Peterson v Merck Sharpe & Dohme

Amendment to the Vioxx Product Information 230 The Vioxx Product Information was amended 11 times between December 1999 and September 2004. The only amendment to which detailed reference needs to be made in the present context is that which resulted from the findings in the VIGOR trial. Mr Back was advised about the interim results in a teleconference conducted by Ms Simpson on about 24 March 2000. Although not stated by, or put to, Mr Back, I infer that this was the conference to which I have referred at para 97 above. That being so, Mr Back would have seen the slides distributed by Merck to international subsidiaries for the purpose of that conference (see paras 98‑102 above). I do not, therefore, accept his evidence that the first written information he received was in an email from Ms Simpson on 27 March 2000. Mr Back said that, after receiving that email, he contacted Dr Chipman at the TGA, and told him that the VIGOR study had met its primary endpoint of demonstrating a difference in gastrointestinal outcomes in favour of Vioxx, but that there had also been a difference in serious cardiovascular outcomes in favour of naproxen. Mr Back said that MSDA wanted to file an application to include the results of VIGOR in the current osteoarthritis Product Information. Dr Chipman said that he understood that it might take some time to put a full application together, given that the results were, at that stage, interim ones only. He said that MSDA should immediately consider a safety‑related notification if the serious adverse events were not yet in the existing Product Information, and that the TGA would be happy to include important safety information in the current Product Information, no matter what the patient group. 231 On 11 April 2000, MSDA submitted an interim analysis addressing the cardiovascular and gastrointestinal findings of VIGOR to the TGA. In its covering letter, it stated that a final, complete, data package would be available in July, at which time it intended to make a formal application for inclusion of the study results in the Product Information. Mr Back said (in his evidence) that the reference to July was a mistake on his part, as he thought that this was the date when the complete data package was to be available. 232 In his witness statement, Mr Back noted the publication of Bombardier (2000) in November 2000, but it was apparently not until 12 January 2001 that a submission was made to the TGA to add the VIGOR information to the Vioxx Product Information. He explained that this was a Category 1 application because the requested changes to the Product Information did not meet the TGA's criteria for a safety‑related notification, in that they involved revisions to the "Clinical Trials" section and the inclusion of a revised gastrointestinal safety precaution statement which had the effect of broadening the potential patient population. 233 In the covering letter for the application of 12 January 2001, it was stated: The prevalence of NSAID‑associated side effects, particularly upper gastrointestinal perforations, symptomatic ulcers and upper‑GI bleeds is well known and is a significant public health concern. The current PI contains details of a combined analysis of clinical upper [gastrointestinal] events (PUBS) from all Phase IIb/III studies. These studies with VIOXX, a selective COX-2 inhibitor, demonstrated improved gastrointestinal safety compared with non‑selective COX-l/COX-2 inhibitors. The Company has completed a large, prospective, outcomes clinical trial (VIGOR), assessing the incidence of serious upper gastrointestinal adverse events during chronic treatment with VIOXX or naproxen, in patients at risk for developing serious [gastrointestinal] toxicity. The results of this study provide further evidence of the improved [gastrointestinal] safety of VIOXX compared to non‑selective NSAIDs. We request that details of this clinical trial be added to the Product Information. The letter itself made no reference to cardiovascular events, which Mr Back justified by noting that the purpose of the application was to assess the gastrointestinal outcomes of the VIGOR trial. Amongst the attachments to the letter was the amended Product Information being sought by MSDA. The only change which might be thought to have anything to do with the cardiovascular results of the VIGOR trial were passages that pointed out that Vioxx was not a substitute for aspirin, because of the absence of antiplatelet effects. 234 Attached to the application of 12 January 2001 were two clinical expert reports, one on the gastrointestinal findings of VIGOR by Dr Reicin, and the other on the cardiovascular findings by Dr Eliav Barr, both of MRL. We are presently concerned only with Dr Barr's report. That report appears to be based on the report provided by MRL to the FDA on 13 October 2000, mentioned in para 131 above. Dr Barr set out the same table of CVT adverse experiences as was there referred to. He said that therapy with naproxen was associated with a 58% reduction in the risk for the development of such experiences compared with Vioxx therapy. He referred to four analyses that had been undertaken by Merck. 235 First, Dr Barr referred to the distinction between those patients who were, and those who were not, aspirin‑indicated. He noted that 31% of the confirmed CVT events in VIGOR occurred in the 4% of patients who were aspirin‑indicated. In that group, naproxen therapy was associated with an 80% reduction in risk. In the non‑aspirin indicated group (96% of the patients) naproxen therapy was associated with a 43% reduction in risk. He continued: The high rate of cardiovascular events in the "aspirin‑indicated" sub‑cohort is not surprising. Patients with symptomatic atherosclerotic cardiovascular disease are at particularly high risk of atherosclerotic plaque rupture that can result in arterial thrombosis and recurrent organ ischemia/infarction. Thus, if a study is evaluating compounds with differential effects on cardiovascular homeostasis, such differences would most likely be observed in a high risk cohort such as this group. Secondly, noting that patients who received Vioxx had a higher incidence of hypertension and oedema‑related adverse experiences compared with patients who received naproxen, Dr Barr asked himself whether that circumstance had caused the imbalance in cardiovascular events in the study. He concluded that it had not. Thirdly, he analysed the VIGOR results by reference to the APTC endpoint, and found that risk was reduced by 49% in the naproxen group relative to the Vioxx group. He noted that the difference in the event rates between the treatment groups was due primarily to a difference in the rates of myocardial infarction, and that the incidence of thrombotic strokes was similar between treatment groups. Fourthly, he looked for evidence, other than the CVT results as such, of the antiplatelet effect of naproxen in the VIGOR trial, such as bleeding. He found that, compared with Vioxx, naproxen was associated with a 2.1‑fold and 3.5‑fold higher incidence of ecchymosis and epistaxis, respectively. He continued: These results also suggest that naproxen therapy was accompanied by high‑level platelet inhibition in the VIGOR study. Such inhibition may have contributed to the observed difference in the rates of thrombotic cardiovascular serious adverse experiences between the naproxen and rofecoxib groups in the study. However, it is also fair to say that the relationship between such in vivo manifestations of medication‑induced platelet inhibition and the effect of such medications on cardiovascular event rates has not been well defined. 236 Dr Barr said that there were three potential hypotheses to explain the cardiovascular findings of the VIGOR study, namely: (1) Vioxx caused a prothrombotic or otherwise deleterious perturbation of cardiovascular homeostasis; (2) naproxen had potent antiplatelet properties throughout its dosing interval; and (3) the findings were a play of chance, given the relatively small number of cardiovascular events in the study. He said that, taking the VIGOR results in isolation, it was difficult to eliminate any of these hypotheses from consideration. 237 Considering whether Vioxx was prothrombotic, Dr Barr referred to the results of other studies involving the drug, to the extent that they were then available (his data was current at 15 September 2000). He commenced with the Alzheimer's disease studies. His conclusion with respect to them was: [T]here was no evidence in these studies that therapy with rofecoxib was accompanied by increased cardiovascular risk compared with placebo in this elderly, relatively high‑risk patient population. These results substantially reduce the likelihood that the cardiovascular findings in the VIGOR study were due to rofecoxib‑mediated prothrombotic or otherwise deleterious perturbations of cardiovascular homeostasis. 238 Dr Barr turned next to the Phase IIb/III osteoarthritis studies. He noted that they involved comparisons of Vioxx with NSAIDs, although in the case of some studies there were also placebo arms. He said that, in the NSAID comparison, the incidence of CVT events was 2.05 events per 100 patient‑years in the Vioxx arms compared with 2.27 events per 100 patient‑years in the NSAID arms. When the comparator was placebo, the figures were 2.48 and 2.36 respectively, although Dr Barr said that the number of events was small. His conclusion was: Thus, in this group of studies, therapy with rofecoxib and the nonselective NSAIDs (mostly diclofenac and ibuprofen) was associated with comparable incidences of thrombotic cardiovascular events. In the group of placebo‑controlled studies, there did not appear to be any imbalances in cardiovascular event rates between treatment groups. However, there were too few patient‑years of follow‑up and thrombotic cardiovascular events in these trials to draw firm conclusions regarding the relative risk for the development of such events associated with rofecoxib relative to placebo in these studies. 239 Dr Barr next set out the results of the ADVANTAGE study, a gastrointestinal outcomes study conducted between March 1999 and April 2000, of 12 weeks' duration for each patient, comparing Vioxx with naproxen. He noted that there were too few events recorded in that study to enable any conclusions to be drawn. He expressed effectively the same view about the results of Merck's studies of Vioxx in patients with rheumatoid arthritis (other than VIGOR). Finally in this section, Dr Barr mentioned MRL's Worldwide Adverse Experiences Surveillance database, in which it was recorded that there were, as at 13 March 2000, 78 reports of CVT events, a rate of 8.1 reports per 100,000 patient‑treatment-years distributed. He said that this rate was low relative to the background occurrence of such events in the age group of patients in which Vioxx was prescribed, and was not disproportionate to the numbers reported with two other medications marketed by Merck that did not have any known associated cardiovascular risks and which were indicated for treatment populations of similar age (finasteride and alendronate). 240 The next section of Dr Barr's report was headed "Overall Assessment of Cardiovascular Outcomes in Clinical Studies of Rofecoxib and Suggested Guidance to Physicians and Patients", and commenced with an "Overview". Dr Barr said: Platelet aggregation is central to the development of thrombotic cardiovascular events such as [myocardial infarction] … Agents that inhibit COX‑1, such as aspirin, substantially inhibit platelet aggregation and prolong bleeding time … Aspirin and other compounds that generate nearly complete inhibition of platelet aggregation have been shown to reduce the incidence of thrombotic cardiovascular events in high‑risk patients … Because COX‑2 selective inhibitors do not block COX‑1‑mediated platelet aggregation, it was hypothesized that therapy with nonselective COX‑1/COX‑2 inhibitors may result in a lower incidence of thrombotic cardiovascular events in high-risk patients compared with COX‑2 selective inhibitors. Furthermore, the recent demonstration that COX‑2 inhibitors (rofecoxib and celecoxib) selectively suppress the synthesis of prostacyclin (which has vasodilatory and antiplatelet properties) without inhibiting the synthesis of thromboxane (which has vasoconstrictive and proaggregatory properties) has fuelled speculation that these compounds may act as prothrombotic agents … After referring again to the mixed messages that Merck had received from its various studies, Dr Barr said that it was important to address the following questions: 1) Is there evidence to suggest that chronic therapy with naproxen, a nonselective COX-l/COX-2 inhibitor may result in improved cardiovascular outcomes compared with therapy with COX‑2 selective inhibitors such as rofecoxib? If the answer is yes, is this protective effect unique to naproxen, or consistent across the entire class of nonselective COX‑1/COX‑2 inhibitors? 2) Is there evidence to suggest that the cardiovascular findings of the VIGOR study were due to a play of chance? 3) Is there evidence to suggest that chronic therapy with COX‑2 selective inhibitors such as rofecoxib may result in an increased cardiovascular risk? 4) Based on (1) to (3), what guidance should be given to physicians and patients regarding the optimal use of COX‑2 selective inhibitors such as rofecoxib? 241 Dr Barr then turned to an explanation of the mechanism of non‑selective COX-1/COX-2 inhibitors, commencing with aspirin. He explained its antiplatelet action. He next dealt with the like action of other NSAIDs, observing that, if they were to act as "vascular‑protective" agents, "near complete inhibition of TXA2 sustained over time is needed". He referred to Protocol 061 in some detail, and concluded: Thus, this study demonstrated a gradient of antiplatelet effects among the nonselective NSAIDs and the COX-2 selective inhibitor rofecoxib: therapy with naproxen was associated with antiplatelet effects similar to those reported for aspirin (that is, near‑maximal inhibition of platelet aggregation sustained throughout its dosing interval); therapy with diclofenac and ibuprofen resulted in modest antiplatelet effects over their respective dosing intervals; and therapy with rofecoxib (and placebo) was not associated with substantive antiplatelet effects. 