at this 6 language versus language in later depression 7 protocols I would think as we've been saying, 8 this language is somewhat open to interpretation. 9 Q All right. Why would individuals with psychotic 10 features even though they may have been suffering 11 from major depression be excluded from the later 12 protocols? 13 A Well, it gets back to my sort of secondary issues 14 that I raised here. My feeling, perhaps the 15 feelings of others that were involved in this, is 16 that antidepressant medication alone without a 17 concomitant antipsychotic and/or without 18 hospitalization of a patient would not provide 19 potentially optimal care for the patient. 20 Q All right. Well, let me see if I can get 21 something straight. Is there such a diagnosis as 22 psychotic depression? PAGE 75 1 A It is in DSM-III-R, within DSM-III-R a very 2 clearly recognized subtype of major depression. 3 The diagnosis would be as follows: Major 4 Depressive Disorder single episode, severe with 5 psychotic features. Or Major Depressive Disorder 6 recurrent, severe with psychotic features. There 7 are a number of other potential modifiers as 8 well, but those are two recognized psychotic 9 subtypes. 10 Q Is that included in the DSM-IV? 11 A I haven't -- I've read it a couple times. I'm 12 not as familiar with it as DSM-III-R. I believe 13 it's in essence equivalent. There's very little 14 change in the mood disorder section. DSM-III-R 15 and DSM-IV are very equivalent in this area of 16 the mood disorders section. 17 Q And depression is a mood disorder? 18 A Yes. 19 Q So the answer to my question is: Psychotic 20 depression is a part of depression? 21 A Psychotic depression is a subtype of Major 22 Depressive Disorder. PAGE 76 1 Q All right. Is it a subtype such as this like 2 Agitated Major Depressive Disorder or Retarded 3 Major Depressive Disorder that's mentioned on 4 Page 3 of Protocol Number 27? 5 A It could be a nonmutually exclusive subtype. 6 I'm -- in fact Psychotic Depression or Psychotic 7 Major Depressive Disorder may be one of the RDC 8 subtypes. 9 Q All right. So what you're saying is this 10 particular subtype of Major Depressive 11 Disorder -- that is Psychotic Depression -- is 12 recognized as a part of depression, Major 13 Depressive Disorders; right? 14 A That's correct. 15 Q And under the earlier clinical trials which would 16 be all the clinical trials submitted in the IND 17 and NDA up to 1987 up to approval would have been 18 included potentially as individuals who were 19 treated with Prozac? 20 A I believe what I've said is I don't know how this 21 protocol or one that was written similarly would 22 have either been explicitly elaborated on by the PAGE 77 1 Lilly clinical person responsible or interpreted 2 by the clinical investigator. 3 Q All right. That's certainly something that's not 4 clear under Protocol Number 27, is it? 5 A That's right. 6 Q Whether or not psychotic depressive individuals 7 were included within this clinical trial? 8 A That's correct. 9 Q And it's your testimony that psychotic 10 individuals, psychotic depressed individuals, are 11 now excluded from the clinical or were excluded 12 from the later Lilly clinical trials on Prozac? 13 A From at least a subset of trials with which I'm 14 quite familiar. 15 Q What subset of trials is that, sir? 16 A That would have been the ones that I worked on. 17 Q That would be the ones that studied what? 18 A And I'll refer to these by sort of conceptual 19 name as opposed to Lilly protocol numbers. A 20 Desipramine comparator, a Nortriptyline 21 comparator, another Nortriptyline comparator 22 in -- another Nortriptyline comparator looking PAGE 78 1 not only at depression but at cardiac function, a 2 Monoamine Oxidase Phenelzine comparator study, a 3 long-term maintenance study. 4 We had a study in cardiac -- in severely 5 depressed cardiac patients; it was an inpatient 6 study, but I believe we excluded psychotic 7 features in those patients as well. 8 Q So individuals who were psychotically depressed 9 were excluded from all those clinical trials? 10 A That's correct. 11 Q And the reason being that individuals who are 12 psychotically depressed need antipsychotic 13 medication or combination therapy or in-hospital 14 therapy? 15 A In the opinion of some physicians on individual 16 case-by-case basis, those would be appropriate 17 treatment modalities. 18 Q All right. Do you have any knowledge that the 19 Prozac package insert in the United States does 20 not state that psychotically depressed 21 individuals were excluded from particular 22 clinical trials? PAGE 79 1 A No. I believe that the package insert does not 2 make it explicit that psychotic individuals were 3 excluded. 4 Q I'm talking about psychotic depressed 5 individuals. 6 A Psychotic depressed individuals. 7 Q So the Prozac package insert literature does not 8 advise a physician that psychotically depressed 9 individuals were excluded from some Prozac 10 clinical trials? 11 A That's correct to the best of my knowledge. 12 Q The Prozac package literature does not 13 contraindicate Prozac for individuals who are 14 psychotically depressed, does it? 15 A No, it does not. 16 Q And the Prozac package literature does not warn 17 physicians that they should not give Prozac to 18 individuals who are depressed with psychotic 19 features, does it? 20 A I don't recall any such contents in the warning 21 section, no. 22 Q Well, the answer is it doesn't, does it? PAGE 80 1 A No, I don't -- I don't believe it does, no. 2 Q The Prozac package insert though does state that 3 Prozac is appropriate for treatment of 4 depression, does it not? 5 A I believe that it states for the treatment of 6 depression and then it goes on I believe to state 7 something on the order of and the patients in 8 which it was studied were those that corresponded 9 most closely to the diagnosis of Major -- of DSM 10 Major Depressive Disorder. It's -- 11 Q Which includes psychotically depressed 12 individuals, does it not? 13 A As a subtype, yes. There may be some additional 14 wording within the package insert about the level 15 of severity of the patients in which it was 16 tested, and one of the specified qualifiers 17 within DSM for psychotic depression is that it is 18 linked to the qualifier "severe". 19 Q Well, an individual can be suffering from major 20 depression, severe, and be psychotically 21 depressed, can they not? 22 A That's correct. PAGE 81 1 Q And a patient can be moderately depressed and 2 also fit within the subtype of psychotic 3 depression, can they not? 4 A Well, by strict DSM nomenclature that's not the 5 case. It's hard -- and I can't again give you a 6 translation from the Hamilton scores as we're 7 saying what the particular mild, moderate, and 8 severe categories are, but within DSM the 9 psychotic qualifier is linked I believe to the 10 designation of "severe". 11 (Plaintiffs' Deposition Exhibit 20 was 12 marked for identification.) 13 Q Do you recognize Exhibit 20, Dr. Beasley? 14 A It's a DSM. Could you help me with which 15 version? 16 Q I don't know. You're the board certified 17 psychiatrist. 18 MR. MYERS: Well, let me object to 19 the form. 20 Q I don't know which version it is. If you can't 21 tell, tell me you can't tell, but I don't know. 22 MR. MYERS: I object to the form. PAGE 82 1 Paul, he simply asked if you had a designation. 2 It's probably been blacked out because of the 3 copy. 4 A It might not appear on these pages. 5 Q Honestly I can't tell you. I don't know. It 6 looks to me like other documents I've seen and 7 other works I've seen from the Diagnostic 8 Statistical Manual-III or III-R, doesn't it to 9 you? 10 A Yes, it does. There have been, as we were 11 saying, slight changes from III to III-R to IV. 12 Q Okay. Look on Page 2 where it defines major 13 depressive episode codes. Do you see that? 14 A That's correct. 15 Q It has "mild", "moderate" and "severe" as a code, 16 does it not? 17 A That's right. 18 Q And then it has "with psychotic features" as 19 another code? 20 A That's correct. 21 Q I take it from looking at that that this, the 22 DSM-III, doesn't define Major Depressive Disorder PAGE 83 1 with psychotic features under severe? 2 MR. MYERS: Let me object to the 3 form only to the extent you've represented it as 4 III. We don't know whether it's III, III-R or 5 IV. 6 Q All of them are the same, aren't they? 7 A That's what I was -- that's what I was -- the 8 reason I asked the question. This clearly does 9 not link -- this version clearly does not link 10 "with psychotic features" to "severe". 11 Q All right. 12 A My recollection of III-R was that there were two 13 specifications for severe, one without psychotic 14 features, and one severe with psychotic features. 15 Q Well, could -- 16 A This one -- this one clearly does not. 17 Q Well, this one -- maybe this will help you: 18 Under "with psychotic features" it says 19 "mood-congruent" and "mood-incongruent". Does 20 that help you? 21 A No, sir. Those are two different types of -- 22 Q I understand. PAGE 84 1 A -- subtypes of psychotic depression. 2 Q Okay. 3 A We haven't even gotten to those two subtypes, 4 further subtypes. 5 Q So in this categorization then there is no 6 linking of major depression with psychotic 7 features to severe, is there? 8 A No, sir, there is not. 9 Q It can occur in moderate major depression with 10 psychotic features? 11 A There is no -- there is no explicit linking here 12 in this version of the psychosis to any 13 designation of mild, moderate, or severe. 14 Q All right. And there is no language in the 15 Prozac package insert that indicates that -- or 16 takes out major depression with psychotic 17 features out of that group of individuals to whom 18 Prozac can be given -- 19 A No. 20 Q -- is there? 21 A No, sir. 22 Q Let me back up with you. Is it recognized that PAGE 85 1 you can have an individual with major depression 2 with Schizoaffective Disorder? 3 A The criteria for Schizoaffective Disorder have 4 gone through rather significant revision across 5 the evolution of the RDC criteria and the III, 6 III-R DSM nomenclature. I cannot sit here today 7 and cite you the DSM-IV criteria for 8 Schizoaffective Disorder. Under III it was a 9 residual category with no diagnostic criteria. 10 Under DSM-III-R it required during the 11 longitudinal course of the illness that the 12 patient meet full criteria at some point for 13 Schizophrenia and full criteria for either a full 14 manic episode or a full depressive episode -- 15 Q Okay. 16 A -- so -- 17 Q I'm sorry, I didn't mean to cut you off. 18 A So you basically had to meet criteria sometime or 19 the other during the course of your illness for 20 both. 21 Q Regardless of what the criteria is, is it known 22 in psychiatry that an individual can have a Major PAGE 86 1 Depressive Disorder and Schizoaffective Disorder 2 at the same time? 3 A The Major Depressive Disorder would be part of 4 the Schizoaffective Disorder. 5 Q Okay. 6 A It wouldn't be like you've got one and then you 7 get the other. We call it -- if you've got two 8 sets of things, we call it one, one thing: 9 Schizoaffective. 10 Q All right. Well, is it inappropriate to treat an 11 individual who's Schizoaffective Disorder if 12 they're suffering from major depression with 13 Prozac? 14 A Not -- not necessarily. Again, if you ask -- if 15 you ask about the generic populations, these 16 populations are frequently treated with a 17 combination of one or more mood stabilizing drugs 18 plus an antipsychotic potential. 19 Q All right. 20 A So that again given that you've got two 21 full-blown syndromes, sets of signs and symptoms 22 in a patient, they may well receive combination PAGE 87 1 therapy directed to the two sets of symptoms. 2 Q Is it inappropriate to treat individuals with 3 Schizoaffective Disorder as long as they have 4 major depression present with Prozac? 5 A In my clinical -- in my personal opinion, medical 6 opinion, that would -- as a categorical 7 statement -- would not be the case. 8 Q It would not be inappropriate? 9 A It would not be inappropriate as a general 10 blanket statement. 11 Q All right. There are no instructions or warnings 12 or contraindications in the Prozac package insert 13 that restrict the use of Prozac or warn against 14 the use of Prozac in individuals who are 15 suffering from Schizoaffective Disorder as long 16 as they have major depression -- 17 A Well -- 18 Q -- is there? 19 A I think it's -- it to some extent is complicated 20 because to get the diagnosis of major depression, 21 okay, as a clinical entity, you can't have 22 Schizoaffective. There are certain psychotic PAGE 88 1 disorders that you can't have. There are both 2 inclusion criteria and exclusion criteria as well 3 under that, so in a roundabout way of saying that 4 is not an approved, officially approved, 5 indication if you talk about depression where the 6 predominant depression treated was major -- was 7 depression that most closely resembled DSM Major 8 Depressive Disorder. 9 Q All right. I'm not sure I follow you. 10 A There is no explicit injunction in the package 11 insert with regard to treating schizoaffective 12 patients who have a current strong component of 13 depression. 14 Q That happens, doesn't it? 15 A I suspect that it does, yes, sir. 16 Q Well, you know that it does as a psychiatrist? 17 A Yes. Again, we've said that antidepressants are 18 frequently used to treat schizoaffective 19 patients. 20 Q Okay. And there is no contraindication against 21 that? 22 A No, but technically it's not an approved PAGE 89 1 indication. 2 Q But the package insert says it's approved for 3 treatment of depression? 4 A That's correct. 5 Q Which makes it reasonable to assume that for the 6 depressive aspects of a Schizoaffective Disorder 7 that Prozac can be used? 8 A I think that would be a judgment on the part of 9 the individual clinician. 10 Q But there is no prohibition and no warnings by 11 Lilly against using Prozac for such a condition, 12 is there? 13 A No. 14 Q And there is no contraindications for using 15 Prozac in individuals who are schizoaffective? 16 A No. 17 Q And the indication for usage of Prozac is for 18 individuals who are depressed? 19 A Again, the explicit indication language is a 20 short paragraph in length that talks about 21 depression, that talks about the people in whom 22 it was studied in terms of meeting DSM, being PAGE 90 1 most closely resembling DSM criteria for Major 2 Depressive Disorder. And I think there -- as I 3 said, I think there are some qualifiers on 4 prescribing it for a patient. 5 Q But the thing is: Prozac is useful in the 6 treatment of depression? 7 A That's correct. 8 Q Then it goes on and says "in whom it was 9 studied" -- 10 A That's correct. 11 Q -- in the diagnostic criteria; correct? 12 A That's correct. 13 Q A general practitioner is able to prescribe 14 Prozac, is he not? 15 A Yes, he is. 16 Q And when that general practitioner sees 17 depression, he can consider that term 18 "depression" in the general medical sense, can't 19 he? 20 A Can you help me understand what you mean by the 21 general medical sense of depression? 22 Q Okay. All right. Obviously you as a trained PAGE 91 1 board certified psychiatrist have a more in-depth 2 knowledge of depression in the variabilities, in 3 the shades and subtleties of depression than 4 most; correct? 5 MR. MYERS: Than most what? 6 MR. SMITH: Doctors. 7 A Clearly my psychiatric training or psychiatric 8 training of other psychiatrists concentrates on 9 mental disorders of which the mood disorders are 10 one of those. 11 Q You should know more about depression than an 12 internist, shouldn't you? 13 A By virtue of my training unless he's had some 14 incredible amount of specialized additional 15 training or clinical experience, that would be a 16 reasonable assumption. 17 Q You should know more about depression than an 18 orthopaedic surgeon, shouldn't you? 19 A Again, depending upon post-residency fellowship 20 experience, that would be the case. 21 Q You should have more knowledge of depression than 22 a family practitioner? PAGE 92 1 A Again, depending upon training and specialized 2 training post-residency experience, that would be 3 the case. Some family practice programs actually 4 get a fair bit of psychiatric training as part of 5 their training, but that's the one medical 6 specialty over and above psychiatry that 7 sometimes incorporates that. 8 Q But even they don't get as much intensive 9 training as psychiatrists do? 10 A No. No, sir. 11 Q And certainly not as much intensive training as 12 board certified psychiatrists such as yourself? 13 A Well, I'm not sure that the difference in the 14 amount of training between being board certified 15 and not may not be any different. 16 Q Well, you took a path to prove that what your 17 training got you, took you -- 18 A Right. 19 Q -- didn't you? 20 A Right, some of it stuck. 21 Q So when you see the term depression, you may 22 think of it in a different way than an PAGE 93 1 orthopaedic surgeon or a family practitioner? 2 A That's possible. 3 Q That orthopaedic surgeon or family practitioner 4 is not expected to know the same subtleties of 5 these various depressive illnesses as yourself 6 and most psychiatrists? 7 A I think that would be correct. 8 Q But Prozac is not limited to psychiatrists, is 9 it? 10 A No. 11 Q It's limited to any general practitioner or it's 12 available for prescription by any general 13 practitioner, isn't it? 14 A Anyone licensed to practice medicine. 15 Q Right. Which would include a lot of different 16 subspecialties, wouldn't it? 17 A That's correct. 18 Q That don't have any particular emphasis in 19 psychiatry, do they? 20 A As formal training programs, no. 21 Q Or as a regimen of experience either? 22 A Well, again, I can't speak to any particular PAGE 94 1 individuals. 2 Q I'm talking about generally. 3 A Generally, no. 4 Q I mean a family practitioner treats colds, treats 5 pneumonia, treats all kinds of physical 6 conditions; correct? 7 A Treats many things, yes. 8 Q And you know that? 9 A Yes. 10 Q And additionally a psychiatrist -- I mean a 11 general practitioner may come into encounter with 12 an individual that's suffering from depression; 13 correct? 