1 1 NO. 90-CI-06033 JEFFERSON CIRCUIT COURT DIVISION ONE 2 3 4 JOYCE FENTRESS, et al PLAINTIFFS 5 6 VS TRANSCRIPT_OF_THE_PROCEEDINGS __________ __ ___ ___________ 7 8 9 SHEA COMMUNICATIONS, et al DEFENDANTS 10 11 * * * 12 13 14 MONDAY, OCTOBER 24, 1994 15 VOLUME XXI 16 17 * * * 18 19 20 21 _____________________________________________________________ REPORTER: JULIA K. McBRIDE 22 Coulter, Shay, McBride & Rice 1221 Starks Building 23 455 South Fourth Avenue Louisville, Kentucky 40202 24 (502) 582-1627 FAX: (502) 587-6299 25 2 1 2 I_N_D_E_X _ _ _ _ _ 3 4 WITNESS: DOCTOR_NANCY_LORD _______ ______ _____ ____ 5 Examination by Ms. Zettler............................... 5 6 * * * 7 8 Reporter's Certificate...................................209 9 * * * 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 3 1 2 A_P_P_E_A_R_A_N_C_E_S _ _ _ _ _ _ _ _ _ _ _ 3 4 FOR THE PLAINTIFFS: 5 PAUL L. SMITH Suite 745 6 Campbell Center II 8150 North Central Expressway 7 Dallas, Texas 75206 8 NANCY ZETTLER 1405 West Norwell Lane 9 Schaumburg, Illinois 60193 10 FOR THE DEFENDANT: 11 EDWARD H. STOPHER 12 Boehl, Stopher & Graves 2300 Providian Center 13 Louisville, Kentucky 40202 14 JOE C. FREEMAN, JR. LAWRENCE J. MYERS 15 Freeman & Hawkins 4000 One Peachtree Center 16 303 Peachtree Street, N.E. Atlanta, Georgia 30308 17 18 * * * 19 20 21 22 23 24 25 4 1 The Transcript of the Proceedings, taken before 2 The Honorable John Potter in the Multipurpose Courtroom, Old 3 Jail Office Building, Louisville, Kentucky, commencing on 4 Monday, October 24, 1994, at approximately 9:35 A.M., said 5 proceedings occurred as follows: 6 7 * * * 8 9 SHERIFF CECIL: The jury is now entering, all 10 rise. The Honorable Judge John Potter is now presiding. 11 Court is now in session. You may be seated. 12 JUDGE POTTER: Please be seated. Ms. Williams, 13 have you had any trouble observing the admonition about not 14 letting anybody communicate with you on the case? 15 JUROR WILLIAMS: Everything's fine. 16 JUDGE POTTER: How about the rest of you, any of 17 you have any problems? 18 Mr. Smith, do you want to call your next 19 witness? 20 MS. ZETTLER: Judge, at this time the Plaintiffs 21 call Doctor Nancy Lord. 22 JUDGE POTTER: Ma'am, would you step up here and 23 raise your right hand, please. 24 25 NANCY LORD, after first being duly sworn, was 5 1 examined and testified as follows: 2 3 JUDGE POTTER: Please have a seat in the witness 4 box, and would you spell your first and last names and then 5 repeat it loudly for the jury, please. 6 DOCTOR LORD: N-A-N-C-Y, last name, L-O-R-D. 7 Nancy Lord. 8 JUDGE POTTER: Keep your voice up and answer Ms. 9 Zettler's questions. 10 11 EXAMINATION ___________ 12 13 BY_MS._ZETTLER: __ ___ ________ 14 Q. Doctor Lord, how old are you? 15 A. Forty-two. 16 Q. And where do you reside? 17 A. In Atlanta, Georgia. 18 Q. How long have you resided there? 19 A. Since the end of 1991. 20 Q. And are you married? 21 A. Not at this time. 22 Q. Could you give the jury an overview of your 23 educational background starting with high school? 24 A. I went to high school at Northwood High School 25 in Silver Spring, Maryland, and then I went on to the 6 1 University of Maryland, where I graduated with a Bachelor of 2 Science in chemistry in 1973. From there I attended the 3 University of Maryland School of Medicine and I received my 4 medical degree in 1978. I took two years of residency in 5 anatomic pathology, which is the study of disease, performing 6 autopsies, looking at surgical specimens, and then I decided 7 to go into pharmaceutical research. 8 I worked at a company called Abbott Laboratories 9 in north Chicago, Illinois, for four years and, while I was 10 there, I wrote a new drug application on a new benzodiazepine 11 hypnotic that's on the market today under the name of Prosom. 12 After that, I started my own business doing 13 pharmaceutical research on a freelance type of basis for small 14 drug companies and attorneys. And then I went to law school 15 in 1987, graduated from Georgetown School of Law in 1990, and 16 then went into practice in criminal and regulatory law. I 17 assist people, small, medium-size vitamin companies, 18 health-food stores, vitamin distributors, vitamin 19 manufacturers who are having regulatory problems with the Food 20 and Drug Administration or other regulatory agencies. 21 Q. Let's back up a little bit. Tell us again about 22 your internship after medical school. 23 A. I'm sorry? 24 Q. Explain more thoroughly for the jury what your 25 internship entailed in medical school. 7 1 A. I did two years of pathology. In pathology you 2 don't actually have an internship; it's all part of residency. 3 What I did was I performed autopsies. When somebody in the 4 hospital died we'd examine the body; look at the tissues, 5 determine the cause of death if it was a question, confirm it 6 it if it was not; look at specimens that would come down, say, 7 from surgery; perform tissue analyses on, say, blood that 8 would be taken out of a heart of somebody who died, things 9 like that; and looked under the microscope to make a 10 microscopic diagnosis in addition to the actual gross 11 diagnosis of the tissues. 12 Q. Did you take any extraordinary courses in 13 psychiatry in your medical school or internship experience? 14 A. Yes, I did. I took a program called the 15 combined accelerated program in psychiatry while I was in 16 medical school; I took it for the first two years of medical 17 school during the time I had course work. I left it when 18 things got busy with the clinical rotations and so did pretty 19 much everybody else that was in it. As part of that program, 20 we learned a great deal about psychopharmacology, the use of 21 drugs in treating mental disorders. I also had a patient I 22 was seeing in individual therapy for about a year, and I 23 worked on a psychiatric ward evaluating people that were 24 coming in, performing mental-status examinations, recommending 25 medications, things like that, working in group therapy. It 8 1 was very interesting. 2 Q. Just so that it's clear, did you complete your 3 internship right after medical school? 4 A. I completed what is equivalent to an internship 5 my first year of residency. 6 Q. Why did you leave after your first year of 7 residency? 8 A. I left after two years. 9 Q. Why did you leave after two years? 10 A. Because I really wanted to work in a different 11 type of setting. I liked doing research, I liked studying 12 medicine, I didn't really particularly like the clinical 13 aspects of medicine, treating patients, being on the hospital 14 ward. And I looked around for other opportunities and I found 15 pharmaceutical research very, very interesting. The 16 possibility of going to a drug company and assisting them in 17 the whole development of a new drug was something I wanted to 18 do. 19 Q. When did you go to Abbott Labs? 20 A. I went there in February of 1980. 21 Q. And tell the jury what you did throughout your 22 career at Abbott, like which position did you start in and if 23 you were promoted. 24 A. I started out in the position of staff 25 physician, and my duties and responsibilities were the primary 9 1 responsibility for the New Drug Application of my drug, which 2 at that time was called estazolam; that was the generic name 3 for it. It was a new sleeping pill. At the time, Dalmane was 4 on the market, flurazepam. There were a few others in the 5 works. It is a drug like Valium, instead -- because it acts 6 faster, people go to sleep rather than simply calming down. 7 There were only a few studies done at the time I started, and 8 I was responsible for planning what studies were to be done; 9 writing the protocols; selecting the investigators to do those 10 studies; summarizing those studies; preparing an overview of 11 those studies and writing the NDA. Obviously, I had some 12 help; I had a staff of three people at the time I left. I 13 also got promoted while I was there to the position of 14 assistant director of clinical research. 15 I was also responsible for collecting the 16 adverse experiences, developing the case-report forms. A big 17 part of my job was simply designing case-report forms to make 18 sure that the adverse experiences were correctly reported and 19 followed up on. If there was a problem we would call the 20 investigators and find out exactly what happened perhaps and 21 the person for additional tests, things like that, and I was 22 the person primarily responsible for that drug. 23 Q. Why don't we back up a little bit. Explain to 24 the jury what you did in your consulting business. When did 25 you leave Abbott? 10 1 A. I left Abbott at the time I filed the NDA, which 2 was in December of 1983. 3 Q. And tell us what you did after you left Abbott. 4 A. I left Abbott to go out on my own. I wanted my 5 own business. I wanted to stay in the field of pharmaceutical 6 research, and I had hoped to start a business primarily 7 working with small and foreign drug companies, assisting them 8 in new drug development. And I did do some of that. I also 9 worked for some attorneys looking at NDAs, evaluating package 10 inserts, looking at the ways drugs were used or misused and 11 looking at the literature on various drugs. 12 Q. What types of things did you do fro, I think you 13 said, small- to medium-sized drug companies and foreign 14 companies? 15 A. A lot of the things I did was a paper NDA. 16 There was a time when after a drug was off patent, meaning the 17 patent had expired, and anybody could market the drug, the 18 drug company who wanted to market another copy of that drug 19 would have to submit in addition to the scientific studies 20 that showed that it was the same drug, that it broke down into 21 the same things, that it became -- that it dissolved in the 22 same way, that it was metabolized in the same way, would also 23 have to submit a summary of all the information that was 24 published on that particular drug. So they needed someone to 25 look at all those articles and write up a paragraph or two 11 1 about each study, and I wrote one of these for a generic drug 2 company while I had my consulting business. 3 I also assisted some other companies in the very 4 early stages of drug development, trying to decide whether or 5 not the drug was worth developing, worth licensing, looking at 6 the types of studies that would be needed to try to help them 7 make a decision as to whether or not they wanted to invest in 8 these particular drugs. 9 Q. You explained for us earlier some of the things 10 that you did on your NDA at Abbott. What I'd like for you to 11 do now is, first of all, tell us what an IND is. 12 A. An investigational new drug is called an IND, 13 Investigational New Drug Application. Before a company is 14 allowed to give a new drug that hasn't been previously tested 15 to human beings, even in a testing situation you must submit 16 to the FDA animal trials. And these are very specific trials. 17 They have to be in two different species, they have to be 18 different lengths of times. You send those in and that's part 19 of your IND. After you've done that, if the FDA doesn't say, 20 "No, this is not acceptable," you can go ahead and start your 21 clinical trials. The idea of the IND is to show that the drug 22 isn't going to kill somebody. They don't want someone 23 researching a drug that's dangerous. And the idea with 24 animals is you use several multiples of the drugs that you're 25 going to use in human beings and you assume that if the 12 1 animals are okay, people will be okay, too, for the most part. 2 Q. Is this from a behavioral standpoint or 3 physiological standpoint? 4 A. This is a physiological standpoint. In fact, 5 one thing they do with animals is you do what's called an 6 LD-50; you find out how big a dose you have to give to kill 50 7 percent of the animals, so that you know what sort of 8 therapeutic range you're working with in human beings. If, 9 say, 100 milligrams of a drug is going to kill half the rats, 10 you're not going to want to give, say, even 25 to a human 11 being. 12 Q. Tell us briefly what an NDA is. 13 A. An NDA is a New Drug Application. The Food and 14 Drug Administration requires drug companies to submit evidence 15 of efficacy and safety before they're allowed to market a drug 16 for sale. This must include two what they call pivotal 17 studies, which means adequate, well-controlled, randomized 18 placebo-controlled double-blind studies. That means that 19 neither the investigator who's doing the study nor the 20 patients taking the drug nor the drug company personnel, the 21 monitor coming out and checking on it, know what drug each 22 person is on. Some of them will be on placebo; some of them 23 will be on the drug; in some cases you may use a comparitor 24 drug, another drug that's already been established to treat 25 that particular disease. And the reason you do that is that 13 1 you want to make sure that your methodology does in fact pick 2 up the effectiveness of any drug, so you use a drug you know 3 is going to come out right so you can test your methods. 4 Q. What do you mean when you say an adequate 5 well-controlled study? We know what blinding is; what do you 6 mean when you say adequate and well controlled? 7 A. Well, adequate generally means that you used 8 enough people; that enough people went through the study that 9 you would expect to see statistically significant results. 10 The differences you would see would probably be real; that 11 they would be something that would happen in a regular 12 population of people taking the product; that there would be 13 enough to see certain side effects. Everybody in the industry 14 knows that you're not going to pick up everything that can 15 possibly happen to a drug -- with a drug during your clinical 16 trial. Some things are just going to happen so infrequently, 17 say, 1 in 5,000 people; if you look at 2,000 people in an NDA, 18 you're not going to see it. But your basic adequate and 19 well-controlled study, say, of 100 patients should pick up 20 adverse experience that's going to happen to 5 or 10 percent 21 of the population. 22 Q. What do you mean when you say well controlled? 23 A. That means that you have a placebo control and 24 possibly a comparitor drug control and it's double blinded; 25 that you know it's not simply a few people on the drug; that 14 1 someone knows they're on the drug, that they can look at in a 2 biased manner. When they do the evaluations, they don't know 3 what drug the person is on or if they're on placebo. That's 4 how you control a trial; that you look at exactly what 5 happened without the knowledge of what product the person is 6 taking, so that you can get an unbiased view of how that 7 product compares to placebo and to other products that do what 8 this drug is trying to do. 9 Q. Doctor, could you give us an overview of how you 10 put together an NDA? 11 A. Well, you start with a clinical plan. This 12 means you do a proposal of the kinds of studies you want to 13 do. Now, in the case of my drug, my drug was a sleeping pill. 14 So we did some studies in sleep labs where people were hooked 15 to EEG machines all night so we could get a scientific 16 analysis of when they went to sleep, how many times they woke 17 up, how much REM sleep they got, how early they woke up, 18 things of that nature, how much delta sleep they got, and we 19 also looked and did several types of special studies, studies 20 of memory. So you do the studies you plan to do. You have 21 this clinical plan, what years you're going to do; you 22 estimate how much time it will take you to do them and you 23 have this basic outline of the kinds of studies you're going 24 to do; how many outpatient studies, how long they're going to 25 be, what comparitor drugs you're going to use. But then as 15 1 the NDA progresses, as you start looking at what's happening 2 on your various trials, you see problems surface, you see 3 things that need a closer look, types of patients that maybe 4 should be looked at specially. I'm going to make up an 5 example because I don't want to divulge things about my own 6 NDA that might be confidential to the company. 7 Let's say you have an antihypertensive, 8 something that's supposed to control blood pressure, and it's 9 making some people depressed. Some people are just saying, "I 10 just don't feel good on this stuff, I'm getting depressed." 11 Then you may want to look at people who are already a little 12 depressed to begin with, to see if it's making depression 13 worse. You may want to add some special scales for 14 depression. You know, there are special studies that you do. 15 In the case of benzodiazepines, my benzodiazepine was not one 16 of the first ones, so people already knew the properties of 17 benzodiazepines in general when my drug was under development. 18 But when they first started looking at these, one thing that 19 was done was a study with alcohol, because you knew you put a 20 tranquilizer on the market and somebody is going to go out and 21 take your drug and drink, and you want to know that a little 22 bit of alcohol isn't going to kill them. You want to test 23 their psychomotor skills, what's their choice reaction time 24 going to be. You may want to do respiratory studies with the 25 benzodiazepine, how much it affects your breathing because you 16 1 know there's a problem with breathing in any sort of 2 benzodiazepine tranquilizer. So these are the kinds of things 3 you look at, the special studies you get into when you're 4 doing an NDA, and you don't know at the outset everything you 5 may want to do before it's all over. 6 Q. Tell the jury what a protocol is and also tell 7 them how you develop a protocol and put together a protocol. 8 A. A protocol is a recipe, so to speak, for how the 9 study is to be done. You put it together, sometimes you look 10 at other protocols and make changes, you work with the 11 investigators; you get some of their input as to what would be 12 valuable. You start out with inclusion criteria and exclusion 13 criteria; who do you want on the trial, who do you not want on 14 the trial, you know. And then I need to get into Phase 1, 2, 15 and 3, but let me go through it in general first. You would 16 exclude, for instance, pregnant women. On pretty much any 17 drug you're studying you don't want to take a chance of 18 injuring a fetus, an unborn child, so that would be an 19 exclusion for pretty much anyone. You may want to exclude 20 people who have other diseases at certain phases of the study 21 development. Then you list when the people are going to come 22 in, how much of a wash-out period are you going to use. 23 In some types of products like these 24 psychotropics, almost anybody that comes onto the study is 25 bound to have used another psychotropic in the past because 17 1 these are ongoing diseases. So you have to give them a week 2 or so to wash that other drug out of the system. How many 3 times the person is going to visit; are they going to have to 4 come in every day, are they going to have to come in once a 5 week; are they going to take questionnaires home every day. 6 How are the adverse experiences going to be reported? Are 7 they going to ask the people how they felt or are you going to 8 just see what people say. 9 The other important thing is concomitant 10 medications. Now, in the first part of an NDA, Phase 1, you 11 give it to very healthy people and you give them multiples of 12 the dose you're going to use in sick people to see what the 13 toxicity profile is in human beings. These are volunteers. 14 Then you use Phase 2, where you give the product 15 to those with the disease and nothing else wrong with them. 16 In Phase 3, you should open it up to other types 17 of people, and you may allow the people to be on some other 18 product for something else. You wouldn't normally allow 19 people to take another psychotropic during a psychotropic 20 study. This is all part of the design; is it going to be 21 short term; is it going to be long term; when are they going 22 to get their physicals; what tests are you going to run? Are 23 you going to do sleep EEGs; are you going to do EEGs at all; 24 are you going to use questionnaires; are you going to use 25 choice reaction time; are you going to have an evaluation by a 18 1 psychiatrist? What tests are you going to run to measure the 2 effects, both positive and negative, of your product as 3 compared to the control? 4 Q. What about statistical analyses? How does that 5 play -- what role does that play in developing a protocol? 6 A. Well, you should at the outset know what kind of 7 analysis you're going to do. If you're going to do an 8 unbiased study, when you start the study you should already 9 know which ones of the numerous types of statistical tests 10 you're going to use on the data. It's somewhat biased to get 11 the data back in and then say, "Oh, I think this would be good 12 on this test. I think this test will show efficacy. I think 13 this test won't show any difference in side effects." You 14 should know at the outset before you get your data what you're 15 going to do. That's way it's, to put simply, fair. 16 Q. Do you need to have FDA approval before you can 17 start conducting the trial under a protocol? 18 A. You send the protocol in, and I believe that 19 they -- if they don't tell you you can't do it, you can go 20 ahead and start the protocol. Sometimes they'll make comments 21 about it; they may suggest other things, but you're pretty 22 much free to do whatever protocols you want to do. You do 23 have to get the permission of what's called the institutional 24 review board. That is an organization within the study 25 facility. Say if it's a hospital, it would include maybe a 19 1 clergy person, a nurse, a layperson, a group of people who 2 look at it and look at it from an ethical standpoint; is this 3 okay to be doing this to human beings. And they make sure 4 that the informed consent is appropriate. 5 Q. What's an informed consent? 6 A. An informed consent is a form that the patient 7 signs giving you permission to give them the drug, and there 8 are certain requirements of the informed consent. You have to 9 tell them what the drug is; what are they going to be getting; 10 what's known about it already; what are some of the side 11 effects they might expect; what are their alternatives for 12 treatment; if they don't want to be on this trial is there 13 something else they can use; is there something else they can 14 take. You must tell them that if they don't want to be on the 15 trial it won't affect their medical care, because some of 16 these people might be on Medicaid or they might be getting 17 some sort of charity and feel that they can't say no. You've 18 got to tell them, "Yes, you can say no; you can withdraw at 19 any time." There are certain required elements that have to 20 be in that document that you must tell someone before you give 21 them an experimental drug. 22 Q. Could you explain to the jury what a case-report 23 form is? 24 A. A case-report form is the report form that the 25 investigator at the study site -- I have to back up for just a 20 1 minute here. When you do a study, I keep talking about an 2 investigator. The drug company doesn't do it themselves. You 3 hire somebody else to do it, and they may be a university 4 physician; there may be centers that do this all the time for 5 a living; they may be private doctors. But you basically 6 contract with an investigator, a physician, or in some cases a 7 psychologist to perform the study for you. 8 They return their data on what's called a 9 case-report form. This is a printed form in triplicate that 10 the drug company prepares, and one part -- one copy of it will 11 go to the FDA. It is -- it lists out all the data that has to 12 be collected. And even if they get, say, a laboratory 13 analysis back from one of the commercial laboratories, they 14 still have to copy that information onto the case-report form, 15 and that's where you define what data is to be collected. 16 Q. What types of data are generally collected on 17 clinical-report forms? 18 A. Well, you'll have an initial set of pages, which 19 would be the initial physical, the person's workup when they 20 went onto the study, what their disease condition was when 21 they started the study, what their blood pressure is, their 22 weight, their age, that sort of thing. You don't ever have 23 the person's name on it; these things only have initials and a 24 patient number. And then you have each report. If there's a 25 rating scale that's used, that rating scale will be in there. 21 1 If it's a rating scale the investigator has to fill out, say a 2 HAM-D, that would be in there. If it's something the patient 3 does, that would be in there. There's also space for adverse 4 experiences. In the case of Lilly, it was called treatment- 5 emergent symptoms, where every week they were supposed to list 6 what kinds of diverse experiences the person experienced that 7 week. There's also a line for concomitant medications; that 8 means if you had to, say, take an aspirin during the trial, 9 you would put down on that page, "Took aspirin for headache on 10 Tuesday." 11 Now, everything that somebody is treated for on 12 the concomitant medications section must also be reported as 13 an adverse experience. If somebody got a headache and 14 required an aspirin, they got a headache. Everything bad that 15 happens to people, or even not so bad, any unusual event 16 should be reported as an adverse experience. 17 For instance, it may not sound important but 18 let's do one. Let's say somebody had a car accident on a 19 benzodiazepine trial. Say on my drug somebody had a car 20 accident. You'd think, "Oh, well, what does that have to do 21 with the drug." Well, it might have a lot to do with the 22 drug. It might be that the people were still drowsy the whole 23 next day and were just going around having wrecks. Now, if 24 you saw more people who had taken my drug the night before 25 than who had taken placebo driving to work the next day and 22 1 getting into wrecks, that's a very serious problem with the 2 drug. So you have to put down everything and let the 3 statistics determine whether or not the drug had something to 4 do with it. 5 I mean, another for-instance. You give enough 6 drug to enough people, hundreds and hundreds of people, 7 somebody is going to get arrested. I guarantee you, out of 8 all those people, somebody is going to do something very silly 9 and wind up in jail, and it probably had nothing to do with 10 the drug. But if it's a lot of people, or even just a few 11 people out of, say, 100, then you have to get suspicious that 12 there's something about this product that's affecting 13 behavior, and that's when you look at it more carefully. 14 Q. Why do you use a clinical-report form as opposed 15 to, say, a chart like a doctor uses at his office or at a 16 hospital? 17 A. Because you want them to be identical. The 18 case-report forms are absolutely identical from one patient to 19 another. And if you have a multicenter study, where more than 20 one investigator is working on the same study, they will be 21 identical between the different centers; the one that one 22 doctor used is the same as the one the other doctor used. So 23 you can analyze and organize your data in a very meticulous 24 and rigorous manner. 25 Q. You said earlier that the clinical-report forms 23 1 are filed with the FDA. In your experience, does the FDA 2 review each and every clinical-report form for every study 3 that's submitted? 4 A. They can't. They can't. They just don't have 5 the manpower. By the time an NDA is finished, you have 6 thousands and thousands of case-report forms, and each 7 case-report form might be 50 to 100 pages; it's not just one 8 page, it will be a stack like that thick. There's no way the 9 FDA can look at each and every one of them. 10 Q. What do they look at instead, then? 11 A. They might look at one whole trial and then 12 they'll spot-check them. They'll just pick them out at random 13 and take a look at them to make sure they were filled out 14 properly. They have to rely on what the drug company sends 15 them in terms of what's called an adverse-experience report 16 and the tables within the summary of the study, the tables 17 that list how many people got the various types of adverse 18 reactions, and may have a verbal description of some of the 19 more unusual events, because they're not going to have time to 20 look at each and every case-report form. 21 Q. Explain to the jury what a final study report 22 is. 23 A. The final study summary is something that's 24 written usually by the investigator, and that would -- it 25 describes the protocol, it describes how many people went on 24 1 the study, what their demographics was, was there any 2 difference in age or socioeconomic status between the 3 different people, the different groups, you know. Actually, 4 you wouldn't do SES that much; say, weight, general health; to 5 take a look at the group, what the placebo group looked like, 6 what the drug groups looked like going in. And then you would 7 say how many people withdrew for whatever reason. And you 8 look at those withdrawals very closely; it's very important 9 whether someone withdrew from a trial because they got a job 10 in another city or whether they withdrew because the product 11 was making them sick. You have to look at reasons for 12 somebody to withdraw. 13 You look at the efficacy; how did the various 14 groups do. If you're testing more than one dose of the drug, 15 how did this dose do, how did that dose do; how did people do 16 on the other drug; was there any difference in the profile of 17 the drug; were there different measurements that came out 18 different. Like, for instance in this data, one thing that 19 consistently didn't show efficacy in a number of studies was 20 sleep disturbance. People's sleeping didn't get any better on 21 Lilly's drug. So you look at that. 22 Then you look at the adverse experiences, what 23 kinds of problems came up; how many people got headaches; how 24 many people got nervous; how many people were sleepy during 25 the day; how many people were jumpy during the day, restless, 25 1 agitated, all these different things. How many people got 2 colds. Some people are simply going to catch a bug during a 3 drug trial. Again, you want to look at it. It's probably not 4 connected, but it might be. You have to make sure. So you 5 put down a list of pretty much everything, and then you 6 evaluate, and the investigator writes this kind of summary of 7 what he thinks of the results of the study. 8 Q. Let's back up just a little bit. You've given 9 us bits and pieces about adverse events. Why don't you define 10 for the jury what an adverse event is under the regulatory 11 definition, within the NDA process. 12 A. Okay. Well, an adverse event is -- well, 13 there's two types. There are some that have to have what's 14 called a 1639 filled out, and that is what they call a serious 15 or unexpected adverse event, and that would mean something 16 that involves death, hospitalization, congenital anomaly, 17 cancer, hospitalization or the requirement for medical 18 treatment, serious things like somebody developing a fever of 19 104, I mean, that kind of serious event. 20 Then there are sort of nonserious events, things 21 like transient rashes, headaches, things like that, and they 22 would not be placed on a 1639 form right away, but they would 23 be put as part of the study summary and part of the summary 24 for the NDA. Anything that happens to a person on a study 25 protocol should be coded as an adverse event because you 26 1 simply don't know when you're looking at an isolated event, 2 like we talked about car accidents, whether it had something 3 to do with the drug or not. 4 Q. Doctor, we've heard an example earlier of 5 somebody getting hit by a bus walking across the street on the 6 way to get their Prozac prescription filled being reported as 7 an adverse event. Is that unusual? 8 A. No. They're supposed to do that. I'll tell you 9 why. Now, this person hadn't gotten the prescription filled 10 yet, but that's a good baseline number of, you know, what 11 happens normally. If it turned out that people on Prozac were 12 getting hit by buses a lot, maybe there's something about this 13 that's messing up their vision, maybe it's making people 14 inattentive, maybe it's making them dizzy or maybe it's making 15 them careless. If more than the expected number of people 16 were hit by buses on the way to the drugstore, you would want 17 to know that, I'd want to know that. Because you don't know 18 looking at an isolated case whether this is indicative of 19 something going on with the drug. 20 Q. Just so we understand, does the FDA require that 21 the drug manufacturer report every adverse event that occurs 22 during a study? 23 A. Yes. 24 Q. And so if you're reporting things like stumbling 25 or getting hit by a bus on the way to getting your Prozac or 27 1 things of that nature, that's not something that's unusual and 2 in fact is required; correct? 3 A. It's absolutely required. Now, it may not 4 require a 1639 to be sent in within two weeks, but it's 5 required to be listed in the study summary and it's required 6 to be included in the table of adverse reactions. 