MR BURNSIDE: Your Honour, I call Professor Zipes. <DOUGLAS PETER ZIPES, AFFIRMED. HIS HONOUR: Thank you, Professor Zipes. You may be seated.

Transcription

1 HIS HONOUR: Mr Burnside? MR BURNSIDE: Your Honour, I call Professor Zipes. <DOUGLAS PETER ZIPES, AFFIRMED [.22 am] HIS HONOUR: Thank you, Professor Zipes. You may be seated. MR BURNSIDE: Professor Zipes, what is your full name? PROFESSOR ZIPES: Douglas Peter Zipes. MR BURNSIDE: What is your occupation? PROFESSOR ZIPES: I am a cardiologist at Indiana School of Medicine. MR BURNSIDE: What's your professional address? PROFESSOR ZIPES: Indiana School of Medicine, Krannert School of Cardiology, 1800 North Capital Street, Indianapolis, Indiana. MR BURNSIDE: Professor, have you made three reports in this litigation? PROFESSOR ZIPES: Yes. MR BURNSIDE: Can you be shown the first of them, please, which was initially dated 19 February. PROFESSOR ZIPES: Yes. MR BURNSIDE: That report has been altered in accordance with some rulings that his Honour made about admissibility. PROFESSOR ZIPES: Yes. MR BURNSIDE: And you have made some small textural alterations to correct typographical errors and the like. PROFESSOR ZIPES: Correct. MR BURNSIDE: You have recently read that statement and checked it for accuracy. PROFESSOR ZIPES: I have. MR BURNSIDE: I have just got a couple of questions I need to clarify, if I may,.vid1/ P-24 D.P. ZIPES

2 your Honour. HIS HONOUR: Yes. MR BURNSIDE: Can I invite you please to look at paragraph 61 of that report, Professor Zipes. PROFESSOR ZIPES: Yes, sir. MR BURNSIDE: In paragraph 61 you refer to an exchange on February 1997 from Briggs Morrison to other Merck scientists planning a GI outcomes trial. PROFESSOR ZIPES: Yes. MR BURNSIDE: In the you quote him saying: Would allow low dose aspirin. I know this has been discussed to death. Real world is everyone is on it so why exclude and without COX-1 inhibition you will get more thrombotic events and kill the drug. To which there is a response from Alise Reicin: What about the idea of excluding high risk CV patients? This may decrease the CV event rate so that a difference between the two groups would not be evident. If that course were followed, the course suggested by Dr Reicin, what, in your opinion, would be the effect on the outcome of the proposed trial? PROFESSOR ZIPES: The effect would be to minimise any difference between the drugs. MR BURNSIDE: Can I ask you please to look at paragraph 66. In the final sentence of paragraph 66 you say that: In the case of Vioxx many subjects were discontinued because they developed asymptomatic hypertension. Do you see that? PROFESSOR ZIPES: Yes, sir. MR BURNSIDE: Are you able to say to the court what's the source of your observation that many subjects were discontinued because they developed asymptomatic hypertension? PROFESSOR ZIPES: I don't have it referenced. I would have to go back and look..vid1/ P- D.P. ZIPES

3 MR BURNSIDE: Is that something you would be able to find during a break later in the day? PROFESSOR ZIPES: Yes, sir. MR BURNSIDE: Thank you. Can I ask you please to look at paragraph 134. PROFESSOR ZIPES: Yes, sir. MR BURNSIDE: You say in that paragraph that: In preparing this report, I performed a literature review of many recent epidemiological and non-controlled clinical studies about Vioxx. While an occasional article did not support a link between Vioxx and cardiovascular diseases the vast majority did... You then review a sample of some of those articles. PROFESSOR ZIPES: Yes, sir. MR BURNSIDE: Are you able presently to provide a list of all of the articles which you read that you refer to in the first sentence? PROFESSOR ZIPES: I believe I can get them, yes, sir. MR BURNSIDE: Is that something that you would be able to prepare during a break during the day? PROFESSOR ZIPES: Yes, sir. MR BURNSIDE: Thank you. Would your Honour pardon me one moment? Subject to the changes that have been marked in the document and the clarifications that you have identified, are the contents of your statement true and correct? PROFESSOR ZIPES: Yes, sir. MR BURNSIDE: Would you please sign it on the last page and give it today's date. MR GARLING: Before my friend proceeds there is an issue remaining about the first two sentences of paragraph 67. We may have passed over them. MR BURNSIDE: My learned friend is exactly right and I am grateful. Have you got paragraph 67, professor? PROFESSOR ZIPES: Yes, sir. MR BURNSIDE: Just read that and familiarise yourself with it again..vid1/ P-26 D.P. ZIPES

4 PROFESSOR ZIPES: : Despite these drawbacks, several of the Vioxx clinical trials MR BURNSIDE: Just read it to yourself. PROFESSOR ZIPES: Okay. Yes, sir. MR BURNSIDE: Is the first sentence of that paragraph supported by or a reflection of the balance of the contents of the paragraph? PROFESSOR ZIPES: Yes, sir, it is. MR BURNSIDE: Thank you. I tender the document, your Honour. Have you signed that? I am just wondering which page you have signed it on. Is it the page that PROFESSOR ZIPES: I thought you said the last page. MR BURNSIDE: There is no text on the last page? PROFESSOR ZIPES: It's references. MR BURNSIDE: Sorry. Could you sign it again on the last page of the report proper. PROFESSOR ZIPES: Yes, sir. MR BURNSIDE: And give it today's date, if you would. Thank you, Professor Zipes. I tender that, your Honour. HIS HONOUR: Yes, I will receive the copy as the exhibit signed by Professor Zipes. You are going on to the next statement, are you, Mr Burnside? MR BURNSIDE: Yes. HIS HONOUR: Before you do that, there is something that I couldn't understand, Professor Zipes. Would you turn to paragraph 22 of your statement. At the end of the first sentence you use the expression:... as originally postulated by FitzGerald. PROFESSOR ZIPES: Yes, sir. HIS HONOUR: When was that postulation?.vid1/ P-27 D.P. ZIPES