14 A That's correct. 15 Q And more than likely that general practitioner 16 that encounters depression on the general theme 17 of things isn't going to know as much about the 18 subtleties of depression as the psychiatrist is; 19 correct? 20 A Speaking in general terms hypothetically and 21 about -- the word you used was -- "subtleties", I 22 would agree with you. PAGE 95 1 Q Well, do you think that the ordinary general 2 practitioner with just the ordinary experience 3 and training can give you much -- can make that 4 distinction between psychotically depressed and 5 agitated depressed in any particular office 6 visit? 7 MR. MYERS: Before he answers, let 8 me object to the form. This is getting awfully 9 speculative as to what an unidentified 10 practitioner of any specialty can and can't 11 assess without more factual basis. I object to 12 form. Go ahead and answer, Dr. Beasley. 13 A Well, I think it's interesting that you use -- 14 you know, you make reference to psychotic. 15 Most -- 16 Q Why? Just because you've already made that 17 diagnosis on me? 18 A No, sir. No, sir. No, that's probably the one 19 thing that probably doesn't even take a medical 20 degree to recognize. And not to be -- 21 Q I understand. 22 A No levity, sir. PAGE 96 1 Q You're not talking about me; you're talking about 2 in general? 3 A No levity, sir. But I mean we could go down on 4 the streets of Indianapolis and walk around the 5 downtown area and that's probably the one 6 distinction that psychosis -- and we haven't 7 talked about what that is in definitions and 8 stuff -- but that's something that should be 9 relatively easily recognized relative to other 10 mental states because it is so abhorrent. 11 Q Okay. Well, let's use some definitions that 12 maybe are not as common. How about Agitated 13 Depressed versus Endogenous Major Depressive 14 Disorder? 15 MR. MYERS: Same objection as to the 16 form. Go ahead. 17 THE WITNESS: Okay. 18 A These are not mutually exclusive categories. I 19 think you'd recognize the individual as being sad 20 depressed. It may well be that people without 21 expert training would not be aware of the 22 criteria for endogenicity or melancholia, that a PAGE 97 1 patient was agitated, and you've described the 2 activity. I think that would be something that 3 would be pretty easily recognized, although an 4 individual without specialized psychiatric 5 training might not be able to apply that label. 6 Q But the package insert doesn't make any 7 distinction as to whether or not the particular 8 physician will be able to make that distinction, 9 does it? 10 A No. 11 Q Could an individual with Schizoaffective Disorder 12 be included in Protocol Number 27? 13 MR. MYERS: Did you say would or 14 could? I didn't hear you. 15 MR. SMITH: Could. 16 A I would -- I would read the -- since the 17 diagnosis requires a diagnosis of Major 18 Depressive Disorder and I believe, although I'd 19 need to confirm, that in DSM-III that this was 20 operating under a diagnosis of Schizoaffective 21 Disorder was mutually exclusive, you couldn't be 22 Major Depressive Disorder and Schizoaffective, PAGE 98 1 that that would preclude the inclusion of a 2 patient meeting that criteria. 3 Q But the Prozac package insert doesn't specify 4 that those two diagnoses are mutually exclusive, 5 does it? 6 A No, it does not. 7 Q And an individual can have major depression 8 features and be schizoaffective? 9 A That's correct. 10 Q Is there a difference between Bipolar Disorder, 11 the old Manic Depressive illness, and 12 Schizoaffective Disorder? 13 A There -- there is. 14 Q What is it? 15 A There are. There are a number of psychiatric 16 diagnoses that can look fairly similar. Let me 17 name them going across a continuum of sort of 18 increasing from patients with psychotic features 19 and no mood disturbance progressing across a line 20 to increasing mood disturbance, okay? 21 Q Okay. 22 A Let's start with Schizophrenia and I also want to PAGE 99 1 include there another term, Schizophreniform 2 Disorder, but they basically look the same. If I 3 sat and interviewed a patient and just asked him 4 how he'd been doing the last two weeks, I 5 couldn't tell the difference. 6 Q What was that other disorder? 7 A Schizophreniform Disorder. 8 Q Okay. All right. 9 A Okay. These patients at least at the time 10 they're interviewed and very little during their 11 course have any disturbance of mood; in other 12 words, no depression and none of the mania stuff. 13 Now, they could have a little bit on occasion. 14 There is some debate about whether it should be 15 allowed to have a diagnosis of Schizophrenia and 16 concurrent Major Depressive Disorder which is not 17 some of these other diagnoses, but this gets into 18 real intense, a real intense theoretical debate. 19 Let me stay away from that, okay? 20 So, we've got Schizophrenia and 21 Schizophreniform Disorder, lots of psychotic 22 features, no mood disturbance. Okay. Then we PAGE 100 1 can move to Schizoaffective Disorder, and quite 2 frankly in DSM-III this was a category you put 3 people in when you just couldn't tell where they 4 ought to be in spite of all your good psychiatric 5 training. As I said, there were no operational 6 criteria. In DSM-III-R they tried to beef it up 7 some and they said basically patients had to meet 8 full criteria for both a major mood disorder, 9 either mania or depression, and Schizophrenia. 10 Q Mania or depression? 11 A Yeah, either of those. See, those are the 12 affective component. 13 Q Okay. So for Schizoaffective Disorder now under 14 DSM-III-R you must have mania -- 15 A Or depression and -- 16 Q Or depression plus -- 17 A -- Schizophrenia. 18 Q Full-blown Schizophrenia? 19 A Yeah, full-blown. And again, I'm being -- sir, 20 I'm being a little bit simplistic, but probably 21 not as simplistic as you'd like. I mean it's 22 complicated, okay? So that's -- we've gone from PAGE 101 1 Schizophrenia to Schizoaffective Disorder. 2 Q All right. We didn't have any depression in 3 Schizophrenia? 4 A No, that -- but -- 5 Q Or mania? 6 A Or mania. 7 Q But now we've got depression in Schizoaffective 8 Disorder? 9 A Right. Now, we're going to go to Bipolar 10 Disorder. Now, here's where we're going to get 11 really complicated. Remember in that little 12 thing you read about, you mentioned the terms 13 mood-incongruent and mood-congruent features? 14 Q Yes. 15 A If you have mood-incongruent features, your 16 psychoses -- your psychotic features are more 17 like Schizophrenia psychosis. 18 Q Okay. So if you've got mood-incongruent 19 features, you're more likely going to have 20 schizo -- 21 A Your -- your psychotic features are going to look 22 like schizophrenic psychotic features and they PAGE 102 1 have to do with the bizarre quality and no 2 relationship to mood. 3 Q Okay. 4 A Okay. Now, there are also psychotic features 5 which are called mood-congruent, meaning that if 6 your mood is depressed, you think the world's 7 about to end or that you've got some horrible 8 disease. Or if you're manic, you think you're 9 Jesus Christ or you're talking to Jesus Christ. 10 See, those are -- or that you have some special 11 powers to control the world. 12 So now with that as a little background, 13 we've gone from Schizophrenia to Schizoaffective 14 Disorder to either Bipolar Disorder or Unipolar 15 Depression with mood-incongruent psychotic 16 features. 17 Q Okay. What if you had mood-congruent? 18 A Okay. Well, that's the next. That's the next. 19 That's the next one down, okay? 20 Q Okay. So bipolar, if you were graphing it off, 21 ought to come down with two arms to it? 22 A And so should unipolar depression. I want to put PAGE 103 1 those both sort of in the same -- in the same 2 spot. I'm sorry we don't have a blackboard here. 3 Q Let's get to the state of bipolar. We've done 4 mood-incongruent with psychotic features. 5 A Okay. 6 Q Now, let's do mood-congruent. 7 A Okay. There you're looking a little -- it's a 8 little bit easier to say this is not 9 Schizophrenia, this is just a mood disorder. 10 See, what you are trying to do is make the 11 distinction between a patient who's got 12 Schizophrenia who needs just an antipsychotic. 13 The reason this is important is making a decision 14 of whether a patient's needs most appropriately 15 would first be treated with an antipsychotic 16 medication or an antidepressant or mood 17 stabilizing medication such as Lithium or a 18 couple of other agents that are commonly used. 19 So we've moved from Schizophrenia, 20 Schizophreniform Disorder. That looks pretty 21 much -- pretty much easy for a psychiatrist to 22 identify. PAGE 104 1 Q You wouldn't use Prozac for that? 2 A Generally -- with a qualification generally not. 3 There are some -- there are some pieces of 4 literature that suggest that Prozac may have some 5 utility for some patients with that diagnosis, 6 but with particular features. But moving on -- 7 it's not a primary indication, okay, to 8 Schizoaffective Disorder -- then to a mood 9 disorder with mood-incongruent features. 10 Q I thought we were on bipolar. 11 A Well, again, I want to sort of say either bipolar 12 with mood-incongruent features or unipolar 13 depressed with mood-incongruent features. 14 Q Okay. 15 A And what I should really be saying when I say 16 bipolar, I mean manic. 17 Q Okay. 18 A Okay. Then we would move to either mania or 19 depression with mood-congruent psychotic features 20 Q Did you say with mood-congruent? 21 A With mood-congruent psychotic features. 22 Q Okay. PAGE 105 1 A And then we would move down to either just mania 2 without psychosis, without psychotic features, or 3 depression without psychotic features. 4 Q Okay. 5 A So that gives you from pure psychosis with no 6 mood to this (indicating), these things in 7 between, to pure mood disturbance without 8 psychotic features. 9 Q All right. So you've gone through a pretty broad 10 continuum there of disorders? 11 A You're going through changes on two dimensions 12 of -- and we frequently refer to psychosis in 13 terms of cognitive changes. You're going through 14 from no cognitive disturbance to a lot of 15 cognitive disturbance. And you're going through 16 from no mood disturbance to a lot of mood 17 disturbance, and both -- they can have a lot of 18 both in the middle. 19 Q Is depression just on the mood disturbance side? 20 A That's right. And that's the other complication 21 is that on mood disturbance you can get -- you 22 can get -- you can get disturbance, but you can PAGE 106 1 get it in two sorts, either mania or depression. 2 Q So you may have a situation where the 3 practitioner, the physician, is treating the 4 depression side of these illnesses with Prozac? 5 A Potentially. 6 Q But there may be some psychosis along with that 7 illness? 8 A There -- in these diagnoses that we've talked 9 about? 10 Q Yes. Is that correct? 11 A That's correct. 12 Q And this psychosis may not be appropriately 13 treated with Prozac; in other words, you may need 14 an antipsychotic in those individuals? 15 A You've said you -- if -- you may. 16 Q All right. 17 A You may not. If it's a pure mood disturbance -- 18 Q Probable? 19 A -- even with psychotic features; although many 20 people as we've said would use combination 21 therapy and hospitalization, some people might 22 elect to treat with just a mood improving agent. PAGE 107 1 Q Prozac was tested on individuals suffering from 2 bipolar disorders; was it not? 3 A I believe that there was one protocol looking at 4 patients with bipolar illness with their 5 presenting episode being depression. 6 Q Yes. And Prozac is approved for treatment of 7 individuals with bipolar illness for the 8 depression aspect of their episode, is it not? 9 MR. MYERS: Let me just object to 10 the form. You've now drifted into some real 11 regulatory areas. That may call for some sort of 12 a legal or regulatory conclusion about -- 13 MR. SMITH: I'm talking about 14 medical conclusions since he's a doctor. 15 MR. MYERS: Still object to the form 16 of the question. 17 A Well, I guess it's hard for me to read the 18 package insert as anything but a Lilly employee, 19 and I guess our general sense is that it's not 20 approved officially for bipolar disorder given 21 that it's been an effective treatment for 22 depression. If I were a practitioner in the PAGE 108 1 community, although there have been a few studies 2 other than this one that have been done sort of 3 based on our understanding of the way 4 antidepressants work, I might consider using it. 5 Q But doesn't the package insert indicate that it's 6 appropriate for use in bipolar disorder if 7 depression is indicated in that condition? 8 A As I read the package insert, it says depression. 9 Q Okay. 10 A And then it goes on to specify the nature of 11 patients in whom this was studied. 12 Q And doesn't that include bipolar depressed 13 individuals? 14 A Actually in the package insert it doesn't state 15 that. 16 Q All right. 17 A It states the majority of patients met criteria 18 for or were most comparable to Major Depressive 19 Disorder, which excludes bipolar patients. 20 Q Okay. But it's being used you know as a Lilly 21 employee for treatment of bipolar disorders? 22 A Yes. PAGE 109 1 Q And there is no contraindication by Lilly for use 2 of Prozac for bipolar disorders, is there? 3 A No. 4 Q Beg your pardon? 5 A No, sir. 6 Q And you wouldn't have any criticism of a 7 physician who prescribed Prozac for a bipolar 8 disorder? 9 A In the abstract, no. 10 Q And you know that it's being used, you as a Lilly 11 clinical research physician, know that Prozac is 12 commonly being used to treat individuals with 13 bipolar disorder -- or regularly. Let's don't 14 say commonly; let's say regularly. 15 A I believe that it is. I'm not sure what my hard 16 concrete data is to prove that to me. 17 Q Well, number one, you did -- Lilly did clinical 18 trials on individuals suffering from that and 19 administered this drug to individuals suffering 20 from that; correct? 21 A That's correct. 22 Q And what were the findings of that clinical PAGE 110 1 trial? 2 A I believe they were positive for the compound. 3 Q In order words, that Prozac was effective in 4 treating those individuals; correct? 5 A Correct. 6 Q So do you have any criticism of Prozac being used 7 for an individual with a bipolar disorder? 8 A As I said, in the abstract, no, sir. 9 (A discussion was held off the record.) 10 MR. SMITH: We'll take a break. 11 (A lunch recess was taken) PAGE 111 1 A F T E R N O O N S E S S I O N 2 DIRECT EXAMINATION (CONTINUING) 3 QUESTIONS BY PAUL SMITH: 4 (Plaintiffs' Deposition Exhibit 21 was 5 marked for identification.) 6 Q Dr. Beasley, Exhibit 21 is another Lilly Prozac 7 protocol, is it not? 8 A Yes, it is. 9 Q And this is a protocol used to compare Prozac in 10 the treatment of Major Depressive Disorders with 11 placebo and another antidepressant by the name of 12 Amitriptyline; correct? 13 A That is correct. Let me -- but actually let me 14 correct myself. Placebo was used in the lead in. 15 This was a comparison of Fluoxetine versus 16 Amitriptyline that can be found on Page 6 for the 17 dosing schedule, shows only Fluoxetine and 18 Amitriptyline. 19 Q Okay. This then is going to be a head-to-head 20 comparison of Amitriptyline and Prozac comparing 21 how they do against each other versus how either 22 one of them did against placebo, which is no PAGE 112 1 drug; correct? 2 A No, sir. This would just -- this would just be 3 the two drugs compared head to head. 4 Q That what's I said. 5 A Oh, okay. As opposed to, yes, sir -- 6 Q A situation where -- 7 A -- where there was a third one. 8 Q Right. 9 A Right. As in it would be in contrast to 10 Protocol 27. 11 Q Yes. Protocol -- two of the major differences is 12 Protocol Number 27 had a placebo arm as part of 13 the comparison during the treatment phase of the 14 study; correct? 15 A Yes, sir. 16 Q And Protocol 27 uses a different antidepressant 17 as a comparison? 18 A Yes, sir. 19 Q Protocol Number 27 uses Imiprimine which is a 20 tricyclic; correct? 21 A Yes, sir. 22 Q This Protocol Number 22 uses Amitriptyline. Is PAGE 113 1 that a tricyclic, also? 2 A Yes, sir, it is. 3 Q Why would there be comparisons with a variety of 4 different tricyclics which are generally 5 considered drugs within the same class of 6 antidepressants? 7 A I'm speaking now hypothetically. I don't know 8 specifically why this protocol as in contrast to 9 the other was put together, but different 10 individual practitioners might well have their 11 own favorite antidepressants and would want 12 comparative -- or like to potentially see -- 13 comparative data with a variety of other agents. 14 Q Even though those other agents are agents of the 15 same chemical nature? 16 A That's correct, yes. 17 Q And work in basically the same chemical way as 18 far as their action on neurotransmitters or 19 neurotransmissions? 20 A Some differences, some similarities. 21 Q All right. Do you know when Protocol Number 22 22 was done? PAGE 114 1 A No, I don't. I believe that it was clearly done 2 and finished before I began working for Lilly. 3 Q I see the date 3/11/80 down at the bottom 4 left-hand corner of the page which would indicate 5 to me at least that the protocol was drawn up in 6 March of 1980. 7 A I believe that would -- that would be my 8 understanding of this date. 9 Q This was a pivotal study, also, was it not, 10 Protocol Number 22? 11 A In that it does not have placebo in it, it would 12 be my understanding that it was not. 13 Q Not be, okay. Now, this protocol excludes -- 14 well, let's strike that. This protocol includes 15 many of the same type of depressed individuals 16 that Protocol Number 27 does; is that correct? 17 A I haven't done a line-by-line comparison, but it 18 would appear that they are roughly comparable. 19 The formal diagnostic criteria are different in 20 that RDC -- I refer to that distinction between 21 that and DSM -- are used for this protocol, but 22 they would be quite comparable. PAGE 115 1 Q What's the difference in the RDC and the DSM? 2 A RDC was a diagnostic system that predated; in 3 fact, it gave -- sort of gave birth to the DSM 4 system. They for the most part are quite 5 comparable with regard to the major diagnostic 6 categories that they provide criteria for. RDC 7 gives operational diagnostic criteria for a much 8 more limited set of disorders than does DSM. 9 Q DSM is broader? 