7 Q. Now, we talked a little bit about somebody 8 getting hit while crossing the street or getting in a car 9 accident. Is it your understanding that it is not just 10 medical events that need to be reported under the FDA 11 requirement? 12 A. Right. It's any kind of unusual event. 13 Q. So if somebody fell down the stairs and tripped 14 over one of their kids' toys or something and sprained their 15 ankle, that would be reported? 16 A. Absolutely. That would be a very important 17 thing to report because that might be evidence of some sort of 18 incoordination. Basically, a person is not going to come into 19 the study center on Monday for their weekly visit and say, "I 20 had an adverse experience this week. I developed 21 incoordination and ataxia." They're going to say, "I tripped 22 over my child's toy"; "I fell down the stairs"; "I got hit by 23 a bus." They're going to tell the investigator what happened. 24 It's the investigator's job to put that down, to talk to the 25 people to try to assess what happened, whether they were 28 1 ataxic or whether it was just an accident. But it really 2 doesn't matter what they think; it goes in anyway, accident. 3 Q. With any given single adverse event, does the 4 FDA require that the drug company try to make a causal 5 connection between the event and the use of the drug? 6 A. No. The statistics are supposed to do that job. 7 You're not supposed to make an assessment of what you think. 8 The statistics -- if everything is reported accurately, at the 9 end of the trial the statistics will tell you the truth. If 10 it's connected to the drug and you report it honestly and 11 accurately, it will show, if you use enough patients, a 12 difference between the drug and placebo groups. Now, if it's 13 so rare that it doesn't show a difference, that's another 14 problem. 15 Q. When you say "that's another problem," what do 16 you mean? 17 A. Well, that's one of those things that may pop up 18 after a drug is marketed. 19 Q. When a drug is approved by the FDA, does that 20 mean that it has been proven to be safe and effective? 21 A. Yes, to the satisfaction of the requirement 22 today. 23 Q. Is it something that has -- is it your 24 understanding that there are no other indications after a drug 25 is marketed that would determine whether or not a drug is 29 1 actually safe to be used in a general population? 2 A. I'm sorry. I don't understand your question 3 exactly. 4 Q. We've heard testimony that the FDA here has 5 stated that or believes that a drug is not necessarily -- they 6 don't know everything about a drug profile necessarily when 7 they place it on the market? 8 MR. FREEMAN: Object to the leading. 9 JUDGE POTTER: I'm going to sustain the 10 objection; it's leading. 11 Q. Does the FDA know everything about the safety of 12 a drug when they place it on the market? 13 A. No. It's a matter of numbers, and we talked 14 about that a little earlier. If you look at 2,000 patients 15 and something only happens in 1 of 5,000 patients, you're not 16 going to see it within a clinical trial; it may turn up later 17 on. But you may see indications of it, you may see things 18 like it, stuff like that. But there have been cases where 19 something simply didn't come up in U. S. clinical trials, but 20 it did come up after a drug was on the market. Sometimes it's 21 come up in foreign trials, sometimes it's come up overseas 22 before, because generally these products are on the market 23 overseas before they're on the market here. But you may not 24 see everything in a sample of 2,000 people, because there are 25 reactions that only occur in 1 in 10,000. 30 1 Q. Explain for the jury how a clinical investigator 2 would report an adverse event that occurs during a clinical 3 trial. We've talked about 1639s. Are there other methods for 4 reporting adverse events? 5 A. The other way you would report it is as part of 6 the study summary. Say the person took an aspirin for a 7 headache. First you would try to find out, and you say, 8 "Well, did you have to take any medicine this week," and they 9 say, "Well, I took an aspirin." So you put that down, 10 concomitant medication, aspirin; why, headache. Then you put 11 headache on whatever case-report form you used to report the 12 adverse experiences for that week. And then at the end when 13 you tabulate up the summary, you'll list headache and there 14 might be four or five other patients who also got headaches, 15 so you may have six headaches during the course of the trial, 16 and that would be part of the table that would be part of the 17 study summary. 18 Now, when you do the NDA, you do a summary of 19 the summaries. You have a summary of certain types of 20 studies. Say you summarize all your outpatient studies 21 together, all your sleep studies together, all your long-term 22 studies together, so you do a summary of that, and you again 23 list that adverse experience. And then you would do the NDA 24 overview, which would tally them all up in a total, a combined 25 total of how many people got headaches. 31 1 Q. Are you familiar with the COSTART dictionary, 2 Doctor? 3 A. Yes, I am. We used it when I was at Abbott. 4 Q. Explain to us what the COSTART dictionary is and 5 how it was used. 6 A. Well, the COSTART dictionary was a method by 7 which there would be a unified system of reporting adverse 8 experiences where everybody would be using the same word to 9 define the same thing because, you know, a lot of different 10 investigators might define the same exact reaction different 11 ways, so they were trying to create a unified reporting 12 system. And what they did was, they had a thesaurus and there 13 would be a term, say, dizziness, that would map to four or 14 five or even sometimes nine or ten other terms that somebody 15 might spontaneously report, and you would call them all 16 dizziness. The idea was to get an accurate sample of how many 17 people were getting something like dizziness rather than 18 having. You know, three percent getting light-headedness, two 19 percent saying they fell down, five percent saying they were 20 dizzy; call them all dizziness. 21 There's no requirement that COSTART be used, but 22 it is a way that purportedly makes things easier, and it's 23 supposed to be used not just with psychotropics; it's a system 24 that was designed to be used with anything, with any type of 25 drug you would use the same words to code the various types of 32 1 adverse experiences. 2 Q. So I understand, does the FDA require that drug 3 companies use the COSTART dictionary? 4 A. No. 5 Q. Why not; do you know? 6 A. No. I don't know why they don't but... 7 Q. In your experience -- well, for instance, did 8 Abbott use the COSTART? 9 A. Yes, we did. Not all along, but at the end we 10 recoded everything according to COSTART. 11 Q. Did you have your own dictionary that you used 12 at Abbott before you started using COSTART? 13 A. We didn't really have a dictionary. We just 14 kind of used the terms that they put down. I think we thought 15 that was the most accurate way, we just used the terms that 16 the investigator originally chose. 17 Q. You mean the clinical investigator that was 18 conducting the study? 19 A. Right. Right. Because sometimes there's a 20 price to pay. Sometimes you lose a little data when you 21 change one thing into something else in certain situations. 22 Q. I'd like you to explain to the jury how a 23 company goes about hiring clinical investigators, what type of 24 professionals are they and how their sites are conducted. 25 A. For the most part, clinical investigators, the 33 1 majority of them are excellent, excellent physicians. They 2 are really at the top of their field; they're university 3 trained, often department heads; they've published a lot of 4 papers, but it kind of all goes hand in hand. It's good for 5 their careers to do drug studies because they bring a lot of 6 money into their institutions, so it helps them, it helps them 7 get ahead; they want to do this; it gives them more 8 publications. Then there are some that do this, this is all 9 they do. I mean, there are some centers that are simply 10 stand-alone centers, not affiliated with hospitals, where 11 they're just really good at putting a lot of people on drug 12 company trials. There's a few that only do Phase 1 trials. 13 They have a big kind of dormitory where people come in and get 14 a dose of a drug and get their blood taken 20 times a day, and 15 that's all the investigators do and that's all the subjects 16 do. They kind of go around from one of these to another, and 17 that's what they do for a living, doing drug trials. But the 18 majority of them are generally well-respected physicians in 19 their field of expertise or psychologists. 20 You find them through professional meetings. 21 Sometimes they send you promo pieces in the mail because they 22 want to do more trials. Sometimes other investigators may 23 recommend them. There's a number of different ways you might 24 locate investigators. You might run a MedLine search and see 25 who's written in a particular field that you want to study and 34 1 see who's very expert in that field. But it's generally no 2 trouble. Whatever kind of study you want, if you're willing 3 to pay for it, somebody will do it. 4 Q. Give the jury an idea of how generally an actual 5 clinical trial is conducted. 6 A. Well, after you've selected your investigator, 7 they then have to get the institutional review board approval. 8 Once you have that approval, the informed consent -- there are 9 some other documents, the investigator's CV, the contract with 10 the investigator, there's another form you have to use -- you 11 send that into the company to another department and they 12 provide drug, along with case-report forms. And the drug -- 13 which is randomized and double-blind. Within the company they 14 take the drugs and they make them all look alike, and only 15 that little division of the company knows which patient number 16 has which drug. 17 So you go down or you have delivered the 18 case-report forms and the drug, and the drug goes by patient 19 number. Like you already know what Patient No. 1 is going to 20 get, Patient No. 2, Patient No. 3; what you don't know is 21 who's going to be Patients 1, 2, 3, 4. So they go down and 22 they start accessing patients, and as you go, the first 23 patient becomes Patient 1; the second becomes Patient 2 and 24 they start filling out the case-report forms as they collect 25 the data. 35 1 Periodically, the drug company personnel will go 2 out and check, you know, take a look at, say, their lab 3 values, make sure that they wrote everything in correctly, 4 make sure that they're recording all the adverse experiences, 5 make sure that if somebody got a concomitant medication for 6 something, it also was coded as an adverse experience, make 7 sure everything is done properly. The drug company person 8 should never actually write on the case-report form. 9 Q. You say the drug company goes out and audits the 10 investigation site. In your experience, does the FDA itself 11 ever audit investigator sites? 12 A. They can; not all of them, but they sometimes 13 do. That's generally more to check on the investigator. They 14 go around and they check various investigators and sometimes 15 people, like, don't pass, and then they send a list of 16 investigators that are not okay to work with. And the drug 17 companies get that and those people don't get any new drug 18 studies. 19 Q. You talked about the blinding. Is it typical 20 for the clinical monitor at the drug company, the person such 21 as yourself who was in charge of the NDA, to be blinded as to 22 what drugs any given patient is on? 23 A. Absolutely. Absolutely. It's always been done 24 that way. The monitor always is blinded along with the 25 investigator and the patient. I mean, the last thing you want 36 1 is the monitor coming out and saying, "Gee, I know this guy 2 was on estazolam; maybe you'd better give him a better score 3 on your drug evaluation." I mean, that would just be totally 4 unacceptable. You don't want to trust the monitor to not use 5 that knowledge. It's better that they don't have it; that 6 way, no question can ever be raised. 7 Q. If you have a study when you have, say, 150 8 patients that are to be enrolled in the study, do you enroll 9 all 150 patients at once? 10 A. Oh, no. No. As I say, they go on in order as 11 they come in. You would not have 100 people standing outside 12 your study door saying I want to be a patient; bring them all 13 into a room like this, have them fill out all their 14 questionnaires, give them all drugs, send them home, have them 15 come back the next week with their next week's questionnaire. 16 First of all, you don't have the study personnel to do that; 17 you don't have the administrative help to get all that done at 18 once, and you also don't have the patients. Most of these 19 centers will admit maybe 3 or 4 a week, maybe 5. Some of the 20 really big ones may admit 10 or 12 or 15. So you always have 21 people finishing the study up at different times. You know, 22 the first week you're going to have everyone starting. The 23 second week you're going to have some starting and some of 24 them into their second week. The third week you're going to 25 have some of them starting, some in their second, some in 37 1 their third week. Might be the next week is Thanksgiving and 2 they don't put anybody on that week. So there's always 3 different people at different phases. By the time one group 4 is finishing up, you may still have two-thirds of the study 5 left to admit. So it's an ongoing process of accessing 6 patients. 7 Q. Let's back up again a little bit, Doctor. 8 Explain to the jury what a Phase 1 trial is and what the 9 purpose of that trial is. 10 A. A Phase 1 trial is the normal, healthy 11 volunteers. Now, in this case you might put everybody on all 12 at once, just because the kinds of things you have to do it's 13 easier to just do them with everybody at once. What you do is 14 you give them all the drug and you take their blood, and you 15 may have to take their blood every 15 minutes for the first 16 hour or so. So you have them all lined up you just go in and 17 take their blood from each person. And then there are centers 18 that do this; that's what they do. There's a few centers in 19 the country and that's what they do, and the idea is to get a 20 toxicity profile. You want to make sure that it doesn't cause 21 liver damage or kidney damage or cause people to have, you 22 know, convulsions or go into a coma or some horrible toxic 23 effect. I mean, they will show some toxic effect in a higher 24 dose, but you want to make sure it's not going to hurt 25 anybody. 38 1 So then after you're done with that, you do 2 Phase 2. Phase 2 you look at people with the disease. But 3 because you still don't know very much about the drug, you 4 look at people who are otherwise very, very healthy. Now, in 5 our trials and also for Lilly, this was relatively simple 6 because these were mental diseases where people could be 7 otherwise perfectly physically healthy. People can have sleep 8 problems and they ma y not have diabetes; they may not be 9 overweight; they may not have heart conditions. They can be 10 perfectly healthy people with a sleep disorder. And that's 11 the kind of people to put into a Phase 2 trial; they're not 12 supposed to be taking any other what they call concomitant 13 medications; they're not supposed to have any other 14 concomitant disease processes, any other mixing of this with 15 another disease, just the disease you want to test for. And 16 you look at them, and you look at them mainly for efficacy; 17 does this drug help this disease. Of course, you may get some 18 safety problems, too, at that phase. 19 But when you finish the Phase 2, which is just a 20 few hundred patients, you then are supposed to in Phase 3 open 21 up the process and study a group of patients that are going to 22 be more like the patients you would see when the drug is on 23 the market. This is particularly important for a drug that's 24 the first of its type such as this, where no one really knows 25 anything about what the drug is going to do. You have to look 39 1 at what happens to people who are diabetic, what happens to 2 people who have a heart condition, what happens to people who 3 have this condition and another condition. And the other 4 thing you have to think about with a psychiatric drug is that 5 the doctors aren't going to get it right all the time. You 6 know, with any product, with any drug you're going to have 7 some doctors that don't get it right, but it's a lot easier 8 when somebody -- you can take a culture for strep throat and 9 say we've got strep throat; here's your penicillin, than to 10 say you're depressed, here's your Prozac. Because depression 11 can look like other things. You can have somebody who's 12 borderline schizophrenic and if they're not raving like a 13 lunatic, they can come in and the doctor may think they're 14 simply depressed. Nobody wants to give someone the diagnosis 15 of schizophrenia. 16 So you want to look at that group of patients, 17 people that had depression with some borderline schizophrenia, 18 with some schizoaffective disorder, to see what it does for 19 people who might kind of inadvertently and maybe they 20 shouldn't have gotten it but nevertheless did get the drug. 21 You might want to look at bipolar patients. You look at 22 different types of patients, different types of groups, 23 different types of centers. You want to look at, you know, 24 rural centers, big-city centers, centers in low-income 25 housing. You want to make a very broad population so you have 40 1 a good idea, as best you can within the limitations, of what 2 is going to happen when that drug is sold to everybody who 3 comes in to a doctor's office and the doctor feels they could 4 benefit from that drug. 5 Q. Is the patient population in a Phase 2 trial an 6 accurate cross section of the population in general as far as 7 any particular disease, not just in this case? 8 A. No. You look for a very, very pure population 9 of people that have that disease and are otherwise healthy. 10 Q. Why? Why do you do that? 11 A. Because you want to get a feel for the efficacy 12 of the drug in its purest form. You want to get an idea of 13 whether it works without anything else muddling up the data. 14 I mean, if you're looking at an antihypertensive, you want to 15 make sure that if it does work it's because the people had 16 their blood pressure go down, not because they also lost 17 weight or they happened to get more exercise or something like 18 that. You want people to have just that disease so you can 19 get a clear picture of its effectiveness. 20 Q. How are the Phase 2 trials -- are the Phase 2 21 trials relevant from a safety perspective? 22 A. Oh, yeah, of course. The Phase 2 trials will 23 show some adverse experiences are going to pop up during 24 Phase 2 trials and maybe even Phase 1, and it gives you an 25 idea of what might be looked at more carefully later on. 41 1 Q. When you say "later on" what do you mean? 2 A. In Phase 3 where you do more specialized 3 studies. For example, one of the problems with 4 benzodiazepines is some of the shorter-acting ones cause 5 memory problems; people say they're forgetting; they're 6 leaving pots on the stove or they're forgetting to finish 7 their work or whatever. So we did a study that assessed 8 memory where people were given the drug and given a memory 9 test, given choice reaction times, given various types of 10 psychomotor tests. That's the kind of thing you look at; you 11 look at a specialized test to pick up differences in very 12 special types of functioning. You might look at it in a 13 particularly dangerous population, say people who had a 14 breathing problem. 15 Q. What are Phase 4 trials then? 16 A. Phase 4 trials are basically marketing trials. 17 These are trials that the drug company does to promote the 18 drug, to get more people using it, to get more literature out 19 on it. 20 Q. Can you give us an example? 21 A. Well, say a medicine has a new indication they 22 want to get approved, so they look at it, say, in children or 23 in, you know, a different disease process. Maybe you want to 24 say -- you have a hypnotic; you may cut the dose in half and 25 try it in anxiety, or you may want to try it for jet lag or 42 1 something like that. 2 Q. You've told us that you file your INDs after 3 you've conducted the majority of the human studies. Which of 4 studies are filed in your experience with the New Drug 5 Application itself? 6 A. Everything that we file gets filed in the NDA. 7 You do the studies all along and you file a copy of the 8 summary into what they call the IND file at the FDA, but then 9 when you finish everything up, you then refile it as your NDA, 10 that is your actual New Drug Application. And it's volumes; 11 it's a room. I mean, by the time you're done, the volumes 12 could fill that jury box and be six feet tall of all the 13 case-report forms and all the summaries and all the summaries 14 of summaries, statistical tabulations, stuff like that. 15 Q. Are Phase 4 trials required for -- in support of 16 an NDA for the safety and efficacy of the drug? 17 A. No. 18 Q. How about Phase 3? 19 A. Yes. 20 Q. You've reviewed some data and information on 21 your work in this case. Can you tell us what types of things 22 you reviewed? 23 A. I reviewed the summary basis for approval that 24 the FDA personnel prepared. I reviewed some case-report 25 forms, certainly not all of them; I reviewed I guess about 43 1 100. I reviewed some study summaries of maybe 5 or 6 2 different studies. I reviewed some interoffice memos, some 3 correspondence between Lilly and some foreign regulatory 4 organizations -- agencies, rather, and I reviewed some 5 published literature. 6 Q. Did you look at any depositions, Doctor? 7 A. Oh, and some depositions, yes. I looked at 8 several depositions of Lilly personnel. 9 Q. What's a summary basis of approval? 10 A. That is what the FDA medical monitor prepares 11 when they approve the drug. It kind of summarizes the study, 12 summarize the adverse experience protocols. They decide which 13 studies they consider to be pivotal. The FDA decides at least 14 two studies have to be what they call, you know, adequate, 15 well-controlled, placebo double-blind studies, and they would 16 pick for you which studies they consider to be pivotal. And 17 those are the studies they support and on which they base 18 their approval upon, but they actually look at all the studies 19 primarily in terms of safety. So they write up a document 20 that describes what the company did, what the results were and 21 that goes into the file. 22 Q. Who makes the decision on whether or not a study 23 is pivotal? 24 A. The FDA. 25 Q. And if the FDA decides a particular study is not 44 1 pivotal, is it still relevant in the approval process? 2 A. Oh, absolutely. A study could not be pivotal 3 but could have brought out some very serious adverse effect 4 that might become a warning in the package insert. 5 Q. Why did you review clinical-report forms, final 6 reports and protocols? 7 A. Well, I reviewed the case-report forms because 8 that's the first place the data goes. That's the data before 9 anybody plays with it, is what's on the case-report form, so I 10 reviewed that to see if the data was being recorded properly. 11 And then I also looked at the study summaries to look at how, 12 you know, overall the profile of the drug was being reported. 13 But I really felt the most important thing was to look at the 14 actual case-report forms. 15 Q. Define what -- tell the jury what a FD 1639 is. 16 A. An FD 1639 is a form that's required to be 17 filled out by the FDA for what we talked about earlier, 18 serious and unexpected reactions. And it depends -- 3 to 14 19 days depending on the severity of the reaction, and that is 20 filled out along with the case-report form that, if there's a 21 serious reaction, they should also report it in a 1639 because 22 the FDA will look at those. 23 Now, that isn't the only time you get a 1639. 24 Once a drug is on the market, people can send -- can fill out 25 a 1639 on a voluntary basis; it's called the spontaneous 45 1 reporting system. Doctors can do it, attorneys do it, 2 individuals do it; anyone who finds out about something about 3 a drug that's a little strange can fill out a 1639 and send it 4 into the FDA. And what they do with that is they come up with 5 a computerized tabulation, which is publicly available. If 6 one of you-all had a doctor that said, "I want you to take 7 such and such a drug," and you were real nervous about it, you 8 could call up the FDA and get that computerized list sent to 9 you. It would cost some money, but you could get it and see 10 exactly what kinds of adverse experiences were being reported. 11 Q. What is the difference between a spontaneous 12 adverse event and an adverse event that is reported in a 13 clinical trial? 14 A. Well, a spontaneous-reporting adverse event is 15 one that a doctor simply decides to do; they're not required 16 to, but they can do it, and that is the ones they voluntarily 17 just fill out a 1639 and send down to the FDA. On a clinical 18 trial you're required to send one in for every serious and 19 unexpected reaction, and you're required to report everything. 20 Q. Are the manufacturers required to report 21 spontaneous adverse events? 22 A. Oh, the manufacturers -- I'm sorry. Once the 23 manufacturers get it, they must report it. If it comes in to 24 Lilly or Abbott, they have to send it along; where the option 25 comes up is at the level of the doctor's office. The doctor 46 1 does not have to fill one out for everything. 2 Q. Does it matter how Lilly or another manufacturer 3 becomes informed after an adverse event as to whether or not 4 they have to report it? 5 A. No. If they get a 1639, it goes in, period, end 6 of story. 7 Q. What if they get a phone call from a doctor? 8 A. They should fill out a 1639. 9 Q. What if they overhear a conversation where 10 somebody says, "My wife took Prozac and developed a rash"? 11 A. They should probably fill out a 1639. If they 12 find out about it, they should report it. 13 Q. Have you formed any opinions in this case, 14 Doctor Lord? 15 A. Yes, I have. 16 Q. Can you tell us what those opinions are, please. 17 You can start -- we'll write them down and then go back over 18 them, but if you could give us a list of what your opinions 19 are. 20 A. When I looked at the Lilly data, I didn't find 21 that it was adequate to study this drug. The data was flawed 22 for a number of reasons. First of all, the protocols were not 23 well designed; they permitted the use of concomitant meds. 24 Not only did they permit the use of concomitant medications, 25 but they permitted the use of psychotropic concomitant 47 1 medications, medications that acted on the very same system of 2 the body, the brain, that they were studying in a drug of 3 which they had very little knowledge. This was not the 4 seventh or eighth benzodiazepine; this was a drug that really, 5 really was the first. And they then basically treated the 6 adverse experiences. If somebody came on to a trial and got, 7 say, insomnia, they couldn't sleep, or they became jumpy and 8 agitated, instead of having them withdraw and counting that 9 person as someone who couldn't handle the drug, they simply 10 gave them Dalmane to go to sleep, which has a lingering 11 anxiolytic effect during the next day. 12 They broke the blind. As people finished up the 13 trials, the investigators were allowed to break the blind and 14 make a decision whether that person should go on an open-label 15 fluoxetine long-term study, meaning if they were doing well 16 and were on fluoxetine, they could stay on it; if they were on 17 imipramine and were not doing well, they could switch to 18 fluoxetine. But by doing that, the investigator gained some 19 knowledge that they could have been consciously or 20 unconsciously breaking the blind in their mind on future 21 patients. 22 They did not code adverse experiences correctly. 23 Problems that caused the use of concomitant medication were 24 often not reported. In some cases, things were reported as 25 something else. Say they were called severe agitation in one 48 1 place on the case-report form and then it would wind up in the 2 1639 as nervousness or, as I said before, some places they 3 were not reported at all. 4 They never really did Phase 3; they did a large 5 Phase 2. They did the same protocol over and over. They 6 never really opened it up and looked at the different types of 7 people that would inevitably be getting this drug once it got 8 on the market. They never did a special study. They knew -- 9 I mean, they said in their own depositions that 15 percent of 10 depressive people have suicidal ideation. The correct way to 11 handle that is to look at a group of people that we know have 12 suicidal ideation, look at them in a hospital where they can't 13 get hurt and see what happens. They knew that animals very 14 early on had some aggressive behavior. They didn't do 15 anything to study this in people who had a tendency towards 16 aggression. They never looked at the problems; all they did 17 was sort of cover it up. 18 Q. Do you have any criticism of statistical 19 analyses used by Lilly in their data? 20 A. Well, they didn't use adequate samples. They 21 made a big deal out of not getting statistical significance 22 for certain -- you know, a few studies that they did, and they 23 didn't really have adequate sample size to expect statistical 24 significance. 25 Q. Did they plan the statistical analysis that they 49 1 were going to use at the outset of the trial or did they wait 2 till after? 3 A. They never planned it. Every protocol that I 4 looked at said statistical -- the statistical analysis will be 5 sent in later. They didn't decide until they got the data 6 what they were going to do to it. They just let it come in 7 and then they took a look at it statistically. 8 They did some strange things in the way adverse 9 experiences were coded on COSTART. They changed one thing to 10 something else and then they didn't change other things where 11 they maybe should have. It looked like they did everything 12 possible to kind of tone down the problems with the drug 13 rather than give them a rigorous, systematic and comprehensive 14 evaluation to define what the problems were and then put it in 15 the package insert so that doctors could be warned not to use 16 the drug in certain types of patients, or to use it more 17 carefully. 18 Q. Do you have any criticisms about the way the 19 data from overseas was gathered and reported? 20 A. Yes. At one point in 1984, Eli Lilly received 21 word from the British authorities that they were not going to 22 approve this drug because of their concern with suicidality 23 and agitation. They said that people became agitated before 24 the antidepressant effects came on and that increased the risk 25 of suicide. They wrote a memo concerning untoward damaging 50 1 effects, and Lilly then went over there and looked at the data 2 again and pulled out cases that they didn't think were 3 suicide. 4 First of all, how are they to know. The 5 investigator thought it was a suicide attempt. They said, 6 well, they don't think it is. And, even so, if somebody did 7 something really bizarre like cut themselves up with glass, 8 even if it's not a suicide, that's really a horrible, bizarre 9 thing for somebody to do. That's still something to be 10 concerned about it. 11 Then they misrepresented to the FDA what went on 12 with the British authorities. Under their approvable letter, 13 they should report anything that happened with foreign 14 authorities and they deliberately misrepresented what happened 15 with the British authorities; they made it sound like the 16 Germans hadn't made it clear what they were talking about in a 17 particular memo when, in fact, if you look at it in its 18 entirety it's clearly talking about suicide. A particular -- 19 Q. When you kept saying British before did you mean 20 the Germans? 21 A. The Germans. I'm so sorry. 22 Q. Did you see anything that was of importance in 23 the British government or the UK's review of the drug? 24 A. The same thing. They were concerned about 25 safety. And the Danish were very concerned about what 51 1 happened to the dogs; that the dogs had become aggressive. In 2 fact, one dog actually bit one of the handlers. 3 MS. ZETTLER: Judge, we're going to go back and 4 get into these in more detail. This might be a good time to 5 take the break. 6 JUDGE POTTER: Ladies and gentlemen, we'll take 7 the morning recess. As I've mentioned to you-all before, do 8 not permit anybody to talk to you about this case; do not 9 discuss it among yourselves and do not form or express 10 opinions about it. We'll take a 15-minute recess. 11 (RECESS; BENCH DISCUSSION) 12 MR. FREEMAN: We would like for an instruction 13 and standing objection to the Witness characterizing as 14 coverup, intentionally misleading or something of that kind 15 when she's talking about a particular act or action. This is 16 not in the disclosure. 17 JUDGE POTTER: I'm going to sustain the 18 objection. I think your Witness ought to stay away from 19 testifying about what's inside Lilly's corporate head when 20 she's describing any individual event. She can say they 21 failed to report or did not disclose. 