5 PROFESSOR ZIPES: Probably the earliest is in HIS HONOUR: Footnote 4 on page 94 refers to something published in 06. Do you see that is this. PROFESSOR ZIPES: I do, yes, sir. HIS HONOUR: Can you explain that? PROFESSOR ZIPES: I think I chose a recent article by FitzGerald which simply enumerated the hypothesis. It was not the first time it was mentioned. HIS HONOUR: Yes. Thank you. Very well. Yes, Mr Burnside? Sorry, we haven't marked that, have we? EXHIBIT #GP.0690 REPORT OF PROFESSOR ZIPES ORIGINALLY PREPARED ON MR BURNSIDE: Professor, have you also prepared a responsive report dated 19 March 09? PROFESSOR ZIPES: Yes, I did. MR BURNSIDE: Have you recently read that report? PROFESSOR ZIPES: Yes, sir. MR BURNSIDE: Are the contents true and correct? PROFESSOR ZIPES: Yes. MR BURNSIDE: I tender the responsive report. EXHIBIT #GP.0691 RESPONSIVE REPORT OF PROFESSOR ZIPES ORIGINALLY PREPARED ON MR BURNSIDE: Finally, professor, have you prepared a supplementary statement with today's date in which you attach tables that identify by discovery numbers in this litigation the references that are contained in your first two reports? PROFESSOR ZIPES: Yes, sir. MR BURNSIDE: I tender that, your Honour..VID1/ P-28 D.P. ZIPES

6 EXHIBIT #GP.0692 SUPPLEMENTARY STATEMENT BY PROFESSOR ZIPES DATED MR BURNSIDE: Thank you, your Honour. I call Professor Richard Harper. <RICHARD RAYMOND HARPER, SWORN [. am] HIS HONOUR: Thank you, Professor Harper. You may be seated. MR BURNSIDE: Professor Harper, what's your full name? PROFESSOR HARPER: Richard Raymond Harper. MR BURNSIDE: Your occupation? PROFESSOR HARPER: I am a medical practitioner and cardiologist. MR BURNSIDE: What's your professional address, professor? PROFESSOR HARPER: Care of Monash Medical Centre, Clayton, Victoria, MR BURNSIDE: Have you prepared a statement of your evidence in this matter originally dated February 09? PROFESSOR HARPER: Yes, I have. MR BURNSIDE: Are there first of all a couple of alterations that you would wish to make? PROFESSOR HARPER: Yes, there are. MR BURNSIDE: Is the first at paragraph? Your Honour, can I hand up a copy of this? These two changes are slight and they have not been incorporated in the electronic copy, I am afraid. HIS HONOUR: Yes. MR BURNSIDE: May I hand up for your use a copy. HIS HONOUR: Thank you. MR BURNSIDE: Is the first alteration you wish to make in paragraph? PROFESSOR HARPER: Yes..VID1/ P-29 ZIPES/HARPER

7 MR BURNSIDE: In the second line of paragraph do you wish to delete the two words, "by Vioxx"? PROFESSOR HARPER: That's correct. MR BURNSIDE: Have you made that change on your copy of the statement? PROFESSOR HARPER: I have, yes. MR BURNSIDE: Could you please initial that alteration. PROFESSOR HARPER: Yes, I will initial it. MR BURNSIDE: Is the second change you wish to make in paragraph 41? PROFESSOR HARPER: Correct. MR BURNSIDE: Is that in the second last line of paragraph 41? PROFESSOR HARPER: Yes. MR BURNSIDE: Do you wish to delete the three words, "enhancing the production" and substitute the words, "blocking production of PGI2, thereby enhancing the effect"? PROFESSOR HARPER: That's correct. MR BURNSIDE: Have you made that alteration on your copy of the statement? PROFESSOR HARPER: I will, yes. MR BURNSIDE: Would you initial it, please. PROFESSOR HARPER: Yes. MR BURNSIDE: Could I ask you please to look at paragraphs PROFESSOR HARPER: Yes. MR BURNSIDE: Are the contents of paragraphs conclusions based on the contents of paragraphs -49? PROFESSOR HARPER: Yes. MR BURNSIDE: Can I please take you to paragraph 48. PROFESSOR HARPER: Yes..VID1/ P- ZIPES/HARPER

8 MR BURNSIDE: If you would read that to yourself please and tell his Honour what's your foundation for the contents of that paragraph? PROFESSOR HARPER: The foundation is my belief that Vioxx - when a plaque ruptures in the presence of Vioxx, the presence of Vioxx makes it more likely that a clot will form, that the clot will be larger than it otherwise would be and thereby more likely to cause a clinical event. MR BURNSIDE: Is the foundation for your belief about what you have just expressed essentially the FitzGerald hypothesis? PROFESSOR HARPER: I think that's the most likely explanation for that phenomenon. MR BURNSIDE: Can I please ask you to look at paragraph 7. Under paragraph 7 there are subparagraphs (b) and (c). PROFESSOR HARPER: Yes. MR BURNSIDE: In paragraph (b) where you are referring to Mr Peterson's commencement of taking Vioxx, is that date intended to be 1 June 01? PROFESSOR HARPER: The "6" and the "1" have been transposed in the American way so it should be "1/6". MR BURNSIDE: You are referring to a time approximately a month after he began taking Vioxx in May of 01; is that the position? PROFESSOR HARPER: Correct. MR BURNSIDE: Over the page in subparagraph HIS HONOUR: I am sorry, I didn't pick that up. MR BURNSIDE: I am sorry, your Honour. It's under a heading HIS HONOUR: I have got 7(b). There is something to do with the date, is there? MR BURNSIDE: Yes. You will see it reads "6/1/01" and if it were an American witness HIS HONOUR: That would have been June the 1st, wouldn't it? MR BURNSIDE: It would have been. It's meant to be June the 1st but that's not the date convention which appears elsewhere in the statement. In any event it is intended VID1/ P-31 ZIPES/HARPER