242 Dr Barr referred to other such studies in which similar results had been observed, and drew a distinction between NSAIDs (such as, in his view, naproxen) which had sustained, near‑maximal, COX-1-inhibiting properties over the dosing interval and NSAIDs which did not. Of the former, he said that they "may very well provide a vascular protection efficacy profile similar to that of aspirin". In the course of that discussion, Dr Barr referred to the two studies which generated the FitzGerald hypothesis, and pointed out that therapy with rofecoxib had been shown to reduce the production of the urinary metabolite of prostacyclin by 61%. He continued: It has been proposed that the observed reduction in PGI2 synthesis (without corresponding reductions in TXA2 synthesis) associated with COX-2 selective inhibitors could theoretically lead to a mild proaggregatory state in patients receiving these compounds. However, a reduction in PGI2 synthesis of 60% may not be physiologically meaningful given the observation that there were no observed increases in the incidence of thrombotic cardiovascular events in patients who received rofecoxib relative to placebo in the Protocols 078 and 091 (the placebo‑controlled studies of chronic rofecoxib therapy in Alzheimer's disease patients). 243 Under the heading "Cardiovascular Clinical Studies of Reversible Nonselective COX-l/COX-2 Inhibitors", Dr Barr referred to two studies which, despite confusing footnotes, appear to have been Brochier (1993) and Fornaro (1993). Again, he proposed that the data from them "suggest that nonselective COX-l/COX-2 inhibitors that generate potent, sustained COX-l inhibition have vascular‑protective properties similar to those observed with aspirin." 244 After summarising his views as to the cardioprotective effect of naproxen, Dr Barr turned to an"Assessment of the Cardiovascular Effects of Therapy With COX-2 Selective Inhibitors Such as Rofecoxib". Under that heading, he articulated, and argued the case in favour of, the following propositions: · Naproxen mediates aspirin‑like antiplatelet effects. Rofecoxib does not mediate antiplatelet effects. Thus, the reduction in the incidence of thrombotic cardiovascular serious adverse experiences in patients who received naproxen compared with patients who received rofecoxib in the VIGOR study is not surprising. · Exclusion of concomitant use of aspirin or antiplatelet agents, and the enrollment of a subpopulation of patients in whom aspirin therapy was indicated, created a study subpopulation at high risk for thrombotic cardiovascular events. · Protocol features that reinforced compliance with the protocol‑specified study medication regimen ensured a rigorous comparison of COX-2 selective inhibition and sustained, potent nonselective COX-1/COX-2 inhibition. · Selection of a rheumatoid arthritis patient population for evaluation in the VIGOR study was logical from a GI perspective, but resulted in the selection of a patient cohort whose underlying disease confers increased cardiovascular risk. Dr Barr's conclusion on this aspect was: Overall, there is strong evidence to suggest that naproxen's aspirin‑like antiplatelet effects on one hand and the absence of such effects following rofecoxib therapy were responsible for the cardiovascular findings of the VIGOR study. 245 Dr Barr next considered whether the cardioprotective effect to which he referred was unique to naproxen, or was shared by all non‑selective NSAIDs. He concluded that there was "strong evidence" that the effect was seen only in a subclass of such NSAIDs. He then considered whether the VIGOR results might be explained as a "play of chance", and concluded that they should not. In this respect, he said: Although the VIGOR protocol did not include a hypothesis to address cardiovascular findings or standardized methods for assessment of cardiovascular events, MRL had formulated a general exploratory hypothesis that therapy with nonspecific COX-l/COX-2 inhibitors and COX-2 selective inhibitors such as rofecoxib might result in differential vascular‑protective effects. This hypothesis was based on the differential effects of nonspecific COX-l/COX-2 inhibitors and the COX-2 selective inhibitors celecoxib and rofecoxib on thromboxane and prostacyclin metabolism observed in clinical pharmacology studies. Also, the Adjudication SOP was a rigorous process that efficiently identified and classified thrombotic cardiovascular events. Finally, as described above, the findings in the VIGOR study are biologically plausible, given the known benefit of aspirin/antiplatelet therapy in patients at risk for the development of thrombotic cardiovascular events and the differential antiplatelet effects of naproxen and rofecoxib demonstrated in clinical pharmacology studies (and indirectly in the VIGOR study). Overall, it is likely that the cardiovascular results of the VIGOR study represent a true difference in cardiovascular outcomes between chronic naproxen and rofecoxib therapy in a cohort of rheumatoid arthritis patients that included a subgroup of patients with an indication for chronic vascular‑protective aspirin therapy in whom such therapy was not given. 246 Dr Barr then asked the question: "Is there evidence to suggest that chronic therapy with COX-2 selective inhibitors such as rofecoxib results in an increased cardiovascular risk (i.e. compared to placebo)?" The whole of his reasoning in this respect was as follows: Although COX-2 selective inhibitors such as celecoxib and rofecoxib could theoretically generate a mild pro‑aggregatory state in some patients due to partial inhibition of PGI2 synthesis, I do not believe that it is likely that this effect contributed to the cardiovascular results of the VIGOR study. This conclusion is supported by the following observations: 1) In clinical trials that compared rofecoxib to placebo (studies in early Alzheimer's disease, a subset of studies in osteoarthritis patients), there were no differences in the incidences of thrombotic cardiovascular serious adverse experiences between treatment groups. These studies evaluated patients with the greatest baseline cardiovascular risk of all the patients evaluated in the rofecoxib clinical program. Thus, the absence of an imbalance in the incidence of thrombotic cardiovascular events in these studies argues strongly against a prothrombotic or otherwise deleterious effect of rofecoxib on cardiovascular homeostasis. 2) In clinical trials in osteoarthritis patients that compared rofecoxib with diclofenac and ibuprofen, a nonspecific COX-l/COX-2 inhibitor without sustained, near‑complete inhibition of platelet aggregation, there were no differences in the incidences of thrombotic cardiovascular serious adverse experiences between treatment groups. Again, the absence of an imbalance in cardiovascular event rates between rofecoxib and its comparators is reassuring. 3) The absolute rates of serious thrombotic cardiovascular serious adverse experiences were similar in patients treated with rofecoxib in both the Phase IIb/III osteoarthritis combined analyses and VIGOR, suggesting that the difference between rofecoxib and naproxen in VIGOR was driven by a reduction in events in the naproxen group rather than an increase in event rates in the rofecoxib arm. Dr Barr went on to conclude that there was "no evidence to suggest that therapy with rofecoxib is prothrombotic", because CVT event rates were comparable in trials that compared rofecoxib to placebo or to non-selective NSAIDs with modest antiplatelet properties, and the absolute CVT event rates observed in the VIGOR study were comparable to those observed in the Phase III osteoarthritis program. He recommended that the Product Information contain "general guidance" to physicians and other health professionals which reflected that conclusion. 247 The next thing that happened was the making, on 3 July 2001, of a clinical evaluation report within the TGA. The clinical evaluator noted that MSDA had sought amendments to the Vioxx Product Information in the following areas: · the addition of an introductory statement under the heading "gastrointestinal safety"; · the inclusion of a description of the VlGOR study in the "Clinical trials" section and the inclusion of the results; · modification of the "precautions section"; · modification of the "adverse reactions section". 248 Of Dr Barr's report, the clinical evaluator said: The review of the cardiovascular effects was particularly helpful. The author pointed out that the effects of rofecoxib on cardiovascular events was [sic] likely to be real, and possibly due to the lack of platelet inhibition. He suggested that the patient population in the VIGOR study was more at risk of cardiovascular events and was not treated with prophylactic aspirin, and this combination of factors lead to the excess of cardiovascular events in the rofecoxib group. I do not agree with his assessment of the likelihood of increased risk as it is a rheumatoid arthritis population rather than osteoarthritis (ie not as old). However, the expert does include some usefu1 recommendations about the potential need to treat at risk patients with low dose aspirin as well as rofecoxib; unfortunately, there are no data in this dossier to support the safety of this combination. The clinical evaluator noted that - … the adverse reactions section that is proposed makes no mention of the cardiovascular event data, which in my opinion, is completely unacceptable, particularly given the comments of Merck's own expert report! He or she recommended that the cardiovascular results of VIGOR should be set out in more detail than apparently MSDA had proposed, with a cross‑reference to the "Adverse effects" section. In the "Precautions" section, it was proposed that there be a new paragraph in the following terms: In the VlGOR study, treatment with rofecoxib was associated with a higher incidence of cardiovascular events than treatment with a non‑selective COX-1/COX-2 inhibitor, naproxen. These events included hypertension, the development of peripheral oedema, cardiac failure and myocardial infarction. It is possible that this difference was due to lack of effect on platelet aggregation in a population that is potential [sic] at increased risk of cardiovascular events (although the population in the VIGOR study was not generally at increased risk.) It is recommended that patients who are taking rofecoxib for extended periods should be assessed for cardiovascular risk and consideration may need to be given to the concomitant use of low dose aspirin. However, the safety of this combination of treatments has not been established, and physicians should assess the likely benefits and risks of long term rofecoxib therapy carefully. 249 The clinical evaluator expressed his or her conclusions as follows: The VIGOR study contains important data that should be included in the product information document. It obviously is insufficient to establish efficacy for the indication 'rheumatoid arthritis' but this is not a major concern given that the major focus of the study is a question of comparative safety. Provided the changes to the draft PI that are listed above are included, the application could be approved. The issue of concern that is not adequately resolved by the study and that may need to be the subject of further consideration by ADRAC is the question of the serious cardiovascular events. On the basis of these data, it is clear that the company should be asked to comment on the overall risk/benefit of rofecoxib, and that there needs to be ongoing monitoring of the cardiovascular effects of this drug. Mr Back explained that "ADRAC" is the Adverse Drug Reactions Advisory Committee, a subcommittee of ADEC. He accepted that the marketing staff within MSDA would have been aware of the doubts expressed by the evaluator. 250 On 2 August 2001, the TGA wrote to MSDA enclosing a copy of the summary and "proposed action" prepared by the delegate who was to decide the outcome of MSDA's application of 12 January 2001. The delegate, Dr Christine Anantharajah, referred to Dr Barr's report and said that the osteoarthritis, Alzheimer's disease and rheumatoid arthritis studies on which he had relied had not been evaluated or were then under evaluation and continued: Hence, [Dr Barr's report] is of minimum benefit to this application. The claim that the excess cardiovascular events in the rofecoxib group could be explained by the cardioprotective effect (due to the antiplatelet properties) of naproxen is not supported, as, 1. There are no prospective placebo controlled studies of naproxen that show that transient inhibition of platelet aggregation is effective in decreasing the risk of cardiovascular events. 2. The effect size of naproxen in reducing CV thrombotic events relative to rofecoxib in the VIGOR study (58%) exceeds the effect size of aspirin compared to placebo in other trials (25% to 30%) … Having noted the recommendation of the clinical evaluator, Dr Anantharajah provided her own comments, which included the following: 4. The findings relating to cardiovascular adverse events need to be included in the PRECAUTIONS section of the PI. Low dose aspirin is recommended for those taking rofecoxib over extended period of time to address the increase in thrombotic effects. This is supported by the evaluator. However, I do not recommend this as there are no data to support this claim. The sponsor should generate long term data on low dose aspirin with rofecoxib prior to making suggestions in the PI about concomitant therapy. 5. There should be a statement that long term therapy is not recommended for those with a history of cardiovascular disease, especially, as the VIGOR study excluded those with cardiovascular disease and those requiring low dose aspirin for cardioprotection. The excess reports of cardiovascular thrombotic events in the rofecoxib treated group also supports this statement. 251 Mr Back accepted that the delegate disagreed with MSDA that the most likely explanation for the VIGOR cardiovascular results was the beneficial effect of naproxen. He said that no‑one in MSDA had undertaken any investigation as to whether the naproxen effect was greater than the corresponding aspirin effect; and nothing was put to the TGA to demonstrate that naproxen had anti‑thrombotic effects substantially greater than aspirin. 252 On 10 September 2001, MSDA submitted to the TGA its "Pre‑ADEC Response", in which it commented on the reports of the Clinical Evaluator and Dr Anantharajah. The response as such reiterated MSDA's interpretation of the VIGOR results, in the light of the other data which had been referred to by Dr Barr. However, MSDA accepted the recommendation that a new passage of text about the cardiovascular results of the VIGOR trial be inserted into the "Precautions" section of the Product Information. It proposed the following: Cardiovascular Effects A large clinical trial in rheumatoid arthritis patients has compared the long‑term safety of rofecoxib 50 mg once daily (twice the maximum recommended dose) and naproxen 500 mg twice daily. The rate of serious cardiovascular thrombo‑embolic adverse events was significantly lower in patients receiving naproxen than in the rofecoxib group: 0.70 events per 100 patient‑years compared with 1.67 events per 100 patient‑years. In other controlled clinical trials, spontaneous reports of these cardiovascular events were similar between VlOXX and non‑selective NSAID comparators. The difference in antiplatelet activity between some COX-1 inhibiting NSAlDs and COX-2 selective inhibitors may be of clinical significance in patients at risk of thrombo‑embolic events. 