22 MS. ZETTLER: Just don't ascribe any motive to 23 it? 24 JUDGE POTTER: Yes. 25 MS. ZETTLER: Okay. 52 1 (BENCH DISCUSSION CONCLUDED) 2 SHERIFF CECIL: The jury is now entering. All 3 rise. All jurors are present. 4 JUDGE POTTER: Please be seated. Doctor Lord, I 5 remind you you're still under oath. 6 Ms. Zettler. 7 Q. Doctor Lord, before the break you listed a 8 number of opinions you have based on the report you have and 9 the experience. Let's go back and go through those in a 10 little more detail. One of your opinions is that the clinical 11 trials were improperly designed. Can you explain to the jury 12 what you mean by they were improperly designed? 13 A. Well, part of the study design is what is to be 14 allowed and what is not to be allowed. In this case, the 15 investigators were permitted to use psychotropic medication 16 and they sedated the people. The people who were on these 17 trials, if they had certain types of adverse experiences, 18 instead of being taken off the drug, whether it was 19 fluoxetine, placebo or whatever, were sedated with either 20 chloral hydrate, Dalmane or, in some cases, other types of 21 benzodiazepines. On top of that, the investigators were 22 instructed not to report as adverse experiences symptoms of 23 depression, and many of those symptoms are exactly the kinds 24 of things that are of concern here: insomnia, agitation, 25 nervousness, restlessness, those types of things. There were 53 1 investigators who did not code those as adverse experiences 2 because they considered them to be symptoms of the underlying 3 disease. And even if they were, how people did with those 4 symptoms is important; whether they got worse or whether they 5 got better was something that the FDA and the doctors who 6 would be using this product deserved to know. To simply 7 sedate them, make those things less of a problem and then not 8 report them, was, in my opinion, improper. 9 Q. Just for clarification, please explain to the 10 jury just quickly what a concomitant medication is. 11 A. A concomitant medication is a medication that 12 someone takes along with a study drug. Now, on a six-week 13 trial, people are going to take something. You can't expect 14 them to go for six weeks never needing an aspirin, never 15 needing a Motrin, not getting an infection and needing an 16 antibiotic. Those sorts of things are expected. But in this 17 case, they regularly, systematically, and in a large portion 18 of the people used tranquilizers, sedatives, to calm people 19 down. It happened in very high percentages of the people on 20 the study, and it completely obscured what this product was 21 doing to people's minds. 22 Q. What types of percentages did you see in the 23 clinical trials that you reviewed? 24 A. I saw between 10 and 30 percent were getting 25 some sort of sedative on these trials. 54 1 Q. Now, were people on the other drugs -- if there 2 were other drugs used in the studies that you reviewed -- were 3 they also given concomitant medications in general? 4 A. Yes. I mean, there were people on imipramine 5 that also got them. But it really doesn't matter because we 6 already know that imipramine is safe and effective; we needed 7 to find out what happens when people take fluoxetine and don't 8 get a sedative. In my opinion, this drug has not been 9 approved. It's been approved with sedatives, but taking 10 fluoxetine all by itself has never been studied. 11 Q. Now, are you saying -- is it your testimony that 12 you can never use a concomitant medication in any clinical 13 trial? 14 A. Absolutely not. It happens all the time that 15 people require some sort of concomitant medication, but it's 16 generally for something completely different. Say they get a 17 sore throat and need some penicillin, they have a headache and 18 take a Motrin; that's the sort of thing you have concomitant 19 medications page for. If their side effects from this drug 20 are so bad that they need to be given a sedative such as 21 IV Valium, which happened and we'll talk about that later, the 22 proper remedy is to take them off the study and analyze them 23 statistically as someone who terminated early because of an 24 adverse experience, and that was not done. We never had a 25 chance to see how many people would have not been able to take 55 1 this drug had they not been allowed to take sedatives along 2 with it. And oftentimes, people who did withdraw, many of 3 whom were taking sedatives and still were so uncomfortable 4 they couldn't continue, they didn't put down that they 5 withdrew because of a problem, but they said, often, lack of 6 efficacy or patient decision. 7 Q. Okay. So let me make sure we understand this. 8 If a patient requires a concomitant medication during the 9 trial, would the reason for that concomitant medication 10 prescription be considered an adverse event? 11 A. Yes. 12 Q. Okay. And it doesn't matter if it's somebody 13 who is becoming agitated on Prozac or somebody who develops a 14 sore throat? 15 A. That's right. They're both adverse events. 16 Q. What if we were to take those people who 17 received concomitant medications during the clinical trials 18 out of the analysis and just analyzed those patients who did 19 not receive concomitant medications for whatever reason? 20 A. You still at that point would get a flawed 21 sample because then you would be studying only those people 22 who were able to take it without a problem. You still need to 23 analyze how many people got so uncomfortable they had to stop 24 taking the drug, and that would have to be part of the 25 analysis. To simply remove those people from the group and 56 1 evaluate everybody else is skewing the data because you've 2 removed the people who had trouble with it. That would be 3 like saying if you had an antihypertensive, a drug for high 4 blood pressure, that was causing 10 percent of the people to 5 get a rash, to say take those 10 percent of the people out of 6 the data base and analyze the 90 percent who didn't get rashes 7 and say nobody got a rash, I mean, that's absurd. You have to 8 evaluate the fact that people had to stop taking the drug or 9 had to take a sedative along with it. 10 Q. You said that in your opinion Lilly instructed 11 the clinical investigators not to list symptoms of depression 12 as adverse events. Is that something you found in the 13 protocols themselves? 14 A. No. It was on the case-report forms, and it was 15 pointed out by the FDA in one of their monitor's notes. 16 Q. Did you in fact see in your review of the 17 clinical-report forms instances where symptoms of depression 18 were not listed as adverse events? 19 A. Numerous, numerous times. 20 Q. Can you give us some examples of what types of 21 adverse events you're talking about? 22 A. Insomnia. A great many people were taking 23 chloral hydrate or flurazepam for insomnia and it was not 24 listed; nervousness, agitation. 25 Q. If a doctor writes on the clinical-report form 57 1 that an adverse -- strike that. 2 If a doctor writes on the clinical-report form 3 that a person is given a concomitant sedative, for instance, 4 or a sleeping pill, isn't that sufficient to put the FDA on 5 notice that that person had had the adverse event, say, of 6 insomnia? 7 A. No. 8 Q. Why not? 9 A. Because they have to be allowed to look at it 10 where they're most likely to find it. To hide it in with 11 other concomitant medications that might be antibiotics is not 12 an accurate portrayal of the data. The FDA was entitled to 13 see how many people got insomnia, whether they were treated 14 for it or not, not to simply list the fact that certain people 15 had to take chloral hydrate. They did that; they did give a 16 list of how many people took chloral hydrate and how many 17 people took flurazepam, but by doing it that way, they never 18 had a chance to see how many of those people could have put up 19 with their insomnia and completed the trial without it and how 20 many people would have had to go off the trial, and that's 21 part of the trial that we'll just never know at this point. 22 Q. You mentioned lack of efficacy earlier. What 23 did you mean by lack of efficacy? 24 A. Well, again, reasons for early termination. And 25 one of them that I found in several cases I saw reading the 58 1 case-report form, it was apparent to me that the reason the 2 person was terminated early was because they became very ill, 3 they got very uncomfortable for a number of different reasons, 4 mostly having to do with some sort of stimulating or 5 activating effects. And the reason given for the 6 termination -- and I'll show you some examples of that later 7 on -- was lack of efficacy. I also saw in some of the 8 protocols -- some of the summaries a number of people who were 9 terminated for patient decision, and I'd like to know what 10 that was, as well. The patient made a decision. Was the 11 decision based on not liking the way the buses ran, or was it 12 based on feeling jumpy and jittery, like they're jumping out 13 of their skin. We don't know. We're just told patient 14 decision. 15 Q. Is it permissible for the investigator or the 16 sponsor or manufacturer of the drug to list that a patient -- 17 the drug was not efficacious with a certain patient? 18 A. Oh, absolutely, and you should. 19 Q. Then how is it that the lack of efficacy 20 determinations that you're talking about impede or somehow 21 affect the data that was gathered during the clinical trials? 22 A. Because the ones that I looked at showed more 23 than lack of efficacy. I mean, there was -- there was one 24 case where somebody had to get IV Valium. There are people 25 that got stimulated, agitated. These are adverse events; 59 1 they're not lack of efficacy. Lack of efficacy would be if 2 the person came into the study center and said, "Doc, it's 3 just not working; I'm still feeling really blue. This is not 4 the drug for me." That's lack of efficacy. 5 Q. Is it appropriate for the clinical investigator 6 or manufacturer to list a patient as having dropped out of the 7 study because of their own decision? 8 A. Yes. 9 Q. Then what is your criticism about the way that 10 it was done here? 11 A. My concern is that, in light of the way other 12 dropouts were reported, that my concern is the patient made 13 the decision for a reason that we weren't given. A patient 14 decision might be, like I said, the bus line just didn't work. 15 It took them too long to get to the center, or maybe they got 16 a job that made it inconvenient to come in for their visit, 17 something like that. My concern is the patient's decision may 18 have been made because they were feeling very uncomfortable on 19 the drug and that we should have been told about. We don't 20 know. Maybe it was that everybody couldn't get on the bus. 21 But when we see an adverse experience profile like I observed 22 on the case-report forms that I looked at and then other 23 studies where four and five patients are dropping out for 24 patient decision, I have to wonder what was the real reason 25 behind that patient decision. 60 1 Q. You also said that one of your opinions was that 2 the adverse events that occurred or some of the adverse events 3 that occurred during the clinical trials were not properly 4 reported. Please explain what you meant by that. 5 A. Well, sometimes they were reported only on the 6 concomitant medications page; sometimes they made it from the 7 concomitant medications page to what they called -- there was 8 a page in each weekly visit called treatment-emergent 9 Symptoms, which was a list of adverse experiences the person 10 had that week. Now, in some cases, as I said, things they got 11 medication for didn't make it to that page; in other cases, 12 they were changed between the concomitant medications and that 13 page. Maybe it was agitation for the concomitants and it 14 became nervousness on the treatment-emergent symptoms. In 15 other cases, they listed things on the treatment-emergent 16 symptoms, but then when they filled out the 1639, they didn't 17 include them. Maybe there was someone who got agitation, 18 insomnia and a headache and then the 1639 said nervousness, 19 insomnia and a headache. They changed it, and they changed it 20 in a way that made it sound less serious. 21 Q. Let's back up just a second to concomitant 22 medications. How would what Lilly did, in your opinion, in 23 this case affect analysis of the data that was gathered in the 24 clinical trials? 25 A. It renders it worthless. You cannot evaluate 61 1 bad data. Statistics can only look at the data they're given. 2 If you have data where people are being sedated and you're 3 looking, say, for the incidence of agitation, only the people 4 were sedated and the agitation that was reported anyway is 5 reported as nervousness, how can you possibly do a statistical 6 analysis for agitation? If people's -- if suicidal ideation 7 is coded as depression and everybody on the study was 8 depressed, how can you possibly look for suicidal ideation and 9 have that data be of any value? The foundation here is so 10 poor and so flawed that no matter what you did statistically, 11 there is no way you could get a meaningful analysis because 12 they made so many errors in how the data was collected and how 13 the patients were placed on the studies. 14 MS. ZETTLER: May I approach the Witness, Your 15 Honor? 16 JUDGE POTTER: Yes. 17 MS. ZETTLER: Judge, I'm showing Doctor Lord 18 what has been marked Plaintiffs' Exhibits 198 through 207. 19 Doctor Lord, I'm showing you Exhibits 198 20 through 207. Could you tell us what those are, please. 21 A. These are some samples of case-report forms that 22 have the kinds of problems that we've been talking about. 23 It's by no means all of them; this is simply a group that I've 24 collected to show the jury what kinds of things were going on 25 in the way the data was collected. 62 1 MS. ZETTLER: Judge, move that Exhibits 198 2 through 207 be admitted. 3 JUDGE POTTER: Be admitted. 4 MR. FREEMAN: These documents, Your Honor, are 5 not complete. 6 JUDGE POTTER: I don't know. You'd just have to 7 get Ms. Zettler to ask the Witness. I assume they're not 8 complete. 9 Q. Doctor Lord, are these the entire case-report 10 forms for each of these patients that you reviewed? 11 A. No. These are only the relevant pages; the 12 entire case-report form would have been about that thick. 13 MR. FREEMAN: They're not complete. They're not 14 a complete case-report form, for example, on Patient No. 0027. 15 DOCTOR LORD: I said that. 16 JUDGE POTTER: Let me see you-all up here. 17 (BENCH DISCUSSION) 18 MS. ZETTLER: Judge -- 19 JUDGE POTTER: What does 0027 -- 20 MR. FREEMAN: That refers to the patient's 21 number at the top of the page. There it is right here and 22 this is a portion of that case-report form. That's not the 23 complete case-report form on that patient. 24 MS. ZETTLER: We did it really to just save 25 space and paper. These things are sometimes this thick and 63 1 what she looked at were these specific pages, and these 2 specific pages were things about safety and adverse event. 3 JUDGE POTTER: If I understand the objection 4 that only for my own information a case-report form is one 5 patient may have 25 case-report forms, that's something that 6 comes in weekly or daily or however it's set up. And the 7 objection is that these are not complete case-report forms; is 8 that the objection? 9 MR. FREEMAN: Yes, sir, on that patient. 10 JUDGE POTTER: And in your view, Ms. Zettler, 11 it's that these are the critical pages from this case-report 12 form that's going to illustrate what? 13 MS. ZETTLER: What actually causes her to have 14 opinions about it. 15 JUDGE POTTER: And everybody has a complete 16 case-report form somewhere? 17 MS. ZETTLER: Right. In fact, if you want, 18 Judge, I can bring in copies this afternoon. 19 JUDGE POTTER: I'm going to overrule the 20 objection as long as it's clear to the jury that these 21 exhibits are not provided as anything other than excerpts from 22 a particular case-report form. 23 MS. ZETTLER: Sure. Absolutely. No problem. 24 (BENCH DISCUSSION CONCLUDED) 25 Q. Just so we're clear, the exhibits that I've 64 1 shown you, are those the entire case-report forms that were 2 available for each of those patients? 3 A. No. 4 Q. Why did you select just portions of these? 5 A. For clarity. The points that I want to make can 6 be demonstrated with what's here. I didn't see any reason for 7 confusing -- you know, for putting a whole lot of confusing 8 stuff and stuff that might otherwise be fine. These were the 9 pages I had a problem with and these were what I selected to 10 bring in. 11 MS. ZETTLER: Judge, we move that Plaintiffs' 12 Exhibits 198 to 207 be admitted. 13 MR. FREEMAN: I'll object. 14 JUDGE POTTER: Be admitted. 15 MS. ZETTLER: We also have copies for the jury, 16 Judge. 17 SHERIFF CECIL: (Hands document to jurors). 18 Q. Doctor, we don't have to go through these in the 19 order they're marked, if there's any particular report you 20 want to start with, but let's give the jury an idea of what 21 types of things we're looking at in these reports. 22 A. Let's start with the one marked HCAA 3 42. 23 Q. Can you tell us which exhibit number that is? 24 A. That would be 199. 25 Q. Okay. Just before you get into the specifics of 65 1 this particular report, just take us through a little bit of 2 what we're looking at when we look at this exhibit. 3 A. Okay. These exhibits are -- well, there's a top 4 page, and either the first page -- we may have put it in the 5 last page -- we have the drug experience report that was filed 6 for that patient. 7 Q. Is this an actual example of a 1639 report 8 that's filed with the FDA? 9 A. Yes, it is. 10 Q. Okay. Go ahead. 11 A. This is a list of the experiences that person 12 had during the study. Then there's another page that has 13 psychiatric diagnosis on it. This is the person's intake; it 14 has information about what their diagnosis was, their personal 15 data, their birth date, things like that, how old they were, 16 whether they were married, and it gives you the data 17 inventory, how long they've been depressed. And one thing I 18 found very important here, in most of these people -- and 19 we'll talk about this more later -- on No. 6, the patient came 20 to the hospital, and it goes: 21 One, the patient's own initiative; 22 Two, others' initiative, relative, friend, 23 doctor, police, et cetera; 24 And, Three, not ascertained. 25 Almost all of these people came into the 66 1 hospital on their own. That means they were motivated to get 2 well. They came in voluntarily and said, "I'm sick. I need 3 help." And whether the person's cooperative or uncooperative. 4 Q. Does this indicate to you that this study was in 5 fact an inpatient study as opposed to an outpatient study? 6 A. That is correct. This was a study done inside a 7 psychiatric hospital. 8 Q. Explain for the jury -- I think some of the 9 differences are obvious, but what the difference between an 10 inpatient study and an outpatient study would be. 11 A. Well, there are several differences. People who 12 are in a hospital obviously are sicker. I mean, depression 13 can be a lot of things. We've all been depressed from time to 14 time; we've all been sad; we've all had things go wrong in our 15 lives, and sometimes that may go on longer than we'd like them 16 to. But some people become so depressed that they cannot 17 function and there's a wide variety of types of depression. 18 Sometimes it can be so severe as to exhibit becoming 19 psychotic, depression where the person is no longer in touch 20 with reality. They may have other types of disorders; 21 personality disorders, schizoaffective disorder. People in a 22 hospital, obviously they're more serious. You don't go to the 23 hospital because you lost your job and you're feeling sad; you 24 go because you really feel you need some serious medical help. 25 The way a hospital has more opportunities to 67 1 study people is that it's a much more controlled setting. You 2 can keep an eye on people. You can see what they're doing 24 3 hours a day. You can prevent them from getting ahold of 4 things that are dangerous where they could hurt themselves or 5 other people. You can observe their interactions with other 6 patients and staff. You know, there's an opportunity to do 7 things here in this population that you might not get a chance 8 to do if you just simply gave the person some pills on a 9 questionnaire every week. So, you know, there's -- that's 10 basically the difference. You have people that are more ill, 11 but you also have a greater opportunity to take care of them 12 in a hospital. 13 Q. Is it your understanding, at least with this 14 patient, that this patient was involuntarily committed to the 15 hospital for this study? 16 A. Actually, with this person I'm not really sure. 17 It does say they came on others' initiatives. This is No. 42 18 that I want to start with. Most of them they're not, but this 19 particular one might be, though it isn't indicated. However, 20 I think it would be very difficult to do a study on someone 21 who has been involuntarily committed because basically an 22 involuntary commitment means that they're so incapacitated 23 they can't be trusted to make the decision not to go in the 24 hospital, so I don't know how valid an informed consent would 25 be on someone that had been involuntarily admitted. 68 1 Q. If you can continue telling us what we're 2 looking at here. 3 A. Okay. Well, there's different things in 4 different forms, so maybe we should start with this one and 5 where it's the same for another form we'll later use, we can 6 say so. These are the pages that are there for everybody. On 7 this one, Patient 42 -- does everybody have them? 8 JUROR BAILEY: 3 42? 9 A. Uh-huh. Yes. 10 Q. Why don't you explain to the ladies and 11 gentlemen of the jury what this little code at the top of the 12 first page is. 13 A. Okay. The code at the top of the first page is 14 what protocol it was, what study. HCAA was a multicenter 15 study. It had several different groups doing the same 16 protocol. HCAA 3 meant Investigator No. 3, and then the last 17 number, 42, is the patient number. Remember I said earlier 18 that you get all the case-report forms and the drug for each 19 patient number, and as someone's admitted to a study, they 20 receive a patient number. 21 Q. I'm sorry. Go ahead, Doctor. 22 A. Okay. So if you go through this, we have the 23 drug experience report which says dizziness. 24 Q. Where is that? 25 A. This is the second page. It says on 3-20-79, 69 1 the person experienced dizziness, describe suspected reaction. 2 And then we have the page we've already talked about. On the 3 next page, which is PZ 12 2996 -- 4 Q. Where do you find that number? 5 A. That would be at the lower right-hand corner, 6 and this is the fourth page in that stack. It says 7 predominant mood, and you note other, schizophrenia, paranoid 8 type. So this person had some co-existent schizophrenia. 9 Q. What visit is this on? 10 A. This is on the first visit. This is before they 11 got anything, placebo, drug, anything. This is what they were 12 going into the trial. 13 On the next page we see the Hamilton D rating 14 scale. This was the psychiatric scale that was used to 15 evaluate these trials, to determine how well people were doing 16 on the different products, whether it be fluoxetine, placebo 17 or imipramine. What I found interesting about this particular 18 guy was that every -- almost every item here is checked zero, 19 which is normal. 20 Q. Would this person be depressed, according to the 21 scale, Doctor? 22 A. According to the scale, they weren't. They were 23 not depressed. I don't know why they're on the trial because 24 the HAM-D was within normal range. 25 Q. What is your understanding of what the purpose 70 1 of this trial was? 2 A. To assess the efficacy in treating depression. 3 Anyway, then if you notice, Visit Three -- let me explain how 4 the visits worked. On Visit One the person came in, okay; 5 they were given a placebo for washout. 6 On Visit Two they came back and that was 7 evaluated, and they were given the randomized -- well, in this 8 case they were all on fluoxetine; this was an open-label 9 study. So they were given fluoxetine for the first time in 10 Visit Two. 11 So the first visit that you have a chance to see 12 what the fluoxetine did is Visit Three, so you'll notice that 13 a number of these things, though I do have some baselines in 14 here, start with Visit Three. 15 If you notice the next page, we have chloral 16 hydrate taken from 3-9 to 3-15 -- that means pretty much the 17 whole week -- for insomnia. 18 Q. Okay. Can you tell us where on the page? 19 A. At the bottom of the page. This is the next 20 page where it says Interviewer's Report, and it's PZ 12 3013. 21 Q. And what is the significance of that, Doctor? 22 A. This person had insomnia and had to get chloral 23 hydrate almost every night -- actually every night, 9th 24 through 15th is 7 days. 25 Then we look at what they call the next page is 71 1 treatment-emergent symptoms. This is the list of symptoms 2 that are going to be used to create a table of adverse 3 experiences for this study. And if you look at the left lower 4 hand -- lower left-hand corner, you will see the words 5 Nonapparent. 6 Q. What is your criticism of that, Doctor? 7 A. Insomnia should have been listed as a symptom. 8 Q. Okay. 9 A. Okay. Is everyone ready to go to Visit Four? 10 Next page, Visit Four, again, we have chloral hydrate, 11 500 milligrams, every night at hour of sleep for insomnia. 12 And the next page, this time it's -- the page is 13 upside down. If you look at the top right you will see a 14 symptom, dizzy on arising for three days. Again, no mention 15 of insomnia. 16 On the next page, again, we have chloral hydrate 17 taken every day for insomnia and, again, on the treatment- 18 emergent symptoms for that week, the next page, we see 19 intermittent dizziness. 20 On Week Seven, -- this is the last day of the 21 study -- again, chloral hydrate every night. You know, and I 22 think we omitted to put that last TES in there. I'm sorry. 23 But you can see that on the adverse experience form, there's 24 no mention of insomnia. 25 Q. When is the adverse experience form filled out 72 1 generally for these types of adverse events? 2 A. They could be filled out at the end of doing the 3 summary; they might be filled out at the very end of the NDA. 4 With us, they filled out a lot of them when the whole thing 5 was over. 6 Q. Just so we make it clear, are there requirements 7 when it should be filed within a specific period of time? 8 A. That would be for the serious or unexpected 9 reactions. 10 Q. Doctor, how does the lack of reporting the 11 insomnia, for which the chloral hydrate was administered, 12 impact the validity of the data? It seems like a very minor 13 thing. 14 A. Because one of the adverse effects that's very 15 indicative of activation -- this is the drug in a certain 16 group of people stimulates them, activates them, makes them 17 restless. One of the symptoms of that is insomnia. When the 18 company added up all the insomnias, they didn't include this 19 guy. They included him in their list of people who got 20 concomitant medications, but they didn't include him in the 21 list of people who got insomnia. So when the package insert 22 says only 9 or 10 percent of the people got insomnia, that's 23 not all the people that got insomnia, and there's many, many 24 of these types of case-report forms; this is just an example. 25 There were many other case-report forms where insomnia was 73 1 treated and not reported as an adverse experience. 2 Q. Are you through with this patient or would you 3 like to... 4 A. Yeah. There are some letters there, but they 5 also are included in some other patients so we can talk about 6 them then. Yeah. We're done with this one. 7 The next one I'd like to talk about is 8 HCAA 4 27. 9 Q. And that's Plaintiffs' Exhibit 198? 10 A. Right. 11 Q. Okay. 12 A. Now, this person did come in on their own and 13 suffered from a primary major depressive disorder. 14 The next page is his treatment-emergent-symptoms 15 page for Week Three, Visit Three, first week on fluoxetine. 16 If you look at the lower left-hand corner you will see 17 agitation. "Comments: agitation, sleep disturbance, pressure 18 in head. Dose related to 20 milligrams daily. Symptoms 19 slowly resolving." 20 And on the next page -- we have another page we 21 haven't talked about before, this is called Clinical Global 22 Impressions. This was -- this is filled out by the 23 investigator. If you look at the middle portion on the right 24 side of the page, you'll see an X marked, and that's for side 25 effects, therapeutic effect over on the left and what this is 74 1 marked as worse, and under the top column it says, "Outweighs 2 therapeutic effect." 3 Q. Okay. What does that tell you, Doctor? 4 A. That in the opinion of this investigator, this 5 person was so much worse that the -- any benefit to the drug 6 was outweighed by the problem that the drug caused. 7 Now we go on to the drug experience report and 8 see what they told the FDA about this patient, and we see 9 three symptoms there: headache, insomnia, nervousness. 10 Q. What is your criticism of that, if any? 11 A. Agitation. It was very important to find out 12 how many people were agitated. And they can't even use the 13 excuse here that these are symptoms of depression because 14 insomnia and nervousness are symptoms of depression, too. 15 Q. To your knowledge, was the event term agitation 16 and COSTART mapped to nervousness during this period of time? 17 A. No. It mapped to agitation. We used it on my 18 trials. 19 Q. What would have mapped to nervousness, if you 20 know? 21 A. Nervousness? 22 Q. If you know. 23 A. I don't know exactly what terms of -- I know 24 nervousness would, things like restlessness, perhaps. Okay. 25 Then skip the next one; we'll go back to that. 75 1 Q. Let me ask you one other question about this. 2 A. Okay. Sorry. 3 Q. How does what happened to this patient impact on 4 the data that was gathered in this study? 5 A. Well, the adverse experience report is not going 6 to provide an accurate assessment of what happened to him. It 7 doesn't list agitation. If the FDA were to go through there 8 and try to figure out how many people got agitation, it 9 wouldn't be there. 10 Q. Okay. Well, but they've got this signs, 11 symptoms and illnesses or -- I'm sorry. This treatment- 12 emergent symptoms form to look at. Couldn't they just look to 13 this and see that agitation is listed there? 14 A. Well, they don't. Very often they look at -- 15 different people look at different parts of the NDA. 16 MR. FREEMAN: Your Honor, I think it's 17 inappropriate for her to say what the FDA looks at and doesn't 18 look at. It says clearly here look at the adverse event form, 19 which refers to agitation. 20 (BENCH DISCUSSION). 21 JUDGE POTTER: What Mr. Freeman is doing is 22 saying your client is not qualified to say what the FDA looks 23 at and doesn't look at. 24 MS. ZETTLER: She filed an NDA on a drug. I can 25 ask her within her own experience. She's familiar with the 76 1 review process. It's not like you just file these things all 2 at once; they're filed intermittently. 3 JUDGE POTTER: I want you to have her lay a 4 foundation for being able to say what she thinks goes on 5 inside the FDA. 6 MS. ZETTLER: Okay. 7 (BENCH DISCUSSION CONCLUDED) 8 Q. Doctor Lord, in your NDA that you filed, did you 9 just file all of the final reports and data on clinic-report 10 forms with the FDA at the end -- when you filed your NDA or 11 was that done intermittently throughout the process? 12 A. We'd send the summary and I believe the 13 case-report forms down to the FDA. As I said, I think the 14 adverse experience reports were done at the end. 15 Q. Okay. Is it your experience that the FDA 16 reviewed every single clinical-report form in every study that 17 you filed with your NDA? 18 A. Absolutely not. Our understanding was that they 19 would be spot-checked, that we might be getting some calls for 20 various questions on them, but it was not something they had 21 the manpower or the time to do. I mean, this is a room full 22 of documents. 23 MR. FREEMAN: There's been no background laid 24 for this. She's never worked for the FDA and doesn't know 25 what they looked at. 77 1 JUDGE POTTER: Objection is overruled. 2 Q. Okay. I'm sorry we interrupted you with that, 3 Doctor. Again, I think you were explaining to us why it's 4 important to list the adverse event on the 1639 as opposed to 5 just on the treatment-emergent symptoms form. 6 A. Because one of the data bases that the FDA looks 7 at is the 1639s; they look at those. Now, somebody else might 8 look at the tabulation of the summaries, but the 1639s are 9 supposed to be accurate. It makes no sense to have one thing 10 on the 1639s and something else on the treatment-emergent 11 symptoms. They're supposed to match. 12 Q. Okay. Which patient would you like to review 13 now? 14 A. Number Nine. This would be -- it's I think the 15 fourth one down with what's left. 16 Q. Can you give us the Plaintiffs' exhibit number? 