10 A I believe that would be a fair characterization, 11 yes, sir. 12 Q And RDC would be more narrow or more restrictive? 13 A I think not necessarily within the diagnoses 14 themselves, so if you diagnose let's say 15 Schizophrenia, the diagnostic criteria would be 16 very comparable. But for example RDC would not 17 have -- did not have diagnostic criteria for a 18 number of the childhood disorders. I don't 19 believe it had a diagnostic criteria for bulimia 20 or anorexia nervosus -- nervosa -- or what we 21 call adjustment disorders or psychosexual 22 disorders as an example. So for those disorders PAGE 116 1 that it diagnosed, it's pretty similar. We 2 pointed out one difference with major depression 3 being that RDC required a month of symptoms for 4 an episode; DSM required only two weeks. But 5 they're pretty close for those conditions that 6 are diagnosed in both. 7 Q In this protocol Exclusion Criteria number 8 8 excluded Schizophrenia and other psychotic states 9 likely to be aggravated by Amitriptyline; is that 10 right? 11 A That's correct. 12 Q Do I take that by that that the tricyclic 13 antidepressants have some history of aggravating 14 Schizophrenia or other psychotic states? 15 A My senses would be that that is a psychiatric 16 speculation about which there would be debate or 17 argument. Clearly it is implied in what is 18 written in here by the authors of this protocol. 19 Q Do some psychiatrists believe, or did they 20 believe in 1980, that the tricyclics aggravated 21 schizophrenia or other psychotic states in some 22 patients? PAGE 117 1 A I believe that they -- they did. 2 Q Does Prozac aggravate Schizophrenia or other 3 psychotic states? 4 A I don't personally believe that it does. There 5 have certainly been reports of adverse events so 6 temporarily associated with Fluoxetine that were 7 of a psychotic nature. There have also been 8 studies not conducted by Lilly looking at 9 patients with psychosis, in fact Schizophrenia -- 10 I mentioned those earlier today -- showing 11 improvement in certain schizophrenic symptoms. 12 Q But aggravation of schizophrenic symptoms in some 13 others? 14 A There have been. 15 Q Or worsening of schizophrenic situations? That 16 same study to be honest, Dr. Beasley, showed 17 worsening in some areas, did it not? 18 A It may have. I don't recall the details of the 19 specific study that I'm thinking about which was 20 Dr. Goss' study at McLean. 21 Q Yes. That's the study I'm thinking about, too. 22 I don't have it with me. But in all honesty that PAGE 118 1 study found that some psychotic states were 2 worsened by the administration of Prozac or 3 aggravated? 4 A As I said, it may have found that some patients 5 during the course of that study did worsen. 6 Q All right. Exclusion Criteria 12 indicates that 7 people should be excluded who were concurrently 8 being given psychoactive drugs including Lithium; 9 is that right? 10 A That's correct. 11 Q Is Lithium a psychoactive drug? 12 A Yes, it is. 13 Q Does Lithium inhibit the reuptake of any of the 14 neurotransmitters? 15 A I do not believe that it has any appreciable 16 impact upon uptake. 17 Q All right. Does Lithium interfere with the 18 actions of Prozac in any manner? 19 A I'm not aware of any reports describing a 20 pharmacologic interaction that would interfere 21 with serotonin uptake inhibition. 22 Q Does Prozac interfere with the actions of Lithium PAGE 119 1 in any manner? 2 A Lithium is a very complex drug in terms of its 3 activities. My understanding -- 4 Q I thought Lithium was just an element. 5 A Oh, it is, but the actions that it has on 6 neuronal cells and neuronal transmission I 7 believe are fairly complex. There is not 8 terribly good understanding of what it actually 9 does. The thought thinking now is that it 10 interferes in a positive fashion or positively 11 affects a -- what we call -- second messenger 12 system, phosphatidyl inositol system, and that 13 this is the way that it treats or prevents the 14 emergence of manic symptoms and may in some 15 patients also have a positive effect on 16 depression. 17 Q Does Prozac affect the secondary messenger 18 system? 19 A My understanding is that it would not have a 20 direct effect on that system. 21 Q I take it from your answer that there is some 22 evidence that it may have an indirect evidence -- PAGE 120 1 an indirect effect on the secondary messenger 2 system. 3 A Well, if one affects the primary messenger, being 4 a neurotransmitter -- 5 Q Yes. 6 A -- then presumably there may be effects, you 7 know. A primary neurotransmitter sends its 8 message, communicates with the cell it's 9 communicating with by a second messenger. 10 Q Which is in Prozac's case? 11 A The primary -- obviously the primary 12 neurotransmitter that is affected is serotonin. 13 Presumably there are changes in serotonergic 14 neurotransmission. There are a number of 15 serotonin receptor subtypes. And, again, I want 16 to say at this point this basic pharmacology is 17 not an area of mine, is not an area in which I 18 would be recognized as an authority or an expert. 19 Some of the second messengers in fact are related 20 to a compound called ATP. Some are related to 21 the phosphatidyl inositol system so that you have 22 serotonin affecting serotonin receptors. Those PAGE 121 1 serotonin receptors are linked to second 2 messengers. There is any number of serotonin 3 receptors. Some are linked ultimately through a 4 second messenger referred to as ATP, some through 5 the phosphatidyl inositol system. 6 Q All right. And those secondary messenger 7 systems, what do they do, Dr. Beasley, generally 8 as far as neurotransmission is concerned? 9 A They facilitate or inhibit the process of 10 transmission, the activity of the -- the activity 11 of the cells in which they become activated or 12 deactivated. 13 Q Okay. Would that activation or inhibition go 14 only to serotonin neurotransmission or would that 15 affect other neurotransmitters, the secondary 16 messenger system effect of Prozac? 17 A I think I understand what you're asking me. 18 Obviously the various neurons throughout our body 19 are interconnected and there are a variety of 20 transmitter systems: Serotonergic, dopaminergic, 21 neuroadrenergic, interneuron -- a number of 22 neurotransmitters. All of these are -- could be PAGE 122 1 potentially considered, I think interconnected. 2 Q Therefore Prozac even though in its primary 3 actions may directly affect the reuptake of only 4 serotonin, via that affect it may have an effect 5 on the secondary messenger system that might have 6 an effect on other neurotransmission of other 7 neurotransmitters; correct? 8 A That's possible, yes. 9 Q Well, that's correct, isn't it? I mean not in 10 every instance, but it is scientifically known or 11 postulated that that can occur and does occur in 12 some instances? 13 A I would say that it is postulated and within 14 certain neurotransmitter systems there is mixed 15 data with regard to the direction or how or 16 whether or not Fluoxetine or augmented serotonin 17 transmission has an effect. 18 Q Is Prozac contraindicated in individuals with 19 Lithium, taking Lithium? 20 A No. Excuse me, may I ask? Sorry I didn't ask 21 this before, but were you asking about that 22 specifically in the package insert? PAGE 123 1 Q Well, let's start with the package insert. Is 2 Prozac contraindicated in depressed patients 3 taking Lithium in the package insert? 4 A No. There is a cautionary note with regard to 5 Lithium. I believe it's with regard to potential 6 changes in Lithium levels. 7 Q It specifically advises the practitioner to 8 monitor Lithium levels because the direct action 9 of Prozac on Lithium hasn't systematically been 10 examined; correct? 11 A I'm not aware of detailed pharmacokinetic studies 12 of the two. 13 Q So my question is correct; right? 14 A I'm sorry, could -- 15 Q You haven't studied -- 16 A Right. 17 Q -- how Prozac affects Lithium, so that language 18 in the package insert advising the physician to 19 monitor Lithium blood levels is because you don't 20 know for sure what the effect is because you 21 haven't studied it? 22 A Correct, we have not studied. I'm sorry. I PAGE 124 1 thought you first said because a study had been 2 done. Sorry. 3 Q Had not been done. 4 A All right. 5 Q All right, so are we clear? 6 A Yes, sir. 7 Q All right. Is administration of Lithium known to 8 be recognized treatment for bipolar disorders? 9 A Yes, it is. 10 Q And is it contemplated by you scientists at Lilly 11 that those patients with bipolar disorders for 12 whom Prozac is prescribed may also be receiving 13 Lithium in addition to the Prozac for treatment 14 of their bipolar disorder? 15 A Yes, and if I could -- you just jogged my memory 16 about something. 17 Q Sure. 18 A And again I would need to check the protocol to 19 clarify this, but I'm virtually certain that the 20 bipolar protocol did not exclude the concomitant 21 use of Lithium, so I might need to sort of 22 correct myself in the sense of Lilly never PAGE 125 1 conducting a study that involved it to -- never 2 conducted a primary study with that as the sole 3 focus, but I believe I may have been in error 4 about, sir, any study looking at Lithium. 5 Q All right. Turn to Page 3 under the 6a, 6 Diagnostic Criteria. 7 A Yes. 8 Q It says "Research Diagnostic Criteria will be 9 used (Appendix A). All patients will satisfy 10 criteria for major depressive disorder and will 11 be further classified if possible, as:" And then 12 it lists seven categories, does it not? 13 A That's correct. 14 Q And the difference in this seven categories and 15 that in Protocol Number 27 is that it includes as 16 Item c here specifically the term Psychotic Major 17 Depressive Disorder, does it not? 18 A That's correct. 19 Q So we can take it from that that apparently it 20 was contemplated by the authors of this protocol 21 that psychotic depressed individuals would be 22 part of the treatment group receiving Fluoxetine? PAGE 126 1 A Yes. 2 (Plaintiffs' Deposition Exhibit 22 was 3 marked for identification.) 4 Q Exhibit 22 is Protocol Number 19 which is a Lilly 5 Prozac study, is it not? 6 A Yes, it is. 7 Q I'm just going to ask you a couple of quick 8 questions about that. That protocol also 9 included concurrent administration of Lithium and 10 other psychoactive drugs; correct? Page 2. 11 A That's correct. One thing that we should check 12 is to see if there were -- if there is a section 13 in here that specifies any permissible 14 medications. Let me just -- under -- 15 MR. MYERS: Take your time, Doctor. 16 A On Page 6. 17 Q Okay. 18 A It appears that chloral hydrate or 19 benzodiazepines could be administered during the 20 study. 21 Q Right. Well, specifically on Page 6 under 22 Section 4, Medication Other Than Study Drug, PAGE 127 1 Point b says "If in the opinion of the 2 investigator it is necessary, chloral hydrate 3 0.5 gm or 1.0 gm may be given by mouth or for 4 sleep. Administration of chloral hydrate will be 5 recorded in the case report form." 6 Part c says "If a patient complains of 7 agitation, the dose of study drug should be 8 reduced and the patient may receive a 9 benzodiazepine at the investigator's discretion. 10 This should be entered in the case report form"; 11 correct? 12 A That's correct. 13 Q While I'm here and we may as well discuss it 14 here, in your re-analysis of the clinical trial 15 in determining whether or not there was any 16 relationship of Prozac and suicide or 17 violent-aggressive behavior, did you ever look at 18 the Case Report Forms to determine what patients 19 were getting concomitant benzodiazepines and 20 whether or not it was for agitation and whether 21 or not the study drug was reduced in those 22 instances where that occurred? PAGE 128 1 A In the analysis of suicidality none of the issues 2 that you just mentioned were evaluated, and I am 3 virtually certain that they were not in the 4 separate analysis of aggressive behaviors. 5 Q Do you think that would be a legitimate area of 6 inquiry? 7 A (No response). 8 Q Good question, huh? 9 A Good question. It -- it might have some bearing 10 on the issue. It might have some bearing on the 11 issue. 12 Q Why is that, Doctor? 13 A Well, there could be individuals who would be -- 14 you know, who would find it to be of interest 15 because of the potential for inducing sedation. 16 There is a school of thought that we discussed in 17 the last -- in the last deposition that believes 18 that mood improves after improvements in 19 psychomotor activity status. This is across all 20 antidepressants, and that patients treated with 21 any therapy may have increases in their drive and 22 their ability to act and carry out suicidal PAGE 129 1 actions prior to their mood being improved. 2 Now, I'm unaware of data that supports this. 3 This is a belief in psychiatry, if you will. I'm 4 unaware of data that support that, but people 5 holding strongly to that view might well be 6 interested in analysis looking at the 7 relationship of sedative use. 8 Q Isn't that particularly true with Prozac because 9 Prozac is a nonsedating antidepressant? 10 A There are people who -- I think I characterize 11 Prozac as both slightly sedating and slightly 12 activating as we talked about before. But if you 13 want to characterize it as nonsedating, I think 14 people would agree with that, yes. 15 Q Generally even Lilly considers Prozac as a 16 nonsedating antidepressant, doesn't it? 17 A That's correct. 18 Q The question simply is whether or not Prozac is 19 an activating medication, isn't it? 20 A Well, I may be in something of a minority, but 21 again I have a lot of faith, belief, in the 22 analysis that I've conducted in both the PAGE 130 1 Protocol 27 database and the two fixed-dose 2 trials. And my interpretation of the data is 3 that one sees changes in both directions that are 4 different from placebo, both activation in some 5 patients and sedation in others. They may have 6 different relationships to dose and they may have 7 different temporal courses. 8 Q In fact, you're in the minority even at Lilly, 9 aren't you? 10 A Yes, sir, I am. 11 Q Because most the scientists at Lilly do generally 12 believe that Prozac is an activating medication? 13 A Well, I would say that it's characterized as 14 nonsedating. I tend to characterize it as in a 15 minority of cases sitting on both ends. 16 Q All right. What does Protocol 27 say about 17 medication other than a study drug? Why don't 18 you turn to Page 8. 19 A (Witness complies). This indicates that chloral 20 hydrate or flurazepam may be given for sleep. 21 Q All right. And in your in-depth study of 22 Protocol Number 27 did you find an amendment to PAGE 131 1 the protocol that allowed for concomitant uses of 2 benzodiazepines in instances of agitation on that 3 study? 4 A (No response). 5 Q It's not there. 6 A It's -- 7 Q I'll tell you it's in a letter, in my 8 recollection. 9 A Okay. I don't recall seeing such a letter. I -- 10 Q But you know that benzodiazepines were -- 11 MR. MYERS: Wait a second. 12 Q -- allowed under that protocol? 13 MR. MYERS: As before, finish your 14 answer to that other question and then answer 15 that question. 16 A I think my answer is actually answered to that 17 question. 18 Q Okay. I'm getting ahead of you, but we're on the 19 same wavelength, aren't we? 20 A As I have been -- 21 MR. SMITH: Don't think so? 22 MS. HUFF: No. PAGE 132 1 MR. MYERS: Go ahead, Doctor. 2 Q I'm sorry, Dr. Beasley. 3 A I coordinated an analysis of first occurrences of 4 activating and sedating events in the Protocol 27 5 population looking at its relationship to 6 baseline psychomotor activity status, 7 agitated/retarded or neither agitated nor 8 retarded. One of the things that we did as a 9 marker for this, it wasn't a direct analysis of 10 impact of benzodiazepines on course, but we 11 looked at any use. As I recall, we could 12 identify both chloral hydrate and benzodiazepines 13 and could separate those two out; that's my 14 recollection of the analysis. If that 15 recollection is correct, I would have to assume 16 that something at some point allowed 17 benzodiazepines to be used. 18 Q Were you aware of criticism issued by the Food 19 and Drug Administration to Lilly and specifically 20 responded to by Dr. Dorothy Dobbs in connection 21 with the use of benzodiazepine in the clinical 22 trial? PAGE 133 1 A I don't recall that, no. 2 (Plaintiffs' Deposition Exhibit 23 was 3 marked for identification.) 4 Q Exhibit 23 is Lilly E-mail dated January 24th, 5 1990 authored by yourself, is it not? 6 A That's correct. 7 Q And the subject is Prozac and Self-Directed 8 Violence? 9 A That's correct. 10 Q And this was one of the first observations that 11 anybody at Lilly made of the Teicher article 12 theoretically linking Prozac and suicide, was it 13 not? 14 A That's correct. 15 Q You say the authors are at McLean and include 16 Jonathan Cole; correct? 17 A That's correct. 18 Q He was a Lilly investigator, was he not? 19 A To my recollection he had the -- he participated 20 in a compassionate use protocol for Fluoxetine. 21 I'm not sure whether or not he participated in a 22 double-blind control trial, either was simply -- PAGE 134 1 I'm virtually certain he didn't with placebo, but 2 he may have participated in one with an active 3 comparator and was either investigator or 4 subinvestigator. 5 Q But he was indeed an investigator for Lilly, was 6 he not? 7 A If you include in that category individuals who 8 participated in a compassionate use protocol, 9 yes. 10 Q And he was participating in a compassionate use 11 protocol involving protocol, wasn't he -- or 12 involving Prozac, wasn't he? 13 A That's correct. 14 Q And in fact one of the patients that's reported 15 in the Teicher/Cole article was one of the 16 patients in that protocol, weren't they? 17 A I believe that's correct. 