253 At its meeting on 4‑5 October 2001, ADEC resolved that there should be no objections to the inclusion of the VIGOR findings in the Product Information for Vioxx, subject to the finalisation of the terms thereof, which should include a statement to the effect that long‑term therapy was not recommended for those with a history of cardiovascular disease, and should not include a recommendation that low‑dose aspirin be used by patients taking Vioxx over an extended period of time. 254 On 15 October 2001, the TGA made a s 31 request to MSDA which, relevantly for present purposes, required the amendment of the draft Product Information submitted on 10 September 2001 by the inclusion of a statement that "long term therapy is not recommended for patients with a history of cardiovascular disease". 255 On 17 October 2001, Mr Back faxed a copy of the ADEC resolution and the s 31 request to Ms Bea Loren, the labelling scientist at Merck, whose role was to co‑ordinate the scientists in the Merck group in developing the worldwide physician circular, the group's core data documents and each of the individual country's Product Information documents. In a contemporaneous email, Mr Back drew attention to the respects in which ADEC had required changes in the Product Information as submitted by MSDA. In a reply of 19 October 2001, Ms Loren said: Well, I think, and as you suggest, we should keep the concom aspirin use, given that this is in the Interaction section and is not intended to be a recommendation. It's a clinpharm statement. The CV sentence is probably more difficult. Do you think we have a chance to argue against the inclusion of such wording? Especially the non recommendation for "long term therapy" does not seem to have a justification on the basis of the data. And if we eliminate this part, what's left is already said in the previous sentence (more or less). How long can we negotiate the label? Shall we have a teleconf to outline our strategy? In a response to Ms Loren of the same date, Mr Back said that he did not think that MSDA would be able to argue against the inclusion of the recommendation against long term therapy, adding that both the clinical evaluator and the delegate, as well as ADEC itself, had requested it. He concluded: "We should try to play with the wording to make it more palatable." Mr Back denied that he meant "palatable" in a marketing sense, referring to Ms Loren's objective to standardise labelling across the world. 256 On 2 November 2001, MSDA responded to that request, but proposed only that the following be added to the draft of 10 September: "Physicians should assess the importance of these data for an individual patient when prescribing long term therapy with a COX-2 inhibitor". In the letter in support of that proposal, MSDA said: At present, the cardiovascular findings in the VIGOR stand without an established explanation. The Company believes that the preponderance of available data strongly suggest the imbalance in thromboembolic events stemmed from cardioprotective properties of naproxen, lacking with rofecoxib. Plausibility comes from known, sustained, inhibitory effects of naproxen, in comparison with many other nonselective NSAIDs, on platelet aggregation, and the VIOXX meta‑analysis data showing no increased risk of thromboembolic cardiovascular events for rofecoxib, compared with placebo or a non‑naproxen NSAID group of comparators (ibuprofen diclofenac, and nabumetone, none of which imparts sustained inhibitory effects on platelets). Mr Back confirmed that this was MSDA's view at the time. However, he also accepted that there was nothing that he had been given which would suggest that any cardioprotective effect of naproxen was substantial enough to explain the VIGOR results. He accepted that, within MSDA at the time, while it was considered that the cardioprotective work of naproxen was the most likely explanation for the VIGOR results, there was nonetheless a view that a pro‑thrombotic tendency of Vioxx was a plausible alternative explanation. In the course of cross‑examination, it was put to him that, by advancing only the naproxen explanation, MSDA was misleading the TGA. He rejected that. He pointed out that the delegate had made it quite clear that she understood the pro‑thrombotic explanation, and that MSDA was in effect countering that with its own view of the science. 257 It appears that, at about this time, a new delegate was appointed in place of Dr Anantharajah. It was Dr Andrew Pengilley. He telephoned Mr Back on 6 November 2001, and sought a revision of the proposed text for the PI by the inclusion of the words "at risk for cardiovascular disease". Mr Back informed Ms Loren of this wording, and her reaction was that the expression "cardiovascular disease" was far too broad. The following day, Mr Back responded to Dr Pengilley with the following proposal: "Physicians should assess the importance of these data for an individual patient at risk for cardiovascular thrombo‑embolic events, if considering long term therapy with a cox-2 selective inhibitor." Dr Pengilley called again the same day to inform Mr Back that the Product Information had been approved. Formal approval was given on 16 November 2001. 258 In the "Precautions" section of the Product Information as approved on 16 November 2001, a new sub‑heading was introduced, "Aspirin", under which it was stated that Vioxx was not a substitute for aspirin for cardiovascular prophylaxis because of its lack of effect on platelets. Then another new sub‑heading, with its corresponding text, was introduced as follows: Cardiovascular Effects A large clinical trial in rheumatoid arthritis patients has compared the long‑term safety of rofecoxib 50 mg once daily (twice the maximum recommended dose) and naproxen 500 mg twice daily. The rate of serious cardiovascular thrombo‑embolic adverse events was significantly lower in patients receiving naproxen than in the rofecoxib group: 0.70 events per 100 patient‑years compared with 1.67 events per 100 patient‑years. In other controlled clinical trials, spontaneous reports of these cardiovascular events were similar between VIOXX and nonselective NSAID comparators. The difference in anti platelet activity between some COX-l inhibiting NSAIDs and COX-2 selective inhibitors may be of clinical significance in patients at risk of thrombo‑embolic events. Physicians should assess the importance of these data for an individual patient at risk for cardiovascular thrombo‑embolic events, if considering long term therapy with a Cox-2 selective inhibitor. From then until the withdrawal of Vioxx in September 2004, there were further amendments made to the Vioxx Product Information, but none that require mention in the present context.

The Marketing of Vioxx in Australia 259 The applicant led a deal of evidence as to the means by which Vioxx was marketed in Australia by MSDA. For the most part, this was done by the tender of documents discovered by MSDA. Many of those documents were provided by the applicant to one of his expert witnesses, Prof Robert Donovan, Professor of Behavioural Research at the Centre for Behavioural Research in Cancer Control, Division of Health Sciences, Curtin University; Director, Mentally Healthy WA, Division of Health Sciences, Curtin University; Co-Director, Social Marketing Research Unit, School of Marketing, Curtin University; and Professor of Social Marketing in the School of Marketing, Curtin Business School, Curtin University. Prof Donovan referred to a number of those documents in his report. For reasons explained at paras 855‑858 below, I found both the documents and the evidence of Prof Donovan of limited utility. In this part of my reasons, I shall undertake a purely factual survey of the main classes of documents which related to the marketing efforts of MSDA, and to the means employed generally to promote Vioxx. It is not intended to be an exhaustive survey: such an undertaking would burden these reasons with much unhelpful material. It is, however, intended to draw attention to the documents which, for reasons which will become clear, are relevant on any view, and to provide a factual context against which the applicant's marketing case may be assessed. 260 The evidence establishes that MSDA used a variety of means of communication to promote awareness of, and ultimately the use of, Vioxx. However, the respondents did not themselves lead evidence of any communication − written or oral − made individually to any doctor, pharmacist or health care professional. They called two witnesses in response to the applicant's marketing case. The first was Ms Penelope Dobson. Between March 1999 and June 2001, she was one of two Sales & Marketing Directors employed by MSDA. In June 2001, as a result a restructure within MSDA, the sales and marketing functions were split. The marketing department was divided into a number of "franchises", to each of which were allocated certain products. Ms Dobson became Marketing Director for the "Musculoskeletal Franchise", which was responsible for the marketing of Vioxx. She held this role until January 2003, after which she was not involved in the day to day operation of MSDA's marketing division. The other witness was Mr Keiran McAuley, Senior Sales Manager (Hospital) for the National Specialty Division at MSDA. In early 2001 when Vioxx was launched, he was a representative in the "Musculoskeletal Team", promoting prescription medicines to general practitioners in the Mornington Peninsula and surrounding areas in Victoria. On 1 April 2001, he was promoted to the position of Sales Manager Primary Care for Victoria and Tasmania, which new position gave him responsibility for the Musculoskeletal Team for the whole of Victoria. The evidence of Ms Dobson and of Mr McAuley was concerned with the practices, procedures and protocols followed by the marketing and sales departments of MSDA. To that extent, it was illuminating and useful, in ways to which I shall refer. It did not, however, descend to the details of communications actually made to a third party in relation to Vioxx. 261 That is not to say that there was no such evidence. It seems that MSDA discovered a great many documents that generally bespoke the existence of such communications, and in some cases I am able to infer that communications in corresponding terms were in fact made. However, as will become apparent, in at least one important respect I have not been satisfied that a generic pro‑forma document discovered by MSDA was in fact sent as apparently intended. 262 Doubtless reflecting the position of Vioxx as a prescription‑only medicine, the focus of MSDA's marketing activities, at least to the extent revealed in the evidence, was upon medical practitioners. As I shall mention below, there were also some communications with pharmacists. There was no evidence of promotional activities directed towards other health care professionals. Save for one media release (the release or publication of which was not proved) there was no evidence of such activities directed towards the public generally in Australia. Clearly the interface with doctors was the most important area for the promotion of Vioxx, and both sides conducted their cases in court by reference to that assumption. 263 The most direct means by which MSDA communicated with medical practitioners generally was the transmission from time to time of pro‑forma "Dear Doctor" letters. There were five such letters in evidence. Because they are few in number, I shall refer to the terms of each of them. There is also a question as to which of these letters was in fact sent to practitioners. All five were tendered by the applicant, but not always for the same purpose. Clearly the applicant was in no position to give evidence that a particular letter had been sent, and none of the three general practitioners called gave evidence that he had received one. In the case of four of the letters, the respondents submitted that they were "final approved pieces" which were "in fact made available to the prescribing community". I take this to be a submission that the documents in question were not merely drafts or versions in the course of preparation, but had official approval to be sent, and were in fact sent, to medical practitioners. 264 The first "Dear Doctor" letter in evidence was that to which I have referred in para 226 above. It was sent in October 2000. Ms Dobson described it, not inaptly in my view, as an "announcement letter". The respondents included this letter on their list of "final approved pieces". The letter was tendered by the applicant through Ms Dobson (in the course of cross‑examination). It was effectively common ground that the letter was sent to medical practitioners generally. 265 In August 2001, Mukherjee (2001) was published in the Journal of the American Medical Association. In evidence are two similar letters, each from MSDA and using the greeting "Dear Healthcare Provider", dated 28 August and 3 October 2001. The letters took issue with the scientific basis of the article with respect to VIGOR. The first letter stated: The reported differences in the incidence of myocardial infarctions (MI) between Vioxx and naproxen in the … VIGOR trial …, which is the main focus of the JAMA paper, can be explained by naproxen's aspirin‑like ability to inhibit platelet aggregation and reduce cardiovascular events. Unlike some NSAIDs, Vioxx does not inhibit platelet aggregation (a desirable attribute when trying to avoid gastrointestinal adverse events) and would not be expected to reduce cardiovascular events as has been shown with naproxen in the VIGOR trial. The corresponding paragraph in the second letter stated: The main focus of the JAMA article relates to the reported difference in the incidence of myocardial infarction (MI) between Vioxx and naproxen in the … VIGOR trial … An explanation for this difference is based on naproxen's ability to inhibit thromboxane A2 synthesis and platelet aggregation. As a result of this activity, naproxen may reduce the incidence of cardiovascular events in a manner similar to that observed with aspirin. Unlike some NSAIDs, Vioxx does not inhibit platelet aggregation (a desirable attribute when trying to avoid gastrointestinal adverse events) and would not be expected to reduce cardiovascular events. Towards the end of both letters, it was stated: Patient safety is of paramount importance to MSD. We routinely review data from completed studies and clinical use of our products, and consistent with this approach, we will continue to evaluate such data on agents that selectively inhibit COX-2 to enhance our understanding of these medicines and assess the potential value of future trials. These letters were tendered without any comment of substance by the applicant, and without objection by the respondents. They were both on the respondents' list of "final approved pieces". It was, I consider, common ground that they were sent to medical practitioners generally. 