17 A. 203. Okay. This one, if you look at his first 18 admitting page, he was a little bit sicker than some of the 19 others. He had primary major depression, endogenous major 20 depressive disorder, recurrent interpolar major depressive 21 disorder and incapacitated major depressive disorder. He did, 22 however, come in on his own. 23 Q. What is endogenous major depressive disorder, if 24 you know? 25 A. Endogenous is kind of a depression that comes on 78 1 for no apparent reason. It tends to happen in the middle 2 ages. People just become depressed. It's not that they lost 3 their job or got divorced or anything; it's just kind of 4 endogenous, it just happened. You don't really know why. 5 Now, this one does have a co-existing event I wanted to 6 demonstrate. On Visit Four, there is a note, "During this 7 rating period, patient learned that wife is filing for divorce 8 and will return all community property. This probably has 9 skewed results." 10 Q. Okay. Why do you highlight that? Why is that 11 important, Doctor? 12 A. Because I think we need to see, this is part of 13 evaluation, what's going on. When you look at an adverse 14 experience, you need to know the context, you know, like we 15 were talking about the bus. Did the person get hit by the bus 16 because the bus was speeding or did the person get hit by the 17 bus because they weren't paying attention or were dizzy? You 18 have to look in the context, and in this context perhaps some 19 of these experiences may not have been drug related, but my 20 criticism is the way they were reported. 21 If you go to the next page, also Visit Four, 22 this is your treatment-emergent symptoms page, agitation, 23 restlessness. "Patient under stress from being informed wife 24 is divorcing him. Some drug-related involvement possible." 25 So they're not sure whether it's his life or the drug. 79 1 So let's go to the next week. He took Valium 2 IM, intramuscular. That means they injected him with Valium. 3 This means, to me, from my experience in using 4 benzodiazepines, that he was more agitated than somebody who 5 would be given simply oral Valium. Generally when you use an 6 IM dose, you want the effects to happen pretty fast. So this 7 indicates to me this was a very serious agitated episode. And 8 the indications were acute agitation and restlessness. 9 "Reason stopped," I tell you the truth, I can't really make 10 that out. Treatment-emergent symptoms for that page, we have 11 it, they've reported it. Acute agitation, restlessness, 12 Valium IM. 13 Again on Week Six, the same thing. Now, this 14 time he's getting a little better because now they're giving 15 it to him orally. Valium p.o., p.r.n.; indications, anxiety; 16 reason stopped: taking it as needed at bedtime five 17 milligrams once a day as needed. 18 Week Six, treatment-emergent symptoms: Anxiety, 19 agitation. Patient reports taking Valium on occasion as 20 needed -- something -- patient status. 21 Week Seven, again, he's still taking Valium for 22 anxiety, agitation. Patient reports taking Valium on 23 occasion. And again on Week Seven, we have the treatment- 24 emergent symptoms of anxiety, restlessness. Patient reports 25 needing Valium on occasion. Outpatient status -- that's what 80 1 it is. They let him out of the hospital. Okay. 2 So this was a fellow that needed Valium from 3 time to time throughout the study. During the early weeks he 4 needed it by intramuscular injection. And now we have the 5 drug experience report which was submitted to the FDA, and you 6 can see there in the top left-hand corner it's coded for one 7 day only, 9-12-80, restlessness. 8 Q. What is your criticism of that? 9 A. Because he had agitation, he had anxiety, and he 10 had these on more than one day. I mean, there was a time 11 early on he was having where several days of the trial he had 12 to take Valium. 13 Q. Does it mention anything on here about 14 concomitant medications on this sheet, the 1639? 15 A. On the drug experience report? 16 Q. Yes. 17 A. No. It does not say he required IM Valium and 18 it's important to put that down. The fact that it was so bad 19 that he had to be injected with Valium is something that the 20 FDA deserved to know. 21 Q. Is it appropriate for a manufacturer of a drug 22 here to say "see case report" as opposed to putting 23 information on the report itself? 24 A. If you had reported the thing accurately, it 25 would be okay to refer them to case-report form for more 81 1 details. But to simply -- to put one of a group of reactions 2 on there, one that's actually very mild and say "see 3 case-report form" is improper, because what is to make a 4 person, whether FDA official or simply anybody interested in 5 going to see that case report. If you don't indicate the 6 seriousness of what's in that case report, why should anyone 7 bother to see the case report. We've all gotten documents 8 that say "see this, see that" and a lot of times we just go 9 ahead and do whatever needs to be done, sign it or whatever, 10 without looking at the referenced document because we're not 11 interested in doing that. 12 Q. Is it your opinion that this drug experience 13 report does not accurately reflect the severity of this man's 14 agitation? 15 A. Absolutely not. It does not reflect the 16 severity of his condition. 17 Q. How does this impact on the quality of the data 18 that is reported by this particular study? 19 A. The data is flawed. The event is not being 20 reported properly. 21 Q. How would something like this impact on the 22 package insert, if at all? 23 A. It could -- it could wind up with having less 24 agitation in the package insert. Now, I don't know how Lilly 25 prepared the package insert, whether they used the adverse 82 1 experience reports or if they used the combined -- the tallies 2 at the end of the summaries. I wasn't there. I don't know 3 how they did it. If they used the adverse experience reports, 4 then you would have a serious reduction, taking all these 5 together, in the numbers of people who experienced agitation. 6 Because you have to realize, I only looked at 7 one box of case-report forms, and that box was selected by me 8 at random. I mean, I went into a room and there were 20 or 30 9 boxes there and I picked one. I had no way of knowing what 10 was in it. I had no way of knowing that all this stuff would 11 be inside. It could be that I picked the only box in the room 12 that contained so many problems with reporting data, but more 13 likely this was a pattern that would have been apparent with 14 almost any box that I picked up. I don't know. But if that's 15 the case, then there are a number of other people, probably 16 hundreds, that got agitation and didn't get it put onto their 17 1639s. 18 Q. Is there another patient you would like to 19 review? 20 A. Yes. Patient 36, this will be Plaintiffs' 21 Exhibit 200. Now, this person was agitated -- if you go to 22 the -- well, let's start with the first page. He's got 23 several diagnoses, and it doesn't say how he came to the 24 hospital. He was agitated on Visit Two. On the next page, it 25 says he needed Sodium Amytal for severe agitation and 83 1 agitation on two different occasions. This is before he got 2 drug, so you have to realize he's already agitated before he 3 starts to receive fluoxetine. But, again, just in terms of 4 reporting, treatment-emergent symptoms, none. Now we go to 5 his first week on drug, this is Visit Three. 6 Q. Tell us where that is within the exhibit. 7 A. Huh? 8 Q. Tell us where that is within the exhibit so we 9 can follow along. 10 A. Next page. 11 Q. Okay. 12 A. He got Sodium Amytal p.o. between the 14th and 13 the 20th, that's pretty much the entire week, for severe 14 agitation. He got Dalmane when he went to sleep, 30 15 milligrams -- that's a high dose of Dalmane -- for 5 days for 16 insomnia, and he got Sodium Amytal IM, it looks to me like the 17 14th to the 17th for agitation. Again, this is a guy who's 18 seriously enough agitated that he required an intramuscular 19 injection of Sodium Amytal. 20 Q. What does p.o. mean? 21 A. p.o. means orally, by mouth. The next page, 22 Visit Three, treatment-emergent symptoms, we have insomnia. I 23 suppose the theory here is that agitation was present before 24 treatment started, so they didn't put it as a treatment 25 emergent symptom. I have a problem with that. I think you 84 1 report the symptoms that they had before treatment started and 2 report the symptoms that you had after treatment started and 3 see how the numbers come out. 4 And then if you look at the next page here, I 5 just wanted to show you this guy's own questionnaire. He's 6 saying "extremely" for almost everything, and he's saying that 7 he's worse. If you look at the bottom of the page, he's 8 saying "very much worse, very much worse." 9 And then on the next page, he's now getting 10 chloral hydrate for insomnia. That's Visit Four. But the 11 treatment-emergent symptoms, which is your next page, we have 12 nausea and blurred vision. And where they say blurred vision 13 it says, "Patient was quite agitated when first made 14 complaint," so, again, he's still experiencing some agitation, 15 some... 16 Q. Are you saying that they should have reported 17 agitation as an adverse event even though he came into the 18 study with some level of agitation? 19 A. Right. Because you want to evaluate what is 20 happening. It appears from looking at this that the agitation 21 got worse. 22 Q. How do you know that? 23 A. Well, because he had to take more Amytal. He 24 did have to take it a little bit the second week here. He 25 even required an IM dose the second week. But then on the 85 1 third week he had to take it every day. No. I'm sorry. It 2 was p.r.n. No. The change of somebody's symptoms is 3 important. You're trying to see if this drug helps 4 depression, and if one of this guy's symptoms of his 5 depression is agitation you want to know if it goes away or 6 not. So if he had it before the study and he continued to 7 have it after the study, at the very worst -- at the very 8 best, the drug is just not working on this. That's important 9 data, but it appears here, too, since they had to add another 10 drug, they had to start giving him a Dalmane and later chloral 11 hydrate, that he may have even been getting worse. And he's 12 saying he's getting worse. So you need this as part of his 13 whole picture. This is what his test scores look like, this 14 is his questionnaire and he's still having this agitation. 15 So, again, on Visit Five he's got insomnia, this 16 is just a few pages before the end. And on the next page he's 17 got blurred vision and lack of appetite. 18 The last page is the drug experience report and 19 you see 9-14, insomnia; 9-21, nausea; 9-21, vision blurred; 20 9-28, anorexia. It's reporting these things as though they 21 only happened once on one day and they're not reporting the 22 agitation that was part of this whole syndrome. 23 Q. Let's take a look at one of the treatment- 24 emergent symptom forms in this patient's clinical-report form. 25 Let's talk a little bit about what the various parts of this 86 1 form are. I'm looking at Visit Five, which is the 2 second-to-last page of the exhibit. Doctor, if you hold it 3 horizontally like this and read across, could you tell us what 4 the various -- what the relevance of the various elements of 5 this form are, for instance, the duration of the event, the 6 onset, et cetera? 7 A. The Date of Onset, Date of Termination shows you 8 how long it lasted; Severity: mild, moderate and severe, 9 that's self-explanatory; Course: That means what happened. 10 Okay. You have recovered. Recovered means they're okay. 11 Sequelae, that means they've recovered from that but they have 12 sequelae. What sequela is is what carries on after it's all 13 over, something like brain damage or a rash that leaves a 14 scar; something is remaining, there's a permanent problem 15 remaining after his initial symptoms went away. Still under 16 treatment means they're still treating him for it. Died. And 17 unspecified means basically they don't know; Action Taken: 18 Several choices here, none; dose reduced; increased 19 surveillance, means you watch them more closely; drug 20 discontinued, you stop the drug; other med required or other. 21 Q. What about the next category? 22 A. Drug Related: Yes, no, or unknown. Here 23 they're putting down yes. And Source: where it comes from, 24 was it the patient reported, was it elicited, was it observed 25 or others. In this case the patient reported it. So the 87 1 patient who filled out the form believes that this is drug 2 related. 3 Q. So when it says "Drug Related: yes, no, 4 unknown," it's not the patient's belief, as far as you know, 5 that it's drug related; it's the physician's belief? 6 A. Right. Exactly. 7 Q. Could they have reported this man's various 8 levels of agitation on the treatment-emergent symptoms form 9 even if they believed that it wasn't related to the drug? 10 A. Yes. 11 Q. Should they have done that, in your opinion? 12 A. Yes. I think they should have. Now I'd like to 13 go to No. 40, this would be -- I think it's the second one 14 down on your pile; it's called Plaintiffs' Exhibit 202. The 15 first page I want you to note that he's a young man, he was 16 only 26 when he was on this study. He came in on his own. He 17 has a number of different diagnoses. The next page I've 18 included, this is the form that he filled out on Visit Two. 19 This is a self-rating form that was used by Lilly to give the 20 patient themselves an opportunity to say how they were doing. 21 Q. So the patient actually filled out the form 22 themselves, as far as you know? 23 A. Right. And you see that it's filled out, 24 different numbers are circled and it's filled out relatively 25 neatly. And the next page is the same thing. He's... Now, 88 1 on the page after that, PZ 2888, he writes one comment on 2 Question 85. It says, "The idea that you should be punished 3 for your sins," and he circled Four, for extremely, and he 4 writes in parens, "That I am." 5 Q. What, if anything, does that indicate to you? 6 A. I'm just using it as a comparative point, that 7 he's writing little notes in his questionnaire, okay. That's 8 all it says at this point. 9 In the Visit Three, we have mild intermittent 10 nausea, even though he acquired insomnia and some aspirin for 11 a headache, which is indicated on the next page, but that's 12 not really what's important about this one. If you go to the 13 following page, this is on Visit Four. Again he's filling out 14 his form. Just look at that in general and you'll see that 15 it's a mess. This guy's no longer able to neatly and clearly 16 fill out this form. Now, if you look at Question No. 63, 17 which says, "Having urges to beat, injure or harm someone," he 18 writes in there, "Yes, myself." On the next page, Item No. 19 67 -- 66, "Sleep that is restless or disturbed," he writes 20 something there which I frankly cannot read. 67, "Having 21 urges to break or smash things," he puts extremely. Now, if 22 somebody had looked at this form, someone, a medical person, 23 they should have seen that this guy's got some suicidal -- 24 MR. FREEMAN: Your Honor, what someone should 25 have looked at this form -- 89 1 DOCTOR LORD: Were I to see this form. 2 MR. FREEMAN: That's a different question. 3 JUDGE POTTER: Okay. 4 A. Were I to look at this form and see the comment 5 that this fellow wrote on Question 63, I would come to the 6 conclusion that he was experiencing suicidal ideation. That's 7 what it means to want to hurt one's self. 8 Q. What about his ability to fill out the form 9 neatly like he could at first, tell you, if anything? 10 A. Well, there seems to be some deterioration going 11 on. The guy is less able to concentrate. He seems to be more 12 disorganized in his thinking. He's having some -- you know, I 13 wish I could read some of this other stuff he's written. I 14 would, had I seen this if I was a study director, have sent 15 this to a psychologist or someone who really knows, had a look 16 at this type of rambling and draw even more conclusions of 17 that. But quite clearly to me, this fellow is not doing well 18 and should have been evaluated. 19 But if you turn beyond the questionnaire to see 20 what they put in their treatment-emergent symptoms report and, 21 obviously, whatever's going on with him is a treatment- 22 emergent symptom because he didn't have it on Visit Two. He 23 has dizziness and nausea and the action taken was none for the 24 dizziness. They don't even fill it out for the nausea. 25 Now, he does on Visit Five, he has -- he takes 90 1 aspirin and choral hydrate and on the treatment-emergent 2 symptoms they do code confusion at that week now, 3 constipation, something I cannot read, and dizzy. Oh, I'm 4 sorry. That third thing is shortness of breath because those 5 are put in the treatment -- in the drug experience report, 6 which is the last page of that case-report form, you can see 7 the drug experience report which lists out nausea, dizziness, 8 confusion, breath shortness and constipation, but doesn't say 9 anything about insomnia, suicidal ideation or disorganized 10 thoughts. 11 Now I'd like you to turn, if you would, please, 12 to the page right before the last page. This is PZ number, 13 12 2927. 14 Q. Second-to-the-last page on the exhibit. 15 A. It reads "Note to file" and it's from -- it says 16 CCs, G. Soyez, E. Ashbrook, Re: Early termination summary, 17 HCAA, Investigator 3, Patient 40. And it reads, "Patient No. 18 40" -- there's something blacked out -- "This 26-year-old male 19 began fluoxetine therapy on 11-29-78 (V2). He discontinued 20 the study on 12-19-78 (V5) due to look of efficacy (see Table 21 3). His daily dosage of fluoxetine was 60 milligrams to 40 22 milligrams. 23 Q. What is your criticism of that, Doctor, if any? 24 A. If this were my study, my reason for terminating 25 this fellow would be for adverse experiences. It's obvious 91 1 that what happened to him is more than lack of efficacy. When 2 he came in and he wasn't taking drugs, he was able to fill out 3 a questionnaire. He got worse. He didn't just not get help; 4 he got worse. And when I see this, I have to wonder what some 5 of those other hundreds and hundreds of patients had. 6 MR. FREEMAN: Speculation about what something 7 else shows is certainly not -- 8 JUDGE POTTER: Well, overruled. 9 A. In all the summaries they mention a lot of 10 people who were terminated for lack of efficacy. Having seen 11 this case, I wonder what really happened to them. 12 Q. Just so it's clear, Doctor, is it your testimony 13 that nowhere on the treatment-emergent symptoms form is 14 suicidal ideation or suicide -- well, suicidal ideation 15 listed? 16 A. Not only is it not listed there, it was not 17 listed anywhere. There was no indication to me that anybody 18 at the study center had even bothered to look at that person's 19 form. 20 Q. Anybody else? 21 A. Yeah. There are two more. HCAB 2 -- I'm sorry. 22 Yeah. Two -- I'm sorry, we have three more. 23 Q. Can you give us an exhibit number, please, 24 Doctor? 25 A. Yeah. There's three more after this. 201. 92 1 Okay. Let's look at the first page. This is a lady who was 2 48 at the time she came into this hospital. She had two 3 diagnoses, primary major depressive disorder and endogenous 4 major depressive disorder. She had never been hospitalized 5 before. And she came in at her own initiative and others' 6 initiative. 7 Q. What does that mean to you? 8 A. My guess would be someone suggested to her and 9 she said okay, but that's just speculation. I don't really 10 know. 11 Q. Okay. 12 A. This is on Visit Three. This is her -- this is 13 simply written on one of her scales. These were scales that 14 had to be filled out by the study personnel as part of the 15 measurements of the effectiveness and safety profile of this 16 drug. Visit Three, this is her first week on fluoxetine, they 17 write as a comment, "Extremely agitated and overtalkative. 18 Cannot stop talking. Content of talk is how she wants to be 19 sick in order to avoid responsibility." 20 On the next page, we have symptoms, signs and 21 illness. "Throbbing over bridge of nose," and they put 22 "possibly drug related." Discussed reasons for the -- very 23 bottom of that page, discussed reasons for discontinuing study 24 drug. "Patient was admitted to hospital and for technical 25 administrative reason it was not possible to continue the 93 1 study." But she did continue it for several weeks because 2 then we have Visit Four. It says, Patient's Global 3 Impressions. "Patient unable to fill out -- to fill this in 4 for herself." So she, too, is having trouble filling out a 5 form. Oh, you know, this patient, by the way, started out as 6 an outpatient. It's a hospital study, but she was an 7 outpatient when she started if you look at the first page. 8 Sorry about that. 9 Visit Four, again, the same page we looked at 10 before for Visit Three, says, "Patient very agitated, extreme 11 lability." This is under Comments. "Crawling out of skin. 12 Rapid thought, racing thoughts." I cannot read that -- the 13 next thing. Something thinking but I can't read that word 14 there. "Marked apprehension -- something I can't read -- 15 doom. Unable to cope. Feels like jumping out of window." 16 And on the next page -- then we have this symptoms, 17 signs and illnesses, we have agitation, racing/disorganized 18 thoughts. And at the bottom of the page, discuss reasons for 19 discontinuation of study drug, "Patient hospitalized at 20 request of patient and family." Comments: "Severe agitation, 21 anxiety, appear drug related, unable to cope, could not be 22 kept at home. Both apply." 23 Q. Do you have an opinion, Doctor, whether or not 24 this patient was exhibiting signs of suicidal ideation? 25 A. Yes. She said she felt like jumping out the 94 1 window. 2 Q. To your knowledge, is that listed anywhere 3 within the treatment-emergent signs and symptoms report or the 4 adverse-event report for this patient? 5 A. No. It was not listed anywhere. I also would 6 like to note that this patient's condition was very serious. 7 This is a somewhat different study we're looking at now. This 8 patient came in as an outpatient. She required 9 hospitalization because of this episode. She had to be put in 10 the hospital after starting this drug. 11 Q. Anything else about this patient that you'd like 12 to comment on? 13 A. Yeah. I want to go through what they say about 14 her. The next page it says -- this is her end of their 15 physical exam and on Other, Explain Reason For Termination, 16 "Patient admitted to hospital and it was not possible to 17 continue fluoxetine in an inpatient setting." That's not the 18 whole reason. I would have circled Number Three, Symptom Sign 19 or Illness, study drug related. And we have a memo about it 20 which is inconsistent with what I just read. Memo to file, 21 CC: G. Soyez and E. Ashbrook, Early Termination Summary, 22 Investigator 2, Patient 1 -- Patient No. 1, blank, "This 23 47-year-old female began fluoxetine therapy on 4-20-79. She 24 withdrew from the study on 4-27-79 (V4), due to 3 days of 25 severe nervousness and confusion, for which she was 95 1 hospitalized. The investigator indicated that the adverse 2 experiences were drug related. The patient's daily dosage of 3 fluoxetine was 60 milligrams to 40 milligrams." And on the 4 adverse experience report which is the last page of your 5 package, it says sensation disturbance, confusion, hypomania 6 and nervousness. 7 Q. If you go back to the previous page for a 8 second, Doctor, does the fact that they say patient's daily 9 dosage of fluoxetine was 60 milligrams to 40 milligrams 10 indicate to you that they were decreasing the dosage 11 throughout the course of the study? 12 A. The normal way that's written is 40 to 60 if you 13 were having a range of dose, but I don't really know here what 14 it says. But we could possibly look and see if they changed 15 her dose. Yeah. On Visit Four she's only getting 40. This 16 is the page that says, "Patient unable to fill this out for 17 herself." A.M. dose, 20, 20; P.M. dose 20, 20. 18 Q. Okay. So when you say 20, 20 in the morning 19 that's per day; it's not 40 milligrams in the morning and 40 20 milligrams at night? 21 A. Right. That's per day. Now, since we don't 22 have that page for the earlier visit, if she ever got 60, it 23 would have to be on the other visit. In fact, there's another 24 one. If we could go back to Patient No. 26, which is 25 exhibit -- oh, it's in the ones we haven't looked at. I have 96 1 them out of order. No. I'm sorry. We don't have it. There 2 was another case I looked at where they actually -- there was 3 a note that instructed them to reduce the dose for someone who 4 had stimulation. 5 Q. Let's double-check your group because I think I 6 might have one or two more than you originally had. I think I 7 gave you a short group because you keep saying that there's 8 three left and I have four left and things like that, so I 9 want to make sure we have it in sync here. 10 A. Yeah. I think I'm missing one. I'm missing 11 No. 26; that's why we didn't go over it. 12 MS. ZETTLER: Can I approach the Witness, Judge? 13 JUDGE POTTER: Yes. 14 Q. What is the exhibit number on that one? 15 A. This is 207. 16 MS. ZETTLER: Your Honor, could you make sure 17 the jury all has a copy, too? 18 JUDGE POTTER: Ladies and gentlemen, did you-all 19 get your last one, 207? 20 MS. ZETTLER: Thank you. 21 A. Okay. This is a 52-year-old male. 22 Q. And now we're talking about that same patient, 23 26? 24 A. This is 26, yeah. And Visit One, if you see he 25 just has an endogenous major depressive disorder. On Visit 97 1 Five, where they have therapeutic effect and side effects on 2 one chart, it says worse and the side effects significantly 3 interfere with patient's functioning. On the Visit Five 4 treatment-emergent symptoms, which is the next page, it says 5 stimulation. And if you look at where it says Action Taken, 6 dose reduced. 7 On the next page for Visit Six, it asks the 8 investigator, "Was regular dosage regimen followed for this 9 therapy period?" They checked "no" and the reason given was 10 adverse reaction, and he writes in this comment, "Stimulation 11 for brief time with sleeping difficulty." The treatment- 12 emergent symptoms for that Visit Six doesn't have anything 13 listed. 14 And then if you skip the next two pages there's 15 a handwritten note on the next-to-last page of your package. 16 It says, "B blank in Doctor Blank's office called. One 17 outpatient who takes two fluoxetine capsules at night is 18 unable to sleep despite chloral hydrate. I suggested shifting 19 to A.M. medication, i.e., either two daily in A.M. or one in 20 A.M. and one at noon. Then see whether chloral hydrate will 21 help. If not, try Dalmane." Now, this is interesting to me 22 because I don't recall seeing chloral hydrate listed but, in 23 all honesty, it may be in one of the ones that we don't have 24 with us here. This shows that the investigators were being 25 instructed to reduce the dose if stimulation occurred. 98 1 On my trials if you reduced a dose, the reason 2 generally was because you felt there was a connectedness 3 between the adverse experience and the drug; that's why you'd 4 reduce it, to see if it went away if you gave a little less 5 drug. It's only logical. This was a very, very early trial. 6 It's an indication very early on that the drug was causing 7 activation, stimulation. People in the company knew, they 8 were instructing the investigators to reduce the dose and give 9 sedatives. They were sedating the patients. 10 Q. Anything else with this patient, Doctor? 11 A. No. That's about it with this one. I think we 12 can go on with No. CAB 21 -- oh, no, we did her. That's 13 already been done. I'm sorry. Our next one is HCAA 14 Protocol 9, Patient 16. This is Plaintiffs' Exhibit 204. 15 Okay. This is a patient who became seriously ill. He became 16 psychotic while on the drug. It was coded as a -- he had a 17 discontinuant and it was again coded as a discontinuation for 18 lack of efficacy. 19 Let's go through it. The first page is a drug 20 experience report and this one is -- tells what happens. It 21 says, "Onset, 6-16-78, psychosis manifested by paranoid 22 delusions. Existing antidepressants may precipitate psychosis 23 but otherwise no known association with fluoxetine exists." 24 The next page is his psychiatric diagnosis and 25 he has everything except for retarded major depression. He's 99 1 a 53-year-old man. He came on his own. He was first 2 hospitalized at the age of 48. Now, this is another one who 3 revealed in the way he filled out his questionnaires that his 4 mood had changed. If you look at the next page for Visit One, 5 you see he fairly neatly checks off the answers he wants and 6 the same thing on the next page and the next one. At Visit 7 Two -- and he's not on fluoxetine at this point -- he requires 8 Mylanta for indigestion; that's an appropriate concomitant 9 med, and chloral hydrate for agitation. Visit Two on the 10 treatment-emergent symptoms they reported a decrease in blood 11 pressure, may be due to patient's inactivity. Again, I don't 12 know why he was inactive. 13 Q. And, again, at this point he's not on the study 14 drug? 15 A. Right. He's not on the study drug yet. The 16 first week on the study drug. And this guy's an inpatient. 17 No. This is HCAA. Again, this is not a mixed protocol. 18 Q. And at this point they didn't record agitation 19 on the emergent symptoms list? 20 A. No. They did not record agitation on the 21 treatment-emergent symptoms list there. 22 On Visit Three now he has anxiety being treated 23 with chloral hydrate. There's also something about an 24 endocrine study, don't worry about that. The chloral hydrate 25 he got three times, he got it p.o., he got it for anxiety. 100 1 And on the treatment-emergent symptoms for that week, we again 2 see blood pressure drop. We don't see anything about anxiety. 3 On Visit Four, the next page, he got chloral 4 hydrate, only once, though, for agitation and again on Visit 5 Four, on the treatment-emergent symptoms, the blood pressure 6 dropped and that was it. 7 Now we have Visit Five. At this point he's been 8 on the drug about three weeks and the assessment is -- and 9 this is the chart that they combined how the therapeutic 10 effect is versus the side effects. They have it in that lower 11 right-hand corner like that other one we looked at that says 12 worse, outweighs therapeutic effect. That means the person is 13 worse and the side effects outweigh any benefit the person is 14 getting from the drug and there's a comment here. It says, 15 "Psychotic nature of illness exacerbated. Extreme paranoia, 16 most prominent symptom. Extraneous something and tense ward 17 atmosphere and visit of patient's son." 18 Then we have a chart here and again he's looking 19 a little bit messier. On Visit Five they do code, "Paranoid 20 delusions, paranoid features previously noted delusional by 21 this date, a clear exacerbation into florid psychosis." And 22 they code the drug relatedness as possible. Sorry. I need to 23 correct myself. When I talked about him earlier, I was 24 looking at the wrong number. I was talking about Patient 1, 25 that he was showing emergent -- they're very similar, but this 101 1 particular guy what I said when I first introduced this case 2 is not the same one. I was looking at the wrong place on my 3 notes here. I'm sorry. 4 Q. Right now you're talking about Exhibit 204? 5 A. Exhibit 204. That's right. 6 Q. Okay. Now, the next page is Visit Six and 7 there's a concurrent illness they describe and they said, "Was 8 regular dosage followed, no. Adverse reaction, concurrent 9 illness. "On 6-21-78, patient developed abrasion on left 10 heel, lateral aspect, which was apparently the result of 11 excessive pacing and tight shoes. The abrasion became 12 secondarily infected. Required topical treatment: hot soaks, 13 Betadine, bacitracin ointment. Basically, they're talking 14 about this guy walked so much that he messed up his feet. 15 Predominant mood, this is the next page, "Other: Mainly 16 paranoid delusions (bizarre) and agitated." 17 Q. That's the bottom of the page? 18 A. At the bottom. And the next page is simply a 19 vital signs chart; that's all it is. But if you looked at the 20 bottom, you see a note that says, "Patient eloped 6-23, 21 returned 6-24, and transferred to locked ward." 22 Q. Okay. Explain what it means for a patient to 23 elope. 24 A. That means he ran away, he left. He just got 25 away from the hospital. But, if you recall, when we first 102 1 looked at this one on the first page, how did he come to the 2 hospital, patient's own initiative. That means he came in 3 voluntarily and he was brought back and put on a locked ward. 4 Now, in the next adverse experience report, it's about four or 5 five pages later, the middle one, it says, "Paranoid delusions 6 began 6-16-78, escalated. Patient eloped from unit. Required 7 legal hold. Transferred to locked facility. Foot abrasion." 