18 Q I mean, they were part of -- that one patient was 19 part of the clinical trial group being given 20 Prozac, were they not? 21 A I believe that patient was in this compassionate 22 use protocol, yes. PAGE 135 1 Q You go on to say "Copies are being distributed. 2 We have previously instituted an analysis of our 3 US Clinical Trial Database for byoindication, by 4 time-of-exposure rates of other-directed 5 violence, self-directed violence, and mental 6 states which might be considered by some to 7 predispose patients to the actions"; right? 8 A That's correct. 9 Q Now, what is this? I'm not sure what you're 10 talking about by "byoindication" of 11 other-directed violence and self-directed 12 violence. 13 A That appears to me to be a typographical or a 14 typo. I think it should read "by indication". 15 Q Okay. All right. So it should read "We have 16 previously instituted an analysis of our US 17 Clinical Trial Database for by indication"? That 18 doesn't make sense either. 19 A You, in other words, subcategorize by the 20 indication that was being studied: Depression, 21 Bulimia, Obesity. 22 Q All right. And what do you mean by PAGE 136 1 other-directed and self-directed violence in 2 mental states? 3 A Other-directed violence would be violence 4 directed externally, an otheric action directed 5 at another person. 6 Q And self-directed violence would be violence 7 directed towards one's own self? 8 A Towards one's own self. 9 Q Suicide? 10 A Yes. 11 Q Why were you looking at instances of 12 other-directed violence in connection with this 13 article by Teicher that was talking about 14 suicide? 15 A Well, we go on to say that there are some 16 individuals that think that there may be some 17 commonality between the two. Obviously there is 18 one -- behaviorally there is one commonality, and 19 that is violence; that's bad, destructive 20 behavior. Obviously that's a commonality. 21 Q Yes, but just because I'm mad at Mr. Myers and 22 would like to do violence toward Mr. Myers PAGE 137 1 doesn't mean I would want to do violence to 2 myself. 3 A No, not in all cases and probably highly 4 unlikely. But if one is being I think very 5 thorough and compulsive, one might wish to look 6 at both. 7 Q Why, is that what you were being, thorough and 8 compulsive? 9 A And again sitting here today recollecting -- 10 well, actually not recollecting this until you 11 showed it to me -- that would be my 12 interpretation. I go on to provide some comments 13 about the significance of looking at the two. 14 Q Well, you're directing this to the Lilly Chief 15 Scientific Officer and two individuals who at the 16 time were vice-presidents of Lilly Research Labs; 17 correct? 18 A That's correct. 19 Q And I'm wondering whether or not you intended to 20 say that. I mean apparently you're using some 21 time in evaluating the U.S. clinical trial 22 database to look at not only acts of PAGE 138 1 self-directed violence, but acts of 2 other-directed violence; is that correct? 3 A That's correct. 4 Q Did you do that for a sound medical reason or a 5 sound scientific reason? 6 A Yes, I think so. 7 Q And what is the scientific basis for doing that? 8 A That there are violence -- violence can be 9 directed at a range of objects. It doesn't even 10 have to be directed necessarily at others or 11 self. It can be directed at inanimate objects as 12 an example. 13 Q Such as Mr. Lore? 14 MR. SMITH: I'm sorry. 15 MR. LORE: Now, that wasn't very 16 nice. 17 A The desk. The desk. 18 MR. SMITH: Sorry. Let's start that 19 again. 20 Q What is the scientific basis for the theory in 21 looking at violence, be it other-directed or 22 self-directed, Dr. Beasley? PAGE 139 1 A Okay. Their obviously behavior commonality is 2 the violence. And there are clearly cases 3 existent in the literature where individuals 4 engage in both. And as I go on to say there are 5 certain individuals that have found commonality 6 in terms of biological substrates. 7 Q What do you mean by biological substrates? 8 A I believe that I probably here was referring to 9 low CSF 5-HIAA levels. 10 Q All right. But there is a relationship between 11 suicide, which is directed toward oneself, and 12 violent-aggressive behavior, which is loss of -- 13 is the basis of this loss of impulsivity or I 14 mean loss of impulsivity control -- 15 A I guess from my -- 16 Q -- to some extent? 17 A I guess from my perspective what one sees is bad 18 behavior, behavior that results in damage, 19 potentially damage. It may not result in damage, 20 but some reasonable probability of resulting in 21 damage that can be to yourself or to someone 22 else; that's on the one hand, so that's a PAGE 140 1 commonality. Now, clearly there is a difference 2 there, too. Okay. I think you've sort of been 3 emphasizing to me the difference. There is also 4 some data to suggest that some of the biological 5 parameters that can be identified in patients 6 exhibiting these behaviors are similar. One 7 might well like to know what's the -- what's the 8 thing? Sort of the very, very striking and 9 crucial scientific question, clinical question, 10 could be: If these are common in some sense, 11 what causes a given individual to direct actions 12 at another, at other people versus themselves? I 13 think you see much more -- and again I can't cite 14 you hard numeric data, but my sense is that an 15 individual who or the individual sort of 16 population of individuals who sort of do both is 17 relatively small compared to those who direct 18 their aggression outward versus those who direct 19 it at themselves. 20 Q But there is a population that it's believed that 21 their violence could just as easily be directed 22 outwardly as opposed to inwardly; is that PAGE 141 1 correct? 2 A There are. I think what I have said is that 3 there are some individuals who direct violence 4 both toward themselves and toward others. 5 Q But that there is as you say a similarity in 6 these people's biological substrates? 7 A For individual -- there is a subpopulation of 8 individuals who commit violent acts toward 9 themselves that have a particular biological 10 finding that have presumably never or not 11 substantially noted to have ever directed 12 violence at other people. My understanding is 13 that there is another group of individuals who 14 have directed violence outward who also have that 15 particular biological finding. 16 Q And so is that the reason you were studying them 17 both, because there may be some group that has 18 both? 19 A Well, again I think what I've said, suggested, is 20 that if one wished to be compulsive, one could 21 clearly say that there is a commonality and sense 22 of bad behavior that may result in serious PAGE 142 1 damage, and then there is this potential for 2 biological commonality in one area. 3 Q All right. 4 (Plaintiffs' Deposition Exhibit 24 was 5 marked for identification.) 6 A This is a pretty long document. 7 Q Yes. Let's just identify it. I'm just going to 8 ask you a couple of questions about some specific 9 parts. Again, we'll use the same rules with you 10 that we've always used, that you're certainly 11 free to read the entire document, but that will 12 take most of the afternoon and I don't think it's 13 necessary, but if you're uncomfortable with your 14 answer, you're certainly free to look at the 15 other part of the document. 16 MR. MYERS: Let me suggest this, 17 Doctor, take a look at the document quickly -- 18 Q It's two articles. 19 MR. MYERS: -- as you have the other 20 documents. 21 Q It's two articles that -- 22 A May I read the cover letter? PAGE 143 1 Q Well, absolutely. I thought you had already read 2 the cover letter. 3 A No. 4 MR. MYERS: Go ahead and do that. 5 Q Sorry about that. 6 A I've read the cover letter. 7 Q Dr. Beasley, Exhibit 24 is a letter written to 8 Dr. Tollefson by Dr. Mario Savelloni; correct? 9 A Excuse me, but you referred to Mario Savelloni as 10 doctor? 11 Q Okay. 12 A He's mister. 13 Q He's then not a doctor? 14 A Right. 15 Q Mr. Mario Savelloni. Who is Mario Savelloni? 16 A He is a retired clinical research coordinator. 17 Q Where does he reside? 18 A In the Boston area. 19 Q Was he retired at the time this document was 20 authored? 21 A Did we -- 22 Q The letter is not dated, but if you look at the PAGE 144 1 articles, you'll see that they were written 2 somewhere in 1991 or 1992, that they were 3 presented in 1991 to some Italian conference. 4 A Mr. Savelloni did not retire until I believe 5 December or January of this year. 6 Q So you think he probably was an employee of Lilly 7 when he forwarded these on to Dr. Tollefson? 8 A That's potential. I don't know the -- I don't 9 know when these were forwarded, but I think there 10 is a good potential. 11 Q And he encloses two Lilly-funded studies, does he 12 not? 13 A Let me -- 14 Q Well, look on the first page of each of the 15 studies. It says "Work partly supported by a 16 grant from Eli Lilly and Company", doesn't it? 17 A I -- 18 MR. MYERS: Paul, he hasn't found 19 the second one. That's why he's flipping through 20 them. 21 MR. SMITH: He'll just have to keep 22 looking then. PAGE 145 1 MR. MYERS: Okay. 2 A I believe that these were substudies of -- both 3 substudies of a Lilly-sponsored study. 4 Q Okay. And the author of these papers -- 5 A Right. 6 Q -- on the cover sheet of these papers says "Work 7 partly supported by a grant from Eli Lilly and 8 Company", doesn't it? 9 A That's correct. 10 Q All right. And what I'm trying to do, 11 Dr. Beasley, is point to you in this work some 12 support for your earlier statements that there is 13 a -- I believe a -- that self-directed and 14 other-directed acts are similar in their 15 biological substrates; correct? 16 A Uh-huh. 17 Q Now, these two works are done by a Dr. Fava and 18 Rosenbaum; are they not? 19 A That's correct. 20 Q And Dr. Rosenbaum is one of Lilly's experts; 21 correct? 22 MR. MYERS: When you say "experts", PAGE 146 1 you mean in what context? I mean I don't 2 think -- 3 Q Well, expert psychiatrists? 4 A I believe that Dr. Rosenbaum is on the advisory 5 panel. 6 Q The Lilly advisory panel; correct? 7 A Yes. 8 Q And Dr. Rosenbaum has been designated as an 9 expert in Fentress versus Shea Communications 10 pending in Louisville, Kentucky? 11 A I wasn't aware of that. 12 Q Well -- 13 MR. MYERS: Not by us. 14 MR. SMITH: Uh-huh. 15 MR. MYERS: No, sir. 16 MR. SMITH: Okay. 17 Q But he's on the Lilly advisory committee? 18 A Yes, sir. 19 Q All right. Turn to Page 13 of the first article. 20 And this is an article on anger attacks, isn't 21 it? 22 A That's correct. PAGE 147 1 Q And do you recall reading this article? You were 2 copied in on the letter. I was just wondering if 3 you recall? 4 A I'm virtually certain I received the package. I 5 probably read the abstract. Whether I read the 6 article or not is hard to say. 7 Q Look with me at the last paragraph there. 8 A On Page 13? 9 Q On Page 13. It says "There are some important 10 clinical implications for our findings. As 11 Yesavage found an association between direct and 12 indirect hostility and self-destructive behavior, 13 the significant changes in hostility and anger 14 are reported by our patients with treatment with 15 fluoxetine may imply a reduced risk for suicide 16 or suicide attempts. In addition, a study by 17 Collins and Bailey on incarcerated male felons 18 found a direct relationship between a lifetime 19 diagnosis of depression and a history of violence 20 since age 18"; correct? 21 A That's correct. 22 Q And you might look back at the list of references PAGE 148 1 there. There apparently in addition to 2 Dr. Rosenbaum and Fava, there are other 3 authorities who believe that there is a 4 relationship between hostility and anger and a 5 risk for suicide and suicide attempts and that 6 there is a direct relationship between hostility 7 and self-destructive behavior; correct? 8 A You asked me a long question. Let me think about 9 it. 10 Q Sure. 11 A Okay? 12 Q There is no time limit. You know, you don't have 13 to answer within a particular period of time. 14 A I may ask you to sort of break it down -- 15 Q I will. 16 A -- for me a little bit. 17 Q And let me -- in all truthfulness you probably 18 have just seen that sentence. Let me give you a 19 minute to digest it, too. 20 A Okay. Because the first part I think -- the 21 first sentence is full of a lot of potential 22 subtlety, okay, can I start by giving you my PAGE 149 1 interpretation of the sentences? 2 Q Sure. 3 A Okay. I'm not familiar with the Yesavage work 4 and I'm not sure what Dr. Fava means when he's 5 talking about Yesavage's description of direct 6 and indirect hostility, whether that means 7 outwardly directed thoughts. But apparently he 8 found some sort of association, temporal -- I 9 don't know what -- between that and 10 self-destructive behavior, suicidal acts I'm 11 assuming, okay? So what based on -- based on 12 this previous finding by Yesavage, what Dr. Fava 13 is speculating is that because anger goes down, 14 and I'm assuming that from what he has here is 15 the conclusion. I haven't like I said confirmed 16 that looking at his data, but that in fact 17 because hostility goes down, he speculates that 18 the potential for suicidality goes down, so he 19 gives this one paper as a support for his 20 speculation and then goes on to speculate that 21 decreases in hostility may result in decreases in 22 suicidality. I don't see from here that he has PAGE 150 1 any empirical data to support that. 2 Let me go on to the second sentence. The 3 second sentence points out a longitudinal 4 association between depression and violent and -- 5 I'm sorry. 6 (A discussion was held off the record and 7 William J. Downey, III enters the deposition.) 8 A -- that amongst people who are incarcerated there 9 seems to be a relationship between depression and 10 violence. 11 Q Well, my question simply is, Dr. Beasley, is the 12 thoughts that are set forth in Page 13 concerning 13 hostility and suicidality related to the same 14 genesis of thoughts concerning that you talk 15 about in Exhibit 23 when you're talking about 16 self-directed and other-directed acts? 17 A I'd say what we're talking about I referred 18 specifically in my sentence to biological 19 substrates, the 5 HIAA that I was talking about. 20 I think this is somewhat different in that it's 21 talking about relationships between the overt 22 behaviors. PAGE 151 1 Q Okay. But they both come to the same basic 2 conclusion; that is, there is some relationship 3 between violent-aggressive behavior and suicidal 4 behavior? 5 A There -- there may be. I mean there is definite 6 commonality in that they both involve bad 7 actions. There are -- there are some very 8 definite biological commonalities. And then from 9 a long-term behavioral perspective, okay, you may 10 see some relationship. 11 Q Okay. So you are as a scientist doing what is 12 scientifically valid, and that is examining both 13 issues at the same time together with each other, 14 the issues of suicide and violent-aggressive 15 behavior is simply all I'm saying. 16 A Yes. 17 Q In other words, it's of scientific validity to 18 look at suicide and violent-aggressive behavior 19 in the same scientific method, manners? 20 A Well, you would apply a number of the same 21 techniques to assess those. I mean if you were 22 talking about method, yes. PAGE 152 1 Q Well, maybe that was a poor word. If you're 2 making an inquiry as to the genesis both 3 psychologically and physiologically of these 4 acts, it's valid scientifically to look at them 5 together? 6 A I think that if one did that, one would also wish 7 to look at them separately because you -- and 8 perhaps what we've done here in parallel because 9 you've got two in some respects distinct issues, 10 again with regard to the object at which the 11 destructive behavior is directed. 12 Q But there are some common -- 13 A There are some things that are common; there are 14 some things that are not common. 15 Q And it's valid to look at each? 16 A Each, yes. 17 Q It's valid to look at each of them together and 18 separately? 19 A My preference would be to look at them both, but 20 first look at them separately. 21 Q All right. But you were looking at them 22 together? PAGE 153 1 A I believe that what is implied here is that they 2 were being looked at but in parallel. 3 Q All right. At the same time? 4 A At the same time. 5 Q For same common factors? 6 A Well, we were interested in whether or not as 7 this evolved there were any differences in rates 8 across our treatments. 9 Q Well, the reason that you say that is, and I 10 quote you here the last sentence, "It is 11 important to keep in mind that some of the more 12 prominent researchers in this area (violence) 13 consider self-directed and other-directed acts to 14 be very similar in their biological substrates"; 15 correct? 16 A That's correct. 17 Q Did you agree with that then? 18 A Yes. 19 Q Do you agree with it now? 20 A Yes. 21 Q And that's the reason you were doing what you 22 were doing? PAGE 154 1 A That's correct. 2 MR. SMITH: Break time? 3 MR. MYERS: Sure is. 4 (A brief recess was taken and Plaintiffs' 5 Deposition Exhibit 25 was marked for 6 identification). 7 THE WITNESS: I've read the 8 document. 9 Q Dr. Beasley, Exhibit 25 is an in-house Lilly 10 document authored by Gisele Soyez to a number of 11 individuals; correct? 12 A Yes. 13 Q Ms. Soyez was who in 1982? 14 A I wouldn't be familiar with her title in 1982. 15 At the time I began at Lilly she was a CRA, 16 Clinical Research Administrator. 17 Q The subject of this document is Case Report Forms 18 for Fluoxetine Study in Bipolar Patients; 19 correct? 20 A That's correct. 21 Q And you of course had mentioned earlier that 22 there were Lilly Prozac clinical trials examining PAGE 155 1 bipolar patients? 2 A That's correct. I believe there was one study. 3 Q All right. Was that a single-site or multi-site 4 study? 5 A I believe that that was a single-site study, but 6 I'm uncertain. 7 Q In Point 4 where she's talking about revising the 8 Case Report Forms she said, "The sentence 'Do not 9 include adverse experiences caused by depression' 10 on the adverse experiences page will be changed 11 to 'Do not include adverse experiences caused by 12 bipolar disorder' on all follow-up report forms." 