266 The next "Dear Doctor" letter in evidence bore the date December 2001. It corresponded with the then recent amendment of the Vioxx Product Information to refer to the results of the VIGOR trial. It was unsigned, although over the name of the Medical Director of MSDA. It was in the following terms: Merck Sharp & Dohme wishes to advise that the Product Information for VIOXX (rofecoxib, MSD) has been updated and includes new information of current interest. - Results of VIGOR (VIOXX Gastrointestinal Outcomes Research) Trial - landmark study in over 8000 rheumatoid arthritis (RA) patients The results from the VIGOR study confirmed the GI outcomes from previous studies and demonstrated a significant reduction in serious GI complications for patients treated with VIOXX compared to naproxen. The results from VIGOR also raised the question as to whether COX-2 selective inhibitors increase the thrombotic risk of patients with RA. A recent meta‑analysis, which included a number of studies in RA patients, showed that except in the comparison to naproxen (in VIGOR), VIOXX was not associated with an excess of thrombotic events compared with either placebo or traditional NSAIDs (ibuprofen, diclofenac or nabumetone). Physicians should assess all patients at risk of thromboembolic events if considering long‑term therapy with COX-2 selective inhibitors. - Low-dose aspirin for cardiovascular prophylaxis Available evidence suggests that aspirin is underutilised in certain patients at risk of a cardiovascular event. To help ensure the appropriate prescribing of VIOXX and low‑dose aspirin, it is important to be aware of the following information: - VIOXX can be used with low‑dose aspirin; - Irrespective of traditional NSAID or COX-2 selective inhibitor use, low‑dose aspirin for cardiovascular prophylaxis should be considered for patients at risk of a thromboembolic event; - VIOXX is not a substitute for aspirin for cardiovascular prophylaxis. Before prescribing, please consult the accompanying full Product Information. If you require any additional information, please call our Medical Information toll‑free number …. 267 The letter of December 2001 was tendered by the applicant as part of a large bundle of documents which were the subject of comment by Prof Donovan. The respondents did not object to it, but it was not one of their "final approved pieces". Rather, they made the following submission about this and many other documents: (a) unless otherwise specified, documents are properly characterised on the basis that they are not a promotional piece nor evidence of the information about Vioxx that MSDA, in fact, made available to the prescribing community; (b) they do not evidence any departure by MSDA representatives from the [final approved pieces]; and (c) in that regard, it is not sufficient for the applicant to attempt to side‑step the direct marketing material in favour of selective reference to draft, internal or non‑Australian documents. This I take to be a submission that it had not been established on the evidence that the letter of December 2001 was in fact sent to medical practitioners. For his part, the applicant did not submit that the letter had been sent. There was no evidence (eg from a practitioner) that it had been received. As I have said (alone of the five letters here being dealt with), it was not signed. In the circumstances, I am not prepared to find that it was sent to medical practitioners generally. 268 The fifth and final letter in this sequence was dated March 2002, and had the purpose of announcing that Vioxx had been approved by the TGA for the symptomatic treatment of rheumatoid arthritis. Amongst other things, the letter stated: In two efficacy studies involving approximately 2,000 patients with RA, Vioxx demonstrated a significant reduction in the number of tender/painful joints and number of swollen joints versus placebo. Vioxx 25 mg and naproxen 500 mg bd showed generally similar efficacy. The landmark VIGOR Study conducted in 8,000 patients with RA showed that serious [gastrointestinal] complications (perforations, obstructions, ulcers and bleeds) were halved with Vioxx, 50 mg od (twice the recommended dose in RA) versus the comparator NSAID, naproxen, 500 mg bd. This letter was also part of the bundle which related to Prof Donovan's evidence, but it was not referred to by him. Rather, it was tendered by the applicant on the basis that it had been provided to him. There was no objection to the tender by the respondents, who accepted that it is what it purported to be. It was on the respondents' list of "final approved pieces". In the circumstances, I am prepared to find that it was sent to medical practitioners generally. 269 There were also five standard form "Dear Pharmacist" letters in evidence. Each was tendered by the applicant and described by the respondents as a "final approved piece". Consistently with the way I have approached the "Dear Doctor" letters, therefore, I infer that each of these letters was sent to pharmacists generally. I have referred to the first two at paras 227 and 228 above. 270 The third "Dear Pharmacist" letter was dated August 2002, and reminded recipients that Vioxx was available as an oral suspension and in tablet form, at doses of 12.5 mg and 25.0 mg daily. The letter continued: VIOXX is indicated for the symptomatic treatment of osteoarthritis and rheumatoid arthritis. Before dispensing VIOXX Oral Suspension, please review the enclosed product information. We are aware that Naprosyn … suspension is being discontinued this year. As some of these patients may be switched to VIOXX Oral Suspension, you may like to ensure that your dispensary is stocked with a sufficient supply of this product. Merck Sharp & Dohme is adequately stocked with VIOXX Oral Suspension in order to meet the expected increase in demand. To order VIOXX Oral Suspension, please contact your pharmacy wholesaler. If you would like any additional information about VIOXX, please contact your representative. 271 The fourth "Dear Pharmacist" letter was not dated, but, from the MSDA code endorsed on it, I infer that it too was sent around August 2002. Enclosed with the letter was an "arthritis information kit", which included a copy of the Vioxx Product Information and Consumer Medicine Information. Otherwise, the letter contained nothing of apparent relevance to the present proceeding. 272 The final "Dear Pharmacist" letter was dated 6 September 2004 and is, for present purposes, somewhat more controversial than the other four. It was over the hand of the Medical Director of MSDA, and read as follows: You may have seen or heard media coverage this week of a story about the risk of heart attack occurring in patients taking VIOXX® (rofecoxib). More than 84 million patients worldwide have been prescribed VIOXX since the product first became available in 1999. VIOXX has been extensively studied with more than 24,000 patients being treated with VIOXX in randomized, controlled clinical trials. Based on all the data available, Merck stands behind the efficacy, overall safety profile and cardiovascular safety profile of VIOXX. A number of health agencies around the world have reviewed the data on Cox-2 inhibitors and have drawn similar conclusions - these agencies include the Therapeutic Goods Administration (TGA) and the Pharmaceutical Benefits Advisory Committee (PBAC) in Australia, the Food and Drug Administration in the USA, and the Committee for Proprietary Medicinal Products at the European Commission. In April 2004, the European Commission announced its adoption of an opinion confirming that Cox‑2 selective inhibitors, including VIOXX, have a positive balance of benefits and risks based on a comprehensive review conducted by the Committee for Medicinal Products (now referred to as the Committee for Medicinal Products for Human Use). This opinion was supported by an extensive analysis of data provided by Merck confirming the overall safety profile, including gastrointestinal and cardiovascular tolerability of VIOXX. The analysis was based on a review of 27 VIOXX studies. Also this year, the Australian PBAC completed its two‑year review of Cox-2 selective inhibitors. They concluded that the data do not support an increased risk of cardiovascular tolerability for patients on rofecoxib (VIOXX) compared with traditional NSAIDs. The Product Information for VIOXX states: "The difference in antiplatelet activity between some COX-1 inhibiting NSAIDs and COX-2 selective inhibitors may be of clinical significance in patients at risk of thrombo‑embolic events. Physicians should assess the importance of these data for an individual patient at risk for cardiovascular thrombo‑embolic events, if considering long term therapy with a Cox‑2 selective inhibitor." Patients at risk of cardiovascular disease should be on low dose aspirin. This is independent of whether they are taking a Cox-2 selective inhibitor such as VIOXX or Celebrex or a traditional NSAID. The Product Information for VIOXX states that "VIOXX can be used with low dose aspirin. At steady state, VIOXX 50 mg once daily had no effect on the anti‑platelet activity of low-dose (81 mg once daily) aspirin, as assessed by ex vivo platelet aggregation and serum TXB2 generation in clotting blood. In 3 six‑week, double‑blind, randomised clinical trials, VIOXX 12.5mg or 25mg was administered to osteoarthritis patients concomitantly with low-dose aspirin (less than or equal to 325mg daily) (N = 161). No clinically important differences were noted for users of VIOXX plus aspirin versus VIOXX alone in the overall incidence of clinical adverse experiences. However, concomitant administration of low dose aspirin with VIOXX may result in an increased rate of GI ulceration or other complications, compared to use of VIOXX alone. Because of its lack of platelet effects, VIOXX is not a substitute for aspirin for cardiovascular prophylaxis." Finally, it should be noted that the major finding from the VIGOR study, a prospective study designed to evaluate the gastrointestinal safety of this new class of therapy in comparison to the traditional NSAID, naproxen, was that VIOXX was associated with significantly fewer clinically important upper and lower gastrointestinal events. This was the prespecified endpoint of the VIGOR study. The PBAC review into Cox‑2 inhibitors determined that VIOXX does have substantial advantages in gastrointestinal tolerability compared to traditional NSAIDs. Again, a copy of the Product Information was included with the letter. As pointed out by the respondents, this letter was not the subject of evidence by any witness. It was not put to any of the respondents' witnesses. It was listed, without further comment, in the applicant's final submissions as an instance of MSDA having failed to provide any adequate information, advice or warning to health care professionals that consumption of Vioxx materially increased the risk of suffering the pleaded cardiovascular conditions until the withdrawal of the product in October 2004. 273 The position ultimately reached in relation to the "Dear Doctor" and the "Dear Pharmacist" letters is that I would find that, with the exception of that dated December 2001, those letters were sent to doctors and pharmacists in Australia generally as apparently intended. Whether any particular letter was received by the doctor or pharmacist whose position may become relevant to the circumstances of a particular group member is, however, another question, the answer to which cannot be regarded as conclusively tied to that finding. My provisional view is that the finding would in effect place the evidentiary onus on any party who desires to contend that, in relation to a particular doctor or pharmacist, the position is not as it appears to be. I make an exception in the case of the letter dated December 2001 because the finding I make is that it was not sent: any further debate on the question whether it was received by a particular doctor would be inconsistent with that finding. 274 Another important means by which MSDA communicated with general practitioners involved the use of senior members of the profession. Ms Dobson said that the use of speakers as part of an "education cascade" or a "communication cascade" was a commonly-used approach by MSDA and other companies. By that she meant, for example, that MSDA would have a small group of usually very senior physicians who had been involved in clinical trials with a particular product. There would then be a slightly larger group of senior physicians who were, perhaps, specialists in the area. The next level down would be other specialists, after which there would be general practitioners. Asked how the senior physicians were identified, Ms Dobson said that that was usually done by MRL. Then the other senior physicians would almost "self‑select in a therapeutic area", in the sense that they were usually very eminent, were very well‑published, and held important university appointments. Asked how the information and opinions would "cascade to the rest of the profession", Ms Dobson said that MSDA would often ask the senior physicians if they were prepared to be part of an education program, such as by acting as speakers, by authoring slide kits, or by speaking to groups (large or small) of general practitioners. She agreed that the ultimate objective was "to get word about the product out to the broadest market, within the profession". 275 In 1999, MSDA established an Arthritis Advisory Board. That companies such as MSDA should have such boards seems not at all uncommon. Dr Bertouch (to whom I refer in para 277 below), for example, either had been or was (ie at the time of giving evidence) a member of nine industry advisory bodies, including that established by MSDA. The Board was to consist of 11 key specialists from around Australia, and had the following objectives: - To ensure ongoing high profile for VIOXX in specialist arena - To ensure a group of highly trained specialists are available to communicate VIOXX messages other specialists and GP's. - To help to block Searle/Pfizer activities - To assist with advising MSDA on other issues as required. The applicant submitted that the Board was "part of the marketing budget" and, whether or not that was so as a matter of MSDA's internal accounts, on any view significant effort was put into the education of Board members apparently with a view to them being well‑informed about Vioxx for the achievement of the above objectives. According to the Vioxx "launch" marketing plan for 1999‑2000, the first official meeting of the Board was to be held on 31 July 1999, and after which − … the entire Advisory Board will be sponsored to travel to the William Harvey Research Conference on the "Potential of COX-2 Inhibition" to be held in Lisbon, Portugal from the 18th to the 20th October 1999. This will then be followed by a visit to MRL to meet with some of the key VIOXX researchers. This activity is designed to fully prepare the Advisory Board for the launch of VIOXX and to gain their ongoing support for MSDA into the future. 