8 Q. In your opinion, what do they mean here when 9 they say required a legal hold? 10 A. There are only two things it could mean. Number 11 One, it could mean a legal hold, meaning he was facing some 12 charges, that he committed some sort of crime and maybe an 13 adjoining county jurisdiction or a neighboring county had a 14 legal hold on him, when he got out of the hospital he had to 15 come and stand trial for whatever he did. The other thing 16 could mean that it was an involuntary commitment; that he was 17 acting so bad, a danger to himself or others, that they 18 voluntarily committed him. Because if he was still voluntary, 19 they couldn't have brought him back. They brought him back 20 against his will. In fact, in the summary regarding this 21 patient, it mentions that he was placed in a cell. You don't 22 do that with a voluntary admission. A voluntary admission can 23 leave whenever they want. They can just say, "I don't want to 24 be here anymore. I'm leaving." And to be involuntarily 25 admitted generally, I don't know which state, but most of the 103 1 states require that a person be a danger to themselves or a 2 danger to somebody else; it's either that or he committed some 3 sort of a crime. I'm very curious about what happened because 4 this happened right after his son visited. But we don't know 5 what happened. 6 Q. Do we have any way of telling from this 7 case-report form or the summaries that you reviewed or the 8 drug experience report what actually happened to this 9 gentleman once he got out of the hospital? 10 A. There is nothing anywhere that tells us what 11 this man did outside the hospital that caused him to be 12 brought back in custody. 13 Q. Do we have any way of telling from this 14 case-report form the summary that you reviewed on the study or 15 the adverse event form what happened to him in the rest of the 16 course of his hospitalization? 17 A. No. They don't even give us that. See, when I 18 was doing these trials, if we had something this serious 19 happen, we would collect more data. We would send them for 20 further physical exams or mental exams or whatever was needed, 21 special tests, EEGs, whatever, and then bring them back to the 22 company and look at it. I don't see anything appended to this 23 case-report form. It's like he left, they put him on this 24 locked ward, and the case closed. The company never appears 25 to have obtained any further information as to what this guy's 104 1 result was. Did he get better once they stopped the 2 fluoxetine? Did he continue to get worse? Is he on death 3 row? We don't know. 4 Q. Anything else about this patient that you found 5 significant? 6 A. I thought it was interesting again with the 7 questionnaire. His questionnaire got rather -- if you look at 8 the couple pages we skipped. It shows a lot of anger the way 9 he's marking on that questionnaire. 10 Q. Can you point us to a specific page, Doctor, so 11 we could follow with you? 12 A. Yeah. PZ 532 2166 (sic), this is Visit Six. 13 He's checking it off, but he's checking it off making multiple 14 lines to do the checks. It all goes with this whole center 15 that this guy's become very ill, very paranoid. 16 Now, on Visit Seven, actually they did 17 continue -- they didn't send him for any special test, but 18 they did finish up the study, though they gave him -- Visit 19 Seven, I think that's the next page after the adverse 20 experience report. Now he's on the locked ward now. 21 Q. Where are you at? 22 A. Visit Seven, the first page. The interviewer's 23 report for Visit Seven. 24 Q. Okay. 25 A. There's a whole list of drugs there. There's 105 1 chloral hydrate for agitation; betadine soak for his foot; 2 Haldol for agitation, that's a phenothiazine, that's an 3 antipsychotic drug. Again, chloral hydrate for agitation. 4 Bacitracin for foot infection. And then again in the 5 predominant mood -- the next page under Predominant Mood it 6 says, "Extremely paranoid. Bizarre delusions. Anxious." 7 The next page is End of Therapy Physical 8 Examination. Under Reason for Termination, Treatment Emergent 9 Symptom/Sign Drug Related, possible. Required locked unit." 10 Q. So at least at this point there was a question 11 in the investigator's mind as to whether or not this man's 12 deterioration was related to the drug? 13 A. Right. 14 Q. Do you know if there was anything else done on 15 this patient? Can you tell from what you reviewed indicating 16 an attempt by the investigator or anybody from Lilly to make 17 the determination as to whether or not this man's 18 deterioration was related to the use of Prozac? 19 A. I see nothing further after this Visit Seven. I 20 mean, I don't even see the police report here. 21 Q. If somebody is brought back on a legal hold, 22 does that mean they're brought back by the police? 23 A. Probably, yeah, or sheriff or somebody. Some 24 law enforcement officer would be bringing them back. If they 25 have a legal hold, they're in custody. 106 1 Q. And if that were the case, would a police report 2 have to be filled out, to your knowledge? 3 A. I don't know what state it was in, but it would 4 have to be filled out in Georgia. 5 Q. In your experience on your NDA, if something 6 like this had happened on your drug, would you have attached a 7 police report to the clinical-report form? 8 A. Something this serious I might have. We did 9 have one person that was arrested and I don't recall that we 10 got the police report, but it was something pretty minor; he 11 had a fight with his dad or something like that. But we did 12 get him worked up by a doctor and seen. 13 Q. Okay. I'm sorry. I didn't mean to interrupt 14 you. Is there anything else about this patient you'd like to 15 tell us about? 16 A. No. That's about it. 17 Q. Do you feel that the drug experience report on 18 this patient properly reflects the severity of this man's 19 condition of deterioration? 20 A. Well, actually, this drug experience report is 21 better than most in that at least it lists the most serious 22 consequence of the treatment, the paranoid delusions, and it 23 doesn't deny that it may be drug related. My problem with 24 this is we don't know what he did. We have this gap where he 25 was loose somewhere and brought back in custody, and I don't 107 1 know what he did, and that bothers me. He did something that 2 caused them to either place a legal hold on him, meaning he 3 had been charged, or involuntarily committed him and we don't 4 know what that was. And I find that very, very disturbing. 5 That's why, as I said, if I was in the company I would have at 6 least have wanted to see a police report, find out what he 7 did. 8 MS. ZETTLER: Your Honor, this might be a good 9 time to take lunch, if you'd like. 10 JUDGE POTTER: Ladies and gentlemen, we'll take 11 the lunch recess at this time. As I've mentioned to you-all 12 before, do not permit anybody to talk to or communicate with 13 you about this case; do not discuss it among yourselves or 14 form or express opinions about it. We'll stand in recess till 15 2:00. 16 (BENCH DISCUSSION) 17 MR. SMITH: On our designation of expert 18 witnesses as per the Court's order, as well as a motion for 19 leave to accelerate time within which to answer 20 interrogatories and request for production of documents we 21 got, regarding the punitive damages aspect of it, do I need to 22 get this filed or can I go ahead and give that -- 23 JUDGE POTTER: Go ahead and give it to them, and 24 I'll make sure it gets clocked in today. 25 MR. SMITH: Okay. 108 1 (LUNCH RECESS) 2 MR. FREEMAN: Your Honor, my paralegal is on the 3 way with the exhibit that I've been working with. 4 SHERIFF CECIL: The jury is now entering, all 5 rise. All jurors are present. Court is back in session. 6 JUDGE POTTER: Please be seated. Doctor, I'll 7 remind you you're still under oath. 8 Ms. Zettler. 9 MS. ZETTLER: Thank you, Your Honor. 10 Okay. Doctor, before we broke for lunch, you 11 were in the process of running through the patients you wanted 12 to share with the jury that regarded their interview in the 13 clinical trials. Are we done with those? 14 A. No. There's two more. 15 Q. Please let us know which exhibit you're looking 16 at, too, so we can follow along. 17 A. Okay. The exhibit number next I'd like to talk 18 about is No. 206. This is HCAB 3, Patient 1. This is another 19 patient who became psychotic while on the study drug and 20 required Valium IV. He was also discontinued for, quote, lack 21 of efficacy. 22 I'd like you to turn, if you would, to the first 23 page, which is his admitting page, and his diagnoses at that 24 time were primary major depressive disorder, endogenous major 25 depressive disorder and agitated major depressive disorder. 109 1 He was also pretty young, he was only 27 at the time, and he 2 came in on his own initiative. 3 The next page is Visit Three. This is the first 4 visit after study drug has started. He was taking 60 5 milligrams a day of fluoxetine. At that time he had required 6 Valium IV and p.o. for agitation. It says, "Reason Stopped, 7 see below. Transferred to another ward for brief period, 8 protocol meds continued." Also on Visit Three on the next 9 page we have the Covi Anxiety Scale and there's a comment, 10 "Patient is markedly more depressed." 11 The next page, Week Three, we note that this is 12 on -- this is the same thing as the treatment-emergent 13 symptoms sheet of the other study. This is signs, symptoms 14 and illnesses. This is where they're coding the adverse 15 experiences. And his sign, symptom and illness was agitation 16 which he had for three days and it was severe, it was rated a 17 3, and it was called possibly drug related. 18 On Week Four, the next page, again he's taking 19 60 milligrams a day. At this time he has -- he's taking 20 chloral hydrate for sleep. Looks like he took it for about 21 five days, and the patient's impression was that he was much 22 worse. 23 The next page is still Visit Four, and I want to 24 read this to you because it's somewhat hard to read. At the 25 bottom of the comments under the Covi scale, "Patient is 110 1 showing emergent signs of thought disorder. He is worse over 2 last weeks and neuroleptics are indicated. Protocol will be 3 discontinued." Now, a neuroleptic is a phenothiazine. It's a 4 drug that's used to treat people who are psychotic, who have 5 lost touch with reality, something like Thorazine, Haldol, 6 Mellaril. These are drugs you give people who have become 7 very, very crazy, and that's what happened to this gentleman. 8 If you look at the next page, have a symptom 9 here, suicidal. Had it for five days. They say, "Thought 10 disorder indicated. See note on Page 14." And then at the 11 bottom they discuss the reasons for discontinuing the study 12 drug, "Lack of efficacy. Patient became and remained suicidal 13 for long period. Symptoms of thought disorder arose which 14 were not evident when patient was accepted into protocol." 15 There's a small word there I cannot read and then it says, 16 "latent schizophrenia." 17 Then the next thing says Visit Seven. I believe 18 that what happened here was that they -- because the final 19 evaluation forms were all supposedly for Week Seven, they went 20 ahead and used those. That's what we did on my study. If 21 somebody dropped out early and we still did a final 22 evaluation, we would use the forms for that last week, and 23 this is something about X-ray changes. 24 On the next page we have the person's 1639 form, 25 and if you turn that over sideways, it says, "Abnormal ECG; 111 1 nonspecific abnormal T waves. Abnormal chest X-ray; there 2 were increased bronchovascular markings and slight degree of 3 pneumonitis in both bases. Abnormal ophthalmologist report; 4 injection of conjunctiva." On the next line it says, "Also, 5 comma, patient experienced agitation." This patient got a 6 little more than agitation. He became psychotic. He required 7 neuroleptics. He had to be moved to another ward. He became 8 suicidal with a thought disorder while taking fluoxetine, and 9 this adverse experience report fails to mention that. 10 On the next page, there's the memo: "This 11 26-year-old male began fluoxetine therapy on 7-30-79 (V2). 12 The patient terminated the study on 8-16-79 (V5), due to lack 13 of efficacy. His baseline HAM-D was 33; on 8-10-70 it was 20, 14 and the CGI score was No Change. His daily dosage of 15 fluoxetine was 60 milligrams to 40 milligrams." 16 Q. Do you have any criticism of the company or the 17 investigator for discontinuing the patient for lack of 18 efficacy in this case? 19 A. Yeah. Well, there was obviously a lot more 20 going on here than lack of efficacy. Lack of efficacy is, as 21 I said earlier, "This doesn't seem to be working on me, Doc, 22 I'm not feeling any better." It doesn't mean developing a 23 thought disorder, requiring neuroleptics, become suicidal and 24 psychotic. That is worse than lack of efficacy. I mean, it's 25 no different than someone whose blood pressure doesn't go down 112 1 as opposed to someone whose blood pressure goes way up and 2 they have a stroke. I mean, that's what it's equivalent to. 3 If I were testing an anti-high blood pressure medicine and 4 somebody took my medicine and had a stroke and wound up in the 5 hospital, and then I told the FDA it didn't work on them, 6 there was lack of efficacy, that's what was done here. 7 Q. Doctor, if you turn to the last page of that 8 patient there appears to be a 1639 form. 9 A. Uh-huh. Yeah. Okay. Nervousness and suicidal 10 thoughts, but it doesn't say anything about agitation; it 11 doesn't say anything about psychosis; it doesn't say anything 12 about requiring neuroleptics. And it only says -- the way 13 this is described it looks like he only had these on one day. 14 Q. Any more patients, Doctor? 15 A. Yeah. There is one more. 16 Q. Okay. Again, if you could give us the exhibit 17 number so we could follow with you. 18 A. This is Exhibit No. 205, HCAA 3, No. 44. Now, 19 if you recall, this is again the inpatient study. This is a 20 woman, she was born in 1915, so she would be 64 at the time 21 she came on to the study. She was a widow. She came in on 22 her own initiative and she had a number of diagnoses, though 23 she was not diagnosed as being either psychotic or agitated at 24 the time she came in. On Visit Three she required Thorazine. 25 Q. What is Thorazine? 113 1 A. For agitation. Thorazine is another 2 antipsychotic drug, a neuroleptic. These drugs are very, very 3 potent tranquilizers; they are called the major tranquilizers. 4 If it was given to someone who was normal, you'd be out cold 5 for three days. Only someone who is psychotic and completely 6 bouncing off the wall can even handle them and stay awake. 7 They are given to people who are really crazy. People who are 8 institutionalized have to take them. Now, occasionally there 9 may be someone who will take one dose. She must have been 10 acting very, very bad. Now we have the treatment-emergent 11 symptoms for that visit, Number Three, and it says confusion. 12 On the next page is a summary, if you-all can 13 read along with me on this, Patient No. 44. "This is a 14 64-year-old widowed female who was admitted to this hospital 15 for participation in the fluoxetine study. She was 16 hospitalized for depression in 1964, and then was seen as an 17 outpatient by a local psychiatrist from March 1978 until 18 August 1978, when she was hospitalized -- when he hospitalized 19 her at another Indianapolis hospital for treatment of her 20 depression. When he transferred her to this hospital, he 21 reported that he had treated her with several tricyclic 22 antidepressants, ECT and even major tranquilizers, all with 23 limited effect. We do not have more specific information. 24 "She received another study antidepressant one 25 week prior to starting fluoxetine. Doctor Slater was 114 1 contacted for permission to include this patient in the 2 fluoxetine study because her age is more than would be 3 included according to written protocol. This permission was 4 given. She was included in this study because of repetitive 5 delusional behavior which has responded to Nisoxetine, a 6 similar type drug. 7 "The first day the patient did not receive 8 medication she appeared to feel better. She was more outgoing 9 and talked more freely to me and was interacting more with 10 other patients. By the following Monday when the fluoxetine 11 placebo was started, she was again very withdrawn and had to 12 be urged to converse or otherwise interact. By the end of the 13 placebo period this patient was not interacting with other 14 patients and was spending most of her time in her room. She 15 would answer all of my questions with short answers and rarely 16 offered any additional comments. She would tell me only that 17 she was not feeling any change (good or bad) from the 18 medication. She was fairly pleasant and cooperative when seen 19 for ratings before active medication was initiated, and 20 completed the self rating without difficulty or any particular 21 urging from me. 22 "Active medication was initiated after one full 23 week of the patient's being without medication. The first day 24 of medication she showed no change, but over the weekend 25 apparently she became more confused. The second day of active 115 1 drug she wanted to refuse to go to meals, saying that she was 2 dirty and smelled bad; staff indicated that this was not true. 3 The next day she became very agitated and screamed until the 4 house physician was contacted and ordered an injection of 5 Thorazine. She refused to eat and took only one carton of 6 milk, and then after much urging. She is reported to have 7 eaten some in the evening. The fourth day of active drug she 8 again started with screaming and refusing to go to breakfast. 9 She refused all food and fluid. She was extremely withdrawn 10 and spending all of her time in her room sitting in a 11 fetal-type position. She had not communicated with staff at 12 all since her episode of screaming. She at first just mumbled 13 to me, but I eventually could get her to talk enough to say 14 she was feeling more confused and her thinking was jumbled. 15 She reported she had been feeling like screaming for a long 16 time but had been able to control it until the last few days. 17 She said she couldn't eat or drink but wouldn't say more. 18 "Her breath was foul of odor and she looked 19 dehydrated with very dry, cracked skin. Weight loss was five 20 pounds in the last week. She also said she felt too weak to 21 sit or stand. She did recognize me and called me by name. 22 She agreed with me that she was feeling miserable. She 23 appeared to be tense with clenched fist and jaw. Fluoxetine 24 was discontinued due to the clinical worsening. The next day, 25 or first day of no medication, the patient did eat about half 116 1 of all of the food offered her and talked to me more freely. 2 "This patient was then tried on a combination of 3 Haldol, Aventyl and Lithonate, which did not offer any 4 apparent improvement. When her physical condition continued 5 to deteriorate, she was transferred to University Hospital for 6 a medical workup. At this time (1-11-80) she remains there 7 and her condition has not improved. Extensive testing is 8 being done and so far we have not been told of any positive 9 findings." 10 Q. Doctor, this woman seems like she was pretty 11 sick to begin with when she was put on the study. What's your 12 criticism of this report? 13 A. Well, that's true. She was pretty sick to begin 14 with, but that's what happens when you market an 15 antidepressant. Somebody is going to mistakenly give it to 16 someone who is a little crazier than the kind of people you 17 saw in most of the clinical trials. The appropriate thing to 18 do would be, A, code this properly; it was a lot more than 19 confusion. And, B, you should have noted that, gee, we have a 20 real problem when someone who is a little worse than just 21 depressed happens to get this drug, they seem to really freak 22 out. We've had a few cases of people just really freaking out 23 and acting bizarre. We need to try the drug in a population 24 that we know is a little worse than just depressed and see 25 what happens. Do it in an inpatient setting where they'll be 117 1 safe. 2 The other option you can do, if you're really 3 afraid -- since the position that you're hoping will be 4 apparent is that the drug helps, you shouldn't be afraid of 5 using it in people that are really sick. If you really are 6 that afraid, then the right thing to do is do a 7 contraindication. There would have been nothing wrong with 8 saying this drug is not indicated for severe major depression. 9 This drug is for people who are basically normal but might be 10 having situational problems, maybe they're going through a 11 divorce, maybe they just lost their job. There would be 12 nothing wrong with marketing it for people who are not 13 terribly, terribly ill. There's a market there. There are 14 people who need something short term; they are not people who 15 are going to be on the drug for their whole lives. There is a 16 market there. 17 but when they developed the package insert, they 18 didn't mention it. They didn't mention any particular problem 19 in people who got this drug who had something a little worse 20 than depression, maybe schizoaffective disorder, maybe 21 borderline schizophrenia. Whatever was wrong with this lady 22 and the other man we talked about and the one we just finished 23 talking about, they didn't bother to figure out what it was, 24 what was that preexisting condition that caused these people 25 when they took fluoxetine within days to become very, very 118 1 crazy. 2 Q. Explain to the jury what you mean when you say 3 contraindication, and give them an example of how it might 4 work in a package insert. 5 A. A contraindication is a situation where you 6 don't use the drug. I'll give you one for my own drug. 7 You're not supposed to use benzodiazepines with glaucoma. It 8 does something to the eye. I mean, it's just contraindicated. 9 There's reasons that you wouldn't give certain types of high 10 blood pressure medicines. There are drugs you can't take if 11 you have kidney disease or liver disease. There are a number 12 of things that you don't want to use certain drugs with a 13 person who has that disease. That's why a lot of pharmacies 14 want to knoweverything you're taking so they can figure out in 15 case the doctor missed it. You may not want to combine 16 certain types of drugs. 17 So if this drug was doing something -- was 18 causing people to become very bizarre, psychotic, suicidal, 19 possibly violent, if they got it when they were schizophrenic, 20 borderline schizophrenic, worse than just your garden variety 21 depressed person, it should have been in the package insert to 22 warn doctors to make sure before they put somebody on this 23 drug that they made certain that that person had nothing more 24 than a depressive episode. 25 Q. Are you aware of any trial performed by Lilly 119 1 specifically to look at the effects on the drug of people 2 suffering from schizoaffective disorder? 3 A. No, I am not. 4 Q. Let's go back real quick and give us just a 5 one-sentence wrap-up on your major complaints with each of 6 these instances that we have showed the jury. 7 A. Okay. Patient 42 had insomnia throughout the 8 study, required chloral hydrate, and this was not reported as 9 a treatment-emergent symptom. 10 Patient No. 27 was coded as stimulation and 11 agitation, but the adverse experience page listed only 12 nervousness, and the investigator was instructed to reduce the 13 dose. I'm sorry. That was 26. It was 26 that they were 14 instructed to reduce the dose. 15 Q. Why is that important that the investigator was 16 told to reduce the dose? 17 A. That demonstrates to me that whoever said that 18 knew that there was a causal link between that symptom and 19 this drug. 20 Q. You mean the dose of the drug? 21 A. The drug itself. Because the hope was if you 22 don't give as much, maybe it won't happen. Maybe it will get 23 better if you don't give them as much. 24 Q. Do you know where that instruction came from to 25 reduce the dose? 120 1 A. It came from Lilly. It's that handwritten note 2 in here. They had called Lilly and this is what they were 3 told. I don't recall exactly who. We can look at it. 4 Q. That's okay. Go on. 5 A. Patient 9 required Valium for agitation and 6 anxiety, including an intramuscular dose, and the summary said 7 it was just nervousness. The 1639 said restlessness. 8 Patient 36 required Sodium Amytal for severe 9 agitation. The 1639 did not mention agitation. 10 Patient No. HCAA No. 40 had disorganized thought 11 and suicidal ideation expressed on his questionnaire when he 12 answered the question, "Do you have the urges to beat, injure 13 or harm someone," and he said, "Yes, myself." He was 14 terminated for lack of efficacy without investigation of 15 suicidality or any mention of suicidal thought in any report 16 of adverse experiences. 17 HCAB Investigator 3, No. 1 -- well, let me go in 18 the order that we did them. 19 Patient No. 16 of Investigator No. 2. This is 20 the one who became psychotic and paranoid after his son 21 visited on one week and the next week he escapted from the 22 institution. He had come in as a voluntary admission and was 23 brought back under a legal hold. No information was given as 24 to what happened to him while he was outside the hospital that 25 necessitated the placing of a legal hold on him. 121 1 HCAB, Investigator 3, No. 1. This is the one 2 who developed an emergent thought disorder while under 3 treatment with fluoxetine. He became and remained suicidal. 4 Suicidality was mentioned in the 1639; however, the 5 termination given -- the reason for termination given was lack 6 of efficacy. No mention was made in terms of termination of 7 how much -- that he got worse and how much worse he actually 8 got. 9 Patient 44 is the one we just talked about, HCAA 10 Patient 44, who was screaming and refusing to eat and sitting 11 in a fetal-type position for four days after beginning 12 fluoxetine. Prior to that, she was withdrawn but able to 13 communicate. This was coded as confusion. At the time the 14 investigator wrote in her final memo this person was still in 15 the hospital; they didn't know what was wrong with her. And 16 all they coded was confusion. 17 Q. In your experience, who fills out the 1639 18 that's filed with the FDA? 19 A. Anybody can fill it out, but in my -- when I was 20 at Abbott we filled them out. When the study was completed, 21 we had to go back and fill out 1639s on all of the adverse 22 experience, and the drug company personnel made the 23 determination as to what to write on them. 24 Q. Is this true for clinical trials as well as 25 spontaneous reports? 122 1 A. Well, spontaneous reports sometimes the doctor 2 will get a 1639, but more likely they will call in and the 3 drug company then writes up the report. The drug company has 4 1639s around to send in. Not all doctors keep 1639s in their 5 offices just to fill out. And on the studies it was standard 6 that we would fill it out ourselves. There may have been 7 occasions where the investigators would fill them out on their 8 own, but for the most part, we filled them out. 9 Q. Does the clinical monitor -- and if I asked you 10 this before, I'm sorry, but does the clinical monitor have a 11 duty to investigate adverse events that occur on clinical 12 trials? 13 A. Yes. 14 Q. In what circumstance would that occur? 15 A. When something very serious or unusual happens, 16 I would always call the investigator and find out more detail. 17 Things they might not have put out on the report form they 18 might tell me on the phone. In one case I made a trip to find 19 out. You might say, "Yes, get the person to the doctor, we'll 20 pay for it. Get them back for a status exam, if it's a 21 psychiatric diagnosis. You want to find out if the person is 22 really recovered, if they have any sequela, why the thing 23 happened, have them see a doctor to determine what's going on. 24 Q. Do you need to do that with every adverse event 25 that occurred? 123 1 A. Not every. But -- well, I'll give you an 2 example. When I very first started, this was very traumatic 3 to me, I had just started working with this big company, and I 4 went to do a pharmacokinetic study; it was just, you know, 5 testing blood levels. And I came there and I was all alone, 6 the investigator had not gotten there, and the guy was 7 complaining of terrible, terrible stomach ache, and I ordered 8 an abdominal flat plate. I called the ER X-ray department, it 9 was in a big medical institution, and explained to them, I 10 said, "This guy has to have an X-ray," and it turned out he 11 had appendicitis. But we paid for his treatment. I mean, he 12 got sick on the drug study and we had to make sure that it was 13 resolved. 14 Q. I'm not sure I understand. You went to the 15 site? 16 A. No. I was there to monitor the study, and when 17 the guy was complaining the investigator hadn't gotten there. 18 So I managed somehow to get him to X-ray. 19 Q. Okay. Let's see. You also gave us the opinion 20 this morning that the drug company never defined the treatment 21 group. What did you mean by that? 22 A. Well, they only used one group, the same -- with 23 rare exceptions, the same inclusion and exclusion criteria 24 remained throughout the clinical trials. They never moved 25 from Phase 2 to Phase 3. They excluded people who were 124 1 suicidal; they excluded people who were schizophrenic. In an 2 outpatient study, I think that that was appropriate. I don't 3 really see ethically that you can put someone who's actively 4 suicidal on outpatient trial because even if the drug was a 5 wonder drug, they might get placebo and go ahead and kill 6 themselves. And, you know, it's just dangerous. 7 But I think it would have been appropriate in 8 that you did feel the need to exclude them, probably not for 9 those reasons but for one thing, but you then do another study 10 in people who you know are suicidal to see if they get better 11 or worse, and you would do that in a hospital setting where 12 you could watch them and make sure they didn't hurt 13 themselves. 14 You would want to look at people because people 15 were getting agitated. You would want to look at people whose 16 behavior might be dangerous to others, who might have some 17 violent tendencies, maybe people who had some problems with 18 some domestic -- you know, some domestic trouble that brought 19 them into the clinics. There were a lot of different types of 20 groups of people that you could have looked at here to get a 21 better definition of who the drug was good for and who it was 22 not good for and who it was absolutely contraindicated in. 23 Q. What kinds of studies would you have suggested 24 in this instance from your review of the records that you've 25 seen? 125 1 A. I would have suggested a study in people who 2 were suicidal; I would have done a study in people who had 3 borderline schizophrenic disorder, schizoaffective disorder; I 4 would have looked at a study in people who had some aggressive 5 tendencies along with their depression, and for that I might 6 have looked at people who had been sent to a psychologist, 7 say, by the court system; bipolar people, I understand they 8 attempted to do that. But there are a lot of different 9 diagnoses, and I would have gotten a psychiatrist to tell me 10 what other things can look like simple depression coming in 11 but turn out to be something more serious. But just from this 12 data here, it appears that people who have some borderline 13 schizophrenic states should have been looked at specially. 14 Q. From your review of the information, the 15 case-report forms and the depositions and the SBOA, are you 16 aware of any study that Lilly has performed specifically on 17 schizophrenic patients? 18 A. No. 19 Q. Are you aware of any study that Lilly has 20 performed specifically on suicidal patients? 21 A. They haven't performed a study on suicidal 22 patients. What they did was they went back after this drug 23 was on the market and people were suspicious there was a 24 problem and did some additional reanalysis of this data. 25 Q. Okay. Are you aware -- but as far as you know, 126 1 they never set up a trial specifically to look at the effect 2 of the drug in people who were suicidal? 3 A. No. They never took and looked at a group of 4 patients who had suicidal ideation who were talking about 5 suicide and given them a very specific rating scale to 6 evaluate that and given them the drug and seeing if it helped. 7 No, that was never done. 8 Q. Are you aware of any trial that Lilly has done 9 from your review of the records to look at the effect of the 10 drug on people who may pose a risk of violent behavior towards 11 others? 12 A. Again, they did the same thing there. They did 13 not look at people who had a tendency toward violence; what 14 they did was they went back and did another reanalysis of this 15 bad data. 16 Q. What did you see in your review of the 17 information and the memos, et cetera, that you talked about 18 earlier, that put you on notice or gave you an indication that 19 they should have run these types of studies? 20 A. Well, the first thing I noticed was the cat 21 study back in the late '70s, when they first gave this to 22 cats. And it wasn't in a huge dose, it was a dose that was 23 very close to the dose you would be giving in people, and they 24 said the cats had been previously friendly and then began to 25 growl and hiss while taking fluoxetine, and once they were 127 1 stopped, those behaviors stopped. 2 Now, animals are not a perfect model for people. 