9 HIS HONOUR: What do we do? Do we just read it as though it reads, "as of about one month after commencing Vioxx medication"? MR BURNSIDE: Yes - I think perhaps to be more clear, if it could be altered to read, "as of June 01". Is that what the intention is? PROFESSOR HARPER: Yes, that's what the intention is. HIS HONOUR: Yes. MR BURNSIDE: In subparagraph (c) the date, "8/1/03", was that meant to read "8/12/03"? PROFESSOR HARPER: Yes, it was put "8/12/03" so it's meant to be 8 December 03. MR BURNSIDE: With those corrections and explanations are the contents of your statement true and correct? PROFESSOR HARPER: Yes. MR BURNSIDE: Would you please sign it at the end of the statement and give it today's date. I tender the statement, your Honour. EXHIBIT #GP.0693 WITNESS STATEMENT OF PROFESSOR HARPER ORIGINALLY MADE ON.2.09 MR BURNSIDE: Your Honour, I think following the pattern of the previous hot tub, we leave the tendering of the joint report until all four witnesses have been sworn. At least that's what we did for the biostatisticians. HIS HONOUR: Yes, that's convenient. The others should next be called by Mr Garling. MR BURNSIDE: Thank you, your Honour. HIS HONOUR: Is that convenient to you, Mr Garling? MR GARLING: Yes, your Honour. I call Professor Celermajer. <DAVID STEPHEN CELERMAJER, SWORN MR GARLING: Professor, would you give the court your full name? [.44 am].vid1/ P-32 ZIPES/HARPER/CELERMAJER

10 PROFESSOR CELERMAJER: David Stephen Celermajer. MR GARLING: Your occupation? PROFESSOR CELERMAJER: I work as a clinical and academic cardiologist. MR GARLING: Your professional address. PROFESSOR CELERMAJER: My primary professional address is the Department of Cardiology at the Royal Prince Alfred Hospital, Missenden Road, Camperdown, 0, Sydney, Australia. MR GARLING: In respect of this proceeding, professor, have you made a number of statements? PROFESSOR CELERMAJER: I have. MR GARLING: Can I show you the first of those. Have you recently read through that statement? PROFESSOR CELERMAJER: I have. MR GARLING: Subject to such deletions or minor handwritten amendments in it, if any, are the contents of it true and correct? PROFESSOR CELERMAJER: I believe them to be so, yes. MR GARLING: Turn to page 66 and would you sign and date the document. PROFESSOR CELERMAJER: Mr Garling, there are just two handwritten corrections on page 8. I just want to be sure that you have them as I have them because they have been made very recently. MR GARLING: All right. Please tell us in paragraph 163 at the top of page 8 what those two are. PROFESSOR CELERMAJER: In the first line, the words, "relative risk" have been changed to the words, "hazard ratio" to reflect what was actually in the reference and the figure, "2." has been changed to "2.3" to reflect the correct line of that table. MR GARLING: On 16 there's been a handwritten amendment from "1" to "1.1". I have a copy with this written on for your Honour. HIS HONOUR: I see. All right. I don't need to keep abreast of what you are doing for the moment? MR GARLING: Not for the moment, your Honour. We hopefully have done it for.vid1/ P-33 ZIPES/HARPER/CELERMAJER

11 your Honour and I am about to hand your Honour a copy. HIS HONOUR: Then I interrupted you. You were dealing with 16. MR GARLING: I was just going to say, is there also a handwritten amendment at 16? PROFESSOR CELERMAJER: Yes, in the very last line of that paragraph. MR GARLING: With those corrections, professor, and your statement that it's true and correct would you sign it on page 66 and date it today. I tender the statement of Professor Celermajer originally dated 17 February 09 and may I hand to your Honour a copy. EXHIBIT #MX.0039 STATEMENT OF PROFESSOR CELERMAJER ORIGINALLY MADE ON MR GARLING: Also at the same time as you made that statement, professor, did you prepare a report which separately to the first one addressed Mr Peterson's specific situation? PROFESSOR CELERMAJER: I did. MR GARLING: I hand you a copy of this report. Would you have a look at that statement. Are the contents of that and the opinions you express in it true and correct? PROFESSOR CELERMAJER: I believe them so to be, yes. MR GARLING: Would you turn to page 14 and sign it again and date it today. I tender that document, your Honour, and I provide a working copy of the statement to your Honour. It doesn't have the curriculum vitae repeated. EXHIBIT #MX.00 MEDICAL REPORT BY PROFESSOR CELERMAJER WITH RESPECT TO GRAEME PETERSON ORIGINALLY MADE ON MR GARLING: Thank you, your Honour. Professor, may I show you a third statement headed "Statement in Reply". Is that a statement you made in connection with this litigation? PROFESSOR CELERMAJER: Yes..VID1/ P-34 ZIPES/HARPER/CELERMAJER

12 MR GARLING: Are the contents of that true and correct? PROFESSOR CELERMAJER: I believe them so to be, yes. MR GARLING: Please sign and date on page 11 that statement. I tender that, together with a copy for your Honour. EXHIBIT #MX.0041 STATEMENT OF PROFESSOR CELERMAJER IN REPLY ORIGINALLY MADE MR GARLING: Your Honour, that's the evidence-in-chief of Professor Celermajer. I call Professor Vaughan. <DOUGLAS EUGENE VAUGHAN, SWORN [.2 am] MR GARLING: Professor, would you mind giving the court your full name? PROFESSOR VAUGHAN: Douglas Eugene Vaughan. MR GARLING: Your occupation? PROFESSOR VAUGHAN: I am a physician, a cardiologist and a vascular biologist. MR GARLING: And your professional address? PROFESSOR VAUGHAN: The Department of Medicine, Northwestern University, Feinberg School of Medicine in Chicago, Illinois, United States of America. MR GARLING: Professor, in this case have you made a number of statements? May I show you the first that you prepared on 17 June 09. Do you see that? PROFESSOR VAUGHAN: Yes. MR GARLING: Are the contents of that true and correct? PROFESSOR VAUGHAN: Yes, they are. MR GARLING: Would you turn to page 21 and again sign it and date it. That's 21 at the end of the statement itself. PROFESSOR VAUGHAN: I think there was a confusion on the date of this original tendering. It was February..VID1/ P- ZIPES/HARPER/CELERMAJER/VAUGHAN