13 Do you see that? 14 A Yes, I do. 15 Q My question is how was the investigator to 16 determine whether an adverse experience was 17 caused by the condition being examined, 18 depression, or in the bipolar study, bipolar 19 disorder, versus being related to other factors 20 such as study drug or outside life circumstances 21 even? 22 A Quite frankly I wouldn't know. I don't know what PAGE 156 1 instructions were given or how this was explained 2 or elaborated on. 3 Q Did you know in your analysis of the relationship 4 of Prozac in suicide that the clinical 5 investigators had been given instructions not to 6 include as adverse events experiences caused by 7 depression? 8 MR. MYERS: Object to the form of 9 the question. I don't know that there is any 10 testimony that happened in all trials, but tell 11 him if you know. 12 A I do not believe I was aware of this language or 13 the existence of any such language at the time I 14 conducted -- supervised the conduct of the 15 analysis. 16 Q In any of the clinical trials? 17 A In any of the clinical trials. 18 Q You didn't know that there may have been some 19 clinical trial investigators that weren't 20 reporting adverse events because it was that 21 clinical investigator's impression or opinion 22 that in fact what that was was the underlying PAGE 157 1 disease of depression? 2 MR. MYERS: Same objection as to the 3 form. Go ahead. 4 A If what you're -- if you're suggesting that there 5 was no indication on the Case Report Form of any 6 change, I'm not sure I would agree with that 7 position. Presumably these events were being 8 picked up on rating scales; however, it would 9 appear that this language would clearly indicate 10 that those events were not to be included on the 11 specific adverse event pages, and I was not aware 12 of that. 13 Q To be specific in how this could affect your 14 work, if you looked at the clinical trial data 15 and wanted to see adverse experiences or adverse 16 events reported concerning, let's say agitation 17 for instance, you would think that those reports 18 of agitation would be made as adverse events, 19 would you not? 20 A Yes. 21 Q All right. In other words, if the patient came 22 in and reported to the investigator, say only PAGE 158 1 three of the clinical trials, "Gosh, this last 2 week I felt a lot more agitated and anxious", you 3 would suspect that most probably the investigator 4 would rate that as an adverse experience with the 5 drug normally, wouldn't you? 6 A Well, I would -- what I would -- I agreed with 7 you up until the very end of your last statement, 8 the adverse event experience with the drug. My 9 view of adverse events is that they're 10 independent of anything. 11 Q Okay. Let me revise that. If a patient came in 12 on Week 3 and says, "Gosh, this last week I've 13 been feeling a lot more agitated and anxious", 14 you would expect that to be reported as an 15 adverse event? 16 A Yes. 17 Q All right. But you know that agitation and 18 anxiety are also classically known as parts of 19 depression, parts of the symptoms of depression, 20 and can be caused by depression; correct? 21 A Agitation is one of the diagnostic features. 22 Anxiety is not, but it's commonly seen in PAGE 159 1 depression. 2 Q All right. So if the investigator were getting 3 instructions such as these in the Case Report 4 Forms where the investigator is saying it could 5 be a situation where the investigator instead of 6 reporting that as an adverse event isn't 7 reporting it as an adverse event, but is saying 8 "Oh, that's just to be expected in someone with 9 depression", that's really not an adverse event; 10 correct? 11 MR. MYERS: Same objection to the 12 form. Go ahead. 13 A Again, I have no knowledge about how -- and 14 obviously this refers to one protocol -- how this 15 or any other protocols that had similar language 16 were implemented, what additional instructions 17 were given or anything else. All I can address 18 is a hypothetical answer to your question which 19 is, yes, there would be potential for impact 20 certainly on the absolute rates of these events. 21 Q You might have a situation where you're not 22 picking up events such as anxiety because the PAGE 160 1 investigator is not recording them as adverse 2 events but felt at the time that they were part 3 and parcel of the depression; correct? 4 A Well, again, I would want to qualify that with 5 the issue of rating scales. 6 Q We're not talking about rating scales. 7 A Okay. 8 Q This is not a rating scale question. This is an 9 adverse event issue because she's talking about 10 adverse experiences on the Case Report Forms and 11 there are specific areas -- 12 A Right. 13 Q -- on the Case Report Forms for adverse 14 experiences, is there not? 15 A That's correct. I guess as I understood you, you 16 were asking me whether or not increases or 17 changes in anxiety might be detected anyplace or 18 recorded anyplace in the Case Report Form. There 19 is a potential given this language for them not 20 to be recorded as adverse events. There are 21 other components of the Case Report Form that do 22 systematically assess anxiety as the example that PAGE 161 1 we used. 2 Q But if you're looking only at adverse events 3 reported and not looking at the scales 4 themselves, if you're making your determination 5 of what occurred during the clinical trials by 6 looking at the adverse experiences reported 7 during the trials, then you're not going to see 8 this, are you? 9 A Hypothetically this could influence those rates. 10 Q All right. And you weren't aware that this was 11 even an instruction to the investigator until I 12 just showed it to you, were you? 13 A I believe that you in the last deposition may 14 have jogged my memory with or actually revealed 15 this to me. I don't recall that specifically, 16 but you might have. But before that, I was not 17 aware of this. 18 Q Certainly you weren't aware of it when you made 19 your analysis -- 20 A No. 21 Q -- of the relationship between Prozac and 22 suicide? PAGE 162 1 A No. 2 Q No, you were not aware of it? 3 A I was not aware of it. 4 Q When you came to Lilly in 1987, the issue of 5 Prozac being approved in Germany had not yet been 6 decided, had it? 7 A You mean the -- I believe that the compound is 8 approved now. I'm not sure when it was approved. 9 Q The record I think is pretty clear that it was 10 approved for use in Germany in December 1989. 11 A Okay. 12 Q And you came to Lilly in '87. 13 A That's correct. 14 Q And do you remember work being done to answer 15 questions raised by the German government, 16 specifically the BGA, in connection with issues 17 they were concerned about with Prozac? 18 A My work with Prozac was virtually exclusively 19 focused at that time on beginning studies in the 20 United States. As I've said, at some point I 21 became aware of the analysis of suicidal acts 22 that I understood was prepared for the Germans. PAGE 163 1 I'm not sure exactly when I first became aware of 2 that document. That's the one piece of 3 information or analysis or document that I'm 4 familiar with. 5 Q The response that was prepared for the German 6 government by Lilly? 7 A Which -- which response? I mean -- 8 Q Well, I thought you said that was the one piece 9 of information you were familiar with, and I was 10 just clarifying which that was. Are you saying 11 it was the response to the issues raised by the 12 German government? 13 A No. What I have seen and recall is a document 14 that looked at I believe suicide attempts and 15 then I believe there were two cover letters 16 associated with this, one that I think was 17 associated with the document and then one as I 18 recall that I somehow became aware of that was in 19 a statistical file, but I don't recall any sort 20 of a comprehensive point-by-point response to a 21 number of questions. The one thing that I recall 22 is this document that related to what I PAGE 164 1 understood to be a question that had been raised 2 by the Germans. 3 Q In connection with suicide and Prozac? 4 A That's correct. 5 Q And was this before the issue was raised by 6 Dr. Teicher? 7 A I believe that I was aware that the document had 8 clearly been prepared and as I recall, I'm 9 virtually certain that I was aware of the 10 existence of the document before Dr. Teicher's 11 article. 12 Q Certainly you knew that the German government had 13 raised the issue of Prozac and suicidality before 14 you heard of this Teicher article that we've 15 already described, earlier described in 16 Exhibit -- 17 MR. MYERS: 23. 18 Q -- 23 to your deposition? 19 A Yes. 20 Q And you knew when you first got to Lilly or 21 shortly after you got to Lilly that Prozac was 22 still under consideration by the German PAGE 165 1 government? 2 A Again, I'm not sure when I ever became aware of 3 what was going on in Germany. My focus was on 4 U.S. work and I don't recall being directly 5 involved in activities with regard to the German 6 application. 7 Q But you were aware that there was work that had 8 occurred in connection with the German 9 application? 10 A Yes, I knew that -- well, I assumed that the 11 application had been made for approval throughout 12 the world in a number of countries. I don't 13 recall my recollection of or my knowledge of the 14 status of any of those at any point in time. At 15 some point I became aware of this piece of work 16 relating obviously to a question raised by the 17 German regulatory authorities. Exactly when I 18 became aware of that, I'm sorry I can't specify 19 that. I'm virtually certain it was sometime 20 before Dr. Wernicke -- Dr. Wernicke left Lilly. 21 I'm virtually certain it was sometime before 22 Dr. Teicher's paper appeared. PAGE 166 1 Q Did you and Dr. Wernicke discuss the issues 2 raised by the German government or the issue in 3 general of Prozac and suicide? 4 A We could have. I don't recall those discussions. 5 Frankly my recollection is again that I was 6 pretty much focused on U.S. activities and others 7 were involved with international activities. 8 Q In your analysis of whether or not Prozac and 9 suicide were related, did you ever go back and 10 look at any of the work that had been done for 11 the German government by Lilly? 12 A Again, I keep referring to a set of three 13 documents: One being a document and two being 14 letters about this document. That's what I 15 recall looking at. 16 Q Did you ever review any experts that were called 17 in to examine this issue's opinions in doing your 18 work in connection with analyzing the issue? 19 A I think that there was an expert involved in the 20 preparation or one or more of the components of 21 the three documents that I was looking at. 22 Q Did you know the names of any of the individuals PAGE 167 1 in Germany at the Lilly affiliate that was 2 coordinating this work? 3 A No, I did not. 4 Q Did you know Dr. Hans Weber? 5 A I know Dr. Weber because he was assigned as I 6 believe Director of Endocrine during a period of 7 time that he spent in Indianapolis. That was the 8 first I met him. 9 Q Did you ever talk to Dr. Weber in the issue of 10 Prozac and suicide? 11 A I can't recall any conversation with him. 12 Q Did you know a Dr. Schulze-Solce? 13 A I know him as Medical Director in Japan. 14 Q You knew he was in Germany at one time? 15 A Well, I knew he was German, but my only contact 16 with him has been since he has been in Japan that 17 I recall. 18 Q How about Dr. Johanna Schenk? 19 A I'm sorry, that's a name that doesn't even -- 20 Q How about a Professor Herrmann? 21 A It seems to me that I recall that name from the 22 last deposition. PAGE 168 1 Q All right. 2 (Plaintiffs' Deposition Exhibit 26 was 3 marked for identification.) 4 A This is obviously a long document. 5 Q Why don't you glance at it for the purpose of 6 seeing whether or not you've ever seen this 7 document. 8 A I can't recall seeing this document. I note -- 9 well, I think I note the date that I assume is 10 pertinent to its transmission is about three 11 years before I arrived at Lilly, so it was in 12 some sense around I would think, I'm not sure 13 where but -- 14 Q Exhibit 26 is a document that has a cover letter 15 of two pages and then has, oh, 40 pages attached 16 to it. 17 A Let me see if I've got two documents here. Looks 18 like I've got it in several sections but it's a 19 long document. I'm not sure what the pages are. 20 Q Let me make sure I see what you're saying. 21 A The page numbers, I thought I could see where 22 these are. PAGE 169 1 Q Oh, it came in two pages? If you'll look at the 2 PZ numbers -- 3 A Right. 4 Q -- you'll see they're marked consecutively on the 5 report itself and is titled Fluoxetine, Reply to 6 the Medical Opinion within the "List of 7 Concerns". You'll see that third page is 8 PZ 281 1651. 9 A Oh, down in -- 10 Q In the lower right-hand corner of the page. 11 A Yes. Yes, up to 97. 12 Q I've got to 91. 13 A I've got to 97. 14 Q Let's see, I may have stapled something with it. 15 A Maybe your 7 is -- 16 Q I misread it. My 7 is 91, so it would be 46 17 pages long; correct? 18 A That's correct. 19 Q I understand that this would not have been 20 something that you would have seen when it was 21 generated because you weren't working for Lilly 22 when it was generated apparently; correct? PAGE 170 1 A That's correct. 2 Q But my first question is to you did you see this 3 document since you joined Lilly, since it was 4 transmitted to Indianapolis and Dr. Zerbe? 5 A I don't recall ever -- I don't recall ever seeing 6 this. 7 Q It looks like it was transmitted to Dr. Weinstein 8 in Indianapolis. 9 A That's correct. 10 Q It looks like it was transmitted to Dr. Wernicke 11 in Indianapolis. 12 A That's correct. 13 Q And Dr. Emmick in Indianapolis; correct? 14 A That's correct. 15 Q Who is Dr. Emmick? 16 A I'm not sure what position Dr. Emmick held. 17 Q What was his title? 18 A I don't know. 19 Q Was he there ever at Lilly when you were there? 20 A I think that he was. I'm certain I've seen the 21 name before. I believe the T stands for Tom and 22 I don't believe he was a physician; I believe he PAGE 171 1 was a Ph.D. 2 Q Was he on the vice-presidential level at Lilly or 3 Lilly Research Labs? 4 A He may have been. 5 Q All right. The first two pages are the cover 6 letter enclosing this report, are they not? 7 A That's correct. 8 Q And it is entitled Reply to the Medical 9 Opinion with the "List of Concerns"; correct? 10 A Draft of the Reply to the List of Concerns. 11 Q Right. But if you look at the -- 12 A Oh, at the top? 13 Q Did you know of the existence of this document? 14 A I don't recall knowing anything about this 15 document. 16 Q All right. You never discussed it with 17 Dr. Wernicke or Dr. Weinstein as far as you 18 recall? 19 A Not as far as I recall. 20 Q Or Dr. Zerbe? 21 A Not as far as I recall. 22 Q Can you tell from looking that this is indeed a PAGE 172 1 reply to issues that were raised by the BGA, the 2 German governmental authorities? 3 A Let me just look at some of the head titles here. 4 Q Yes, do. 5 A Looking at the early pages of this it looks to me 6 as though it's sort of an overview of the 7 database presented, present probably in their 8 application and results. I'm about a third of 9 the way through. 10 Q Okay. The BGA sent a list of concerns and sent a 11 medical opinion to Lilly that addressed the 12 subject of depression generally and that talked 13 about side effects, talked about suicide, talked 14 about inpatient treatment and things of that 15 nature, and this appears to be directed in some 16 rough form as a response to this list of 17 concerns. Did you ever see the list of concerns 18 raised by the BGA? 19 A Not that I'm aware of. 20 Q All right. 21 A Well, I inferred one from the knowledge of this 22 suicidality document. PAGE 173 1 Q Okay. And it does discuss suicidality on in 2 there? 3 A Yeah. Again, as I flip through this and again 4 it's from just looking at the underlying topic 5 headings, I wouldn't necessarily know that this 6 was constructed to answer specific questions or 7 concerns. That's all I'm -- 8 Q Well, if you look at the transmittal letter, 9 obviously it indicates that it's drafted to do 10 that, doesn't it? 11 A Right. 12 Q Okay. Let's go through this a little bit and 13 talk about some of the things that Dr. Schenk 14 says in this reply. 15 A Okay. 16 Q On Page 1651 and I'll use the PZ numbers. 17 A Right there, (indicating)? 18 Q In the middle of the page it mentions that 19 psychotic depressed patients were studied, does 20 it not? 21 A From reading this I don't know whether or not all 22 of these subtypes were or were not included in PAGE 174 1 trials. You've clearly shown me two protocols 2 today, I believe two, that would have made it 3 explicit that psychotic patients could be 4 included. 5 Q Yes. 6 A It's interesting in that the ones that we've 7 looked at although incapacitating is an RDC 8 subtype. I don't recall that that was a subtype 9 that was explicitly documented at least on the 10 protocols that we looked at today. 11 Q If you look back, you'll see on the two they 12 include psychotic. They included I believe 13 incapacitating, also. 14 A Okay. This one definitely has incapacitating. 15 Q Which one is that? 16 A That's 19. 17 MR. MYERS: Protocol 19 as opposed 18 to Exhibit. 19 A And Protocol 22 as well. 20 Q Includes incapacitating? 21 A Incapacitating. 22 Q So the statements she makes there are accurate or PAGE 175 1 at least supported by the language of the 2 protocols? 3 A That's correct, for the potential to include 4 those patients. 5 Q All right. Turn with me now to Page 1653. You 6 see at the top of the page it says Activity 7 Profiles of Antidepressant Drugs? 8 A Yes. 9 Q Look with me at the second paragraph of that 10 section where Dr. Schenk, the Lilly author of 11 this draft, says "Unfortunately, there exists no 12 practicable routine method to identify the 13 possibly underlying deficiency of a transmitter 14 in a certain patient, and a causal relationship 15 between primary action and antidepressant 16 potential is not yet established. Therefore, the 17 choice of a specific antidepressant will mainly 18 depend upon the symptomatology and the clinical 19 profile of action of the respective drug"; 20 correct? 