3 Animals are very simple, and particularly when you're getting 4 into some psychiatric type of problems it's very hard to 5 predict with an animal what's going to happen in a human 6 being. So in this case where you have an animal that's very 7 simple, growling and hissing, you should have been thinking 8 about increased aggression in human beings. What would it do 9 in the complexity of the human mind if a little cat suddenly 10 became aggressive for the first time in her life. And then 11 there were problems with dogs. One of the handlers was bitten 12 by a dog. Dogs became aggressive. They got ataxic, they 13 couldn't walk properly. So they had warnings all the way back 14 to the animal data that there was a problem. 15 The German authorities, as we talked about 16 earlier, had pointed out the problems with agitation and 17 suicidality. And then there are these studies. These were 18 early studies. To see that many cases in one study of people 19 becoming psychotic after they took this drug, somebody running 20 away from the hospital and having to be brought back in 21 custody; a woman screaming and refusing to eat for three days; 22 a guy developing a thought disorder, these are very serious, 23 unusual events and they should have been looked at and 24 evaluated. Not just these people, but something else should 25 have been done to determine what was going on here. 128 1 Q. Did Lilly do anything in response to the German 2 government's questions regarding suicidality in the data that 3 they reviewed? 4 A. Well, they went over there and looked through 5 the data and, from what I read, it looked like they simply 6 pulled out certain reports and said no, that wasn't suicides. 7 Q. What do you mean when they pulled out certain 8 reports and said no, that wasn't suicides? 9 A. They said this wasn't really a real attempt; 10 they reevaluated them. 11 Q. Who was it that originally reported the suicide 12 attempts, to your knowledge, that they were reviewing? 13 A. Doctors in Germany. 14 Q. Okay. Clinical investigators? 15 A. Yeah. Because it wasn't approved yet. 16 Q. Okay. 17 A. Or it may have come through the clinical trial 18 process. 19 Q. Do you have an opinion on whether or not the 20 animal studies that you discussed and the early clinical 21 trials put Lilly on notice of the drugs affecting humans or at 22 least in some population of humans? 23 A. Yes. 24 Q. Could you explain that to us? 25 MR. FREEMAN: That's a question that's 129 1 inappropriate with respect to what put whom on notice or 2 anything like that. 3 JUDGE POTTER: Objection is overruled. 4 Q. You can answer. 5 A. The very purpose of an animal study is to get an 6 idea of what's going to happen in human beings. To see 7 something weird in animals and just dismiss it is bad 8 research. I mean, there have been cases where animals got -- 9 you know, they'd also look for cancer in animals, and if 10 animals get cancer, in some cases they don't go ahead with the 11 drug. In some cases where they have, there have been 12 problems. I mean, this was a case of animals becoming very -- 13 acting in a very aggressive and hostile manner. 14 Laboratory animals bond with their handlers just 15 like pets do. They'll get to know the person that comes and 16 feeds them every day. They're not mean animals. You can 17 handle them. You can make them do various -- you know, like 18 rats, they teach them to run around little mazes and stuff 19 like that. So they're domesticated; they're tame. You don't 20 expect them to be growling and hissing like wild animals, so 21 that should have been a warning. 22 The situation with the Germans was a clear 23 warning. The German government told them plain and simple 24 you've got a problem here. And these cases in this inpatient 25 study, they had to have known. These were people from reading 130 1 their depositions who were very interested in what's going on 2 within the brain with this drug, what kind of neurochemical 3 changes were taking place that affected behavior. I find 4 it -- it's incredulous that nobody noticed that there was 5 something going on here. 6 Q. When you talk about the early signals, what are 7 you talking about, the studies that we reviewed? 8 A. I'm talking about this stuff, these people. I'm 9 talking about the high incidence of activating adverse 10 effects, the numbers of people, the raw numbers of people who 11 got insomnia, activation, agitation, anxiety, restlessness, 12 nervousness. When you lump all those together, there are 13 studies that were running 30 percent, where 1 out of 3 people 14 was showing up with something that showed that this drug was 15 wiring people up. 16 Q. And what in your opinion did the company do in 17 response to what they were learning from that? 18 A. Well, they permitted benzodiazepines to be given 19 in the protocols. They instructed the investigators not to 20 list symptoms and signs of depression. 21 Q. Okay. I think you also testified this morning 22 that it was your opinion that they failed to properly report 23 to the FDA actions by the German government. Do you remember 24 that? 25 A. Yes. 131 1 Q. Let me back up just a little bit. Could you 2 explain to the jury what an approvable letter is? 3 A. Yes. Before an NDA is approved by the FDA, they 4 write the company a letter saying it's approvable, meaning 5 this is a drug we can approve. You can also get a 6 nonapprovable letter. The approvable letter may ask for some 7 things that need to be taken care of before the approval is 8 given. And in the case of this drug, the one thing they 9 wanted to see was what sort of actions had been taken by 10 foreign regulatory agencies. Now, the German problem had 11 taken place in 1984. This was 1987. They had a clear duty to 12 report that comprehensively, completely. 13 Q. Is it unusual for the FDA to ask a manufacturer 14 to give them information about what's happening with their 15 drug in other countries? 16 A. No, not at all. 17 Q. What purpose -- in your experience, what reason 18 does the FDA have for wanting to see that kind of data or 19 information? 20 A. Well, because generally drugs are on the market 21 sooner in other countries, so sometimes things come up sooner 22 in other countries than they do here. 23 Q. Why is it that you feel that Lilly failed to 24 properly report the activities in Germany to the FDA? 25 A. Well, there was a letter that Lilly had received 132 1 from Germany that talked about untoward damaging effects in 2 the context of suicidality that people -- that they were 3 worried about the agitation, that people were becoming 4 agitated before this depression was going away and that left 5 them at a greater risk for suicide, and this damaging effects 6 was mixed in with that. Then they also talked about something 7 about liver damage. 8 Well, Lilly initially sent parts -- sent that 9 correspondence to the FDA, but the FDA wrote back to them, and 10 it was apparent from their letter that the FDA was confused as 11 to what damaging effects they were talking about, and in its 12 response Lilly did not straighten that out. Lilly allowed 13 them to think that the damaging effects referred to organ 14 damage as opposed to suicide. 15 Q. Is it Lilly's duty to correct such a confusion 16 with the FDA? 17 A. Absolutely. Absolutely. 18 Q. Why? 19 A. If it's apparent that the FDA thinks the German 20 government is talking about one thing when you know they're 21 talking about something else, you should tell them, no, that 22 sentence applied to suicide. 23 Q. Do you have an opinion as to whether or not the 24 activities in Germany related to the registration of Prozac 25 there had any impact on the approval process here in the 133 1 United States? 2 A. Well, the FDA lost an opportunity to become 3 alerted to a problem. Another reason they wanted to see that 4 was to see what other regulatory agencies thought of it. The 5 more people look at something, the more likely you are to pick 6 up on a problem, and they obviously wanted to know what the 7 other regulatory agencies thought. Had they seen it, I think 8 it's quite likely that they would have taken another look at 9 this stuff and required a contraindication or warning or an 10 exclusion of certain types of patients or something to be done 11 to prevent tragedies from occurring on this drug. 12 Q. Doctor, these things that you have testified to 13 today, in your opinion, how does that impact the package 14 insert or product label, the various things that you've 15 discussed, the underreporting of adverse events, the lessening 16 of the severity of adverse events, things of that nature? 17 A. They don't get into the package insert because 18 they weren't reported properly. The package insert contains 19 different sections, and they're pretty much the same for all 20 drugs. You have the pharmacology of the drug, the chemical 21 structure, what's it indicated for, what's it used for, how 22 well does it work. And then you have all the bad stuff, the 23 very worst thing, if a drug has a really serious problem 24 that's occurring in several percent of the people, you will 25 have what's called a black box warning, where they actually 134 1 highlight the warning so that anyone looking at the package 2 insert can't help but see it; that's called the black box 3 warning. Then you have warnings; the most serious thing can 4 be a warning. Then you have precautions, and then you have 5 contraindications; that's where you list what -- maybe someone 6 with this particular disease shouldn't get this particular 7 drug. The other thing you list is adverse experiences, and 8 they're listed in different sections. I mean, there's one -- 9 they'll first list the ones that are seen fairly frequently, 10 fairly commonly, and then they list infrequent ones. And then 11 they have a chart at the end, they have a chart that has 12 certain adverse experiences. But where it goes in that 13 document is determined by how often that adverse experience is 14 reported. So if they're not reporting it as much as they 15 should be, it's not going to be found where someone is going 16 to be looking for a reaction of that frequency. 17 Q. How about the use of concomitant medications, 18 how does that impact the product label? 19 A. Well, they didn't tell anybody in the label that 20 they were using concomitant medications. Let's assume that 21 this -- as it stands, none of this stuff happened. Okay? 22 None of these people wound up with a legal hold. The lady 23 didn't scream on the floor. Everybody was fine who took this 24 drug. You'd still have a drug that was only given to people 25 who also, if they had a problem, were taking something else, a 135 1 sedative. So what you have approved is fluoxetine plus a 2 sedative for those who need it. The doctor looking at the 3 package insert doesn't know that; he thinks it's perfectly 4 okay without a sedative, so he gives it without a sedative. 5 And if he's a responsible doctor, he's not going to want to 6 put someone on a sedative who's already taking one 7 psychotropic drug. 8 Q. How about the fact that they didn't run a trial 9 specifically on people like Mr. Wesbecker who was 10 schizoaffective? How does that impact the label? 11 A. Well, again, you don't have a warning. Looking 12 at these people, had they run that study they might have found 13 60 percent of them who are completely off the wall, went 14 completely psychotic. They may have put and they should have 15 put in the warning "rule out schizoaffective disorder." Make 16 sure somebody doesn't have it before you put them on that 17 drug, but they don't know because they never ran that group. 18 Q. The fact that they didn't run a trial at all to 19 study the use of the drug with that disease, does that in and 20 of itself -- outside of what was seen from the clinical-report 21 forms that we've seen, does that impact the label or should 22 that impact the label? 23 A. You shouldn't recommend a drug for use in a 24 group that hasn't been studied. You shouldn't market it in 25 such a way that people are going to get it who have not been 136 1 studied. And when you're dealing with depression, you're 2 going to wind up with some people who have schizoaffective 3 disorder that looks like depression. That's why it's called 4 schizoaffective disorder; it has effect on the affect, which 5 is your mood. 6 MS. ZETTLER: Your Honor, may I approach the 7 Witness? 8 JUDGE POTTER: Uh-huh. 9 Q. Doctor, I'm going to show you a copy of the 10 current package insert for Prozac. 11 MR. FREEMAN: (Reviews document) This is the 12 1993 package insert. 13 MS. ZETTLER: Right, Your Honor. It's a 1993 14 package insert. 15 Q. Doctor, I'm showing you a 1993 package insert 16 for Prozac. 17 A. Uh-huh. 18 Q. If you look in that package insert under the 19 Adverse Events section, I think you'll see that some of the 20 things that we've been talking about today are listed there. 21 A. Right. 22 Q. Okay. For instance, on nervousness. 23 A. Right. 24 Q. In your opinion, does that reflect the clinical 25 experience with this drug, at least to the extent that you 137 1 have reviewed it, percentagewise and qualitywise? 2 A. Well, the nervousness at 14.9 percent, I don't 3 know whether that's a high or low tab because some things that 4 should have been coded as something else were coded as 5 nervousness, so it may actually be less people reported 6 nervousness itself. Agitation I don't see. I don't see it on 7 that list because that list is only going to be things that 8 affected a certain number of people. Some of them are listed 9 further down. We don't see agitation. Some of the people in 10 the nervousness, some of that 15 percent that were nervous, 11 actually were more than nervous; they were agitated. We don't 12 know that. Anxiety probably was higher than what we see 13 there. Insomnia definitely was higher. I would say it's 14 probably double than what we see in that package insert. 15 Tremor. We have eight percent with tremor, 7.9 percent. That 16 may be higher. I don't know. Anorexia is another thing. 17 They reported people that lost weight and some of them got 18 into the package insert, some of them got into the adverse 19 experience; some of them didn't. You might have a higher 20 incidence of that, than what they say. I don't see anything 21 about that -- 22 Q. I think if you look at the portions following. 23 A. The less frequent ones, the ones that are listed 24 in Paragraph 4. Well, at the very bottom here, there's 25 something about -- (Reviews document) Yeah. Under Nervous 138 1 System, under Infrequent Reactions they do list psychosis. 2 Q. Okay. And what is your understanding of what it 3 means to be infrequent? 4 A. Infrequent, I believe, is 1 in 1,000. 5 Q. Okay. To be fair, Doctor, you haven't looked at 6 every single clinical trial that has been run by Eli Lilly in 7 reviewing the case-report forms, have you? 8 A. No. 9 Q. You haven't looked at the final reports for 10 every single clinical trial run by Lilly on Prozac in tallying 11 up or at least getting a feel for what the rates of 12 occurrences have been in these different adverse events in the 13 clinical trials, have you? 14 A. No. 15 Q. Doctor, we've talked about what Lilly didn't do; 16 let's talk about what Lilly did do in response to the issues 17 being raised regarding suicidal ideation or suicidality. What 18 did they do, as far as you understand it? 19 A. Well, what they did was they went back and they 20 rehashed some old data, they took another look at some of 21 these trials. One thing was called a meta analysis; they went 22 back and they looked at 17 of these trials, 2 of which were 23 not even for depression. They were bulimia studies or 24 something. And they went back and they looked at the change 25 in the HAM D-3 scores; that's the score about, you know, 139 1 suicidal ideation. 2 Well, there's a couple of problems with that. 3 First of all, the people were sedated. I mean, no matter what 4 else they did, they were looking at a population that up to 30 5 percent of them were also taking something else that was 6 calming them down. So how could you possibly take that figure 7 and say, oh, everything is fine, when as many as 30 percent of 8 them were taking some other drug along with it? And even if 9 that, even with all those -- and then they also looked at the 10 reports of suicidal ideation, suicidal act. Well, as we saw 11 this morning, many of those never made it into either the 12 treatment-emergent symptoms or the 1639s because they weren't 13 coded that way. At one point they coded suicidal ideation as 14 depression on the COSTART coding. All these people were 15 depressed, so they didn't really have an adequate base to work 16 with. 17 But even with all those problems, what I found 18 striking about that study is for most of the parameter study 19 they got double the number, the percentages, on Prozac as 20 comparitor or placebo. It was not statistically significant. 21 Well, you know what statistically significant means? It means 22 that if something has a P value of less than .05, which is 23 generally what the industry uses to say it's statistically 24 significant, if it's got that P value of less than .05, that 25 means that the chance that you could have seen that simply by 140 1 chance and it has no meaning is less than 5 percent. Well, 2 great. So if it's greater than 5 percent, it means you might 3 have a 5-percent chance, or whatever the P value is, that that 4 difference is only accidental. Well, I don't want to take a 5 drug that says I've got twice the likelihood of wanting to 6 kill myself on it, but don't worry, there's a 5-percent chance 7 that that's a sporadic finding, that's a meaningless finding. 8 I don't know if I'm making this clear or not. 9 Q. It is. But go ahead and explain it one more 10 time just to be sure. 11 A. Okay. The P value means it's the chance that 12 those -- that determination could be due to chance alone, that 13 it has no meaning. Let's say I'm testing an antihypertensive, 14 and I give some to you and I give some to you, okay, and it 15 works on you but it doesn't work on him, or I use two 16 different ones; the one I give you works, the one I give him 17 doesn't work. If the chance -- the P value would say there's 18 less than a 5-percent chance that those differences are not 19 real, meaning that it was just by chance that there was a 20 difference. 21 So something that has a P value of 7 or 8 or 15 22 simply means that that is the chance that these results are 23 due to chance alone. So when you see something where the 24 amount is very big, say it's doubled or it's tripled or 25 quadrupled on a drug, but it's not statistically significant, 141 1 all that means is, well, they saw double the amount, but the 2 statistics say that there is that 5-percent chance that that 3 was an accident, that it doesn't really mean anything. 4 Q. Doctor, what did the company do in response to 5 this case which raised the issue of violent-aggressive 6 behavior in the use of Prozac, at least publicly? 7 A. Well, they went back and they looked back at the 8 adverse experience report and they developed a list of 9 symptoms that were associated with violent-aggressive. And 10 there were 15 or 20 on the list and I can't memorize it all. 11 And then they picked 3. I don't know why, but these are the 12 three they picked: antisocial reactions, hostility -- I don't 13 recall the other one. 14 Q. I think it was personality disorder. 15 A. Personality disorder. And they again ran this 16 data back through and looked for those reactions. Again, 17 you're looking at a flawed sample. You're looking at a sample 18 of people who were sedated. You're looking at data that was 19 never -- when they were collecting, they weren't looking for 20 these things. When you do a study, you have to set out your 21 parameters and your evaluations to look for very specific 22 things. It's not good research to do something for one 23 purpose and then go back and look at it again for something 24 else. And that's what they did here. They took data that was 25 collected mainly for efficacy and general safety parameters 142 1 and then went back and looked at it as though it had some sort 2 of very specific scale, which it didn't. 3 MS. ZETTLER: Judge, may I approach? 4 JUDGE POTTER: Certainly. 5 Q. Doctor, this is an exhibit that we used with 6 Doctor Breggin the other day, and he testified that these 7 numbers are numbers that we had gotten from the spontaneous 8 reporting system from the FDA, but as far as the analysis that 9 you reviewed, are some of these adverse events ones that were 10 not listed? 11 A. Right. 12 Q. Okay. And when I say "not listed" I mean they 13 were looked at initially but not run through the final 14 analysis? 15 A. Exactly. 16 Q. Okay. Are things like suicide attempt and 17 overdose and psychotic depression, things that pose a risk for 18 violence towards others? 19 A. Yes. 20 Q. In your opinion, should those have been run as 21 part of those aggression analyses? 22 A. Yes. 23 Q. What about things such as agitation, anxiety, 24 CNS stimulation, emotional lability, insomnia, abnormal 25 dreams, manic depressive reaction and manic reaction? 143 1 A. All of those things should have been looked at. 2 See, the problem here is that people are feeling depressed, 3 and a lot of times depression is anger turned in. And what 4 happens here is they get stimulated but they still feel the 5 anger, they haven't really calmed down in terms of their own 6 anger, so they're simply agitated and having all these fits of 7 anger. 8 MR. FREEMAN: I don't know how this witness can 9 know what the patient knows, Your Honor. 10 Q. Just generally, aggravation reaction; antisocial 11 behavior; hostility, which those two we know they did run; 12 irritability; paranoid reaction; intentional injury. 13 A Intentional injury definitely, and paranoid 14 reaction, definite. Only hostility, antisocial behavior and I 15 think it was aggravation reaction. 16 Q. We know one gentleman on the early clinical 17 trials became psychotic and eloped from the hospital and got 18 into we don't know what. Are people who are psychotic, in 19 your opinion, at a higher risk for violent behavior? 20 MR. FREEMAN: Your Honor, that's another 21 psychiatric opinion. 22 JUDGE POTTER: Let me see you-all here just a 23 second. 24 (BENCH DISCUSSION) 25 JUDGE POTTER: I'm sorry, Ms. Zettler. Your 144 1 voice trailed off and I didn't really hear the question. 2 Repeat the question about becoming violent. 3 MS. ZETTLER: She has some extraordinary 4 experience outside regular doctors. I mean, she's testified 5 as to psychiatry, plus this stuff is known generally through 6 the medical community. 7 MR. FREEMAN: They didn't list any of this stuff 8 of giving any psychiatric opinions in disclosure or anywhere 9 else. 10 MS. ZETTLER: She discussed this in the 11 deposition, Judge. 12 MR. FREEMAN: No, she did not. 13 JUDGE POTTER: I'm going to sustain the 14 objection. 15 (BENCH DISCUSSION CONCLUDED) 16 Q. To your knowledge, was the effects of that 17 psychosis used in the reanalysis of the data that Lilly did 18 with regards to aggression and violent-aggressive behavior? 19 A. No, it was not. 20 Q. Are you aware of anything else -- specifically 21 with regards to violent-aggressive behavior that Lilly did in 22 response to the issue being raised whether or not Prozac 23 causes violent-aggressive -- or exacerbates violent-aggressive 24 behavior other than this reanalysis of preexisting data? 25 A. No. The only other special reanalysis -- it 145 1 wasn't a study, is they looked at agitated depression, how 2 well people did who started out with agitated depression as 3 compared with retarded depression. But they didn't do another 4 study specifically looking for violence and aggression and 5 they never did a study in people who were at the outset having 6 a tendency toward violence and aggression. 7 Q. I think that's all we have right now, Doctor. 8 Thank you. 9 MR. FREEMAN: May I proceed, Your Honor? 10 JUDGE POTTER: I know one of the jurors has got 11 a baby-sitting problem, so I know we're going to be quitting 12 right at five, so we'll go ahead and take our afternoon recess 13 right now. Ladies and gentlemen of the jury, as I mentioned 14 to you-all before, do not permit anybody to talk to you about 15 this case; do not discuss it among yourselves and do not form 16 or express opinions. We'll take a 15-minute recess. 17 (BENCH DISCUSSION) 18 JUDGE POTTER: One of the reasons I took the 19 recess was because Ms. Zettler had said there was something 20 she wanted to take up before you did your cross-examination, 21 and since you were a little late getting here, I didn't get a 22 chance to alert you to that fact. 23 MS. ZETTLER: Your Honor, we want to renew our 24 motion in limine to any reference to Doctor Lord's religious 25 or political affiliations. She is a Libertarian. She has 146 1 some -- in some people's minds radical views on things, and as 2 far as it being relevant to her opinion in regarding how the 3 clinical trials were conducted or any medical opinions she may 4 have rendered, it's not -- it doesn't even come close to 5 relevant and would be nothing but highly prejudicial. 6 MR. FREEMAN: Your Honor, I think I have a right 7 to show all of the different things that this 8 jack-of-all-trades has done in her life. She went to medical 9 school. She dropped out of her residency, she took a 10 psychiatric course. She dropped out of that. She went to 11 Abbott, she dropped out of that. She went in the consulting 12 business in terms of rendering opinions with -- she ran for 13 mayor of Chicago for political career. She ran for 14 Vice-President of the United States. She's done all of these 15 things that bear upon her credibility in terms of being an 16 expert here. You would think that all she had done all of her 17 life was make study of clinical studies records, and that 18 ain't so. She doesn't know anything more about clinical 19 studies than I do, and I know nothing about it. I'm willing 20 to show that she did these other crazy things related to 21 credibility and -- 22 MS. ZETTLER: You've already ruled on this, 23 Judge. We just wanted to raise this again so that you could 24 remind Mr. Freeman not to drag that stuff out of the closet. 25 JUDGE POTTER: We've got two issues. I take it 147 1 Libertarians is a party in Illinois, maybe here, too, so we're 2 down to two issues. Have you run for mayor of Chicago, did 3 you run on the Libertarian ticket. Mr. Freeman, assuming I'm 4 going to rule in your favor that you can ask her have you run 5 for the mayor of Chicago, what difference does it make what 6 ticket she did? 7 MR. FREEMAN: None, except she and Doctor 8 Breggin are both Libertarians. 9 JUDGE POTTER: I'm going to sustain the 10 objection about her ticket. What do you say about the fact 11 that she has spent presumably a substantial amount of her time 12 on something other than being a doctor? 13 MS. ZETTLER: He can ask her every other 14 question he talked about except what are her political 15 affiliations, and I think in that situation whether or not she 16 ran for the mayor of Chicago has absolutely no relevance. 17 MR. FREEMAN: It's Washington. I was getting it 18 confused with where you're from. It's Washington, D.C. 19 JUDGE POTTER: Okay. She has come along 20 presumably running for mayor, but notwithstanding, running for 21 mayor of Washington takes a good deal of time. Have you run 22 for mayor of Washington; I'm going to allow it, but I don't 23 think you can ask her what ticket she ran on. 24 MS. ZETTLER: What I'm concerned is he's going 25 to try to make an issue out of the Libertarian party's 148 1 position on drugs, et cetera. 2 MR. FREEMAN: Letting every drug in America be 3 street drugs. 4 MS. ZETTLER: My understanding is that it's a 5 political article and not a scientific article. 6 JUDGE POTTER: Let me see it, Mr. Freeman. Have 7 you got it? 8 MS. ZETTLER: I guarantee you it's not in 9 Penthouse, either, Judge. 10 MR. FREEMAN: The Decriminalization of Drugs, an 11 Idea Whose Time Has Come, Nancy Lord, M.D. -- not M.D. 12 Libertarian. 13 JUDGE POTTER: Mr. Freeman, where -- what do you 14 anticipate the answers to be to your question: "What is 15 this"? 16 MR. FREEMAN: Well, she's written it as a 17 doctor. She's testifying here as a doctor. She's given 18 medical citations throughout the article. She's talking about 19 the effects these various drugs have on people. 20 JUDGE POTTER: Is this a doctorate dissertation? 21 MR. FREEMAN: It's an article she wrote for 22 publication on this issue. 23 JUDGE POTTER: Has it been published, do you 24 know? 25 MR. FREEMAN: Has it been published, Larry? 149 1 MR. MYERS: Let me check on that. 2 MR. FREEMAN: I don't know. Someone knows. 3 MR. SMITH: We've seen him checking on stuff 4 before. 5 MS. ZETTLER: Why don't we get Doctor Lord in 6 here and ask her if it's been published and where. 7 MR. FREEMAN: It bears upon the whole issue of 8 her ideas about the administration of drugs and otherwise. 9 MS. ZETTLER: This has nothing to do with the 10 conducting of clinical trials, Your Honor. All they're trying 11 to do is muckrake her. It's a political article that espouses 12 views that she has politically, not as a doctor, and it just 13 has no bearing. 14 MR. MYERS: I'm not sure it has been, but she 15 has spoken publicly on the subject numerous times. 16 MR. FREEMAN: She wrote it as a doctor about 17 controlled drugs. 18 JUDGE POTTER: Let me look at it. 19 MS. ZETTLER: Okay. Are you trying to get that 20 into evidence besides just asking her questions on it? 21 JUDGE POTTER: Mr. Freeman, again, tell me why 22 this is relevant to what's going on here today. 23 MR. FREEMAN: In the first instance, this lady 24 has appeared on the stand appearing as an expert that knows 25 everything on earth about clinical trials and 1639s and 150 1 case-report forms. I am entitled to show the totality of her 2 background, including how little time she's spent on the 3 subject she's now testifying today, how long it took her to 4 compile all this information, who compiled it with her, 5 whether or not she has spoken from it, expounding it as a 6 medical doctor. To show that on the front page of it, she 7 purports to be an M.D., -- 8 MS. ZETTLER: She is an M.D. 9 MR. FREEMAN: -- and she's expounding these 10 ideas as a doctor. She didn't put Nancy Lord, Libertarian; 11 she put Nancy Lord, M.D., medical doctor. 12 MS. ZETTLER: Number One, Your Honor, he is not 13 offering this to try to show that she had written papers and 14 was taking up a lot of time. He's trying to paint her with 15 this idea that she should legalize drugs and he's hoping to 16 offend the jury with that. We have not seen this paper. Mr. 17 Myers I believe confirmed it has not been published. I'd like 18 to have an opportunity to have a thorough look at it and make 19 sure there are no things that have her religious views in it. 20 I mean, who knows what else is talked about in there. I just 21 think this is the kind of surprise that you talked about 22 earlier. 23 JUDGE POTTER: What do you mean, you haven't 24 seen it? 25 MS. ZETTLER: No, absolutely not. They did not 151 1 talk to her about this on her deposition at all. This is 2 something that's fallen on us. Third, if this is not 3 published we want to know where they got it from. 4 MR. FREEMAN: You obviously made a motion in 5 limine. 6 MS. ZETTLER: No. We did it because of her 7 affiliation, not because of her specific document. 8 JUDGE POTTER: We're down to unlike the 9 Penthouse article it's not going to be introduced as an 10 exhibit? 11 MR. FREEMAN: That's correct. 12 JUDGE POTTER: At most we're going to ask about 13 it? 14 MR. MYERS: To answer your question in another 15 lawsuit called Volotus (phonetic) versus Ortho, June 15, 1989, 16 at Page 234 and, in fact, if you look on the inside cover of 17 the article there's a court reporter's note as to the exhibit 18 to the deposition. 19 MS. ZETTLER: That doesn't make it relevant for 20 this case, Judge. That was a deposition; that wasn't a trial 21 deposition. 22 JUDGE POTTER: I'm going to rule that whatever 23 tangential relevance to the fact that she advocates legalizing 24 some but apparently not all drugs. Apparently PCP doesn't 25 pass the test, whatever relevance that might have is greatly 152 1 outweighed by the prejudicial value it's going to have. 2 MS. ZETTLER: And that goes for the subject 3 generally, I mean, not just the paper? 4 JUDGE POTTER: Do you believe drugs should be 5 legalized? What relevance does it have besides the fact that 6 she's got the same opinion that got Jocelyn Elders in trouble? 7 MR. FREEMAN: She's been carrying it around as 8 her qualifications in other cases citing it as an article 9 she's written, Summary of My Evaluation of These Articles. 10 JUDGE POTTER: For better or for worse -- 11 MR. MYERS: I want to note this also says she 12 wants to legalize amphetamines, which she and Doctor Breggin 13 say it is. I mean, it is relevant on this point. 14 JUDGE POTTER: We can introduce it as a file 15 exhibit. 16 MS. ZETTLER: What does that mean? 17 JUDGE POTTER: So they'll have something to 18 argue on when they go up on appeal. 19 MS. ZETTLER: So it doesn't come in? 20 JUDGE POTTER: Right. 21 MS. ZETTLER: Judge, can we take five minutes? 22 JUDGE POTTER: We'll take ten. 23 (RECESS; BENCH DISCUSSION) 24 JUDGE POTTER: We're going to mark this, okay. 25 That will be Exhibit 200 is admitted for purposes of avowal. 