276 The applicant submitted that, in addition to the objectives referred to above, there were "unofficial objectives" which MSDA had for the Board. In this regard, he relied on an email said to have been sent by Ms Annette Wakeford on 10 June 1998. Ms Wakeford was a product manager with MSDA, and she did send an email on that day. However, hers was an insignificant email in response to a more important one from Mr Sumeet Sud, the Asia Pacific product manager for Vioxx. It was Mr Sud's email that proposed the adoption of "unofficial objectives", but they were not for the Advisory Board in Australia. They were for an Asia Pacific Advisory Board which had just then been established. There was no evidence that MSDA harboured such unofficial objectives for the Australian Board. Indeed, when Mr Sud's list of objectives was put to Ms Dobson, she said that she was unaware of it, and she strongly disapproved of the notion of having unofficial, uncommunicated, objectives in the case of the Board. She said: I don't think Merck … - the way we conduct ourselves or the way we try to conduct ourselves [-] would support this. Sumeet put this down. I don't think many people would have supported having something unofficial. … What I am reacting to is the sort of notion that this is unofficial. This could have been discussed quite openly with them and they would have either agreed or not, so whether they did these things or not is their choice in some cases. In the circumstances, I am not prepared to find that MSDA had the unofficial objectives for the Australian Board as proposed by the applicant 277 Two members of the Board were called by the respondents. The first was Dr Jim Bertouch, consultant rheumatologist and Chairman of the Department of Rheumatology at Prince of Wales Hospital, Sydney. He answered questions about the public statements he had made on coxibs. He agreed that he came to view Vioxx as a highly specific COX-2 inhibitor that offered efficacy comparable to traditional NSAIDs and greater gastrointestinal safety. He stated that proposition publicly at lectures, forums and the like, not in the sense of talking about Vioxx as such, but in the sense of talking about the whole range of anti‑inflammatory medications that were available, and what the advantages or disadvantages of each might have been. However, he considered that Vioxx was better than Celebrex with respect to gastrointestinal tract outcomes, and said so at symposia, conferences and the like. He wrote positive articles about coxibs as a class of drug, and accepted that it was likely that he would have said that Vioxx was superior to Celebrex in those ways. He never sought to persuade practitioners that Vioxx ought to be part of their formularies. He was never asked by MSDA to make public statements, media statements or the like in relation to Vioxx. He was also on the Celebrex advisory board, and did not remember "singling out one agent and promoting that agent or in some other way putting it across as being the agent that I thought was the best one …" He did not recall being involved in training sessions for MSDA representatives, but allowed that he may have done so. Asked whether he was invited to speak to practitioners at dinners, for example, and to make presentations concerning Vioxx, he replied: I do a lot of talks for GPs. In fact, that's part of the process, I suppose, of being appointed to a teaching hospital, that one would talk to groups of GPs in the local community, apprise them of what was happening in the field, but one would not do a presentation just about a single product. One would always balance that with whatever else was in that field. So if I did talks to GPs about anti‑inflammatory agents or to medical students or to people training to be physicians, it would have been usually across the board talking about the broad area of those things rather than an individual agent. Pressed to recall whether, because of his views about the gastrointestinal superiority of Vioxx, "those present would have understood that you thought Vioxx was the best choice in that area", Dr Bertouch said: Yes, but I guess there would be some qualifications for that because Celebrex was also a good agent to use as far as anti‑inflammatory effect was concerned and it did show almost a gastrointestinal advantage over its comparators but didn't quite get there. So it wasn't that it was no good but it wasn't quite as striking in the sense of the results, so far as the gastrointestinal tract was concerned. 278 The other member of the Board called by the respondents was Prof Neville Yeomans, Foundation Dean of Medicine, University of Western Sydney. He agreed that he had given speeches at meetings, symposia and the like concerning the increased gastrointestinal safety of Vioxx. He did not provide information or advice to regulatory authorities or pricing authorities on behalf of MSDA, but there were instances in which he, as a member of the Board, participated in discussions on such questions as, for example, whether certain data were "robust in terms of [gastrointestinal] safety". He wrote "at least two or three articles … about Vioxx". He was not aware whether MSDA had used the things he had written for promotional purposes, but he accepted that it may have. He talked at a number of meetings - often in the context of NSAIDs generally rather than of robecoxib as such - about ways of protecting against the damage to the stomach. He did so "in many fora and overseas meetings". He provided a gastrointestinal opinion for inclusion in a CD‑ROM which featured Prof Weir, who was brought to Australia by MSDA. He did not recall having provided training to MSDA representatives. In re‑examination, Prof Yeomans denied that he was acting as the mere mouthpiece for MSDA. Indeed, the way he responded to the question which was designed to elicit that denial gave me the distinct impression that he felt a sense of affront that anyone might consider that he was so acting. He said that, as an academic, his job was to teach people and that, like any specialist, he had a job to teach his colleagues in his area of specialty. It was not suggested on behalf of the applicant that I should reject this evidence. 279 The opinions of members of the Board were also used by MSDA in "advertorials" on occasions. There were three examples of such advertorials in evidence (in referring to them as "examples", I do not mean to imply a finding that there were others − the evidence would not permit the making of such a finding). They all appear to have been produced in the period around October/November 2001. Save in one respect, the applicant's submissions went no further than to note that these advertorials confirmed "statements supportive of Vioxx" made by the Board members concerned. The exception related to a statement by A/Prof Henry Krum, Head of the Clinical Pharmacology Unit at the Department of Medicine, Alfred Hospital (but said in the applicant's submissions to be a cardiologist) that Konstam (2001) was "a more rigorous meta‑analysis of rofecoxib trials" than Mukherjee (2001). I did not understand the applicant, however, to have proposed that A/Prof Krum did not in fact hold that view, or that it was a view which was not legitimately open to him or to anyone else. Reference to the advertorials did not advance the applicant's case against MSDA. 280 Although the applicant made much of what he proposed was the use of senior specialists and other opinion leaders in the profession as part of MSDA's promotional efforts for Vioxx, his submissions focused upon process rather than content, as though I should consider that the existence of such a modus operandi on the part of MSDA was of itself indicative of culpability apropos the causes of action on which he sued. There was, however, no evidence of any actual communication made by any of these specialists or opinion leaders that was other than a conscientious statement of his or her views as a scientist made independently of the commercial interests of MSDA. I accept that the enrolment of such specialists and opinion leaders was done by MSDA to spread the good word, as it were, about Vioxx among the prescribing fraternity, but this practice was quite innocuous apropos the applicant's causes of action, and seems to have been regarded by the people concerned as legitimate and conventional for a drug manufacturer such as MSDA. 281 The next important means by which MSDA communicated with general practitioners, and the means which most obviously involved sales and marketing as such, was by way of its sales representatives. The MSDA representatives visited doctors' rooms to advance the cause of Vioxx (and of other products supplied by MSDA) in face‑to‑face discussion. Since doctors themselves did not (at least in the typical situation) purchase Vioxx, such representatives were not engaged in direct selling, but their broad purpose was to influence the prescribing practices of those whom they visited, and their role was, in that sense, effectively that of sales representatives. 282 There seems generally to have been every attempt made to ensure that a consistent marketing message was conveyed about Vioxx (and, I infer, about other drugs being marketed by MSDA). Mr McAuley said that sales representatives had various different categories of resource materials provided to them by MSDA. A standard form of document provided to the representatives was the "Detail Aid", described by Mr McAuley as a brochure - which might include graphs or charts based upon clinical studies − designed to be used by representatives as a framework for discussion with health care providers, usually containing visual aids to help explain product information. Mr McAuley said that detail aids were not intended to be given to or left with practitioners, but Ms Dobson said that they might be, depending on the choice of the representative concerned. On any view, detail aids were intended to be shown to practitioners, at least to the extent necessary to facilitate the understanding of the points being made by representatives from time to time. If the respondents' schedule of evidence is to be believed, there were 39 detail aids marked as exhibits in this proceeding. 283 By reference to MSDA marketing plans, the applicant submitted that detail aids were much more than as described by Mr McAuley and Ms Dobson. For example, the plan for 2003 (prepared in November 2002) had a section headed "Tactics To Influence Brand Choice - Choose Coxibs, Initiate VIOXX And Switch To VlOXX". Within that, there was a sub‑section headed "Detail Aid For Switching To VIOXX, Targeting Medicated But Not Dissatisfied Patients (Patient I) - Musculoskeletal team". The purpose of the detail aid was described as follows: The detail aid will present data that aims to provoke the doctor to re‑examine his [osteoarthritis] patients and assess their level of satisfaction with their current medication. Patient photographs will be used to facilitate the doctor thinking about actual patients rather than focussing on clinical data. Breakthrough pain and/or GI safety and tolerability will be utilised as the driving reason behind the need to reassess patient satisfaction. Again, satisfaction will be the central message for VIOXX with strength, safety and simplicity being drivers of the satisfaction. However, the applicant did not draw attention to any statement in a detail aid as such which was false or misleading. Although the above text from the marketing plan, and similar statements in some other material MSDA documents, suggest that practitioners should have the "safety" of Vioxx impressed upon them, in none of the examples admitted into evidence did a detail aid go further that to proclaim the gastrointestinal safety of Vioxx. Otherwise, the applicant's complaint about the detail aids was that they omitted to refer to cardiovascular risk, and made no mention of VIGOR. This is true, but the circumstance is relevant to the applicant's allegation that MSDA failed to warn, an allegation that was separate from his criticism of MSDA's marketing campaign. 284 The next category of marketing material referred to by Mr McAuley was the "leave‑behind" card. He described it as typically a double‑sided card that included information about a specific aspect of an MSDA medicine. It was designed to convey information in a concise format, and to serve as a ready reference for the practitioner. As the name implied, such a card was intended to be left behind with the practitioner. No submission of the applicant was based upon any leave‑behind card. 285 Another document that was produced by the marketers at MSDA was the "Objection Handling Module". Mr McAuley explained that the purpose of this document was to enable sales representatives nationally to respond to concerns raised by health care professionals with consistent and accurate information. Under cross‑examination, Mr McAuley explained the intent of objection handling modules as follows: The intent of this is to ensure that a representative truly understands the doctor's questions so they can answer those in the most appropriate way with the most appropriate materials, discussion points, whatever they need. Often you will hear a question that once you seek to understand that question a little further you get to understand the best way to answer the question for that doctor so that you actually can address potentially an underlying concern as opposed to a superficial question and that way you can either get to the end point of agreeing or disagreeing with a doctor; you can agree to disagree over the outcome of a discussion but it allows you to make sure that you are addressing that specific request. … [I]f we are able to ensure we make best use of their time with those doctors without wasting it then the objection handling model is a fantastic way to make sure you understand the question being asked properly before you provide an answer. 286 What Ms Dobson described as an "early" objection handling module was organised by reference to a series of questions, or objections, that might be posed by a general practitioner, for example. They were:

1. "I've already got Celebrex. It works and I'm comfortable with it. Why should I use Vioxx?"
2. "What about the problems that Vioxx has with an increase in cardiovascular events as shown in your own large outcomes trial (VIGOR). There were no such problems with Celebrex in their study (CLASS)".
3. "Vioxx has more renal problems than Celebrex." Or "Vioxx has more problems with causing hypertension than Celebrex." Or "Vioxx has major problems with oedema and much more than Celebrex".
4. "There are some problems with Vioxx. After all, it doesn't have an indication in rheumatoid arthritis because of its drug interaction with methotrexate."
5. "VIOXX - another sulfur drug! Why create another COX-2 that is contraindicated for patients with 'sulfa' allergies?"