21 A That's correct. 22 Q Do you agree that there still does not exist the PAGE 176 1 possibility of determining a deficiency in a 2 neurotransmitter in a particular patient? 3 A Yes, I would emphatically. I think it's 4 important to emphasize that she includes in that 5 first sentence "possibly underlying deficiency". 6 In fact what's emphasized here is that we don't 7 know in fact that neurotransmitter deficiencies 8 are the things that produce depression. 9 Q Okay. She doesn't underline it in my copy. 10 A No. No. I'm suggesting emphasis here. 11 Q All right. So you agree with her 100 percent 12 where she states that you really don't know that 13 depression is caused by a deficiency in a 14 neurotransmitter; correct? 15 A I agree with that and I take that as the first 16 long clause up to the comma. 17 Q And you certainly agree that you can't identify 18 any particular deficiency in any particular 19 patient of a neurotransmitter? 20 A That's correct. 21 Q Then she has under that the heading 22 Antidepressant Drug Treatment With Regard To PAGE 177 1 Phenomenology; is that right? 2 A That's correct. 3 Q What does that mean? 4 A That refers to more a detailed description of the 5 signs and symptoms that the patient presents 6 with, so it's a detailed description of the 7 behaviors that you observe, the verbal 8 productions of the patient in interviewing the 9 patient that lead you to making that diagnosis. 10 Q That leads you to make either determination with 11 respect to whether or not Prozac as an 12 antidepressant drug is efficacious because you 13 can't establish it by looking at laboratory 14 values? 15 A I'm sorry, I'm having a little trouble following. 16 What I think we're talking about are -- you know, 17 are subtyping of patients with depression or 18 looking for specific features that would be 19 potential markers or indicators of better 20 antidepressant response. We've said since we 21 can't do it with a laboratory test, what we're 22 left with are the signs and symptoms. PAGE 178 1 Q Okay. Then she starts talking about the clinical 2 profile of action of Prozac; correct? 3 A That's the heading here, yes. 4 Q And she talks about pooled studies comprising 22 5 trials? 6 A Let me just -- okay, so similar protocols were 7 combined. 8 Q Right. She combined these into seven similar 9 protocols, but they comprised -- I counted them 10 up -- she comprised 22 studies; right? 11 A I haven't counted them. Some of these -- for 12 example, Protocol 27 is referred to here as six 13 studies. I believe this was always intended as a 14 multicenter study to begin with. It might be 15 more appropriately referred to as a single study 16 with six sites. 17 Q Okay. And then she goes on to make an analysis 18 of the findings; correct? 19 A I haven't looked at that, but I believe that's 20 what she is going to do. 21 Q All right. Turn to 1656 and she gives you the 22 results. PAGE 179 1 A 1656. 2 Q Or a heading of results. 3 A Okay. Results. 4 Q Do you see that? 5 A Yes. All right. I have it. 6 Q Turn with me to 1657 and look at where she talks 7 about early discontinuations due to lack of 8 efficacy. 9 A I have read the paragraph III.3, Early 10 Discontinuations Due to Lack of Efficacy. 11 Q All right. The middle sentence there says "More 12 early drop-outs in fluoxetine agitated patients 13 were observed in fluoxetine vs. imiprimine 14 vs. placebo studies, in the doxepin geriatric 15 study, the imiprimine in-patient study and the 16 fluoxetine q.d. vs. b.i.d. trial"; correct? 17 A That's correct. 18 Q Did you know that when you did your analysis of 19 the Prozac clinical trials for suicidality? 20 A I was not aware as I said of this document or -- 21 Q I'm not talking about this document. I'm talking 22 about did you know that was -- PAGE 180 1 A No. 2 Q -- a finding? 3 A No. And I was not aware of this finding -- 4 Q All right. 5 A -- reported by Dr. Schenk. 6 Q As early as 1984? 7 A That's correct. 8 Q Now, look back at what she reviewed. She and you 9 reviewed basically the same things, didn't you? 10 A They are quite similar. 11 Q All right. Now, look at the Section III.4, Early 12 Discontinuations due to Adverse Experiences on 13 Page 1658. 14 A I have read that. 15 Q Do you see there where Dr. Schenk states "More 16 agitated than retarded fluoxetine patients 17 discontinued early because of adverse experiences 18 in the placebo phase-II trial, the amitriptyline 19 comparison and the fluoxetine q.d. vs. b.i.d. 20 study"? 21 A Yes, I do. 22 Q Did you find that in your review of the PAGE 181 1 fluoxetine clinical trial data in your analysis 2 of whether or not Prozac is suicidal related? 3 A This was not a component of our suicidality 4 analysis. 5 Q All right. Does this surprise you, this finding 6 that Dr. Schenk mentions here, that more agitated 7 than retarded fluoxetine patients discontinued 8 early because of adverse experiences? 9 A Well, I guess I would like to -- as I read the 10 whole paragraph? 11 Q Yes. 12 A Okay. Notice that in some trials more agitated 13 patients discontinued. In some trials no 14 preference for a subtype. And it's very 15 interesting that that was in the fluoxetine 16 versus imiprimine versus placebo which probably 17 accounts for more than half the total patients in 18 this patient population. And then in apparently 19 two studies there were more dropouts for retarded 20 depression, so as I read this, my interpretation 21 is that with regard to discontinuations for 22 adverse experiences, it looks like across studies PAGE 182 1 random distribution. 2 Q Okay. Well, do you see where she says there 3 "IN SUMMARY there was a preference for 4 retarded patients treated with fluoxetine as 5 compared to fluoxetine agitated patients having 6 more significantly different efficacy parameters, 7 a better HAMD response and less early 8 discontinuations due to lack of efficacy"? 9 A I believe that is summarizing that first 10 paragraph that we discussed on the previous page. 11 Q Did you know that when you made your analysis of 12 Prozac and suicidality in -- 13 A No. 14 Q -- 1990? 15 A No. 16 Q It looks like Dr. Schenk then goes on and makes 17 some comparisons of significant differences in 18 efficacy between Prozac and placebo and 19 imiprimine. 20 A Where are we? 21 Q We're now on 1659. Section 11.5 (sic). Do you 22 see that? PAGE 183 1 A Yes. Qualitative Comparisons of Significant 2 Differences in Efficacy between Fluoxetine 3 and Placebo, Imiprimine, Amitriptyline, and 4 Doxepin. 5 Q All right. 6 A -- resp(ectively) with Regard to Agitated and 7 Retarded Subtypes. 8 Q Turn with me to Page 1660, the next page, where 9 she's comparing fluoxetine with imiprimine. Look 10 at the last sentence of the second paragraph 11 there where it says "In the group of patients who 12 were neither agitated nor retarded imiprimine was 13 superior to fluoxetine in decreasing the score of 14 the HAMD item suicidal tendencies which seems to 15 be pronounced in the early stages of treatment 16 (1/2 to 2 weeks)." 17 A Yes, I see that. 18 Q Did you know that that was her finding or did you 19 have any idea that that was her finding when you 20 made your suicidal review? 21 A No, I did not. 22 Q Turn with me to Page 1662 where she starts PAGE 184 1 talking about in 11 -- I mean in Section III.6, 2 Spectrum of Adverse Experiences which 3 Characterize Fluoxetine's Clinical Profile of 4 Action (Regardless of Severity). Do you see 5 that section? 6 A Yes, I do. 7 Q All right. Turn with me to Page 1663 where she 8 states specifically -- well, no, let's go back 9 and read the whole thing to get it in context. 10 Starting on the last paragraph of Page 1662, 11 "Those adverse experiences which were frequently 12 observed during treatment with fluoxetine and 13 were to be perhaps related to activation are 14 tabulated as well as those adverse experiences 15 which are known to frequently occur (sic) during 16 treatment with tricyclic antidepressants." 17 "On the one hand, those adverse experiences 18 were anxiety/nervousness, headache, insomnia, 19 nausea, excessive sweating and tremor. On the 20 tricyclic side, those side effects were 21 anticholinergic ones, dizziness/lightheadedness 22 and drowsiness/sedation." Do you see that? PAGE 185 1 A Yes. 2 Q Did you know that she had made a finding that the 3 adverse experiences that she puts under the 4 Clinical Profile of Action of Prozac were 5 anxiety/nervousness, headaches, insomnia, nausea, 6 excessive sweating and tremor when you did your 7 analysis of Prozac and suicide, Dr. Beasley? 8 A I was not aware of her finding but -- 9 Q Is that consistent -- 10 A But -- 11 Q -- with what you knew? 12 A But what I was going to say is that possibly with 13 the exception of the excessive sweating and 14 tremor, I think this is generally the way the 15 adverse events are described in the package 16 literature for Prozac. 17 Q All right. You see there where it says 18 anxiety/nervousness specifically? 19 A Yes. And she then makes reference to Table 10? 20 Q Right. She says in the second paragraph over 21 there "Overall, there is a definite trend that 22 more agitated than retarded patients report this PAGE 186 1 kind of side effect". Do you see that? It's the 2 second paragraph under Anxiety/Nervousness. 3 A "There is a definite trend that more agitated 4 than retarded patients" -- yes. 5 Q Then someone has written in there "but this would 6 be expected"; correct? 7 A That's correct. 8 Q Do you agree that you would expect to see more 9 anxiety and nervousness in agitated depressed 10 patients than retarded depressed patients? 11 A This is to me a very interesting area and an area 12 that I've looked at in again several of the 13 controlled clinical trials, both Protocol 27 and 14 then the large fixed-dose studies that we had 15 available as well. I can't comment on her 16 methodology. I find it fairly interesting that 17 she talks about a trend. These are not 18 inconsistent with my findings that slightly more 19 patients treated with fluoxetine who started off 20 agitated at baseline experienced more treatment 21 emergent activation than those who were neither 22 than those who were retarded. The thing that I PAGE 187 1 found quite interesting about that was it -- and 2 this was in a very well-analyzed large patient 3 database. I think the total number of patients 4 included in that began as a single study all 5 under the same protocol and I think was close to 6 700 patients. It did represent only a trend and 7 was not statistically significant. So it would 8 be consistent with people's preconceived notions. 9 I guess my sort of -- I was a little shocked that 10 it wasn't more pronounced than it was. 11 Q Well, you don't disagree with her observations, 12 do you? 13 A No, sir. I'm saying this is -- that I'm very 14 much agreeing with her. It's consistent with 15 data that I reported and know much more about the 16 details of the analysis of. 17 Q All right. Turn with me to Page 1666. You see 18 there where it says Summary? 19 A Yes, at the top. 20 Q She says "Fluoxetine does induce a different 21 spectrum of" adverse events -- "adverse 22 experiences as compared to the sedating tricyclic PAGE 188 1 antidepressants with usually more insomnia and 2 anxiety/nervousness (and nausea) and much less 3 anticholinergic side effects and dizziness, and 4 less drowsiness/sedation." Do you agree with 5 that statement, Dr. Beasley? 6 A I would word it somewhat differently in that I 7 would say "is associated with". I would place 8 nausea first and then I would refer to activation 9 to include insomnia, anxiety/nervousness. 10 Q Okay. But you don't have any qualm with her 11 summary of the clinical trial data? 12 A With -- no. 13 Q Now, turn with me to Page 1668 under the heading, 14 Choice Of An Antidepressant Depending Upon 15 Symptomatology. Do you see that? 16 A Yes, I do. 17 Q Do you agree that it is important to choose an 18 antidepressant based on symptomatology of the 19 patient? 20 A No, I don't. 21 Q Why? 22 A I am unaware of robust published data to suggest PAGE 189 1 that any given antidepressant is any more 2 effective or less effective in any particular 3 subtype of depression; that's one reason I say 4 that. The second reason has to do with the issue 5 of looking for medications that have improved in 6 an absolute sense profile of adverse events, 7 okay, so we have no drug, no one drug being 8 better than any other. In an overall sense we 9 have no really hard data that is consistent that 10 says a particular drug works better or not in a 11 given subtype of depression. 12 She -- I believe it's a she -- is reporting 13 that in some Prozac studies here in contrast to 14 what I've just said sort of that overwhelming -- 15 my personal overwhelming sense of the reading of 16 the data, so what it comes down to is choosing a 17 drug based on adverse event profile, total 18 adverse events. I believe that's where a 19 physician would work with a patient to make a 20 decision about specific medication selection. As 21 an example, the tertiary amine tricyclic 22 antidepressants imiprimine, amitriptyline, have PAGE 190 1 much more in the way of total adverse events 2 associated with them than the secondary amine 3 tricyclics nortriptyline, desipramine. They are 4 somewhat both groups of -- both of those groups 5 are fairly comparable at sort of severity in 6 numbers. 7 The class of drugs of serotonin reuptake 8 inhibitors would appear to have less total 9 adverse events associated with them. There are 10 clearly some patients for whom one -- 11 particularly if one's concerned with nausea -- 12 might well choose to avoid that class of 13 compounds. There are other classes with 14 different adverse event profiles. So what I'm 15 saying is I would choose a medication at this 16 point in time based on a particular patient's 17 interest and my own concern with adverse events. 18 Q All right. So can I boil down what you're saying 19 that since there is no real evidence that any one 20 antidepressant is any better at treating 21 depression, in relieving symptomatology of 22 depression, then it's reasonable for a doctor to PAGE 191 1 look at an antidepressant and make that selection 2 based on side effects that a particular 3 antidepressant might present? 4 A That's one very significant factor that he could 5 use, he or she could use. 6 Q And sometimes it might be the deciding factor? 7 A That would be correct. 8 Q And do you believe since you are an employee of a 9 drug company that a drug company, specifically 10 Eli Lilly, should give the physician as much 11 information as they have concerning a particular 12 side effect profile of a particular drug? 13 A Yes. 14 Q And specifically Prozac and its side effects? 15 A Yes. 16 Q Read with me then the third paragraph that 17 Dr. Schenk at Lilly in Germany states. She says 18 "Since fluoxetine is less sedating than 19 amitriptyline and doxepin, the concomitant intake 20 of a benzodiazepine is recommended in those 21 patients (of mostly agitated subtype) who should 22 be tranquillized." Do you see that? PAGE 192 1 A Yes, I do. 2 Q Were you aware of that recommendation by her -- 3 A No, I wasn't. 4 Q -- when you made your analysis of Prozac and 5 suicidality? 6 A No, I was not. 7 Q Read with me the last paragraph which Dr. Schenk 8 states in connection with the choice of an 9 antidepressant depending on symptomatology where 10 she states "Precautions which have to be 11 considered in patients at serious suicidal risk 12 will be discussed in the paragraph 'Suicidal 13 Tendencies, Suicides and Suicide Attempts during 14 Fluoxetine Treatments'." Do you see that? 15 A Yes, I do. 16 Q So it appears here that she's going to address 17 the issue specifically in a specific heading 18 later on in this paper, doesn't it? 19 A That would appear to be the case. 20 Q All right. Her area where she discusses suicidal 21 risk begins on Page 1691, does it not? 22 A Yes, it does. PAGE 193 1 Q Did you ever see this analysis? 2 A No, I have not. 3 Q And in doing your work in connection with whether 4 or not Prozac and suicide presents a -- whether 5 Prozac presents a risk of suicide? 6 A No, I have not. 7 Q Look at the fourth paragraph on Page 1692. She 8 says in there "Thus, attempted or successful 9 suicides were observed in 1 out of 71 patients on 10 amitriptyline, 12 out of 1352 patients on 11 fluoxetine, 0 out of 134 doxepin patients, 0 out 12 of 394 patients on imiprimine and 0 out of 378 13 patients on placebo (post-randomization)"; 14 correct? 15 A That is a -- that is a correct quote. 16 Q I mean is that your recollection of what that 17 data is, reveals in connection with those studies 18 that she looked at? 19 A Again, I don't know the details of any of the 20 analyses that led her to these numbers. 21 Q But these numbers aren't surprising to you, are 22 they, or are they? PAGE 194 1 A Attempts or successful suicides. I believe that 2 they are -- and, again, since we have said that 3 we're looking at relatively speaking a relatively 4 comparable set of studies with possibly some 5 differences but a lot of them in common, I'm not 6 sure to what extent these agree with our findings 7 with regard to attempts. 8 Q In the last paragraph -- well, she goes on after 9 that. It says "The issue of suicidal tendencies 10 during treatment with an antidepressant has to be 11 taken very seriously. Therefore, a careful 12 analysis of respective patients' data was 13 performed." Do you see that? 14 A Yes, I do. 15 Q Do you agree with the fact that suicidal 16 tendencies should be taken seriously and that a 17 careful analysis should be made, don't you? 18 A Extremely seriously. 19 Q She goes on to say "The above mentioned table 20 demonstrates that the successful suicide and 3 21 attempts...occurred in the early stage of 22 treatment up to day 20, where psychomotor PAGE 195 1 activating effects might well be present at a 2 time when the full mood-elevating effects are not 3 yet evident"; correct? 4 A That's correct. 