13 MR GARLING: Sign it today's date. PROFESSOR VAUGHAN: Of course. MR GARLING: You have already signed it and dated it some time ago in February. I tender the statement of Professor Vaughan originally dated 17 February. You have a copy of that with you, professor? PROFESSOR VAUGHAN: Yes. MR GARLING: If you need a copy, please tell me. EXHIBIT #MX.0042 STATEMENT OF PROFESSOR VAUGHAN ORIGINALLY MADE MR GARLING: Thank you, your Honour. Professor, did you also make a further statement which responds to various matters that have been provided in this case and was that made in March 09? PROFESSOR VAUGHAN: Yes, I did. MR GARLING: Can you have a look at this document. Are the opinions set out in that document true and correct? PROFESSOR VAUGHAN: Yes, they are, to the best of my knowledge. MR GARLING: Would you sign it again and date it today on page 18 of the document. I tender that document. May I just see it, your Honour, just to make sure it's the correct copy? I just want to check one thing. Yes, I tender that document. EXHIBIT #MX.0043 RESPONSIVE STATEMENT OF PROFESSOR VAUGHAN ON ORIGINALLY MADE MR GARLING: That's the evidence-in-chief of Professor Vaughan. HIS HONOUR: Thank you, Mr Garling. Yes, Mr Burnside? MR BURNSIDE: Professor Zipes, have the four of you prepared a joint report as a result of your meeting yesterday? PROFESSOR ZIPES: Yes, we have. MR BURNSIDE: Do you have a copy of that report? I tender that..vid1/ P-36 ZIPES/HARPER/CELERMAJER/VAUGHAN

14 HIS HONOUR: That's the one that's been handed to my associate just before I came on to the Bench, is it, Mr Burnside? MR BURNSIDE: I hope it is. HIS HONOUR: Yes. It's a five and a half page document, single sided, of 13 paragraphs? MR BURNSIDE: That's correct. EXHIBIT #GP.0694 CARDIOLOGY CONCURRENT EVIDENCE REPORT DATED HIS HONOUR: Earlier this morning a draft was ed to my chambers and I have been reading that. In point of content is that the same as the final document? MR BURNSIDE: Substantially. I think there are two changes of substance between the earlier draft and the current exhibit. HIS HONOUR: It might be useful if someone draws those to my attention because I have been working by reference to the draft which you kindly provided this morning. MR BURNSIDE: Yes. Professor Harper, could you please draw to his Honour's attention the changes that were made this morning - changes of substance, leave aside typos and so on - the changes of substance that were made this morning to the joint report. PROFESSOR HARPER: Yes. On page HIS HONOUR: Page 2 of the final version? PROFESSOR HARPER: Yes, it's page 2 of both, the second last paragraph, "RH/DZ", we have slightly altered this to say: We have not examined in detail the data linking Vioxx with thrombotic stroke. It is important to note that thrombotic stroke consists of both atherothrombotic and non-atherothrombotic types of ischaemic stroke. There is another alteration. The other alteration, actually it's not present on my copy but I believe that it was 6(b), and I can be corrected by Professor Celermajer. 6(b), the third paragraph, the word "numerous" should be "two". Is that right? PROFESSOR CELERMAJER: No, that's in a different spot. PROFESSOR HARPER: I am sorry, sir. I am sorry..vid1/ P-37 ZIPES/HARPER/CELERMAJER/VAUGHAN

15 MR BURNSIDE: Does your Honour have paragraph 6(b)? PROFESSOR CELERMAJER: May I, your Honour? HIS HONOUR: Yes, Professor Celermajer. PROFESSOR CELERMAJER: In (a) on the first page towards the bottom there were formerly three paragraphs. The second and third have been run together and attributed to DC and DV and the HIS HONOUR: But they reflect otherwise just a putting of them together, do they? PROFESSOR CELERMAJER: There is one word we have changed. The word "numerous" at the beginning of DV's previous comments has been replaced by the word "two". HIS HONOUR: Yes. Thank you. So there is nothing, Professor Harper, that arises under 6(b)? MR BURNSIDE: I think the corresponding change appears in 6(b), your Honour. MR GARLING: I think there is an addition certainly that I have noted. I may be wrong but I believe, your Honour, under 6(b) in the first paragraph there have been a number of words added on the third line, namely the words I understand that have been added on the two copies; after "animal data" I understand that the words were added, "with regard to COX-2 inhibition". HIS HONOUR: That seems to be the case. Mr Burnside, you were saying something about a corresponding change somewhere? MR BURNSIDE: Yes. In 6(b) if you go in the earlier version you have to the third paragraph which begins "DC/DV: We disagree", and the second sentence you see says, "numerous studies have examined", the "numerous" is now replaced PROFESSOR HARPER: No, it it's not. I looked for the word "numerous" and that was not correct. HIS HONOUR: But the first sentence of the previous paragraph is no longer there. Is that the position? MR BURNSIDE: No, it's been placed down at the end of the paragraph. It's just a change in the order of the sentences. PROFESSOR HARPER: Your Honour, can I draw attention to the fact that I inadvertently dated it the th rather than the 21st on my document. HIS HONOUR: The report itself?.vid1/ P-38 ZIPES/HARPER/CELERMAJER/VAUGHAN