153 1 MS. ZETTLER: It occurred to me when we were on 2 the break that just asking her if she ran for vice-president, 3 for instance, is going to suggest that she -- everybody knows 4 who ran for Vice-President of what party, and that's just too 5 prejudicial. 6 JUDGE POTTER: She can run as an Independent. 7 She ran for Vice-President of the United States? 8 MR. FREEMAN: Oh, yes. 9 JUDGE POTTER: I think he's entitled to ask her 10 if she's had some major undertakings outside of the scholarly 11 pursuits we've heard about. 12 MS. ZETTLER: He can't ask her about her 13 platform or anything about that, just the time it took out for 14 her campaigning, et cetera? 15 JUDGE POTTER: Right. 16 (BENCH DISCUSSION CONCLUDED) 17 SHERIFF CECIL: The jury is entering. All 18 jurors are present. Court is back in session. 19 JUDGE POTTER: Doctor, I'll remind you you're 20 still under oath. 21 Mr. Freeman. 22 23 EXAMINATION ___________ 24 25 BY_MR._FREEMAN: __ ___ _______ 154 1 Q. Mrs. Lord, I would like to get, if I might, a 2 little bit clearer picture, so we can put it together sort of 3 in a time line, of your background and experience. First of 4 all, if I understand it, you are from Maryland; is that 5 correct? 6 A. That's right, sir. 7 Q. And you went to medical school at the University 8 of Maryland from 1973 until 1978? 9 A. That's not exactly true. I graduated from 10 college in December of 1973. I started medical school in 11 September of 1974, and I completed a little early. I think I 12 got done in March of '78, though I didn't get my degree until 13 May or June. 14 Q. All right. And during that particular time 15 frame, you took, as I understand it, for the first two years 16 of your medical school curriculum an accelerated course in 17 psychiatry? 18 A. No. That was not -- the accelerated course was 19 an addition. I took the regular course work for the first two 20 years. The combined accelerated program in psychiatry was an 21 additional program; it was a special program that I took on 22 top of all the things that everybody else took. 23 Q. So you were spending your everyday school career 24 taking all of the courses that other students were taking and, 25 in addition, you were taking this accelerated course in 155 1 psychiatry? 2 A. Right. And I think we spent a summer, a summer 3 between the first and second years I spent full time on a 4 psychiatric ward at the University of Maryland Hospital 5 Psychiatric Institute. 6 Q. And you dropped out of that program? 7 A. Well, everybody did. I think there were maybe 8 one or two people left. Once the clinical rotation started 9 and you had to be on call every third night, not too many of 10 us were able to continue seeing patients two or three times a 11 week. I think one or two of them did, but most of them 12 stopped after two years, like I did. 13 Q. Do you have any preference as to what I call 14 you? Should I call you Nancy since you're calling me Joe, or 15 should I call you Mrs. Lord or what -- 16 A. I don't recall that I called you Joe. 17 Q. I thought I understood you to say that. Maybe 18 I'm wishful thinking. 19 A. No. I will call you Mr. Freeman; you can call 20 me Doctor Lord. That will be fine. 21 Q. Well, Nancy -- I mean, Doctor Lord, you are now 22 practicing law in Atlanta? 23 A. That's correct. 24 Q. And that's where I practice. And we have never 25 met except when I met you in Judge's court some months ago; is 156 1 that correct? 2 A. That's right. 3 Q. Now, in 1978, after you graduated from medical 4 school, you took a pathology residency, didn't you? 5 A. That's correct. 6 Q. And in that pathology residency you were 7 principally working with cadavers and with microscopes and 8 with tissue to try to determine what went on with a patient 9 prior to the patient dying? 10 A. Well, usually we were able to do that, sir. I 11 mean, there weren't too many cases where we couldn't figure it 12 out. Once somebody is dead, it's generally easy to figure out 13 what happened. It's sad that we can't figure it out before 14 that more often. It wasn't just trying; we usually did it. 15 Q. But I was just trying to get the picture. You 16 were not seeing patients in the hospital? 17 A. No, not at all. 18 Q. You were not prescribing any prescription 19 medication for any patient? 20 A. No. 21 Q. You were certainly not treating any psychiatric 22 patient in life? 23 A. No, I wasn't. 24 Q. All right. Now, in 1980, before you completed 25 your pathology residency, you again quit, didn't you, or you 157 1 quit, I should say, and went to Abbott? 2 A. Yes, I did. I think I had the job -- I looked 3 for a job before I left. 4 Q. But you didn't complete your pathology 5 residency? 6 A. No, I didn't. 7 Q. Now, so that I will understand it, you were with 8 Abbott almost four years, lacking maybe a couple months? 9 A. That's right. 10 Q. In other words, you went in February of 1980, if 11 I understood it, and you left in December of 1983, if I 12 understood that correctly? 13 A. That's right. 14 Q. And while you were at Abbott's, you had occasion 15 to work only on one NDA; is that correct? 16 A. That's right. It was one NDA. 17 Q. And when you left Abbott in December of 1983, 18 what was the status of the NDA in connection with it having 19 been filed with the FDA? 20 A. Well, I left -- I signed it and I thought it was 21 ready to file. It may have taken them another few months to 22 actually file it. It did get filed rather quickly after I 23 left. It had not yet been approved. 24 Q. Now, when you say it had not been filed, do you 25 know whether it was actually filed under your name, in other 158 1 words, as your signature for Abbott signing the NDA that went 2 to the FDA? 3 A. I signed an NDA. Whether they used my NDA or 4 made changes afterwards, I have no way of knowing. 5 Q. Now, isn't it a fact that the FDA turned down 6 the initial NDA, that is, the one that you prepared, turned it 7 down? 8 A. Well, I didn't learn about this until my 9 deposition, sir, but I was told by your co-counsel that there 10 was a nonapprovable letter given by the FDA for my drug. The 11 nonapprovable letter required additional studies, which 12 happens very frequently in the pharmaceutical industry. 13 Several additional studies were done and then the NDA was 14 approved I believe it was in '89. I didn't even know it was 15 approved for two years after it was approved. I really 16 haven't stayed in touch with the company. 17 Q. Now, let's talk about that a little bit. In 18 connection with dealing with the FDA, when you were there for 19 that nearly four years, did you find it appropriate or 20 inappropriate to pick up the telephone, if you needed to, and 21 call a person at the FDA to discuss something about the 22 medication that you were studying? 23 A. That was not my job. I was the clinical 24 monitor. There was a regulatory affairs division that would 25 handle the direct contacts with the FDA, though on several 159 1 occasions I did actually go to Rockville and take part in 2 meetings with the FDA. I think I was involved in a meeting 3 where they were developing guidelines for hypnotics, and I 4 actually addressed a rather large group. But it wouldn't be 5 part of my responsibility to actually call up a particular 6 individual, unless it was just someone I may have gotten 7 friendly with or something because I was going to another 8 meeting or something. 9 Q. But there was nothing wrong with your regulatory 10 person calling the FDA and finding out a bit of information or 11 asking if they needed anything in addition? 12 A. That's what they were supposed to do. 13 Q. And you were supposed to attend meetings with 14 the officials of the FDA, if called upon to do so, to answer 15 any technical questions that they might have? 16 A. Yeah. I suppose. Yeah. 17 Q. Let's get back to that. You said you went to 18 Rockville on a couple of occasions? 19 A. That's right. 20 Q. Is that the location where the office of the FDA 21 was at the time you were at Abbott? 22 A. I believe it's still there, sir. 23 Q. Is that where it was at the time you were at 24 Abbott? 25 A. Yes. 160 1 Q. And did you have an occasion to go there for any 2 meeting with any FDA official? 3 A. Yes. On several occasions. 4 Q. On several occasions? 5 A. That's correct. 6 Q. How many occasions? 7 A. I recall two, but there may have been more. 8 Q. Did they ask you questions about what was going 9 on in the clinical trials? 10 A. Yes. There were a number of questions and 11 problems with my drug that they wanted more information on. 12 Q. Did you attempt to give them the information 13 that they asked about your drug? 14 A. Absolutely. 15 Q. And did you attempt to give it to them in the 16 completest form that you knew how to do? 17 A. Yes. 18 Q. Did you ever suggest to them that while studying 19 your drug it might be appropriate to do a study on hostility? 20 A. There was no problem with people going whacko on 21 my drug, sir. There were problems, but that wasn't one of 22 them. 23 Q. Have you seen the package insert for your drug? 24 A. Not recently, no. 25 Q. I'll ask you, please, ma'am, first of all, 161 1 satisfy yourself that that's the package insert for your drug. 2 MS. ZETTLER: Joe, can we have a copy of that, 3 please? Thank you. 4 Q. Do you see where nervous system is on the page? 5 A. Right. It says, "Frequent: Anxiety. 6 Infrequent: Agitation, amnesia, apathy, emotional lability, 7 euphoria, hostility -- 8 Q. Just a minute, please. First of all, it's got 9 Nervous System in italics; correct? 10 A. Yes. 11 Q. And then after that, it's got "Frequent," colon; 12 correct? 13 A. Uh-huh. 14 Q. And after that, it's got anxiety; correct? 15 A. That's correct. 16 Q. And after that, it's got infrequent; correct? 17 A. That's right. 18 Q. With a colon. And it's got agitation, amnesia, 19 apathy, emotional lability, euphoria. What is euphoria? 20 A. Some people say they get high on it. 21 Q. Like being manic, or not? 22 A. No. It's not really being manic. Manic is 23 more -- people who are manic, it's more -- they're more 24 pressured, they're more hyperactive. Euphoria is just sort of 25 a pleasant, you know, kind of tranquilized feeling. 162 1 Q. And the next one is hostility? 2 A. Yeah. That's true. 3 Q. And then you've got seizure, sleep disorder, 4 stupor, twitch, and then you've got rare events after that; is 5 that correct? 6 A. That's right. 7 Q. Now, did you while you were at Abbott do any 8 study to determine what effect the medication that you were 9 seeking to have approved would have on a person who was 10 hostile? 11 A. No, we did not. 12 Q. Now, getting back, please -- nor did you do any 13 study on any person that was agitated or group of patients? 14 A. No, we did not. Those were not the problems 15 that -- we did do some special studies which I'll tell you 16 about if you'd like, but that was not the area that was the 17 problem with my drug. 18 Q. You didn't do any studies on people that were 19 manic or depressed? 20 A. Actually, we did do some studies of -- not manic 21 and depressed specifically, but we did do studies that used a 22 broad group of patients, and some of them may have had mania 23 or depression. 24 Q. And you didn't do any studies on any patients 25 that had a schizoaffective disorder? 163 1 A. No. The special studies that we did to test the 2 drug to define the problems that we saw could become apparent 3 after marketing did not involve schizoaffective patients, they 4 involved other things that we saw as potential problems. 5 Q. That you and the scientists at Abbott thought 6 were potentially a problem? 7 A. That's correct. 8 Q. Now, so that the jury and I can evaluate this, 9 if you would, a pharmaceutical company will have an idea about 10 a condition that they would like to provide a compound for the 11 treatment of that condition; is that a fair statement? 12 A. That's accurate, yeah. 13 Q. And then when this idea comes up to them, they 14 do studies in the laboratory to determine what the best 15 compound is for that condition according to their scientists' 16 best judgment; is that correct? 17 A. Well, I don't really know much about how they 18 develop the drug, you know, in the chemical laboratories. I 19 know there are ways to do it with computers and changing 20 molecules here and there, but that's really not my field of 21 expertise. 22 Q. Do you know about them doing studies in test 23 tubes where they see what happens in a test tube before they 24 ever put the compound into an animal? 25 A. In vitro studies, yeah. But, again, that's not 164 1 my area of expertise. 2 Q. But you do know that companies like Lilly and 3 Abbott do in vitro studies to determine what those are going 4 to show so they can see if the drug has promise as respects 5 animals and then, later, humans? 6 A. That's right. 7 Q. And then the FDA says to you, Abbott, or to Mr. 8 Lilly, we want you to do studies in animals to determine their 9 toxicity or to determine if they're poisonous or to determine 10 what major organ systems might be affected from the ingestion 11 of the drug? 12 A. Well, the FDA doesn't just call you up and say 13 that that's part of the rules and regulations for getting a 14 drug approved, and it applies to everybody. It's not that if 15 I just were deciding to get a drug put on the market, the FDA 16 might say to me, "You're Nancy Lord and we're going to trust 17 you; you don't need to do animal studies," that's not the 18 case. Everybody who wants to put a drug on the market has to 19 do animal studies first. 20 Q. I understand that to be the case, that every 21 drug that's approved as a prescription drug must have these 22 animal studies done by way of FDA regulation; right? 23 A. Right. 24 Q. By the way, are you expert also on the FDA 25 regulations? 165 1 A. I do a lot of work today with FDA regulations. 2 That's part of my practice, sir. 3 Q. Can you tell the Court and jury under the FDA 4 regulations at what point it became obligatory for a 5 pharmaceutical house to tell the FDA what was happening 6 abroad? 7 A. When the FDA asked them to. The FDA 8 specifically requested that in a letter to them. 9 Q. I'm asking you if you know insofar as federal 10 regulations are concerned when it is obligatory for the FDA to 11 learn of what is happening abroad, either yes or no. Do you 12 know what the FDA regulation is? 13 A. I know that when I developed my drug we were 14 required to report all foreign adverse events. I don't know 15 at what date prior to my being at Abbott and having to be 16 involved in that that regulation was made, nor can I quote you 17 the number of the regulation. But I do know that when I was 18 there you were required to report foreign adverse reactions. 19 Q. Do you have any feel for when the FDA asked to 20 know about any of these matters -- excuse me -- by way of 21 federal regulations required reporting? 22 A. The day that the regulation was implemented? 23 Q. Yes. 24 A. No, I don't. 25 Q. So, if I understand it, you are not purporting 166 1 here to be an expert on FDA regulations, or are you? I just 2 want to know. 3 A. It depends on how much of an expert I'm expected 4 to be. I know the regulations as they apply to the areas that 5 I work. I know how they apply to the clinical development of 6 drugs. I know the regulations that apply to the kind of cases 7 I work with today, the 333.A.2 violations. I know what is a 8 label, what is not a label, what kind of claims are allowed, 9 that sort of thing. But can I quote you chapter and verse 10 everything in Title 21? No, I can't. 11 Q. Now, in 1983, that is, in -- I believe it was 12 December of that year; right? 13 A. Right. 14 Q. You left Abbott; right? 15 A. Uh-huh. 16 Q. And you went out and formed your own consulting 17 firm? 18 A. That's correct. 19 Q. And 95 percent of what you did while you were 20 employed as a consultant in your own firm, 95 percent of your 21 income came for testifying for lawyers representing the 22 plaintiff? 23 A. I'm not sure if it was 95 percent. I tended to 24 get -- there were more lawyers that I worked for, but in terms 25 of the actual amount of work, when I did work for a drug 167 1 company it was usually a longer and more lucrative project, so 2 it probably came to maybe 10, maybe 15, maybe only 5 percent, 3 I don't really know at this time. 4 Q. What I'd like to ask you, have you previously 5 testified on occasion that your testifying or your consulting 6 with lawyers, that is, giving depositions, testifying in court 7 and things of that nature, that 98 percent of your income came 8 from lawyers in one place, and in another place you testified 9 95 percent of your income came from lawyers? 10 A. I may have said that. It would depend on the 11 year that I was talking about. When I first got out of Abbott 12 I did have some drug companies I was working for. You're in 13 the ballpark. It's not worth quibbling about. Maybe it was 14 that much. 15 Q. And you did that consulting work as a full-time 16 effort from 1983 until 1987; did I get that correct? 17 A. That's right. When I started law school.. 18 Q. And you started law school in -- did you tell me 19 September, I've forgotten? Tell the jury. 20 A. I think it was August of 1987. 21 Q. August? All right. And then you got out of law 22 school in 1990? 23 A. That's right. 24 Q. Now, in an effort to get an appreciation for 25 what you have done with your time, after you got out of law 168 1 school -- which was in Washington, D.C.; is that right? 2 A. That's right. 3 Q. You ran for mayor of Washington, D.C., did you 4 not? 5 A. No. I started my campaign before I graduated. 6 I was still in law school when I was running for mayor. 7 Q. I'm sorry. I didn't get that detail correct. 8 So while you were in law school, you were running for mayor of 9 the City of Washington, D.C.? 10 A. That's right. 11 Q. And who were you running against? 12 A. Well, I was asked to run and -- 13 MS. ZETTLER: Your Honor, objection. 14 JUDGE POTTER: Sustained. 15 Q. How much time did you devote to the campaign of 16 running for mayor of Washington before you got out of law 17 school and up until the election was held? 18 A. I don't remember exactly. There was generally a 19 forum a couple of times a week that I would attend and debate 20 the other candidates, and maybe on the weekends we'd go to 21 parades and street fairs and things like that. I didn't keep 22 track of my hours. 23 Q. Was it a pretty full-time exercise in terms of 24 running for mayor of Washington, D.C.? 25 A. Well, I finished law school at the same time, so 169 1 I guess not. 2 Q. And did you appear on various media programs in 3 connection with your running for mayor of Washington, D.C.? 4 A. Oh, yes, I did. 5 Q. Were you able to obtain through any source any 6 training in media handling? 7 A. No. I've learned that on my own, sir. 8 Q. And this has been from interviews and things of 9 that kind that have to do with media as it may relate to the 10 public affairs and other political activities; is that 11 correct? 12 A. What is your question? I don't understand. 13 Q. Let me restate it; it was awkward. 14 Your political career that you started before 15 you got out of law school has given you opportunities to 16 appear in the published press, that is, in written press; 17 right? 18 A. Uh-huh. 19 Q. On radio; is that correct? 20 A. That's right. 21 Q. Is that correct? 22 A. Oh, yes. I've appeared on radio. I've also 23 hosted a show. 24 Q. And on television programs? 25 A. Yes. Well, I appear rather regularly on CNN and 170 1 Company, and that's really at this point more as an attorney 2 than as a political figure. 3 Q. All right. And so you've learned from these 4 things how to relate subject matter to the public that you 5 want to relate to them; is that a fair statement? 6 A. Actually, where I've really learned that is with 7 the help of people like yourself, sir. Cross-examination is 8 far more difficult than any television appearance. 9 Q. So all of the times that you have appeared by 10 way of deposition and in court, such as this setting, has 11 enabled you to, in your judgment, become a better 12 communicator? 13 A. That's correct. 14 Q. So far, is there anything particularly difficult 15 about the questions that I've asked you? 16 A. No, sir. 17 Q. Now, along that subject, since you brought it 18 up, you have appeared in various and sundry kinds of cases, 19 have you not? 20 A. Yeah. I've appeared in some cases; it's been 21 awhile, though. 22 Q. If I understand it, you do not have a degree in 23 pharmacology? 24 A. Well, my training was at Abbott. There are 25 postdoctoral programs in pharmacology. There are Ph.D.s in 171 1 pharmacology. But a large number of M.D. pharmacologists such 2 as myself, there's no residency program in pharmacology, 3 per se. 4 Q. There is a Ph.D., though, in pharmacology, is 5 there not? 6 A. Oh, there is a Ph.D. You can get an M.D./Ph.D., 7 but there's no residency in pharmacology. 8 (REPORTER'S NOTE: THE FOLLOWING CASE 9 CITATIONS ARE ALL SPELLED PHONETICALLY) 10 Q. You recall appearing in the Supreme Court of New 11 York? That's that same court at this level, though in New 12 York they have a very elevated idea of what they call their 13 courts. But that court is just the same as our's here, called 14 their supreme court. Do you recall appearing in Hamner versus 15 Montenolla? 16 A. I don't remember the name, sir. I'm sorry. 17 Q. That was in June of 1986. You don't recall 18 criticizing the doctor there in connection with his practice? 19 A. Perhaps I did, but if you don't tell me what the 20 issue -- if you tell me the medical issue, I'll be more likely 21 to remember it than the names. You're talking eight years 22 now. 23 Q. I'll see if I can find that in just a minute. 24 A. Okay. 25 Q. Do you recall appearing in a case against 172 1 Richardson Merrill called E-A-L-Y? 2 MS. ZETTLER: Your Honor, can we be heard on 3 this? 4 JUDGE POTTER: Let me see you up here for a 5 second, Mr. Freeman. 6 (BENCH DISCUSSION) 7 MS. ZETTLER: Your Honor, if Mr. Freeman is 8 going to go through every single one of these cases, we want 9 the opportunity for us to get what the facts of the case were, 10 what the wrongs of the case were. I think this is just 11 slightly prejudicial. If he wants to ask how many times she 12 testified he can just ask her the question. 13 MR. FREEMAN: I think I have every right to show 14 that she's appeared -- tried to appear on numerous occasions 15 testifying on everything from ophthalmological cases, eyes, to 16 birth defects to orthopedics to anything of that nature. And 17 I can go into more detail if she wants to hear it. 18 MS. ZETTLER: I'm concerned about the subject 19 matter and the facts and the liability and what was found in 20 the cases. He's making it sound like she's running around 21 testifying and he's not going to give her any information 22 about them. 23 JUDGE POTTER: If she testified in 56 cases or 24 whatever it happens to be, you can say have you testified on a 25 topic of ophthalmologic, gynecologic care in these cases. 173 1 You've got to have the package before you ask the question. 2 (BENCH DISCUSSION CONCLUDED) 3 Q. What kind of company is Richardson Merrill? 4 A. It's a drug company. 5 Q. Do you recall that you criticized them in 6 connection with a case in which you appeared for the plaintiff 7 about a birth defect? 8 A. Yes. I do recall that one. 9 Q. All right. 10 A. That was not in court. I didn't appear in court 11 on that case. 12 Q. You just gave a deposition? 13 A. That's correct. 14 Q. Now, have you had an occasion to testify in the 15 case of Major versus Line? 16 MS. ZETTLER: Your Honor, same objection. 17 JUDGE POTTER: I think you need to describe the 18 topic, Mr. Freeman. 19 Q. In which you talked about specialized drugs in 20 women's health issues? 21 A. No. I don't recall that. 22 Q. Have you been consulted and given opinions, 23 either by way of deposition or otherwise, in medical 24 malpractice cases on the standard of care for the treatment of 25 patients with various conditions? 174 1 A. Sometimes I've done -- I've looked at cases as a 2 screening, and a lot of that is simply telling a lawyer he 3 doesn't have a case, you know, that the doctor did everything 4 fine from my best, you know, assessment of it. 5 Q. Have you also given depositions or criticisms of 6 doctors and how they took care of patients? 7 A. On occasion. Usually in the case of a 8 misprescribed drug, but it may have been something else, but 9 if it was, it was something very basic. 10 Q. Now, did you appear in an orthopedic medical 11 malpractice case brought against Jackson and Merrill-Dow and 12 others? Merrill-Dow is a pharmaceutical house, isn't it? 13 A. If that was the Bendectin case. I don't recall 14 testifying on an orthopedic matter for them, no. 15 Q. In 1987? 16 A. I don't recall that at all. 17 Q. All right. What about obstetrics in a medical 18 malpractice case by the name -- the same name, Jackson versus 19 Merrill-Dow? 20 A. Oh, okay. Yes, I do recall that one. I 21 remember the case now. 22 Q. Now, you are not an obstetrician, are you? 23 A. The issue in that case was the teratogenic 24 effects of the drug, and what I testified to was based upon 25 the published literature, my opinion as to whether the drug 175 1 given at a particular time during pregnancy was capable of 2 causing the very serious birth defects in that young woman. 3 Q. Do you remember in the same case talking about 4 conditions that developed with the eye? 5 A. Again, it would have been a birth defect 6 condition. I wasn't talking about something that occurred in 7 a pediatric practice. 8 Q. Do you remember Balardosis versus Ortho, which 9 involved you as a toxicology expert? 10 A. Yes, I do. 11 Q. And in that same case, you also talked about 12 drug reactions, didn't you, ma'am? 13 A. Yes. That was a case involving a young woman, 14 32 years old, who got in a stroke after being prescribed oral 15 contraceptives. And the package insert, while the chart very 16 clearly indicates the risk of strokes in smokers goes up at 17 the age of 30, the verbal portion of the package insert says 18 that the risk is apparent at the age of 35, and that was 19 basically the substance of my testimony explaining that. 20 Q. Now, in connection with making the situation 21 plain here, have you ever been hired by the FDA or any other 22 foreign -- local or foreign regulatory -- 23 A. No, I have not. 24 Q. -- regulatory agency, either from Germany, 25 Japan, Holland, Canada, Mexico, United States, or any foreign 176 1 country? 2 A. No. 3 Q. Have you ever served on any advisory committee 4 for the FDA where you were called in in some sort of capacity 5 expert to give an opinion about a particular medication or 6 medical issue? 7 A. I have not served on an advisory committee, but 8 I did give testimony before an advisory committee. 9 Q. Now -- and I believe you earlier testified that 10 you had never worked at the FDA? 11 A. No, I have not. 12 Q. One of the people that you knew while you were 13 at Abbott had worked with the FDA, had they not? 14 A. Probably more than one. I don't know. I know 15 one that did, but I'm sure there were others. 16 Q. Who comes to mind immediately? Dottie Dobbs' 17 name ring a bell? 18 A. Yes, it does. 19 Q. Was she at Abbott while you were there? 20 A. For part of the time I was there, sir, yes. 21 Q. Did you know her in terms of being a competent 22 physician? 23 A. Yes. I thought she was very competent, very 24 ethical. 25 Q. And was she a psychiatrist? 177 1 A. Yes, she was. 2 Q. And did she -- did you have an occasion to read 3 her testimony in this case about what she read and what she 4 studied while she was at the FDA for a period of over five 5 years? 6 A. No, I have not. 7 Q. Now, there has been some questioning earlier 8 about eligibility for becoming board certified. Do you know 9 what is required, for example, to become eligible to be board 10 certified in pathology or psychiatry or anything? 11 A. I don't recall that there was any testimony 12 earlier, that I heard, about board eligibility. My 13 understanding is that first you must complete residency. 14 Q. All right. Did you read Doctor Breggin's 15 deposition or testimony in court? 16 A. No, I did not. 17 Q. You did not read his? So you didn't read what 18 he had to say about whether he was board certified or not? 19 A. No. 20 MS. ZETTLER: Objection, Your Honor. 21 JUDGE POTTER: Sustained. 22 Q. In any case, you are not eligible to become 23 board certified in any medical field, are you, ma'am? 24 A. No, I'm not. 25 Q. Also, while you were at Abbott, did you attend 178 1 night school in an effort to get an M.B.A., Master's in 2 Business Administration? 3 A. I forgot all about that. Yes, sir; I did. I 4 took one course in statistics. 5 Q. And nothing after that one course in that area? 6 A. It was very difficult to get from north Chicago 7 all the way down to Northwestern at night. 8 Q. And so that it's plain, you have not in this 9 case made a detailed statistical analysis of Lilly's 10 case-report forms and clinical trials, have you, ma'am? 11 A. No. 12 Q. So that I can understand how the FDA works, 13 after the animal trials are largely completed -- and I 14 understand that some of the long ones must go on for a number 15 of years to determine if the drug over a long period of time 16 may have an effect on the animal. After that is done and the 17 clinical trials are put in place, first of all, as I 18 understand it, an investigator for a -- excuse me -- a monitor 19 would be like you were; is that correct? 20 A. Uh-huh. 21 Q. A monitor for a pharmaceutical company will 22 develop certain protocols or plans? 23 A. That is generally correct. 24 Q. And the protocols and plans will hopefully be 25 designed so as to get reproducible results if you're going to 179 1 do them in several different locations with several different 2 investigators? 3 A. That's basically the idea. You want to show 4 that something that's happening, say efficacy, really, that 5 more than one person can find it. If you only have one 6 investigator that shows the drug to be efficacious, you've got 7 a problem. You've got to show that five or six people doing 8 the same thing showed the same thing. That's just good 9 science. 10 Q. Now, generally speaking, talking about those 11 plans or protocols, they are sent, before the plans are 12 implemented, to the FDA for a look-see at them -- for the FDA 13 to look at them? 14 A. That's right. 15 Q. And if the FDA sees a plan that some person at 16 Lilly has done that they don't think is correct, they can call 17 up the person at Lilly and say, we do not believe your 18 protocol should exclude this person or that it should include 19 another person or it should provide for various tests to be 20 done? 21 A. That in fact happened in this case, sir. They 22 contacted Lilly that they were very concerned about the blind 23 being broken and -- 24 MR. FREEMAN: May I have the question read back, 25 please, and I'd like an answer to the question. 180 1 MR. ZETTLER: Your Honor, she's allowed to 2 finish her answer. 3 MR. FREEMAN: She has not answered the question. 4 JUDGE POTTER: Why don't you restate the 5 question or reask your question. 6 Q. In connection with the protocols, to go back to 7 that, when the protocol is sent from the pharmaceutical house 8 to the FDA, if the FDA thinks something needs to be added or 9 subtracted they can call up the pharmaceutical house and say 10 you need to add or subtract the following, can they not? 11 A. They can, and they do, and they did in this 12 case. However, the drug company is not required at that point 13 to follow their advice. They don't follow it at their peril, 14 as they did in this case in the case of continuing to allow 15 the investigators to break the blind once a particular patient 16 had completed their treatment. 17 Q. Now, so that we can understand it, you talked 18 about Phase 1 studies, did you not? 19 A. Yes. 20 Q. And that's where they were given to healthy 21 individuals for purposes of seeing that if the compound was 22 poisonous or was going to affect some major organ system? 23 A. That's right. You want to see the toxicity 24 profile. 25 Q. And then you have talked about -- do you have 181 1 the ten studies up there with you that you talked about, the 2 ten case-report forms? 3 A. Yes, I do. 4 Q. All right. Would you mind putting them up here, 5 please, in terms of so we can compare the two stacks of 6 papers. 7 A. (Witness complies). 8 Q. Now, I represent to you that on my left the blue 9 folders are the complete forms that relate to those patients. 10 Is that about the full volume of material? 11 A. That does appear to be what they would look like 12 completely. 13 Q. All right. So that I can get an appreciation 14 for those documents, the documents contain in them everything 15 from X-rays reports to blood studies to thoracic or breathing 16 or blood studies and everything else, don't they? 17 A. No. I don't recall any thoracic breathing 18 studies done in this case. They had some ophthalmology tests 19 done. There are some reports of X-rays and EKGs but not the 20 X-rays and EKGs themselves. They report the blood pressure 21 and things like that. 22 Q. What about heart function? 23 A. The EKGs are reported as being normal or any 24 abnormality, but the EKG itself is not in here. 25 Q. Is the EKG itself the thing that when we go to 182 1 the doctors we see the little -- 2 A. Yeah. The little chicken scratches; right. 