6. "What about the serious drug interaction between VIOXX on warfarin?"
7. "How does VIOXX compare to NSAIDs?" It is the second objection set out above which is of present concern. The advice to the representative was, first, to clarify where the doctor had heard this information, and to clarify the "real concern" from the doctor. The following was then set out: Doctor, this is just mischief and misinformation created by Representatives of the other COX-2. Vioxx has no problem with cardiovascular disease compared to conventional NSAIDs or the other COX-2. In all clinical trials with Vioxx, overall mortality and cardiovascular mortality is low and comparable to conventional NSAIDs. Of course, Vioxx is not a substitute for low‑dose aspirin, as it has no effect on COX-l in humans even at up to 80 times the dose. Should the doctor require further clarification, the representative was advised to point out that the lower number of myocardial infarctions observed in the VIGOR trial in the case of patients taking naproxen was consistent with the COX-1 selectivity of that drug, and with its aspirin‑like ability to block platelet aggregation. It was said that Vioxx, like all COX-2 inhibitors, did not block platelet aggregation, and therefore would not be expected to have similar effects. If the doctor required even further clarification, the representative was advised to inform the doctor that the incidence of myocardial infarctions in the VIGOR trial was 0.4%, that the like figure over "the entire VIOXX clinical studies database of over 5,000 patients" was 0.6% (said to be similar to placebo and comparator NSAIDs), and that the like figure with celecoxib in the CLASS trial was 0.5%. The document continued: Based on these facts and figures, it is fair to say that VIOXX does not cause cardiovascular disease and that there is no difference between VIOXX, the other COX-2 [ie celebrex] or conventional NSAIDs. 287 The objection handling module just referred to was the subject of a letter of complaint to MSDA from Pharmacia Australia Pty Ltd (the manufacturer of Celebrex) dated 16 February 2001. The comparisons which placed Vioxx in a favourable light appropos Celebrex were objected to, as were the statements that the rate of myocardial infarction in VIGOR was similar to that reported in other studies, and that the VIGOR results were explicable by the reference to the cardioprotective effect of naproxen. As to the latter, it was pointed out in the letter that such an effect had never been shown in the public literature, and that the manufacturers of naproxen had publicly stated that they were unaware that their product had that kind of an effect. It seems that, from about this time, there was much mutual disparagement by MSDA and Pharmacia of each other's coxibs in the marketplace. The evidence contains a number of examples of exasperations being expressed by sales and marketing people at MSDA about the practice of Pharmacia representatives pushing the line, as it were, that the consumption of Vioxx was associated with cardiovascular risk. For their part, the MSDA representatives likewise had criticisms of Celebrex. Ultimately, a meeting between senior management from the two companies in September 2001 reached a loose consensus that they would not disparage each other's products. As minuted by Mr Back, there was general agreement that - both products have obvious superiority over NSAIDs. We should be looking at other issues, rather than putting down both products. Market is difficult at this time, pressure from PBAC over pricing, fighting each other may not be in either companies [sic] interest at this time. We also need to have a close look at how we promote the class with MOBIC about to enter. The companies also agreed "to only include comparisons to NSAIDs on the [gastrointestinal] issue". There are suggestions in the evidence that these agreements were fragile, and that MSDA at least was noticing a resumption, to some extent, of the disparagement of Vioxx on cardiovascular-related grounds by about the middle of the following year. 288 The applicant also drew attention to an objection handling module produced MSDA in response to Mukherjee (2001) which had been published in August 2001. If a practitioner were inquiring about the problems that Vioxx had with an increase in cardiovascular events, as shown in the Mukherjee article, the sales representative was advised to provide the following "answer": Dr I can understand your concern however let me reassure you that when you consider all of the available data, there is no difference in cardiovascular events between Vioxx and placebo. Vioxx is an appropriate and efficacious therapy for your patients with osteoarthritis. Dr, with regard to this article it is important to note that: 1. Compelling evidence is available that confirms that there was no difference in the overall incidence of cardiovascular events among patients taking Vioxx and placebo and between patients taking Vioxx and other non‑naproxen NSAIDs 2. Vioxx can be used in patients at risk of cardiovascular disease. Importantly Vioxx is not a substitute for aspirin for cardioprotection 3. Even the authors have conceded their analysis has "several significant limitations". The representative was advised to inform the doctor: Compelling data from a rigorous meta‑analysis of data from 19 controlled clinical studies with over 28,000 patients showed there was no difference in the overall incidence of cardiovascular events among patients taking Vioxx and placebo and between patients taking Vioxx and other non‑naproxen NSAIDs. The doctor was to be informed that the results of VIGOR were consistent with the aspirin‑like properties of naproxen, and to be reminded that aspirin itself was not allowed in the study. The doctor was to be informed that COX-2 inhibitors may be used in patients at risk for cardiovascular events, but reminded that the prescribing information for both Vioxx and Celebrex stated that they should be used with caution, and should be introduced at the lowest possible doses in patients with concomitant conditions such as hypertension or heart failure. That information (again, for both products) also clearly stated that they were not a substitute for aspirin for cardio‑protection. The document concluded as follows: Extensive cardiovascular data already exist on Vioxx and these data - which were not incorporated into the authors' analysis - suggest that there is no increase in the risk of cardiovascular events as a result of treatment with Vioxx. 289 I shall refer also at this stage to the MSDA marketing plans that were developed during the period that is relevant to the present case. I do so merely to give an impression of the headline marketing messages which were proposed by those plans, and to touch upon the way that issues of safety, and of cardiovascular safety in particular, were dealt with. As I explain in para 858 below, however, evidence of the existence of such plans, and the formulation of those messages, can be regarded as little more than a necessary foundation for later evidence about the communications in fact made consistently with them. For that reason, what I set out below is intended to be indicative rather than exhaustive, and to leave open the prospect that any aspect of the evidence relating to the applicant's marketing case may be the subject of specific consideration in the context of a particular group member at the appropriate stage. 290 As Marketing Director after June 2001, Ms Dobson was responsible for Vioxx strategy, a key aspect of which involved the approval of Vioxx marketing plans. She identified the marketing plan for the launch of Vioxx in Australia in February 2001. In that document, the "Key Promotional Messages" were:

part iv − vioxx and the risk of cardiovascular disease

Introduction 297 Central to the applicant's case were his allegations that the consumption of rofecoxib, and therefore of Vioxx, materially increased the risk of suffering the pleaded cardiovascular conditions, and that the respondents knew or ought to have known of that circumstance. Consistently, substantial sections of the applicant's submissions were devoted to establishing, first, that there was such an increase in risk, and, secondly, that the respondents knew or ought to have known of it. In the first section of his submissions, the applicant relied upon the current state of scientific understanding, drawing attention to a number of sources of information and opinion running well beyond the date when Vioxx was withdrawn from the market. In the second section, the focus was on the unfolding science as it existed from time to time until the withdrawal, but with an emphasis on the proposition that the respondents at least ought to have known of the risk by about the end of the first quarter of 2000. 298 The concept of "risk" is, of course, much used in personal injury litigation, especially in product liability cases. The relatively uncomplicated denotation of that word, however, conceals a veritable thicket of connotations, which I have little option but to penetrate with a view to explaining the kind of "risk" to which the applicant refers in his submissions in this case. In some situations, for example, a "risk" refers to the danger that something of conspicuously obvious causation will follow upon some injudicious course of conduct, such as the risk of injury from jumping from a moving train or diving into shallow water. In other situations, a "risk" refers to the likelihood of events or influences acting or taking place in a way which would be regarded as unwanted, such as the risk of it raining when one ventures out on a cloudy day without an umbrella, or the risk which a motorist takes when he or she fails to return to his or her parked vehicle within the allowed time. 299 Closer to the facts of the present case, it seems that there may be some situations in which surgery involves inherent risks. Apart from the prospect of something going wrong, or the patient having an allergic reaction to a drug or anaesthetic, there is the classic case, of which Rogers v Whitaker (1992) 175 CLR 479 was an example, it seems, where every so often some unwanted outcome results from a particular procedure. Here I have in mind a situation in which it is established, as a matter of medical science, that such an outcome will occur, albeit very infrequently. The "risk" which the patient takes, when properly informed, is the risk that he or she might be one of the unlucky few. As a matter of common experience, one would think that, if the surgery were going to give the patient a significant improvement in his or her wellbeing in some respects, he or she might well decide to take a very small risk of the unwanted outcome occurring (as the trial Judge held would have been the case, had a warning been given, in the matter which reached the High Court as Rosenberg v Percival (2001) 205 CLR 434). 300 In the present case, in what I have described as the first section of the applicant's submissions on risk, he alleges that sufficient is now known about the consequences of consuming Vioxx to justify the conclusion that it leads to an increase in the risk of suffering the pleaded cardiovascular conditions. He limits his case to an allegation of an increase in risk, because he accepts that such conditions occur from time to time in any event, so there will always be a risk of them. He uses the word "risk" in the sense of alleging that there was − either as a known fact or as something that may reliably be inferred - a feature of the operation of Vioxx in the vasculature that caused or contributed to the occurrence of the pleaded cardiovascular conditions. That is to say, the applicant alleges that we now know that Vioxx had such a tendency, and that anyone who took it was exposed to the "risk" that the tendency would come home, as it were. 301 In this part of my reasons, I am concerned with whether the consumption of Vioxx involved an increase in risk in this sense. I am not here concerned with the question whether, in an environment in which the existence of that actual risk was unknown to science, or was attended by uncertainty, the respondents, by continuing to market Vioxx, were exposing their customers to the "risk" that it might, ultimately, be found to be harmful. That question is the subject of a later part of these reasons. 302 The applicant's case was opened substantially by reference to the FitzGerald hypothesis, but, in closing, counsel relied primarily on the results of the APPROVe trial for their submission that the consumption of Vioxx in fact contributed to the occurrence of the pleaded cardiovascular conditions. They submitted that, since APPROVe, the existence of the risk was no longer the subject of any realistic scientific uncertainty, or at least should be found to be established on the balance of probabilities. 303 The applicant submitted that this conclusion based on APPROVe derived support from what was described as "other clinical trial evidence". In this respect the applicant relied on the results of the VIGOR trial, upon the arthritis and Alzheimer's studies conducted by Merck, upon the data available from the terminated VICTOR study, upon the meta‑analyses of Kearney (2006) and Juni (2004) and upon other coxib studies to which I shall refer. It was submitted that the conclusion derived support from such evidence as there was of a plausible physiological mechanism by which rofecoxib contributed to vascular disease, namely, the FitzGerald hypothesis, the progression of atherosclerosis and the development of hypertension. It was submitted also that the decision in September 2004 to withdraw Vioxx from the market demonstrated an appreciation by Merck itself of the risk alleged by the applicant and that a vote of the FDA Advisory Committee in February 2005 (to which I shall come in due course) provided additional support for that allegation. The applicant submitted that the elevated cardiovascular risk was immediate (in the sense of arising promptly upon a patient commencing a course of Vioxx) and enduring (in the sense of existing well after a patient had discontinued taking Vioxx). It was submitted that the risk was particularly evident in the case of patients who might normally be expected to be taking drugs for the relief of arthritic pain.