16 PROFESSOR HARPER: My expert report I dated May rather than the 21st. HIS HONOUR: I see. That's all right. It probably is the th somewhere in the world. MR BURNSIDE: I think it's the th for Professor Zipes. HIS HONOUR: Professor Zipes, it's my practice to have a five minute break in the middle of the morning so if that's time for your night cap then you might be able to have a glass of water instead. MR BURNSIDE: I think that picks up the alterations, your Honour. Your Honour, I am just reminded. I am not sure if we have tendered the agenda, although we should do. MR GARLING: Yes, I agree. HIS HONOUR: Can you recall whether it's been tendered? MR GARLING: It hasn't been. It should be. EXHIBIT #GP.069 CARDIOLOGY CONCURRENT EVIDENCE AGENDA MR GARLING: Your Honour, I have got some copies if the witnesses require them. I don't know if they have them. Perhaps I can pass them along. HIS HONOUR: Gentlemen, the way things will proceed is there are a few matters of clarification that I wish to raise with you. Yes, Professor Celermajer? PROFESSOR CELERMAJER: Your Honour, would it be in order for me to point out a small typographical error that hasn't been made to the very final cardiology concurrent evidence report? HIS HONOUR: Yes. Where? PROFESSOR CELERMAJER: It's in (a), paragraph (ii), line 2. The "I" should be "we" as it reflects the views of two of us. HIS HONOUR: Yes. Yes, as I was saying, I will raise a few things with you and then, then each of Mr Burnside and Mr Garling respectively will raise the things with you that he wishes to raise. The typical pattern is that usually I or Mr Burnside or Mr Garling will ask one or perhaps two of you to comment on something and then ask the others either to make their own comment or to agree or disagree with the first comment that's been made. We will try and deal with the matters in groups so that if any of you has a contribution to make about some particular aspect, we will try and.vid1/ P-39 ZIPES/HARPER/CELERMAJER/VAUGHAN

17 deal with that aspect and get it out of the way with everyone's contributions before moving on to another aspect, although, of course, as is apparent from your report, many of these aspects are interrelated and it will probably be impossible to compartmentalise things strictly. My first question relates to paragraph 4 of the joint report and to the opinion expressed by Professor Harper and Professor Zipes in the second paragraph or in the second subparagraph of that paragraph, namely that Mr Peterson's consumption of Vioxx increased his risk of having his heart attack by approximately a factor of 2. Is that the same thing as saying that now that we know that Mr Peterson did in fact have a heart attack and the task that you have is to express your opinion as to whether that heart attack was related in some way to Vioxx, and if so how, is that the same thing as saying that you believe it twice as likely that Mr Peterson's consumption of Vioxx in fact caused or in some material way contributed to the heart attack which in fact took place? Professor Zipes, would you express a view on that? PROFESSOR ZIPES: Yes, sir. That number comes primarily from the APPROVe trial where the relative risk was around 2. When an individual has multiple risk factor and suffers a myocardial infarction it's very difficult to say one specific risk factor was responsible for the infarct versus the constellation of risk factors all interacting and that summation producing the infarct. I think more likely than not had he not been taking Vioxx he would not have had an infarct at that time but it's difficult to say that Vioxx was the specific cause of that infarct. I think we are dealing with statistics and the likelihood of him having an infarct is increased by him taking Vioxx, so I think to a reasonable degree of medical probability Vioxx played a substantial contributing role. Does that answer your question? HIS HONOUR: Yes. That's very helpful. Professor Harper? PROFESSOR HARPER: I believe that Vioxx doubled his risk of having a heart attack. So if his risk, for argument's sake, was per cent by taking a heart attack his risk was increased to per cent of having a heart attack over a period of time. HIS HONOUR: That's really the problem I have. I can understand that. From the point of view of community medicine or from the point of view of people who manufacture drugs, perhaps you would have to take a forward looking approach, don't you? You would have to say, "If we continue to let people smoke in hotel bars we have a community risk which perhaps can be measured of lung cancer". If you were making a particular type of drug you might be able to say, "Looking at all the information we should be very cautious about this and we shouldn't continue to make this drug because it doubles the risk", or whatever. But the question is if you are not looking forward but looking backwards and you know that someone has had a heart attack and you say that before he had it there was a risk, perhaps, which went up from per cent to per cent and then he has had it, how likely is it that he had it because of taking Vioxx compared to a situation in which you could say he would have had it anyway?.vid1/ P- ZIPES/HARPER/CELERMAJER/VAUGHAN

18 PROFESSOR HARPER: That's a difficult question to answer but if it is more than two times then it's more likely than not that Vioxx contributed to the heart attack. In other words, it increased the probability by 0 per cent. HIS HONOUR: You would be able to say that - your statement about risk in effect directly converts into an ex post statement about probability of causation? PROFESSOR HARPER: I agree entirely with Professor Zipes, that if a person has five risk factors and has a heart attack there is no way in determining from that heart attack which of those risk factors was the sole or the predominant or whether they all contributed equally or they contributed in unequal parts. I think all you can say is that if the risk was a certain percentage - in respect to Vioxx if the risk of a person was 1 per cent it would have increased to 2 per cent; if it was per cent it would have increased to per cent. The same risk roughly applies to smoking and to high cholesterol and other risk factors. HIS HONOUR: Yes. Professor Zipes, do you wish to add to that? PROFESSOR ZIPES: There is a very large study in the United States that's been going on for over 0 years called the Framingham study in which they follow a group of individuals living in Framingham, Massachusetts and they have been able to deduce a great deal of information about risk factors. So, for example, if we go to Framingham data, having an elevated cholesterol, which I think everyone would accept is a risk for having myocardial infarction or coronary disease has a relative risk of 1.3, 1.4, so someone who has a heart attack with an elevated cholesterol, that risk has been increased by that elevated cholesterol but you can't say the cholesterol did it. I think with Vioxx it's the same thing, the relative risk is even higher than the elevated cholesterol, in the range of 2, and more likely than not played a major contributing role and as I said, absent the Vioxx it's not likely that he would have had his infarct at that time. This is an individual who does have risk factors and he may have gone on to have had an infarct at a later time, but the Vioxx, I feel very strongly, played a substantial contributing factor. HIS HONOUR: Your example about the cholesterol means that if you had two groups of people, one group with elevated cholesterol and the other group without it, you might find for every 0 people who had an infarct in the non-cholesterol group you would get 1 people in the other group with the cholesterol group having an infarct? PROFESSOR ZIPES: It's something like that, though we know that almost half of patients admitted with myocardial infarctions have relatively normal lipids, cholesterol and so on, so it's - cholesterol unquestionably is a risk factor but there are other things going on in a very complex system of man. HIS HONOUR: Taking the cholesterol example, doesn't that mean that if all you knew was that someone had a heart attack and had high cholesterol you couldn't say it was most likely that the cholesterol was a cause because of the 1 people who are.vid1/ P-41 ZIPES/HARPER/CELERMAJER/VAUGHAN