5 Q And is that again a discussion of the theory that 6 you had mentioned to us earlier that there is a 7 body of thinking that one risk inherent in 8 suicidality in depressed patients is that a 9 particular antidepressant may create a 10 psychomotor activation before its antidepressant 11 activity sets in and thus lead to increased risk 12 of suicide in the patient? 13 A Let me offer a slight modification of what you've 14 just stated, that there is a body of thinking 15 that believes that antidepressants in general 16 first modify psychomotor activity status. They 17 allow patients to become more activated. They 18 may activate them, but they may simply take a 19 patient from a retarded state to a state of 20 neutral psychomotor activity but increase the 21 ability to act. That change in the individual 22 comes before a change in mood and cognition in PAGE 196 1 suicidal thinking and that if you get this, the 2 patient is more prone to suicide in that 3 particular period. If you increase the 4 psychomotor activity level, and this is sort of 5 consistent with thinking that most depression is 6 retarded, okay, that you eliminate the 7 retardation, but you've still got the depressed 8 mood, then people can act. 9 Q And isn't that particularly a concern with 10 respect to Prozac because it's not a sedating 11 antidepressant; it is more activating generally 12 in a number of individuals than the other 13 antidepressants? 14 A Some people have raised that as a theoretical 15 concern. I think good -- good support for that 16 being raised as a theoretical concern was the 17 German document that we looked at in the last 18 deposition. 19 Q This is reflective of that, also? 20 A I think that that's what she is discussing. 21 Q And the majority of the scientists at Lilly now 22 consider Prozac as an activating antidepressant, PAGE 197 1 don't they? 2 A I think earlier you had suggested to me that they 3 characterize it as nonsedating. I characterize 4 it as both activating and sedating, and clearly 5 right in the package literature there is the 6 indication that nervousness and anxiety occur as 7 prominent adverse events. 8 Q Okay. And nervousness and anxiety are evidence 9 of activation, are they not? 10 A Are manifestations of psychomotor activation. 11 Q Okay. Look at the last sentence of that page in 12 this suicide analysis on Page 1693. She says "On 13 the other hand, imiprimine was significantly 14 better than fluoxetine" -- 15 A Excuse me, where? Let me just see where we are 16 here. We're on page -- which, sir? 17 Q 1693, last sentence. 18 A Oh, last sentence of the page, okay. 19 Q "On the other hand, imiprimine was significantly 20 better than fluoxetine in both the in- and 21 out-patient studies in reducing the HAMD item 22 suicidal tendencies in the early stages of PAGE 198 1 treatment ('neither' patients and 'neither' and 2 all patients" responding -- or "resp(ectively). 3 The same was true for doxepin after 1 week of 4 active treatment (all patients)." Do you see 5 that? 6 A Yes, I do. 7 Q Were you aware of her finding in that regard in 8 your analysis of Prozac and whether or not it 9 presented a potential for suicidality? 10 A I was not aware of these findings. We looked at 11 all of the tricyclics compared and looked at both 12 improvement and worsening. 13 Q All right. Look on Page 1695. 14 A (Witness complies). 15 Q She says "From the number of suicides/suicide 16 attempts during clinical trials with fluoxetine 17 and the time on trial when they happened, a 18 higher incidence of suicide attempts during 19 treatment with this antidepressant cannot be 20 derived. 21 On the other hand, the HAMD factor suicidal 22 tendencies might be more improved by sedating PAGE 199 1 antidepressants at the early stage of treatment, 2 although fluoxetine is of course significantly 3 better than placebo. 4 These findings underline the dogma that - if 5 at all - activating antidepressants should only 6 be used with caution in suicidal patients, at 7 best with concurrent administration of sedating 8 drugs. The latter can be omitted at the time of 9 sufficient elevation of depressive mood." 10 Do you agree with those statements, 11 Dr. Beasley? 12 A Let me carefully consider the three paragraphs. 13 I believe that I understand the first paragraph 14 to mean that given the data, she can't say that 15 fluoxetine is associated with more suicidality. 16 Q No. I think she's saying she can't understand 17 why there was a higher incidence of fluoxetine 18 than the other antidepressants. 19 A No. 20 MR. MYERS: Let me object to the 21 form and Mr. Smith's characterization of what it 22 means. PAGE 200 1 MR. SMITH: Well, I object to his 2 characterization of what it means. It means what 3 it says. 4 MR. MYERS: Well, you asked him and 5 he answered the question. 6 MR. SMITH: No. He's trying to 7 explain it paragraph by paragraph when I simply 8 asked him "Do you agree or disagree". 9 MR. MYERS: Well, Dr. Beasley, you 10 may look at as much or as little of that document 11 as is necessary to answer the question and do not 12 feel constrained in how you go about doing it if 13 you can answer it. 14 A I'm not sure what the first paragraph -- I mean I 15 think I know what the first paragraph says. When 16 she refers to "derived", I interpret that to mean 17 the same thing as "established", "confirmed", 18 "supported". The second paragraph referring to 19 the HAMD analysis of suicide, I have never looked 20 at -- we did not look at the data on an early 21 week basis. I believe we looked at worst cases 22 for worsenings at endpoint for improvement, so I PAGE 201 1 cannot confirm or refute her analysis there. 2 Q She made a different analysis than you did? 3 A That would be my understanding from it. And 4 again we haven't seen tables or methods or 5 anything. I would take the last paragraph. 6 There are components of the last paragraph that I 7 agree with or generally I think that with any 8 suicidal patient you need to be very careful with 9 your antidepressant therapy, okay, particularly 10 if you see a patient who is becoming activated. 11 Q All right. Do you agree in that instance that 12 that patient should have concomitant 13 tranquillizer administration? 14 A From the -- from the outset of treatment? Not 15 necessarily. 16 Q No. When you said that the psychiatrist sees 17 activation, should the psychiatrist put the 18 patient on an anti -- on a tranquillizer? 19 A Under -- you're saying any patient who has 20 activation? 21 Q I'm trying to phrase it as you did, sir. 22 A Okay. With a patient who is suicidal and who at PAGE 202 1 baseline some degree of significant suicidal 2 ideation and who becomes activated in temporal 3 association with therapy, I think that the 4 psychiatrist should consider the potential for 5 needing to add a benzodiazepine. That can vary 6 from case to case to case. There are many 7 alternatives. Perhaps the patient should be 8 hospitalized. Perhaps the patient should be 9 placed under close monitoring. Those are a 10 number of options. I would agree that one of 11 those options that should be strongly considered 12 would be addition of a benzodiazepine. 13 Q Well, let me see if you agree. She says here: 14 "... - if at all - activating antidepressants 15 should only be used with caution in suicidal 16 patients". Do you agree with that? 17 A I don't agree with the "if at all". 18 Q All right. Would you agree with "activating 19 antidepressants should only be used with caution 20 in suicidal patients, at best with concurrent 21 administration of sedating drugs"? 22 A I don't agree with what I read to be a mandatory PAGE 203 1 use of sedating -- concomitant use of sedating 2 drugs. 3 Q Would you agree that an activating antidepressant 4 is more likely to present a risk of suicide to a 5 patient who is depressed? 6 A I don't -- I don't have any evidence to support 7 that position. I've got this hypothesis and this 8 dogma. 9 Q All right. Do you disagree with that then, that 10 an activating antidepressant is more likely to 11 increase the risk of suicidality in a depressed 12 suicidal patient? 13 A Could you restate it once again for me? 14 MR. SMITH: Could you read it back 15 to him. 16 (The previous question was read back by 17 the reporter.) 18 A As a categorical absolute statement, I disagree 19 with it. If the patient does become activated, 20 it may increase the risk for suicidality. 21 Q All right. Is there anywhere in the Prozac 22 prescribing information that statement that you PAGE 204 1 just expressed? 2 A No. 3 Q Do you agree that in some patients that 4 concomitant use of sedatives will reduce the 5 chance that they will become activated and thus 6 reduce the chance of suicidality on those 7 patients' part? 8 A Let me address I think two parts of your 9 question. I would agree that given the intended 10 action of a sedative hypnotic that it would 11 reduce -- it's intended to reduce hopefully, it 12 might not in all cases -- reduce psychomotor 13 activation seen in a patient who is 14 psychomotorically activated for whatever reasons. 15 Now, so that's -- I'm -- 16 Q So you would agree with that? 17 A I'm agreeing with that part, okay. Perhaps not 18 in all cases, but it's intended to do that. Now, 19 the issue does that further reduce the risk of 20 suicidality, I don't know. I don't know what the 21 empirical data are that support or don't support 22 that. PAGE 205 1 Q That's what she's saying here, isn't it? 2 A That's based on this hypothesis or this dogma as 3 she refers to it that if you do psychomotorically 4 depress a patient that that reduces the risk of 5 suicidality. 6 Q That scientific theory is still held by a number 7 of well-known, well-respected psychiatrists, is 8 it not? 9 A I don't know who specifically holds to that or 10 not. 11 Q Well, it hasn't fallen in disfavor since this 12 Lilly physician wrote it in 1984, has it? 13 A Not that I'm aware of, no. 14 Q It's still a significantly valid principal to 15 this day? Whether it be right or wrong, it's a 16 scientifically valid hypothesis? 17 MR. MYERS: Let me object to the 18 form. Go ahead. 19 A I would agree with you that it is a scientific 20 hypothesis or a clinical hypothesis. 21 Q Based on some scientific validity? 22 A I don't know what hard empirical data support PAGE 206 1 that. 2 Q Well, you know that it is supported by some 3 scientists who have examined this issue, don't 4 you? 5 A I know that people have written -- I know that 6 eminent clinicians have written about this. 7 Q And observed this phenomenon? 8 A I assume that they believe that they observed 9 this, that they observed some temporal 10 association between activation in their depressed 11 patients and suicidality. That would be my 12 speculation with regard to the basis for writing 13 this as a hypothesis. 14 Q At some time in the past the scientific community 15 believed that the world was flat, didn't they? 16 A I'm not sure that that was the scientific -- 17 people did, yes, sir. 18 Q Well, people. 19 A That's true. 20 Q Holding themselves out as being knowledgeable in 21 this particular area; correct? 22 A With regard to the -- PAGE 207 1 Q -- the world being flat. 2 A Yes, sir, I believe that's the case. 3 Q That scientific hypothesis was held for a number 4 of years, wasn't it? 5 A I believe it was. 6 Q And that scientific hypothesis was the majority 7 of opinion for a number of years, wasn't it? 8 A From my understanding of history, that's the 9 case. 10 Q They were wrong as rain, weren't they, or wrong 11 as dirt? They were wrong, weren't they? 12 A Sir, I believe so. 13 Q The world is round, not flat, isn't it? 14 A That's correct. 15 Q It looks flat if you look out this window, 16 doesn't it? 17 A Especially in Indiana. 18 Q Especially in Indiana. It may be flatter in 19 Indiana, but it would be round totally, isn't it? 20 A That's correct. 21 Q So what the prevalent scientific opinion is at 22 any time doesn't necessarily mean it's the PAGE 208 1 accurate scientific opinion? 2 A I agree with that, yes. 3 Q Probably those scientists back in Galileo's time 4 who felt that the world was flat had what they 5 thought was good scientific basis for that 6 opinion, didn't they? 7 A Presumably they did. 8 Q Well, I mean it looks flat, doesn't it? 9 A (Affirmative nod). 10 Q Doesn't it? 11 A (Affirmative nod). 12 Q You have to give an audible answer. 13 A Excuse me? 14 Q You have to give an audible answer. 15 A Oh, yes. 16 Q You walk and it continues to appear to be flat? 17 A Let me look. Yes. 18 Q So the point I'm making is just because something 19 is in the scientific majority doesn't make it 20 right 100 percent of the time, does it? 21 A No. 22 Q Wouldn't you say this would be especially true in PAGE 209 1 an area so complicated and so complex as 2 neurotransmission, neurobiology, 3 psychopharmacology and psychiatry in the inner 4 workings of the human brain, Dr. Beasley? 5 A I guess I would agree with you. I would say that 6 there is a great deal that's not known. 7 Q Look at Dr. Schulze-Solce's opinions beginning on 8 Page 1696 which she characterizes as summarizing 9 her opinions. 10 MR. MYERS: You mean Dr. Schenk? 11 MR. SMITH: I'm sorry, Dr. Schenk. 12 Q Do you see where that begins? 13 A Begins on the bottom of the page? 14 Q Yes. She says starting off "Fluoxetine is a new 15 antidepressant which is pharmacologically a 16 selective serotonin reuptake inhibitor. 17 Treatment with antidepressants of specific action 18 might be advantageous in the near future when 19 routine methods may be available to determine 20 deficiencies in distinctive transmitter systems"; 21 correct? 22 A That's correct. PAGE 210 1 Q It appears to me that what she's saying is we're 2 going to be better able and better equipped to 3 prescribe a drug like Prozac when we're better 4 able and better equipped to measure these 5 deficiencies in neurotransmission systems. 6 MR. MYERS: Object to the form. 7 Q Do you agree with that? 8 MR. MYERS: Object to the form. 9 It's speculation. 10 Q That's a reasonable interpretation of what she 11 says there, isn't it? 12 MR. MYERS: Same objection. 13 A I could interpret this paragraph in potentially 14 several ways. The way that I read the paragraph 15 is to suggest that fluoxetine or at least -- let 16 me think. I think she is making a categorical 17 statement about highly selective antidepressants 18 in general, of which fluoxetine is a 19 representative, could be even more useful than 20 the sort of things that are not highly selective 21 and specific if we arrive at a time when we could 22 understand what biochemical level causes PAGE 211 1 depression, subtype patients from a biochemical 2 perspective and have indicators that certain 3 biochemical deficiencies could be assessed with 4 relatively noninvasive laboratory methods or 5 associated with higher degrees of response. 6 Q Well, isn't that basically what I said, too, 7 Dr. Beasley? 8 A Well, I think the other potential interpretation, 9 you know, here is to say that they would be 10 simply useful when we have those methods. 11 Q All right. Or more useful? 12 A That's my interpretation, yes, sir. 13 Q All right. Turn with me to the last page of 14 Dr. Schenk's analysis and summary. 15 A (Witness complies). 16 Q Third from the last paragraph. "Fluoxetine's 17 characteristics side effects are those of mildly 18 activating antidepressants, i.e., 19 anxiety/nervousness, insomnia, nausea, and cause 20 much fewer early discontinuations than the 21 typical adverse experiences of standard 22 antidepressants (mouth dryness, constipation, PAGE 212 1 blurred vision, urinary retention)"; correct? 2 A That's correct. 3 Q Do you agree with that summary? 4 A Yes, I do. 5 Q Okay. Her last paragraph in her summary says "If 6 the drug is used according to the revised package 7 literature"; that is, "in agitated and suicidal 8 patients only together with concomitant sedative 9 drugs, there should be no doubt on fluoxetine's 10 positive benefit/risk ratio in the treatment of 11 depression." Do you see that? 12 A Yes, I do. 13 Q Do you agree with that? 14 A I'm sorry, but again from my perspective, 15 absolute mandatory concomitant use of a sedative 16 hypnotic in a patient with some degree of 17 suicidal thinking across the board is not 18 obligatory. 19 Q Well, apparently what she's saying here is that 20 there is package literature that's been revised 21 that is going to require that in agitated and 22 suicidal patients Prozac be used only together PAGE 213 1 with concomitant sedative drugs; correct? 2 MR. MYERS: Object to the form. You 3 can go ahead. 4 A There is a mention of some revised -- I mean 5 obviously it's in the first and second line, 6 revised literature. 7 Q Sure it is. 8 A I'm not sure specifically what she's referring to 9 here. 10 Q Well, you know that the German package literature 11 now -- 12 A You showed -- 13 Q -- suggests use of tranquillizers and sedatives 14 in irritable and suicidal patients, don't you? 15 A As I'm recalling now, we really -- 16 Q Or excitable and suicidal patients? 17 A You showed me I believe that package literature 18 in the last deposition. I don't recall the 19 specific wording, but it did make recommendations 20 of using them in some patients with some 21 symptoms. 22 Q That's what she is making recommendations of, PAGE 214 1 too, isn't it? 2 A I think she is making -- she's referring to 3 agitated and suicidal patients. 4 Q Right. 5 A I don't know whether that means either/or or both 6 but -- 7 Q Well, the use of the word "and" usually includes 8 both of them, doesn't it? 9 A Both. 10 Q Doesn't it? 11 A Yes. 12 Q She's saying there that there is no doubt that 13 Prozac will have a positive benefit/risk ratio in 14 the treatment of depression if the drug is used 15 in accordance with the package literature, that 16 is, in agitated and suicidal patients only 17 together with concomitant sedative drugs, isn't 18 she? 19 MR. MYERS: Object to the form. 20 A That's her statement. 21 Q I read it word for word what she's saying. I 22 just turned it around a little bit to say the PAGE 215 1 same thing, didn't I? 2 A Yes, sir. 3 Q No difference in the meaning of the way I said it 4 either, is there? 