Overview of expert opinion 304 Probably the single most significant circumstance contributing to the length and complexity of the present litigation is that there is no scientific consensus with respect to the matters referred to above. That lack of consensus is reflected in the conclusions of the scientists called by the parties at trial. The applicant called − · A rheumatologist, Prof Leslie Cleland, Director of Rheumatology at the Royal Adelaide Hospital; · Two biostatisticians, Prof David Madigan, Chair of Statistics at Columbia University in New York City and Prof Mark Woodward, Director of the Epidemiology and Biostatistics Division of the George Institute for International Health (since 2006, on leave of absence, working at the Mount Sinai School of Medicine in New York); and · Two cardiologists, Prof Richard Harper, Emeritus Director of Cardiology at Monash Medical Centre, a Professor in the Department of Medicine at Monash University and Clinical Lead in Cardiology in the Department of Human Services, Victoria, and Prof Douglas Zipes, Emeritus Professor of Medicine at Indiana University and former Director of the Division of Cardiology at the Krannert Institute. The respondent called − · A rheumatologist, Dr Jim Bertouch, Chairman of the Department of Rheumatology at Prince of Wales Hospital, Sydney; · A biostatistician, Dr Ronald Marks, until 2004 a Professor in the Department of Statistics at the University of Florida; and · Two cardiologists, Prof David Celermajer, Scandrett Professor of Cardiology at the University of Sydney and Clinical Director of the Heart Research Institute, and Prof Douglas Vaughan, Irving S Cutter Professor and Chairman of the Department of Medicine at the Northwestern University Feinberg School of Medicine, Chicago, and Physician-in-Chief of Northwestern Memorial Hospital. 305 Notwithstanding that these experts conferred (grouped according to their respective specialisations), there remained fundamental disagreement between them. I shall commence by noting the extent and nature of that disagreement. 306 In his report, Prof Zipes surveyed the published research, and the results of clinical trials, and expressed the following conclusion: It is my opinion that the experimental and clinical evidence strongly support the conclusion that COX-2 inhibition, and specifically Vioxx, increases the risk for cardiovascular complications, particularly when there may already exist some degree of coronary disease or risk factors. The other cardiologist called by the applicant, Prof Harper, said: There is now overwhelming scientific evidence from randomised studies, from meta‑analysis of randomised studies and from observational data that in prone individuals, regular ingestion of Vioxx substantially increases the risk of adverse vascular events such as heart attack. … To my knowledge there is no credible scientific evidence to suggest otherwise. … There is some variation in the scientific literature as to exactly what the degree of increased risk is and how long one needs to take Vioxx before the risk becomes apparent. My interpretation of the scientific data is that the risk associated with Vioxx starts within the first month of initiation of therapy and occurs with both 25mg and 50mg doses, but the risk is higher with the 50mg dose. 307 The biostatisticians called on behalf of the applicant expressed similar conclusions. Prof Woodward examined, and where necessary re‑analysed, the publicly available data as to the link between the consumption of Vioxx and the occurrence of cardiovascular disease. His conclusion was: My consideration of all the publicly‑available evidence relating to the principles of causality … and considering how data accumulated over time, leads me to conclude that the weight of the evidence at all times between March 2000 (when the results from VIGOR were released) and September 2004 (when Vioxx was withdrawn) favoured a causal explanation. I conclude that Vioxx is likely to have caused excess [cardiovascular disease], most particularly [myocardial infarction]. Prof Madigan also studied the available data, but with an emphasis on the studies and trials that had been conducted by Merck. He concluded: I conclude that Vioxx is causally associated with an increased risk of an array of cardiovascular thrombotic adverse events. The statistical evidence is strong and consistent in the major blocks of trials I examined. Even in the short duration, relatively small [osteoarthritis/rheumatoid arthritis] studies the relative risk estimates and p‑values are strongly indicative of a causative association. 308 Prof Cleland held a similar view. He was, from an early date, aware of the FitzGerald hypothesis, and the results of the VIGOR trial came as no surprise to him. In his statement he left no doubt but that he strongly believed that the ingestion of Vioxx predisposed towards CVT adverse events. 309 The experts called by the respondents, however, were of a very different mind. Commencing again with the cardiologists, Prof Celermajer examined the published research, and found that it was inconsistent with the existence of the increased risk alleged by the applicant. He also listed a series of problems which, in his perception, were associated with the FitzGerald hypothesis. His conclusion was: In my view, considering especially the uncertainties outlined concerning proposed mechanisms of harm and the uncertainties outlined concerning interpretation of the clinical data available, the totality of evidence concerning Rofecoxib and acute atherothrombotic CV events is generally not sufficient to establish a "cause and effect" relationship at the level of individual subjects, beyond a reasonable degree of clinical certainty. Prof Vaughan concluded the presently relevant section of his report as follows: Taken together, clinical trials are inconsistent as to whether the administration of COX-2 inhibitors alters the risk of cardiovascular events when administered long‑term. There is little evidence of apparent increased risk when COX-2 inhibitors are taken for short duration at the recommended doses … It is my opinion that a knowledgeable practitioner of the art would view the totality of evidence with equipoise, and conclude that the cumulative data fail to establish such a relationship. The factors that contribute to the development of an acute [myocardial infarction] or stroke in a given patient are exceedingly complex and involve multiple known and unknown factors, unrelated to the administration of a COX-2 inhibitor. Accordingly, I would respectfully submit that, based on my expertise and my review of the evidence, the data linking Vioxx with increased cardiovascular risk fail to meet currently accepted, evidence‑based standards of practice. Furthermore, the totality of the data fails to establish causality. 310 Dr Marks responded to the reports of Profs Woodward and Madigan, and undertook his own analysis of the data available to Merck at various times. He concluded that the results of APPROVe arose substantially from the circumstance that the occurrence of CVT events in the placebo arm was uncharacteristically low. He also opined that, in all of the studies in which the occurrence of such events had been shown to be greater than in the comparator arms, the absolute rate was low and in line with normal community experience. His conclusion was: From my comprehensive review of Vioxx RCT results and of the expert reports by Professors Madigan and Woodward, I do not find evidence to support applicant claims that Vioxx is pro‑thrombotic. 311 I shall commence by identifying the extent of agreement amongst the experts. In preparation for their concurrent evidence session, the cardiologists were asked a number of questions, including the following: On the basis of current scientific knowledge, does Vioxx increase a person's risk of the [pleaded cardiovascular conditions] above what it would have been had the person been: (a) not taking any medication for arthritis instead of Vioxx; (b) taking other COX-2 selective inhibitors; (c) taking a non‑naproxen NSAID instead of Vioxx; (d) taking naproxen instead of Vioxx, in otherwise identical circumstances? 312 The cardiologists addressed first the risk of myocardial infarction. They dealt with the first part of the question (where the comparator was taking no medication at all) as though it related to the applicant himself, rather than to persons in general. Profs Zipes and Harper were of the opinion that, compared with taking no medication, the consumption of Vioxx increased the applicant's risk of having a heart attack by a factor of approximately two (the view of Prof Harper) or of at least two (Prof Zipes). Profs Celermajer and Vaughan said that it was difficult to imagine that the applicant could have had no treatment at all for his arthritis, and that it was, therefore, difficult to assess his risk of suffering a myocardial infarction in the presence of untreated arthritis. They noted that there were two studies which suggested the possibility of an increased risk of a myocardial infarction when Vioxx was consumed in the recommended doses, compared to the consumption of a placebo. Those studies were APPROVe and that published as Kearney (2006). 313 The cardiologists dealt with the remaining parts of this question as they were framed, namely, as relating to persons in general. As to the second part (where the comparators were other COX-2 inhibitors), Profs Zipes and Harper noted that the only other COX-2 selective inhibitor available in Australia at the time when the applicant was taking Vioxx was Celebrex. The standard dose of Celebrex in Australia at that time was 200 mg whereas a standard dose of Vioxx was 25 mg. Profs Zipes and Harper expressed the view that the relative risk for heart attack between Vioxx at that dosage and Celebrex was approximately 1.5 (Graham 2005). Based on several epidemiological studies and meta‑analyses, they opined that Vioxx had the greatest relative risk for cardiovascular events, followed by other COX-2 inhibitors, in an order reflecting their degree of COX-2 inhibition. Profs Celermajer and Vaughan considered that there were insufficient high quality data comparing the cardiovascular outcomes as between different COX-2 inhibitors. They believed that the most reliable estimate came from Kearney (2006), which suggested that the cardiovascular risk of taking Vioxx at a rate of 25 mg daily did not significantly differ from that arising from the consumption of other COX-2 inhibitors. They pointed out that the data in Kearney (2006) were derived from randomised trials, rather than being observational data, as was the case with Graham (2005). 314 As to the third part of this question (where the comparator was a non‑naproxen NSAID), the cardiologists pointed out that there were no randomised controlled data with respect to this comparison. As to such data as there were, Profs Zipes and Harper proffered the interpretation that all NSAIDs (with the exception of naproxen) increased the risk of adverse cardiovascular events, but to a lesser degree than Vioxx. The variation between the data in the various studies highlighted the difficulties and limitations in the interpretation of meta‑analyses and observational data. They considered that the most reliable data came from randomised double blind placebo‑controlled studies. Profs Celermajer and Vaughan took the view that the cumulative data showed similar rates of cardiovascular risk when Vioxx was compared with non‑naproxen NSAIDs, relying on Chen (2007) and on Merck's pooled analyses of the data from its arthritis and Alzheimer's disease studies. 315 As to the fourth part of this question (where the comparator was naproxen), Profs Zipes and Harper said that, although the data were variable, and obtained from meta‑analyses and observational studies, the results suggested, at best, that naproxen had a small cardiovascular protective effect, in the order of 10% or less, in which respect they relied on the report of Prof Woodward, to which I shall come presently. Therefore, according to them, taking Vioxx instead of naproxen would increase the risk of an adverse cardiovascular event by a factor of a little more than two. Profs Celermajer and Vaughan considered that the effect of naproxen on cardiovascular risk most likely depended on whether it was taken regularly: if so, it would have an antiplatelet effect similar to that of aspirin (eg Weir 2003, Capone 2004). They said that this effect may have contributed importantly to the result of the VIGOR study. They noted that observational studies suggested a much smaller protective effect, but they considered that this was potentially due to less frequent usage (in part because of gastrointestinal intolerance). They said that other randomised controlled trials in which naproxen was compared with a different coxib, suggested that it had cardiovascular effects similar to those which, in their view, were seen in VIGOR. 316 In their joint report, the cardiologists then turned to the other pleaded cardiovascular conditions (ie other than myocardial infarction). With respect to thrombotic stroke, Profs Zipes and Harper said that they had not undertaken a detailed examination of the data linking Vioxx with this condition. They considered that it was important to note that thrombotic stroke consisted both of atherothrombotic and of non‑atherothrombotic types of ischaemic stroke. Profs Celermajer and Vaughan said that there were no data linking the consumption of Vioxx to thrombotic stroke. To the contrary, they pointed to what they described as "compelling data to show that Vioxx does not predispose to thrombotic stroke". They further noted the stroke data tabulated in Dr Marks' Appendix B to the biostatistician's joint report, which set out the results from various studies of Vioxx conducted by Merck. 317 With respect to unstable angina, transient ischaemic attack and peripheral vascular disease, the cardiologists said that there were insufficient data to draw meaningful conclusions concerning any Vioxx‑related risk. 318 As will be apparent from the foregoing, in forming their views on the question of risk, the cardiologists relied heavily on the published results of various trials and studies. Given that the mechanistic explanation of the relationship between the consumption of Vioxx and cardiovascular risk was, at all times while Vioxx was on the market, a matter of hypothesis, that reliance was inevitable. That naturally takes one to the evidence of the biostatisticians, whose discipline is concerned with the extent to which useful general conclusions as to associations may be drawn from the data yielded by individual, and collective, studies. 319 The questions upon which the biostatisticians were asked to report were grouped by reference to data available to Merck (i) down to December 2003; (ii) down to September 2004 and (iii) as at October 2004 and thereafter. In each case they were asked whether - … the data from the randomised clinical trials available to Merck … show[ed] a statistically significant difference in the risk of the [pleaded cardiovascular conditions] for Vioxx relative to: (a) non‑naproxen NSAIDs; (b) naproxen; (c) placebo. As at each of the first two mentioned dates, the biostatisticians were asked whether "the data available to Merck suggest[ed] a real (not fanciful) possibility that Vioxx was associated with an increased risk" of the pleaded cardiovascular conditions. With respect to October 2004 and thereafter, they were asked whether the data established that the consumption of Vioxx increased the risk of the pleaded cardiovascular conditions. It is this final aspect of the matter with which I am presently concerned, although, as it happened, each of the biostatisticians would have answered that question the same way as he would have answered the two earlier parts. 320 Of the pleaded cardiovascular conditions, "due to the lack of data on the other endpoints", the biostatisticians were able to answer the questions posed of them only in respect of myocardial infarction. They were also able to comment on the CVT endpoint, but it must be appreciated that that dimension of their evidence related to a basket of conditions rather than to any one event. They interpreted the present question as if asked whether Vioxx was "a likely causation" of myocardial infarction and of CVT events generally. Profs Madigan and Woodward answered the question in the affirmative, while Dr Marks answered it in the negative. That is to say, Profs Madigan and Woodward gave the opinion that Vioxx most likely caused myocardial infarction and CVT events, while Dr Marks gave the opinion that it did not. Their joint report did not contain any direct elaboration upon these conclusions: their views were to be found in their respective individual reports.