3 Q. Let me see if I can find one for you. 4 A. There may be one -- if there was a problem they 5 may have added it, but they're not generally stuck in with the 6 case-report forms unless there's a problem. 7 Q. Also included in the material are numbers of 8 questions that are asked of the patient; is that not so? 9 A. Well, there's the patient's questionnaire where 10 the patient is asked to fill out the questionnaire about some 11 very specific questions regarding how he feels. 12 Q. And things of that nature? 13 A. Well, the one that we talked about earlier 14 about, you know, do you feel like injuring somebody, do you 15 feel -- are you having trouble sleeping. You know, there's 16 like 80 different questions. I couldn't possibly just rattle 17 them off from memory, but that questionnaire is in there, yes. 18 Q. Now, tell us, please, ma'am, if the materials 19 contained in both of the sets of documents that you have in 20 front of you on the bench contain what is known as a 21 case-report form. 22 A. Well, this is the complete case-report form 23 here. These are the pages that indicated to me that data was 24 not reported correctly. I didn't see any reason to bore the 25 jury with page after page which, for the most part, was either 183 1 filled out correctly or if there was a problem with something 2 I didn't consider it as serious a problem as what I found in 3 these pages over here. 4 Q. So the folder on the -- my left and your right, 5 in the blue folders contain the complete case-report form on 6 that particular patient? 7 A. Well, actually, if you really want to get 8 precise, the complete case -- it's a copy of the case-report 9 form. The complete report form is on NCR paper, white, yellow 10 and pink. And I believe the white copy stays with the drug 11 company, the yellow copy stays with the investigator and the 12 pink copy goes to the FDA. I may be wrong; I may have gotten 13 my colors mixed up. It has been ten years, but that's 14 basically the idea. 15 Q. I want to be perfectly clear about this so we 16 can see about your testimony. Is it your testimony that on 17 Patient No. 26 that the complete material contained in this 18 folder did or did not go to the FDA? 19 A. It was supposed to. 20 Q. In other words -- let me just leave this with 21 you -- the investigator, that is, the person that was doing 22 the study for Lilly, like in your 198, Plaintiffs' 198, on 23 Visit Number Three, and you see the form there that you need 24 to turn to the side, do you not? 25 A. That's right here. 184 1 Q. All right. And you see Symptoms, Signs and 2 Comments on Visit Number Three, do you not? 3 A. Yes. 4 Q. And you see that the investigator has reported 5 agitation, and then read the remainder of that to me, please, 6 ma'am. 7 A. "Agitation, sleep disturbance, pressure in head, 8 dose related to 20 milligrams daily. Symptoms slowly 9 resolving." And the investigator has coded it, yes, source, 10 patient reported; drug related, yes; action taken, dose 11 reduced; course, recovered. The next I can't read because 12 there's a stamp over it, and it occurred on October 20th, 13 1979. 14 Q. So that we're perfectly clear, on each of the 15 cases that you have testified to, the complete case-report 16 form, including that language, should have gone, and as far as 17 you know, did go to the FDA from Eli Lilly and Company? 18 A. That's right. But as I said earlier, the FDA 19 doesn't have the manpower to read every single page, so it's 20 very important that a company identify the problems with the 21 drug prominently where the FDA personnel are likely to see it, 22 not where they're unlikely to see it. 23 Q. Well, now, let me see if I can understand one 24 further thing. Every time a patient comes in to see the 25 physician or the investigator during the course of treatment, 185 1 the precise language of the investigator is filled out on a 2 case-report form such as that, or forms such as that; is that 3 right? 4 A. The investigator's personnel fill it out. 5 Q. All right. Well, it's filled out by the office 6 of the investigator? 7 A. Right. And I don't really know whether they use 8 the exact terms that the investigator said or the patient 9 said. They fill it out. This is what the drug company gets. 10 Q. They fill out the precise language used either 11 by the doctor or the investigator? 12 A. I don't know that, sir. 13 Q. Let me back up then. On the language that you 14 were looking at just then, that you said you didn't have any 15 information that it didn't go to the FDA? 16 A. I assume it did. 17 Q. All right. That's what I want to make plain. 18 You are not suggesting that when Lilly on a 1639 says "see 19 case-report form" that it has changed anything; only that you 20 think they may have secreted it? Isn't that a fair statement 21 as to what you're testifying to here? 22 A. What I testified to is that it wasn't reported 23 every place that it was supposed to be reported. And in terms 24 of missing case-report forms, I don't think we got into this 25 on direct, but there was a memo here that suggested that there 186 1 were some missing case-report forms where somebody was sent 2 out. It's in one of these -- if you want to find it, we can 3 -- where there was a memo from Lilly about going out to the 4 investigator site and trying to find the four case-report 5 forms. That's really all the information that's given. I 6 don't know that they were lost, but there's a memo that 7 suggests that there may have been some missing case-report 8 forms. 9 Q. Are you making reference to the Doctor Stark 10 letter where he found an irregularity, I believe, with one of 11 the patients? 12 A. No. No. It was Doctor Sig, Doctor J. L. Sig 13 (phonetic) was the one. 14 Q. Have you looked at the letter that Doctor Stark 15 sent to one of them? And it's Patient No. 36. Can you find 16 Patient No. 36 there, please? 17 A. I've got it right here and I don't see a letter 18 in here. 19 Q. Ma'am? 20 A. I don't see a letter here, sir. 21 Q. It's probably 40, 42 or 43. Let's look and see 22 if we can find it. 23 A. I think the letter you're referring to might be 24 attached to Patient No. 44. 25 Q. Here it is. On Patient No. 42, that's your 187 1 exhibit number and the jury's Exhibit No. 199. 2 A. I haven't found it yet. Just a second. 3 Q. Plaintiffs' Exhibit 199. 4 A. I got it. Okay. 5 Q. Now, please, ma'am, if you would look over to a 6 letter dated January 15th, 1980. 7 A. Okay. 8 Q. And you will notice that in the first paragraph, 9 Patient 44 is referred to, and the last paragraph on that 10 page, Patients No. 42 and 43 are referred to. Do you see 11 that? 12 A. That's right. 13 Q. And he's complaining that the HAM-D scores were 14 not high enough? 15 A. That's right. 16 Q. And that's the complaint that you had with this 17 patient where, on the first page you said he never should have 18 been included in the study because he made a zero on 19 everything. 20 MS. ZETTLER: Objection, Your Honor. That 21 mischaracterizes her testimony. 22 Q. Looking back at the Hamilton Psychiatric Rating 23 Scale and the same Exhibit No. 199, it's the third page over, 24 fourth page over. Do you see it? 25 A. I did comment on the person's low HAM-D score. 188 1 Q. And you commented that he had zeros on most all 2 of them? 3 A. That's right. I did. 4 Q. And you said he should never have been included; 5 right? 6 A. I don't think I said that, but given the 7 protocol criteria I think that's an accurate statement. 8 A. And Doctor Stark in his letter wrote to this 9 investigator, in which he said on the last page, "As agreed 10 previously, your fluoxetine study -- talking about Prozac -- 11 will now be considered terminated; therefore, no further 12 patients should be entered and all unused drugs should be 13 returned. Please use the enclosed form and instructions for 14 returning this material," signed Eli Lilly and Company, Paul 15 Stark, Ph.D." Is that right? 16 A. That is correct. Apparently they did terminate 17 this investigator. But I do think -- I do want to make 18 something clear. My reason for bringing this particular form 19 out was because of the way the insomnia was not coded. If 20 you're implying that because this person was relatively 21 healthy that's why he got insomnia, I think that's a 22 mischaracterization of what's going on here. This person had 23 insomnia throughout the study and was treated with chloral 24 hydrate, and that was not coded. 25 So it really doesn't matter. If he was 189 1 improperly admitted, that's unfortunate. But once he was in, 2 they still should have coded his adverse experiences 3 correctly. And the fact that even a healthy person is 4 suffering this much insomnia to me should have still raised a 5 red flag. 6 Q. During a clinical trial at what point are you 7 supposed to put something on a 1639? 8 A. As I said earlier, for nonserious reactions, we 9 do it at the very end of the NDA. If something is serious or 10 unexpected, it goes down within two weeks. 11 Q. Let's see if we can get this straightened out in 12 our minds. Insomnia is mentioned in that man's file how many 13 times? I want you to go through it and count every time that 14 Lilly reported to the FDA that this man couldn't sleep or had 15 insomnia. Would you go through and count every time it's 16 reported, please, ma'am, beginning on Visit Number Three where 17 it's reported insomnia? 18 A. He had it every week, and they reported it once 19 every week with the chloral hydrate, as I stated earlier. 20 Q. Let's count them. We want to see what we've 21 turned in now. 22 A. There's four of them. 23 Q. There's one on Visit Number Three, that's one; 24 is that right? 25 A. That's correct. 190 1 Q. There is one on Visit Number Four, that's two; 2 is that correct? 3 A. That's correct. 4 Q. One on Visit Number Five; is that correct? 5 A. That's correct. 6 Q. Along with reporting intermittent dizziness on 7 the next page; is that correct? 8 A. That's right. And I don't think -- Number Seven 9 we don't have here. It may be in here, I don't know. 10 Q. All right. And it's reported on Number Seven? 11 A. That's right. 12 Q. What date did the FDA approve fluoxetine 13 hydrochloride for the treatment of depression? 14 A. I don't recall the exact date, sir. 15 Q. Do you have an approximation? 16 A. It was the late '80s, '87 to '89, somewhere 17 around there. 18 Q. But you know it was approved? 19 A. Oh, it was approved, yes. 20 Q. Now, can you tell the Court and jury if there is 21 a difference, and I want you to tell them what it is, as to 22 how drug experience reports are handled before a medication -- 23 prescription medication is approved as to any differences that 24 may exist after the medication is approved? 25 A. I don't understand your question. 191 1 Q. All right. Did I understand you to say earlier 2 that insofar as clinical trials are concerned, that for a 1639 3 to be filled out there were two criteria that needed to be 4 met, did I understand that correctly, serious and unexpected? 5 A. That was for one that would have to be turned in 6 quickly. To the best of my recollection, when I was at Abbott 7 we also filled them out at the very end for everything, and 8 that was part of the guidelines, which is kind of a subpart of 9 the regulations, the guidelines for psychoactive drugs. 10 Q. Now, I want to get this plain. At the 11 conclusion of a study, you're testifying here today that 12 you're supposed to go through the study, the pharmaceutical 13 house is, and fill out a 1639 for every drug experience report 14 that a person experienced while they were on the drug? 15 A. My testimony is that we did it. 16 Q. No. No. Is it your testimony here today that 17 it is a requirement of the FDA or a recommendation of the FDA 18 that before approval -- 19 A. It's a recommendation as part of the guidelines. 20 The requirement is that the serious and unexpected adverse 21 reactions get reported and they need to be reported quickly. 22 Q. I want to get it plain as to what your testimony 23 is here today. Say a study is completed in the year 1985. 24 Are you saying that it's an FDA requirement or recommendation 25 that a 1639 be filled out on every symptom or complaint that a 192 1 patient had while on a particular medication? Is that your 2 testimony here today? 3 A. No. It is not a requirement, but it was done at 4 Abbott and it is mentioned in the guidelines for the 5 evaluation of psychotropic drugs that it should be done. It 6 is not an absolute requirement. What is an absolute 7 requirement is that the serious and unexpected reactions are 8 reported. 9 Q. Serious and unexpected; is that right? 10 A. Uh-huh. 11 Q. Now, when you were at Abbott did you have a 12 direct hookup by computer to the FDA? 13 A. No, we did not. 14 Q. Did you transmit to the FDA the complete 15 case-report form on every patient that was included in every 16 study? 17 A. We sent it to them not by computer but we sent 18 the case report down, yes. 19 Q. You sent it either in paper form or otherwise. 20 Did you send it in paper form? 21 A. Yeah. We sent that one sheet that they get. I 22 don't recall the color but part of the triplicate that they 23 were supposed to get, they got. 24 Q. Did you take out the information that the 25 investigator had given you about people's REM sleep, for 193 1 example, or did you send that on to the FDA? 2 A. What we did was we didn't send the actual EEG 3 tracing to the FDA, but the investigator would look at the 4 tracing and respond to whatever was in the case-report form in 5 terms of how much REM sleep people got, how long it took them 6 to fall asleep, how fast they woke up, how many times they 7 woke up during the night, how much delta sleep they got. We 8 didn't do that; the investigator would do it. The 9 investigator would take his raw data, the EEGs, the lab 10 values, the EKGs, the physical exams, and he would write it 11 onto a case-report form, which is a document very similar to 12 this. And then we, the people from the drug company, would 13 come out and make sure that it was accurate. We'd take his 14 raw data and make sure that they wrote down, if somebody's CBC 15 dropped or something, that it was reported on the case-report 16 form. 17 Q. And the case-report form as opposed to the 1639 18 in terms of clinical trials is what the FDA looks at in 19 evaluating a clinical trial, is it not? 20 A. They look at both, sir. 21 Q. So they look at both. But they have -- you're 22 not suggesting here that where on every one of those 1639 drug 23 experience reports, we say "see case-report form" -- it says 24 that on every one of them, doesn't it? 25 A. Yes, it does. 194 1 Q. -- that we undertook to change anything that 2 their investigator reported; that is, that the man was 3 anxious, that he couldn't sleep, that he broke out in a rash 4 -- there's not been a rash there -- but that we didn't send 5 exactly, precisely, what the investigator said word for word 6 to the FDA? 7 A. In the case-report forms, sir; however, there 8 were also some other places that it was sent and those places 9 did not accurately depict that. One of them was as we've been 10 talking about the 1639. The other was when they got around to 11 doing the COSTART dictionary they mapped -- mapping means, as 12 I talked about earlier, a thesaurus that certain terms were 13 supposed to be reported as certain other terms to try to get a 14 more consistent group of words that were being used by various 15 investigators. And in this case they mapped suicidal ideation 16 to depression. 17 Now, that was what you -- that was what COSTART 18 said to do. But you have to realize that this was for any 19 drug. Now, let's say a hypertensive drug was causing some 20 depression. You want to put as much possible that you could 21 call depression in to know exactly how many people were 22 getting depressed on it. But in this case where everybody was 23 depressed, it would have been much more appropriate to put a 24 specific term for the types of depressive symptoms they were 25 experiencing. So when they called suicidal ideation 195 1 depression, they were losing data. They also systematically 2 called agitation nervousness. 3 So there was an opportunity to lose data. Yes, 4 the case-report form itself went along with the other 2,000 5 case-report forms that would fill up, as a said, the jury box. 6 But the summaries and the adverse experience reports, the 7 thing that someone at the FDA who only had a day to spend on 8 this as opposed to three years would see, were not an accurate 9 depiction of what really happened to those patients. 10 Q. Now, let's make it perfectly plain what you've 11 testified to here today. First of all, you have taken ten 12 selected portions of a patient's file and talked about them 13 with the jury, have you not? 14 A. Well, I selected the pages that demonstrated the 15 problems that I saw in these and other case-report forms, and 16 when I picked those case-report forms there was no selection 17 process; it was very much random. I just saw a box and that 18 was the box I used. I had no way of knowing what would be in 19 that box. Just like you say they wrote it down. Of course 20 they wrote it down. How would I know about it if they didn't 21 write it down somewhere? 22 Q. Were you or not hired in this case to be 23 critical of Eli Lilly and Company and its medication, 24 fluoxetine hydrochloride? 25 MS. ZETTLER: Objection, Your Honor. 196 1 JUDGE POTTER: Overruled. 2 A. I was hired to act as a consultant, as a 3 technical consultant to the project to observe what happened. 4 Had I not found anything wrong in the way the clinical trials 5 were done, I would have informed my client of that. 6 Q. All right. Now, what we have found are ten 7 reports that you've sought to bring here today; is that right? 8 A. That's right. 9 Q. Now, what I want you to explain to the jury is 10 that the reports that you brought here today are dated 1978 -- 11 A. Some of them '79 and '80. 12 Q. -- '79 and one in '80; is that right? 13 A. I don't recall the exact dates. I'll take your 14 word for it. 15 Q. Is the latest form you have there 14 years ago 16 or not? 17 A. If it's 1980, that's 14 years ago. Yeah. If 18 you want me to go through and check them, I can. 19 Q. If you would like to do that, you're welcome to. 20 I didn't see any dates other than '78, '79 and '80. 21 A. This was an early study; that's why it was so 22 worrisome that they had this stuff so early on in the process 23 and still did nothing to define it. 24 Q. Let me ask you this question: What is the 25 difference in an open-label study and a double-blind study? 197 1 A. In an open-label study you know the persons 2 getting the drug. You're testing to see what the drug does. 3 Q. In any of those instances that you brought here 4 today from '78 to '80, were any of them other than 5 open-blinded studies; that's where the patient knew what they 6 were getting and where the doctor knew what they were getting? 7 A. Yeah. These were open-label studies; that's 8 correct. 9 Q. All of them were, were they not? 10 A. Right. 11 Q. Now, what does the FDA make a decision based 12 upon in connection with approving Prozac for marketing in the 13 United States? What kinds of studies does it use? 14 A. Well, part of the FDA's determination, a big 15 part of that, is whether or not it's efficacious. And I 16 think, as I explained earlier, it's very important that a 17 study be double-blind because there might be some subconscious 18 bias on the part of both the patients and the investigators to 19 say that a product works that doesn't. So the blinding is 20 very important in terms of efficacy and in terms of 21 comparative safety. They may just say, "Maybe that's really 22 not going on. I think I'll just ignore it. I want to do a 23 good job for these guys." You want them not to know so they 24 don't have an opportunity to skew the data. But if something 25 really weird happens, you can't make that go away just because 198 1 it was an open-label study. That's absurd. Because they knew 2 they were on fluoxetine that's what made the lady curl up in a 3 fetal position and start screaming, and that's what made the 4 guy elope because he knew he was on fluoxetine? Is that what 5 you're implying, Mr. Freeman? 6 Q. I didn't realize I was here to answer your 7 questions. 8 A. Well, I'm trying to clarify what you're trying 9 to get to here. 10 Q. Well, I'll get there if you'll just be patient 11 with me. 12 The FDA bases its approval on double blind, that 13 is, on the medications sought to be approved, and on placebo 14 is one class of double-blind studies, is it not? 15 A. That's right. 16 Q. They also base their approval on studies where 17 you've had placebo, where you've had a comparitor drug such as 18 a competing drug, and Prozac; is that correct? 19 A. That's right. 20 Q. In this connection, the patient doesn't know 21 what they're on; the investigator doesn't know what they're 22 on, whether they're on a placebo, whether they're on a 23 comparitor or whether they're on Prozac? 24 A. That's right. 25 Q. All of the pills are made to look the same? 199 1 A. That's right. 2 Q. All right. And the FDA approved the drug based 3 upon its studies of efficacy and safety, did they not? 4 A. Which would include this. They look at all the 5 trials. 6 Q. And they also had before them 200 other studies 7 that had been done -- 8 A. That's right. 9 Q. -- all over the world, including the hospital 10 study that was done in Germany that caused the German 11 government to approve the product? 12 MS. ZETTLER: Your Honor, I object. Mr. Freeman 13 knows full well that these were the only studies that were 14 produced. 15 JUDGE POTTER: Objection sustained. I tell you, 16 come on up here a second. 17 (BENCH DISCUSSION) 18 MS. ZETTLER: Judge, as the Court knows, we have 19 a limited number of studies that we had access to, and I 20 object to Mr. Freeman implying that we only looked at a 21 certain number of studies and didn't look at other studies. 22 MR. FREEMAN: They had the pivotal trials. They 23 had them. 24 MS. ZETTLER: He's going into this 200 studies 25 routine and making it sound like they're all available, and 200 1 they weren't. 2 JUDGE POTTER: I just think that's something you 3 need to bring out on your redirect, that because of the court 4 process or the masking or however it came up, you have not 5 been able to look at what you've been able to look at. 6 MS. ZETTLER: I can bring out the fact that they 7 didn't produce them in any kind of valuable forms? 8 JUDGE POTTER: I think you can bring out the 9 fact that because of the court system you've only been allowed 10 to get to certain ones. 11 MR. FREEMAN: We object to that. 12 JUDGE POTTER: You opened the door. 13 MR. FREEMAN: She has not discussed the pivotal 14 studies at all. 15 JUDGE POTTER: The question was that was 16 objected to was the FDA had these studies together with the 17 ones that were sent to Germany, and I was maybe incorrectly 18 under the impression -- when were the German studies done? 19 MS. ZETTLER: They weren't done until after 20 1985, and we've never had access to those because you made a 21 specific ruling that we couldn't see anything outside the 22 United States. 23 MR. MYERS: If you remember your ruling, they 24 were specifically asked for and given to them. 25 MS. ZETTLER: That's not true. 201 1 JUDGE POTTER: I was under the misimpression 2 that the German studies were much later. When were the German 3 studies done? 4 MS. ZETTLER: Mid to late '80s. 5 MR. MYERS: They were done after the question 6 was asked about approval in the U. S. and those were produced 7 in your order to produce... 8 MS. ZETTLER: There's a huge difference between 9 final reports and the actual case-report forms in a way that 10 we can look at them. These were never produced in a way that 11 we could look at them. 12 JUDGE POTTER: I was mistaken as to the timing 13 of the studies. If he wants to ask her isn't it true that the 14 FDA had all this stuff, he can. And I think probably what we 15 need to do is take a few minutes tomorrow morning so that you 16 can get your parameters on redirect, because I was quite 17 curious why it didn't come out on direct. 18 MS. ZETTLER: If he's going to open the door... 19 I was perfectly willing to stick to these ten studies, but 20 these are things they have not produced. 21 JUDGE POTTER: I'm overruling the objection to 22 that question. 23 (BENCH DISCUSSION CONCLUDED) 24 MR. FREEMAN: Julie, would you read my last 25 question, please. 202 1 (REPORTER READS THE RECORD) 2 Q. Let me rephrase the question. During the time 3 that you have worked on the case, have you been given the 4 pivotal studies or any of them that the FDA used in approving 5 the product? 6 A. Yes. I also looked at Protocol 27. I looked at 7 some of the case-report forms for that. There were several 8 hundred patients in that study so I did not look at all of 9 those, but in that protocol, as well, there were problems. 10 There was a patient of Doctor Fabre's, as I recall. 11 Q. I just asked you if you looked at it. If they 12 want to come back and ask you additional questions, they may. 13 MS. ZETTLER: Objection, Your Honor. 14 JUDGE POTTER: That is nonresponsive. 15 A. Yes. I have looked at some of the pivotal 16 studies, as well. 17 Q. All right. Now, did you examine the various 18 safety updates that were done by Lilly in connection with the 19 medication prior to the time that it was approved? 20 A. I've seen some of them; I don't know if I've 21 seen all of them. 22 Q. How many of them have you seen the safety 23 updates? 24 A. I don't know the exact number. 25 Q. Did you go over the findings of the advisory 203 1 committee hearing that took place in September of 1991? 2 A. No, I did not. 3 Q. You didn't look at what psychiatrists from 4 around the country thought about the medication? 5 A. No, I did not. My understanding was that this 6 case occurred in 19 -- that it occurred before that. 7 Q. So if the advisory committee found that the drug 8 was safe and efficacious for the treatment of depression, you 9 never looked at that, have you? 10 A. I haven't looked at that, and it might be 11 something I'd consider looking at, their reasons and 12 everything. My job was to look at the clinical trials that 13 were done prior to approval. That's what I did. 14 Q. Now, you say you've looked at part of the safety 15 reports but you don't know whether you've looked at them all; 16 is that my understanding? 17 A. That's right. 18 Q. Have you looked at the FDA's finding on efficacy 19 as it relates to the use of concomitant drugs? 20 A. Show it to me. I may have seen it. 21 Q. (Hands document to Witness) First of all, look 22 at that, please, ma'am, and give us the title of it. 23 A. Review and Evaluation of Efficacy Data. I 24 believe I have looked at this, yes. 25 Q. Now, have you looked at it with respect to what 204 1 it has to say about the use of concomitant medications? 2 A. I don't recall as I'm sitting here right now 3 what it says. If you find the paragraph, I'll be happy to 4 take another look at it. 5 Q. Look, please, ma'am, if you would -- my copy is 6 a little hard to read, but on top of page -- on Page 70 -- 7 it's easier to see if the page before is marked. 8 A. My pages start at 300 and something, 342. 9 Q. Oh, you're looking at the PZ numbers. The PZ 10 number is easier to read. It's FD 4 414. 11 A. Okay. Oh, the last paragraph here. Would you 12 like me to read it? 13 Q. I'm going to ask you about it, please, ma'am. 14 It's talking about concomitant medications, is it not? 15 A. That's right. 16 Q. And it's talking about blinded studies, is it 17 not? 18 A. The paragraph I'm reading is talking about 19 concomitant; I don't see anything about blinded. 20 Q. Let's look at the last two or three sentences of 21 it. "The sponsor -- talking about Lilly -- prepared a 22 complete compilation by study of the use of allowed, 23 disallowed and other CNS effect drugs." Do you see that? 24 A. Uh-huh. 25 Q. "Counts of the numbers of patients using these 205 1 drugs for each treatment in the placebo-controlled studies 2 indicated that the proportion was similar for each treatment," 3 that is each treatment in each trial. Now, each treatment 4 includes placebo, does it not? 5 A. That's what it's saying, yes. 6 Q. And each treatment includes a comparitor drug 7 for the treatment of depression? 8 A. Yes. 9 Q. And each treatment includes Prozac? 10 A. Right. 11 Q. And then they conclude, "Hence, it would appear 12 that concomitant medication use is not a problem in this NDA." 13 Do you see that? 14 A. Uh-huh. 15 Q. And that's what the FDA found about concomitant 16 medication, did they not? 17 A. That's what it says. 18 Q. All right. 19 A. Can I comment on that? 20 Q. If it's responsive, I suppose so. 21 A. That's what they say. They happen to be wrong. 22 I disagree with that statement for a number of reasons. It is 23 true that quite a few people, more in the imipramine group 24 than in the placebo group, also got concomitant medication. 25 But I think, as I said earlier, we know what the profile of 206 1 imipramine is; we don't know what the profile of fluoxetine 2 is. Maybe the imipramine people would have had trouble going 3 to sleep. Maybe the fluoxetine people would have run off and 4 gotten on a plane for Alaska or hit their wife over the head. 5 We just don't know because that was the drug we were testing. 6 And the FDA and the public deserved to know what it would do 7 without concomitant medication. 8 Also, when you talk about this paragraph here, a 9 complete compilation using these drugs, they didn't break it 10 down by type of drug. This is for all drugs. This includes 11 maybe antibiotics. They didn't break it down by how many 12 people got sedatives and for how long and whether the people 13 on the higher dosages of fluoxetine got more sedatives than 14 those on the lower dosages. This is just a compilation of 15 everybody who got a concomitant med of allowed, disallowed or 16 other CNS active drugs on fluoxetine comparitor treatment and 17 placebo. And that may have been approximately equal, but it 18 doesn't give all the information that would have been derived 19 had they not allowed people taking fluoxetine to have gotten a 20 concomitant med. And in terms of what the FDA said, well, 21 this is what they said in the summary. Earlier on there were 22 questions raised about the use of concomitants. 23 Q. I may be missing something, but it says, "The 24 sponsor prepared a complete compilation by study of the use of 25 allowed and disallowed and other CNS active drugs," is that 207 1 what it says? 2 A. Okay. So I was wrong about the antibiotics. 3 There wouldn't be antibiotics, but there would be other CNS 4 active drugs. 5 Q. They're called a CNS active drug; right? 6 A. They may not have all been sedatives, though. 7 There are other types of CNS active drugs besides sedatives. 8 MR. FREEMAN: Do you know -- may I have a moment 9 to confer, Your Honor? We may be about through. Let me ask 10 one other question. Let me see. If I could have a minute to 11 confer, Judge. 12 JUDGE POTTER: Okay. 13 MR. FREEMAN: That's all that I have at this 14 time, Judge. 15 JUDGE POTTER: Ladies and gentlemen, we're going 16 to take the evening recess at this time. I'm going to give 17 you the same admonition I've given you before. Before I do 18 that, we'll be starting at 9:00 tomorrow. 19 Mr. King, could I ask you to come in at 8:45, 20 if everything's okay, and we'll talk about your medical 21 condition? Do you know whether you've got an appointment to 22 see somebody tonight or not? 23 JUROR KING: I know I've called home and talked 24 to one of my family members and they said they're calling 25 right now. 208 1 JUDGE POTTER: Okay. If you could be in at 2 8:45, obviously if you see a doctor or something gets worse, 3 but could you come in a few minutes early so we could talk 4 about this? 5 JUROR KING: Okay. 6 JUDGE POTTER: For everybody else, the time will 7 be 9:00. Also, I'm going to remind you again, do not permit 8 anybody to speak to or communicate with you on any topic 9 connected with this trial, including the news media or any 10 other kind of person, friend or family. Do not discuss it 11 among yourselves and do not form or express opinions about it. 12 We'll stand in recess until 9:00 tomorrow morning. 13 (PROCEEDINGS TERMINATED THIS DATE AT 4:55 P.M.) 14 * * * 15 16 17 18 19 20 21 22 23 24 25 209 1 STATE OF KENTUCKY )( )( Sct. 2 COUNTY OF JEFFERSON )( 3 I, JULIA K. McBRIDE, Notary Public, State of 4 Kentucky at Large, hereby certify that the foregoing 5 Transcript of the Proceedings was taken at the time and place 6 stated in the caption; that the appearances were as set forth 7 in the caption; that prior to giving testimony the witnesses 8 were first duly sworn; that said testimony was taken down by 9 me in stenographic notes and thereafter reduced under my 10 supervision to the foregoing typewritten pages and that said 11 typewritten transcript is a true, accurate and complete record 12 of my stenographic notes so taken. 13 I further certify that I am not related by blood 14 or marriage to any of the parties hereto and that I have no 15 interest in the outcome of captioned case. 16 My commission as Notary Public expires 17 December 21, 1996. 18 Given under my hand this the__________day of 19 ______________________, 1994, at Louisville, Kentucky. 20 21 22 23 24 _____________________________ 25 NOTARY PUBLIC 210 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25