19 in that category, you know that 0 of them would have had a heart attack anyway? PROFESSOR ZIPES: Yes, sir. In talking with my patients I use the analogy or metaphor if you drive your car the wrong way up a one way street some people are going to get up to the end of the block and not have an accident but your chances of having an accident are a lot greater than if you are driving the right way down that one way street and I think it's very similar to the Vioxx situation or cholesterol. HIS HONOUR: Professor Harper? PROFESSOR HARPER: I just wanted to qualify that an elevated cholesterol can mean a cholesterol of 6 or a cholesterol of and there are gradations in risk so that 1.3 doesn't apply to extremely high levels of cholesterol. HIS HONOUR: It always seems to be the case when you use analogies to simplify things. You always end up in some billabong somewhere floating around and not going any further downstream. Professor Celermajer, how would you respond to the question that I posed? PROFESSOR CELERMAJER: Your Honour, as you will see, we have written that we do not believe that Vioxx played a role in causing Mr Peterson's heart attack and with your permission I would like to answer that on three levels: Mr Peterson specific; a word on mechanism; and a word about the clinical trials data. HIS HONOUR: Yes. PROFESSOR CELERMAJER: As you will see in our report, in paragraph 1(a) we are all agreed that Mr Peterson was at moderate to high risk and as you will see in paragraph 2(a), we are all agreed that Mr Peterson had coronary atherosclerosis prior to the commencement of Vioxx. It is no surprise, therefore, that Mr Peterson had a heart attack. There are many 3 year old men with Mr Peterson's risk factor profile who have heart attacks around the world. You wouldn't be staggered at the situation that absent Vioxx Mr Peterson would have had a heart attack and as my learned colleagues have pointed out, there's no footprint of Vioxx, there is no signature of Vioxx to indicate that a particular heart attack was a Vioxx heart attack versus a common garden variety heart attack you have every day. So the first level of response specific to Mr Peterson is we believe he had an adverse risk factor profile, had had coronary atherosclerosis before commencing Vioxx and even absent Vioxx, he was at high risk and there is no way of saying Vioxx was the culprit. The second level is at the level of mechanism. I think we are all agreed, and you will see in our report, that what happened to Mr Peterson most likely in the days before 2 December 03 were that he had a plaque rupture and Professor Vaughan and I find no mechanism whereby Vioxx predisposes to plaque rupture. If anything, your Honour, the fact that inflammatory plaques overexpress COX-2, and has been stated.vid1/ P-42 ZIPES/HARPER/CELERMAJER/VAUGHAN

20 by many authors, COX-2 inhibitors, if anything, will have a plaque stabilising effect through their anti-inflammatory capability. So if one talks about the pathogenesis of his - the cause of his event being a plaque rupture with thrombosis following, we find no evidence that Vioxx is related to the process of plaque rupture. If one then says he had a thrombosis on plaque rupture, we are of the strong belief that there is so much happening in the vicinity of a plaque rupture with other things that predispose to clotting such as tissue factor, plasminogen activator inhibitor 1, thromboxane particularly - you will be familiar with thromboxane. There is an enormous amount of that and that Vioxx compared to what's going on at that local site we biologically don't find it plausible that can COX-2 inhibition would influence that process. The third point I would like to make is about the clinical trials data. According to Mr Peterson's physicians, he was prescribed Vioxx for the treatment of osteoarthritis. There is some evidence to indicate that Mr Peterson thought he had ankylosing spondylitis, a different joint condition, but that was not a condition for which Vioxx could be prescribed in Australia and his physicians prescribed it on the basis that he was suffering from osteoarthritis. We find, as you will see in our report, that there may be some heterogeneity in the risk, if any, that Vioxx poses according to the underlying condition that the patient suffers with. So, for example, we believe that patients with osteoarthritis or rheumatoid arthritis or colon polyps may, from the clinical trials data alone, be seen to be at somewhat different risk and the osteoarthritis data for Vioxx are certainly not compelling. I don't mean to divide patient populations up into little bits but when you pose the question about Mr Peterson it is worth noting that he falls into the osteoarthritis group and there are numerous publications and FDA reports which analyse the clinical trials data for Vioxx as regards adverse CV on outcomes in osteoarthritis and they all, to the best of my knowledge, contain 1.0 in their confidence intervals. HIS HONOUR: Thank you. Professor Vaughan? PROFESSOR VAUGHAN: Yes, your Honour. I agree with the summary provided by Professor Celermajer. I would like to emphasise a couple of points first: that we don't think there is a signature abnormality in a heart attack potentially caused by Vioxx versus any other heart attack that you might see in a human being so as we have all - as several people have noted this morning, myocardial infarctions are quite common events. They occur all the time in Australia and in the United States and the pathophysiology is quite clear. The initiating event in an acute myocardial infarction involves plaque rupture and as Professor Celermajer described, we can appreciate no mechanistic reason to suggest that Vioxx promotes plaque rupture. Once a plaque ruptures, collagen is exposed in the blood vessel wall that initiates thrombosis. That collagen is the powerful driver of clot formation, that collagen promotes the activation of thrombin and that collagen also promotes the activation of platelets. Vioxx has nothing to do with the exposure of that collagen, the activation of tissue factor and the local activation of thrombin and those are the drivers of thrombosis in.vid1/ P-43 ZIPES/HARPER/CELERMAJER/VAUGHAN