5 A No, sir. 6 Q She's saying to paraphrase her "This is going to 7 be a good drug for depressed people if it gets 8 administered in agitated and suicidal patients 9 only with concomitant sedative drugs"; correct? 10 MR. MYERS: Object to the form. Go 11 ahead. 12 A The way I would read this, that's the opinion 13 that she's stating here. 14 Q Did you know this was her opinion when you did 15 your work on the issue of whether or not Prozac 16 and suicide were related? 17 A No, I did not. 18 Q Did you talk to Dr. Wernicke or Dr. Weinstein or 19 Dr. Zerbe who were recipients of this document 20 concerning her opinion in that regard? 21 A No, not that I'm aware of. 22 Q Did you talk with Dr. Zerbe and Dr. Weinstein PAGE 216 1 about your study and what your results were 2 showing? 3 A Certainly to Dr. Zerbe on a number of occasions 4 and I believe to Dr. Weinstein. 5 Q Did you ever know when you did your study that 6 any Lilly employee had recommended the use of 7 Prozac in agitated and suicidal patients only 8 with concomitant tranquillizer use? 9 A No, I did not. 10 Q Do you know if this draft of this response to the 11 BGA was ever sent to the United States Food and 12 Drug Administration? 13 A I wouldn't have any knowledge of whether this was 14 submitted or not, sir. 15 (A brief recess was taken for the reporter 16 to change paper.) 17 Q You sat in on a number of discussions with 18 Lilly's employees and FDA employees concerning 19 the subject of Prozac and suicide, didn't you, 20 Dr. Beasley? 21 A Yes. 22 Q And you heard a lot of interchange between those PAGE 217 1 employees concerning this subject, didn't you? 2 A Yes. 3 Q And you heard Dr. Zerbe make statements about it, 4 didn't you? 5 A I'm virtually certain that Dr. Zerbe was in a 6 number of meetings that I attended. 7 Q Did you ever hear Dr. Zerbe tell anybody at the 8 FDA that one of their employees was making a 9 response to the BGA where the conclusion was, 10 such as Dr. Schenk has concluded here, that there 11 would be a positive benefit/risk ratio in this 12 drug if this drug was used in agitated and 13 suicidal patients only together with concomitant 14 sedative drugs? 15 A I can't recall hearing -- I can't recall hearing 16 any statements like that. 17 Q You never heard Dr. Zerbe tell anybody at the FDA 18 that, did you? 19 A Not that I recall, sir. 20 Q Did you ever hear any discussion initiated by 21 Dr. Zerbe concerning the propriety or impropriety 22 of some kind of recommendation of concomitant PAGE 218 1 sedative medication in this group of individuals 2 that was the subject of these meetings between 3 you people at Lilly and the Food and Drug 4 Administration concerning these people that had 5 been described by Dr. Teicher who were becoming 6 suicidal while being treated with Prozac? 7 A I'm sorry, but I got lost in the question. I 8 think what you asked me again was: Do I have any 9 knowledge of any communication to the FDA by 10 Lilly with regard to concomitant benzodiazepine 11 or sedative hypnotic administration. 12 Q And whether that would reduce the risk of suicide 13 in -- risk of suicide in suicidal or agitated 14 patients? 15 A I can't recall any specific discussion of 16 benzodiazepines with the Food and Drug 17 Administration. It may have occurred, but I 18 can't recall any. 19 Q You certainly don't recall any conversations 20 concerning Dr. Schenk's opinion being relayed on 21 to Dr. Leber or Dr. Laughren or Dr. Temple at the 22 United States Food and Drug Administration? PAGE 219 1 A No, I do not. 2 Q And they were all present at one time or other in 3 these meetings? 4 A Leber, Temple, Laughren, yes. 5 Q Was there ever any discussion, Dr. Beasley, in 6 connection with this issue of prospective trials, 7 of whether or not to do a prospective trial and 8 put somebody at risk on concomitant tranquillizer 9 medication and Prozac and see how they did? 10 A Was there ever -- let me just make sure I 11 understand the question. Was there ever any 12 discussion of a prospective trial with the 13 combination of Prozac and a benzodiazepine to 14 specifically assess suicidality? 15 Q Yes. You know, you were discussing the issue of 16 prospective trials with the FDA for a number of 17 months, weren't you? 18 A There were several discussions with the FDA, 19 actually one, one specifically that I recall -- 20 well, two, I guess -- and then a lot of the 21 discussions certainly within Lilly. I don't 22 recall one specifically. I don't recall any PAGE 220 1 discussion specifically to look at the 2 combination issue, combination of fluoxetine plus 3 a benzodiazepine. 4 Q Would that be a legitimate scientific inquiry, 5 Dr. Beasley? 6 A That would be a legitimate scientific inquiry 7 with regard to the issue of reducing suicidal 8 potential I would think. 9 Q All right. 10 A Okay. My initial thought as we sort of sit here 11 and talk about design issues would be that from 12 the prospective of the issue of induction of 13 suicidality, it would be less of an appropriate 14 approach. 15 Q Well, Dr. Montgomery did a prophylaxis study in 16 England, did he not, sponsored by Eli Lilly and 17 Company? 18 A Yes. 19 Q And in that study -- 20 MR. MYERS: Finish your answer, 21 Dr. Beasley. 22 MR. SMITH: I would assume that PAGE 221 1 answer could just simply be answered yes or no. 2 MR. MYERS: It might or might not 3 have. Finish your answer. 4 MR. SMITH: Tell me how it could be 5 answered any way other than yes or no. 6 MR. MYERS: I'm not here to answer 7 your questions, Paul. Finish your answer, 8 Dr. Beasley. And then ask him another question. 9 A I'm sorry. What I was going to say was it was a 10 prophylaxis of parasuicidal behaviors, suicidal 11 behaviors in personality disordered patients. 12 Q Do you know Dr. Montgomery -- they administered 13 Prozac in that study, didn't they? 14 A That's correct. 15 Q And they administered one other comparator drug 16 in that study? 17 A I believe the comparator was placebo. 18 Q Well, they administered another antidepressant 19 did they not, didn't they, Mansurin (phonetic)? 20 I don't know how to spell it, do you, Doctor? 21 A The drug you're referring to is my answer, and I 22 believe that the study was placebo-controlled or PAGE 222 1 had been my answer in studies conducted in 2 Europe. I could be incorrect, sir, but that was 3 my understanding. 4 Q Well, in your defense I've probably seen a study 5 summary since you have and I don't have it and I 6 don't want to be unfair to you, so regardless of 7 whether or not there was a comparator drug, that 8 drug didn't show any efficacy of Prozac in 9 preventing suicide in those personality 10 disordered patients, did it? 11 A That's my understanding of the outcome of the 12 study. 13 Q And that study do you know, sir, whether it used 14 tranquillizer medications such as is recommended 15 by your Lilly affiliates? 16 A I don't know what concomitant medications were or 17 were not allowed in that protocol. 18 Q Would you have any objections as a senior Lilly 19 clinical research physician, Dr. Beasley, in 20 package literature which indicated that in some 21 patients who may be agitated or suicidal, those 22 patients should be given concomitant sedative PAGE 223 1 medication during the initial stages of 2 treatment? 3 MR. MYERS: Objection as to form. 4 Go ahead. 5 A You are -- let me be very precise in my 6 understanding of the question. You first asked 7 would I have any as a -- would I have any 8 objection -- 9 Q -- as a senior Lilly clinical research physician. 10 A Okay. Then you said to some patients? 11 Q Yes. 12 A Okay. And you stated that this would be a 13 recommendation, not a mandate? 14 Q Yes. 15 A Okay. So with my understanding that it is not 16 all patients and that it is not a mandate, a 17 requirement, I would not have objection to that 18 being included on clinical grounds. 19 Q Are you aware of any instances in which it was 20 the opinion of the clinical investigator that 21 Prozac had caused a psychotic episode? 22 A I am not aware of any -- I can't recall any PAGE 224 1 communications at this point right now that would 2 have indicated that a clinical investigator 3 believed that Prozac induced a psychotic episode. 4 (Plaintiffs' Deposition Exhibit 27 was 5 marked for identification.) 6 A I've read the document, Exhibit 27. 7 Q Exhibit 27 -- 8 A Yes. 9 Q -- is a document dated February 19th, 1982, is it 10 not? 11 A Yes, it is. 12 Q And it concerns a patient in a clinical trial, 13 does it not? 14 A Yes, it does. 15 Q Who had had an adverse experience while on 16 Fluoxetine; correct? 17 A That's correct. 18 Q Who was being treated by Dr. David Dunner? 19 A That's correct. 20 Q Dr. David Dunner was this patient's psychiatrist? 21 A That's correct. 22 Q Dr. David Dunner was the Lilly investigator at PAGE 225 1 the clinical trial, was he not? 2 A I would assume so, yes. 3 Q And Dr. David Dunner is a member of the Lilly 4 Psychiatric Advisory Board, is he not? 5 A That's correct. 6 Q And does that document in the middle paragraph of 7 Page 2 indeed say "Dr. Dunner and (blank) both 8 believe the psychotic episode is 'probably drug 9 related' due to the course of the symptoms"? 10 A Yes, it does. 11 Q Apparently Dr. Dunner considered "the patient's 12 wife report of subtle signs of reaction during 13 the first six days of drug; the culmination into 14 an acute episode on the seventh day of therapy; 15 and the gradual resolution of symptoms upon 16 discontinuation of therapy"; correct? 17 A That's correct. 18 Q Do you believe those are valid factors for a 19 clinical investigator, a psychiatrist to take 20 into account in determining whether or not a 21 particular incidence is related to a particular 22 drug? PAGE 226 1 A Yes. 2 Q It appears what Dr. Dunner was considering was 3 the fact that a subtle reaction occurred within a 4 short time of the time that the drug was given; 5 correct? 6 A That would be my interpretation from what's 7 written here, yes. 8 Q And the fact that this became an acute episode on 9 the seventh day of therapy; correct? 10 A That's correct. 11 Q Looks like he's considering the relationship of 12 the event to the time within which the drug was 13 given. 14 A That would appear to be one of the things that he 15 has taken into consideration here. 16 Q And important to him was the gradual resolution 17 of symptoms upon discontinuation of therapy; 18 correct? 19 A That's correct. 20 Q And then the letter concludes by saying "After 21 discharge, the patient was seen again by 22 Dr. Dunner on February 17. The patient was not PAGE 227 1 depressed, had good morale and was complaining 2 only of occasional headaches. He had no further 3 confusional episodes"; correct? 4 A That's correct. 5 Q Of course, this was all after he'd been taken off 6 Prozac, wasn't it? 7 A That's correct. 8 Q Are you aware of the study done by Dr. Seymour 9 Fisher at the University of Texas Medical Branch 10 in Galveston, Texas concerning a postmarketing 11 surveillance by patients self-monitoring 12 Trazodone versus Fluoxetine? 13 A Yes, I am. I do know of the paper. 14 Q The Department of Psychiatry in Behavior Sciences 15 is a recognized body at the University of Texas 16 medical Branch at Galveston, is it not? 17 A That's correct. 18 Q The University of Texas Medical Branch at 19 Galveston is a well-recognized medical facility, 20 is it not? 21 A I would believe that it is. 22 Q I mean, they don't have sloppy doctors down PAGE 228 1 there, do they as far as you know? 2 A I don't personally know the reputation or the 3 practice patterns or the qualifications of their 4 doctors, but it's an academic medical center. 5 Q You've never heard any criticism of their 6 psychiatrists there, have you? 7 A No. 8 Q Now, this study that Dr. Fisher did wasn't a 9 study that was funded by Lilly, was it? 10 A I don't believe so. 11 Q He came to you asking for assistance, but it was 12 refused by Lilly, wasn't it? 13 A I believe that I have some recollection of that, 14 yes. 15 Q All right. And he went ahead with his study and 16 compared Prozac and Trazodone; correct? 17 A That's correct. 18 Q Now, he did that in a -- not a double-blind 19 placebo-controlled way, did he? 20 A Far from it. 21 Q What he did is he sent questionnaires out to 22 patients taking the medication through their PAGE 229 1 pharmacy; correct? 2 A I believe that it was through one of the 3 prescribing services or one -- he had access to 4 who had gotten prescriptions through -- it was 5 either through one pharmacy chain or one mail-in 6 prescription service. 7 Q I believe it was Eckerd's Pharmacy. Are you 8 familiar with Eckerd's Pharmacy? 9 A I'm familiar with the name. 10 Q It's big in Texas and the southwest. 11 A So it was a chain as opposed to a mail-in 12 service? 13 Q Yes, that's my understanding. But you're aware 14 of the methods he went through? 15 A That's correct. 16 Q And asked the patients to call a specific number 17 if they had a side effect, didn't he? 18 A I don't recall the details of how the patients 19 were to report. 20 Q Your general understanding though was that -- 21 A They had some method. 22 Q And then that patient would talk to an PAGE 230 1 interviewer and the interviewer would elicit what 2 particular -- elicit and record a particular side 3 effect; correct? 4 A Again, my understanding is that he had some way 5 of eliciting from patients adverse events during 6 treatment. The specifics of that I'm not 7 familiar with. 8 Q You're aware that in that study two patients on 9 Trazodone and 19 patients on Prozac reported 10 suicidal ideation, aren't you? 11 A I was aware that there was -- there were more 12 reported with Fluoxetine or Prozac at that time 13 than with Trazodone. 14 Q And that there was a statistical formula placed 15 in that 2 versus 19 figure because there were in 16 all honesty a larger number of people on Prozac 17 than there were on Trazodone that responded; 18 you're aware that he attributed some statistical 19 connotation in that 2 versus 19, aren't you? 20 A I believe he did. I don't recall. I think that 21 that difference was statistically significant, 22 but I don't recall absolutely whether it was or PAGE 231 1 not. 2 Q Is a Fisher exact P of .0784 statistically 3 significant? 4 A P .0784? 5 Q Yes. 6 A Generally we consider -- it sounds like I was in 7 error. Generally we consider statistical 8 significance to be P less than or equal to .05. 9 Q So that would be of a -- 10 A If it was greater than .05, it would not be 11 statistically significant, and I think you said 12 it was .07 something. 13 Q Yes. Well, there was three times using 14 percentage greater people who reported suicidal 15 ideation on Prozac than they did on Trazodone? 16 A In this particular study. 17 Q Yes. 18 A And -- 19 Q That would be statistically significant? 20 A I think -- well, again I'm not looking at the 21 paper. 22 Q I don't have another copy. That's the only PAGE 232 1 reason I hadn't shown you this. I know you've 2 seen it. 3 A Yes. 4 Q Can I come around and look at it with you? 5 A Let's look at it here. That's interesting that 6 he did a one-tail test instead of a two-tail 7 test. You usually do two-tail to be most fair. 8 And let's see what the Fisher is. Okay. That's 9 not generally considered statistically 10 significant. It would have to be .050 or .049 or 11 .00 something. 12 Q But isn't it three times greater in the Trazodone 13 patients than in the -- I mean three times 14 greater in the Prozac patients than in the -- 15 A The numeric rate I would agree with you is. It's 16 a little bit over three, yes, sir. 17 Q Yes, when you're looking at percentages, it's 18 more than three times? 19 A Just a fraction over, yes, sir. 20 Q But you say that's not statistically significant? 21 A Well, I'm assuming -- and, again, this is -- 22 Q Do you know what a one-tail Fisher probability PAGE 233 1 is? 2 A It's one statistical -- it's one form of 3 statistical test used to look at relatively 4 infrequently occurring events amongst large 5 populations of individuals, so across all of the 6 statistical tests the general convention for 7 statistical significance is P less than or equal 8 to .05. 9 Q Okay. Okay. Well, I'm going to have to take 10 your word for it because I can't do exact tails. 11 I'm only in dumb tails when I start talking about 12 Fisher probabilities. I'm just not going to talk 13 with you on those lines if you're going to get 14 into that. 15 MR. MYERS: Paul, it's after 5:00 16 and we have an agreement to quit at 5:00. 17 (A discussion was held off the record.) 18 MR. SMITH: I'm done. Thank you, 19 Dr. Beasley. 20 AND FURTHER THE DEPONENT SAITH NOT. 21 ----------------------------- 22 CHARLES M. BEASLEY, JR., M.D. PAGE 234 STATE OF INDIANA ) ) SS: COUNTY OF MARION ) I, Linda M. Bour, a Notary Public in and for the County of Marion, State of Indiana at large, do hereby certify that CHARLES M. BEASLEY, JR., M.D., the deponent herein, was by me first duly sworn to tell the truth, the whole truth, and nothing but the truth in the aforementioned matter; That the foregoing continued deposition (Volume II) was taken on behalf of the Group of Plaintiffs at the offices of Baker & Daniels, 300 North Meridian Street, Suite 2700, Indianapolis, Marion County, Indiana, on the 30th day of August 1994, commencing at the hour of 9:10 a.m., pursuant to the Applicable Rules of Civil Procedure; That said deposition was taken down in stenograph notes and afterwards reduced to typewriting under my direction, and that the typewritten transcript is a true record of the testimony given by said deponent; and thereafter presented to said deponent for his signature; That the parties were represented by their PAGE 235 aforementioned counsel. I do further certify that I am a disinterested person in this cause of action; that I am not a relative or attorney of either party, or otherwise interested in the event of this action, and am not in the employ of the attorneys for either party. IN WITNESS WHEREOF, I have hereunto set my hand and affixed my notarial seal this _____ day of _____________ 1994. _______________________________ N O T A R Y P U B L I C My Commission Expires: June 19, 1996 County of Residence: Marion