21 an acute coronary syndrome. PROFESSOR ZIPES: Sir, may I respond? HIS HONOUR: Yes, I am coming back to each of you, Professor Zipes, but before I leave Professor Celermajer and Professor Vaughan I just wanted to know whether - each of you has answered my question in a comprehensive way. I want to know whether you have any comment about the relationship between identifying an elevated risk and deciding whether a known event has been caused by the postulated source of that risk. That was one particular aspect of analysis that I was hoping to get a view on. Either of you? PROFESSOR CELERMAJER: Your Honour, in some disease processes a footprint can be left by a putative causative agent. So, for example, in a patient with head and neck cancer, if you suspect the aetiology is a particular virus called HPV, HPV footprint can be seen in the cancer cells, whereas if the cancer is caused by cigarette smoking, for example, that viral signature will not be present. There is a tumour around the lungs called mesothelioma where asbestos bodies can be found in the malignant cells and that strongly implicates asbestos in the causation of a mesothelioma. In coronary disease, to the best of my knowledge, there is no similar pattern of being able to identify which of many putative risk factors are involved other than to say there is a particular pattern of coronary disease associated with diabetes, for example, which is diffuse extensive coronary disease, whereas a more usual pattern with cigarette smoking is a single ruptured plaque with an overlying thrombosis but there are grey zones between those factors. HIS HONOUR: Professor Vaughan? PROFESSOR VAUGHAN: Yes, your Honour. I generally agree with what Professor Celermajer said. I would like to make one modification. I think with regard to cholesterol and coronary artery disease and acute myocardial infarction there are some examples in the real world where you could absolutely attribute the heart attack to cholesterol. There are genetic abnormalities of cholesterol metabolism, a syndrome called familial hypercholesterolaemia. Homozygotes or individuals who have two abnormal copies of the receptor for cholesterol develop malignant atherosclerosis by the time they are six or seven years of age. They will have heart attacks, they will die if they are not treated. That's unequivocally attributed to cholesterol and cholesterol in general is a continuous variable so I think it's a bit simplistic or a bit inaccurate to say that there is simply a 1.3 or 1.4 or 1.9 per cent increase related to cholesterol. It all has to do with how much cholesterol and the duration of time your body has been exposed to high cholesterol as well. HIS HONOUR: Professor Zipes and Professor Harper, if it's convenient to you I might ask you to comment in order on each of the three areas that Professor Celermajer addressed in his answer to me. The first one was the aetiology in.vid1/ P-44 ZIPES/HARPER/CELERMAJER/VAUGHAN

22 Mr Peterson himself by reference to the underlying risk factors; the second one was the mechanistic explanation for the postulated relationship between COX-2 inhibition and myocardial infarction; and the third one was the data particularly with respect to the possibility that there might be heterogeneity as between patient conditions in the impact of COX-2 inhibition, specifically given Mr Peterson's assumed osteoarthritis. If we deal with them under those three categories is there anything, Professor Zipes, that you want to say about the first of those, that is Mr Peterson's own risk factors? PROFESSOR ZIPES: Yes, sir. Could I deviate just slightly because you asked a question that's been hanging in my head: how can you say a specific potential risk was causal of an event. HIS HONOUR: Yes. PROFESSOR ZIPES: The way to do that is to take away the risk. So, for example, the elevated cholesterol we treat with statins and we reduce the risk. Elevated blood pressure, we bring that down, we reduce the risk. If there were an individual who had a response to a drug, we take away the drug and in some instances re-challenge to show that indeed there was a relationship. Obviously with Mr Peterson, you can't take away the Vioxx, though subsequently it was done, so what is the way to do that and show it was Vioxx. Those are the trials that are done versus placebo. Placebo, in essence, is taking away that risk and those - as we have seen, the randomised controlled trials with Vioxx in essence do that by taking away the risk with a placebo group. So I just wanted to answer that specific question you had. In terms of the three categories that Professor Celermajer has introduced, certainly Mr Peterson was at risk, we all agree. That is particularly germane to COX-2 inhibition because there are numerous data indicating that the individual at risk, because of abnormal coronary arteries, is at greater risk from COX-2 inhibition, regardless of the mechanism. I will get to that in just a moment. The diabetics in APPROVe have a higher relative risk. The hypertensives in APPROVe had a higher relative risk. That increase in risk holds true in virtually all - certainly the controlled trials and in many of the epidemiologic or meta-analyses. As an example, the most recent publication by Baron on the long term evaluation of the APPROVe patients makes the statement very clearly, that those at higher cardiovascular risk had a greater effect from the COX-2 inhibition. So Mr Peterson, I think, fits the story quite nicely. Mechanistically HIS HONOUR: Just a moment. Professor Harper, do you wish to say anything about the aspect that Professor Zipes has just talked about? PROFESSOR HARPER: I agree entirely with Professor Zipes. I think it's worth pointing out in response to Dr Celermajer that Vioxx was just one of his risk factors so if Dr Celermajer says this man was at risk of having a heart attack with or without Vioxx, that statement is true. The relevant statement is did Vioxx increase the risk, just as did the fact that he had a high blood pressure increase the risk. Dr Celermajer.VID1/ P- ZIPES/HARPER/CELERMAJER/VAUGHAN

23 can't tell me that the high blood pressure caused his heart attack and likewise, I can't say that the Vioxx did. We are just saying that it increased the risk in someone who was already at high risk. HIS HONOUR: The mechanistic observations that Professor Celermajer made? PROFESSOR ZIPES: The human body is exceedingly complex. HIS HONOUR: I have learnt that. PROFESSOR ZIPES: And obviously to understand mechanisms to a reasonable degree of medical certainty is sometimes difficult. So, for example, we know smoking can cause carcinoma, cancer of the lung, and we don't really understand the mechanism that's involved. We knew penicillin could treat infections without knowing the mechanism so often we don't understand the mechanism. That said, the FitzGerald hypothesis of the balance between thromboxane and prostacyclin fits in terms of the mechanistic effects of the COX-2 inhibition upsetting this balance. I will be the first to say that there are other features in the intact body that may mitigate that effect, that may enhance that effect but nevertheless, as an operative hypothesis to explain what is going on, it's very reasonable - and I have not seen a better hypothesis put forward to explain what we are seeing. Does that mean it's absolutely correct? No, I can't say that like I can't say the mechanism of smoking and cancer of the lung, but it certainly fits very well. In terms of the statement that COX-2 inhibition should stabilise plaque, that's based on several animal studies and there are an equal number showing that COX-2 inhibition, not necessarily with Vioxx but with other COX-2 inhibitory drugs, that destabilise the plaque. So it's tough to say the animal data proved this or proved that. The ultimate source is man; that's the final experiment and in that regard you have a heart attack because of, in large part, plaque instability. So if Vioxx is associated with an increase in heart attacks then it's associated with an increase in plaque instability because that's the end point, how you got there. Can we measure it and document it? No, that's not been done, certainly not in man, and it's difficult enough in animals. So I am not at all concerned that an animal study supports this, an animal study does not support this. Plaque instability is part and parcel of myocardial infarction. We have got randomised controlled trials showing increased infarction with Vioxx. HIS HONOUR: A point that Professor Celermajer made is that all this starts with plaque rupture. PROFESSOR ZIPES: Plaque rupture is a major mechanistic foundation for heart attacks and very likely there are silent plaque ruptures. A very good pathologist in the States has shown the arteries of people who have died with heart attacks, that there is the evidence of plaque rupture healing over, plaque rupture healing over, three and four layers of this before finally the material within the plaque is extruded.vid1/ P-46 ZIPES/HARPER/CELERMAJER/VAUGHAN

24 into the blood vessel and causes the major clotting that Professor Vaughan alluded to. I certainly agree with that. What we don't know is with the rupture, heal, rupture, heal, how do we know that that healing process was not mitigated by prostacyclin? It's certainly possible that it's playing a reparative role until at one point it becomes overwhelmed, a big thrombus develops and plugs up the artery. That's as reasonable an hypothesis as any other. I do want to speak to one other point, if I may, and not monopolise all of this, and that is the suggestion that the randomised controlled trials showing an increased cardiovascular risk with Vioxx is specific to somebody who has rheumatoid arthritis or somebody who has polyps. HIS HONOUR: I will come back to that. PROFESSOR ZIPES: I thought that was the third heterogeneity HIS HONOUR: I haven't lost it. We will stay with mechanism for the moment. Professor Harper, I think you have a view about this that you expressed, didn't you, in the joint report and possibly also in your statement. PROFESSOR HARPER: I think the pertinent factor is that most plaque ruptures are clinically silent and as Professor Zipes said, they heal up. The plaque ruptures, platelet aggregates and a clot forms and either breaks off and goes downstream or gets incorporated into the plaque and the plaque heals and most plaque ruptures are clinically silent. In fact, there were quite a few studies in people who have had heart attacks and they have looked - people have looked at the artery not involved in the heart attack and found plaque ruptures in those circumstances so you have to explain that - I don't believe that Vioxx - I have no evidence to suggest that Vioxx causes plaque ruptures but anyone with atherosclerosis in their coronary arteries are susceptible to plaque rupture. What I believe is if a plaque rupture occurs in the presence of Vioxx it is more likely that that plaque rupture will lead to a clinical event than if Vioxx was not present. HIS HONOUR: What's the mechanism for that? PROFESSOR HARPER: Because I think the amount of platelet aggregation and clot formation is greater in the presence of Vioxx than it otherwise would be. HIS HONOUR: In the vicinity of the rupture? PROFESSOR HARPER: In the vicinity of the rupture. HIS HONOUR: Whether or not the aggregated mass that you are talking about breaks away and moves downstream? PROFESSOR HARPER: Yes, that can happen but it can also become incorporated into the plaque or it can keep growing and completely occlude the artery and produce.vid1/ P-47 ZIPES/HARPER/CELERMAJER/VAUGHAN

25 the sort of heart attack that Mr Peterson had. HIS HONOUR: What happened to Mr Peterson? PROFESSOR HARPER: I think on 2 December when he first got symptoms he had a plaque rupture. Thrombus started forming on that plaque, bits of it broke off. That's why he had intermittent symptoms. But by 8 December the thrombus had grown to the size where it completely obstructed the artery and once it completely obstructed the artery he had his large heart attack. HIS HONOUR: How might that have happened differently if he had not been taking Vioxx? PROFESSOR HARPER: It may have happened exactly the same way. HIS HONOUR: I understand that but how might it have happened differently, mechanistically? PROFESSOR HARPER: If he hadn't been taking Vioxx maybe that wouldn't have resulted in the large heart attack he had. It may have resulted in unstable angina. HIS HONOUR: Why do you say that, mechanistically? PROFESSOR HARPER: Mechanistically because I think the chances of a major heart attack occurring depend on the size of thrombus formed and I think Vioxx - mechanistically the most likely explanation is the FitzGerald hypothesis but I can't prove that. That offers an explanation as to why the clot may be larger. HIS HONOUR: That is to say in a non-vioxx person but otherwise in the same circumstances, the prostacyclin would have a tendency to wash away or dissolve away some of the worst aspects of that clot? PROFESSOR HARPER: Exactly. In the presence of Vioxx it is likely that there is more thromboxane relative to prostacyclin and therefore the clot is more likely to enlarge and obstruct the artery. HIS HONOUR: I will come back to the issue of data and heterogeneity but I will take a short break before that happens. ADJOURNED [11.44 am] RESUMED [11.1 am] HIS HONOUR: Gentlemen, you remain bound by the oaths and affirmations that.vid1/ P-48 ZIPES/HARPER/CELERMAJER/VAUGHAN