The Bradford Hill criteria 321 Towards the end of his written submissions on the matter of risk, the applicant referred to, and relied on, a list of (originally nine) criteria proposed in 1965 by Sir Austin Bradford Hill (Hill 1965), by reference to which questions of causation in epidemiology might conveniently be addressed. Prof Woodward said that the criteria had since been adapted to produce the following seven points: 1) There should be evidence of a strong association between the risk factor and the disease. Weak relationships may be due to chance occurrence and are more likely to be explainable by confounding. 2) There should be evidence that exposure to the risk factor preceded the onset of disease. 3) There should be a plausible biological explanation. 4) The association should be supported by other investigations in different study settings. This is to protect against chance findings and bias caused by a particular choice of study population or study design. 5) There should be evidence of reversibility of the effect. That is, if the "cause" is removed the "effect" should also disappear, or at least be less likely. 6) There should be evidence of a dose‑response effect. That is, the greater the amount of exposure to the risk factor, the greater the chance of disease. 7) There should be no convincing alternative explanation. For instance, the association should not be explainable by confounding. Prof Woodward stressed that none of the criteria was either necessary or sufficient to establish causality, but that each would strengthen the evidence towards such a conclusion. Prof Woodward and Prof Celermajer agreed that the criteria were not a hard and fast set of rules (or, as Prof Woodward put it, that they did not require merely the "ticking of boxes"). Rather, they were points which (in Prof Celermajer's words) could be "useful in trying to assess a body of evidence as regards a potential cause for certain observations", or (in Prof Woodward's words) constituted "a widely‑understood general guide for weighing the evidence of causality". 322 It is important to keep in mind the original purpose of these criteria. It was to help bridge the gap between association and causation. As Hill himself said in his address to the Royal Society in 1965: Our observations reveal an association between two variables, perfectly clear‑cut and beyond what we would care to attribute to the play of chance. What aspects of that association should we especially consider before deciding that the most likely interpretation of it is causation? In his report, Dr Marks captured this sense of the criteria when he said: No single analysis within a study leading to statistical significance and, in fact, no single study showing multiple statistically significant results is generally accepted as proof of causation. It is not unusual, and even expected, that statistical significance will result simply by chance from performing numerous statistical outcome comparisons within a study and across multiple studies. Statistical significance and causation are substantially different concepts. … Proof of causation only results when well accepted criteria, such as those established by Bradford Hill (1965), are met after reviewing all available relevant scientific information. In the application of the criteria, in Dr Marks' view, one should look first at the first, fourth and sixth items, and, if evidence of causation is apparent at that level, one should then move to consider the remaining criteria. 323 There was some minor disagreement between Prof Woodward and Prof Celermajer as to detailed aspects of the Bradford Hill criteria. In his original report, Prof Celermajer identified the first, third, fourth and sixth of these criteria, together with an additional one, "specificity" (giving the example of being run over by a truck as one in which the resulting injuries would be specific to the presumptive cause). Prof Woodward considered that Prof Celermajer was wrong to omit the principle of temporality (the second on the list) which he (Prof Woodward) described as "the most important principle of causality". He considered that Prof Celermajer was also wrong to omit the principle of lack of an alternative explanation, the seventh on the list. He said that Prof Celermajer was being "too prescriptive" by including the principle of specificity, one of Hill's original criteria but, according to Prof Woodward, no longer commonly employed. He said that the specificity requirement - that the cause leads to a single effect rather than to multiple effects - clearly had no application in the case of smoking, which was a well‑known risk factor both for cardiovascular disease and for lung cancer. In his statement in reply, Prof Celermajer criticised the conclusions drawn by Prof Woodward by reference to the criteria on his list, but ventured no criticism of the content of the list as such. 324 It was not suggested by either side - or by any of the experts - that the Bradford Hill criteria did not provide an appropriate framework by reference to which questions of risk arising in the present proceeding might be addressed. The applicant stressed, and I accept, that the existence of a risk of a certain kind and degree was a question of fact which, in a court, had to be decided on a balance of probabilities by reference to all of the available evidence. However, as I have said, he relied on these criteria, as did the respondents. For the most part (and to the extent that it was otherwise I shall deal with it), the major themes of the parties' cases on risk can be accommodated within these criteria. Those themes were (i) the strength of the observed association between the consumption of Vioxx and CVT events including myocardial infarction; (ii) the consistency of that association (including issues of generalisability); (iii) the presence or absence of a convincing alternative explanation for the association observed; and (iv) the presence or absence of a plausible biological explanation. Less conspicuous themes were temporality, reversibility and dose‑relationship. Each of these can be accommodated within the Bradford Hill criteria. 325 The focus of the epidemiological debate before the court was on aspects relevant to the first and fourth of the Bradford Hill criteria - strength and consistency of association. The applicant submitted that the association between the consumption of Vioxx and CVT events, particularly myocardial infarction, was strong and consistent as between study settings. The respondents could not deny that there were studies which had revealed a strong association, at least in relation to myocardial infarction, but they submitted that there were reasons for this that stood in the way of reaching any general conclusion as to causation or risk, and that the evidence of a like association across different study settings was patchy and inconsistent. 326 The applicant relied primarily on the results of the APPROVe trial, because that was the first placebo‑controlled prospective RCT in which the reported excess of CVT events in the Vioxx arm was statistically significant. The only previous RCT to have shown such a statistically significantly excess was VIGOR, but there the comparator was naproxen, not placebo. Some (but not all) other trials and studies had shown an excess of events in the Vioxx arms, but not at a statistically significant level. As Prof Harper put it, "… the APPROVe result … is scientifically sound. Everything else has limitations."

APPROVe 327 As stated elsewhere in these reasons, a result of the APPROVe trial, as reported to the FDA and as published as Bresalier (2005), was that the relative risk of encountering a CVT event (as defined in the CV SOP) from taking Vioxx rather than placebo was 1.92 (1.19, 3.11). The corresponding figure for the APTC endpoint was 2.06 (1.16, 3.64). For myocardial infarction, the relative risk was 2.53 (1.11, 6.28) and for all cardiac events it was 2.80 (1.44, 5.45). Based on these statistically significant results, Profs Zipes and Harper expressed the opinion that the consumption of Vioxx about doubled the risk of the occurrence of a CVT event. Prof Harper pointed particularly to the relative risk figures for cardiac events and myocardial infarction in support of the opinion which he expressed. He said: [T]he APPROVe study to me is the hallmark, is the gold standard. I think the VIGOR study, we are talking about interpretations in 2000 but if you interpret the VIGOR study today with the knowledge we have, with the additional knowledge we have, I think that's the second best evidence regarding the risk of Vioxx and heart attack. I think all the other studies, you can pick about - there are about 10 studies and you can pick whatever result you like, almost, out of the meta‑analysis and observation studies. I think that data is much weaker. But as Professor Zipes has said, if you take it in totality, it generally … shows an increased risk with Vioxx. So I would say that the APPROVe study is … certainly the gold standard that we relied on to say that we think the risk - [the applicant's] risk was increased by a factor of 2, and there has been a follow‑up to the APPROVe study, just following patients for longer, which again … reinforce … the original results of the APPROVe study. 328 The follow‑up analysis referred to by Prof Harper was Baron (2008). I shall refer to it below. It was submitted on behalf of the applicant that the studies mentioned by Prof Harper amply justified the conclusion that the consumption of Vioxx increased the risk of suffering the pleaded cardiovascular conditions. 329 The respondents ventured no criticism of the APPROVe trial, nor of the conclusions reached in it. Profs Celermajer and Vaughan described it as "a good study". However, the respondents submitted that there were four "key limits" on the uses for which the results of APPROVe might be deployed: (a) APPROVe does not sit "in splendid isolation". It is necessary to consider the totality of the evidence properly to understand the results. A large body of data exists that do not support a cardiovascular risk with Vioxx. The data are conflicting and inconsistent. (b) The cardiovascular risk hazard curves reveal that the risk is only apparent after 18 months. Therefore, the data from APPROVe itself are confusing. (c) In the absence of an established mechanism, the data can only be considered at the population level. The data cannot be applied to an individual. (d) APPROVe was tested on patients with colon adenomas, whose "cardiovascular risk profile" differs from that of the general population. Therefore, the APPROVe data cannot be readily applied to the general population with any meaningful results. 330 The first of these points effectively calls up the fourth Bradford Hill criterion. It is best considered in conjunction with the applicant's submission that the APPROVe results derive support from the results of other trials and studies when properly understood. Indeed, the applicant made no suggestion that APPROVe sat "in splendid isolation": quite the contrary. The third of the respondents' points effectively calls up the third of the Bradford Hill criteria - the existence of a plausible biological explanation - but it raises also the question whether the existence of a risk at the population level justifies a conclusion of causation in the case of a particular individual. I shall return to those questions. The fourth point may raise questions under the fourth and the seventh of the Bradford Hill criteria; or it may sit outside them altogether, in the sense that it seems to propose that, even if it might be concluded that Vioxx caused CVT disease in patients with colon adenomas, it did not follow that it did so in other patients. I shall return to these issues also. The second point concerns the way the APPROVe results themselves should be interpreted, and it is to it that I next turn. 331 The point concerns the timing of the occurrence of CVT events in the respective arms of the APPROVe trial. A Kaplan‑Meier plot graphs the cumulative percentage of patients with events over time. The cardiovascular safety report for APPROVe set out the following Kaplan‑Meier plot for the two arms, Vioxx and placebo: The interpretation of this graph given in the report was: The curve for the rofecoxib treatment group appeared generally linear from 0 to 36 months while the curve for the placebo treatment group appeared generally linear during the first 18 months and then the curve flattened during 18 to 36 months. The two curves appeared to be similar during the first 18 months and then started to separate at approximately 18 months. According to a table in the report, over the first 18 months, the relative risk of suffering a thrombotic cardiovascular event from taking Vioxx was 1.18 (0.64, 2.15). Over the balance of the period, the figure was 4.45 (1.77, 13.32). 332 The authors of the report went further and said of this apparent divergence at 18 months: Figure 3 and Tables 6 and 7 demonstrate that the hazard ratio or the relative risk for thrombotic cardiovascular events did not appear to be a constant over time. This was confirmed by the testing of the proportional hazard assumption for the Cox proportional hazards model (p=0.014). A similar conclusion was expressed in the published article setting out the results of APPROVe, written by the members of the Steering Committee and two members of the External Safety Monitoring Board for the trial: Bresalier (2005). That aspect of the article led to some scientific controversy, and to the publication of a correction by the authors in the New England Journal of Medicine in July 2006. In that correction, the authors stated that they had originally used linear time rather than the logarithm of time as specified in the Methods section of their article, in the test for proportionality of hazards. They withdrew the statement that "[t]he changing pattern of the treatment effect over time was confirmed by a failed test for proportionality of hazards (P = 0.01)", and replaced it with a statement that "the results of an overall test of the proportional‑hazards assumption for the entire 36‑month observation period did not reach statistical significance (P = 0.07)." 333 The 18‑month aspect of the APPROVe results was emphasized by Dr Marks and Prof Celermajer in their respective original reports. Dr Marks said: "A visual inspection of the results … clearly indicates a pattern of overlapping Vioxx and placebo curves through 18 months, after which a clear separation occurs." He pointed out that, in both arms, the average age of the patients was 59 years at the commencement of the trial. After 18 months, the average age would have been 60.5 years. Dr Marks opined that it would not be surprising to observe a slight increase in the rate of occurrence of adverse events in the later part of the trial, reflecting the increased risk of cardiovascular events which comes with older age. Such a slight increase was indeed observed in the Vioxx arm. However, the major contributor to the separation in the results after 18 months was a reduction in the rate of occurrence in the placebo arm. 334 While noting the technical complications involved in relying on the visual appearance of the Kaplan‑Meier plot originally published in Bresalier (2005), Prof Celermajer proposed that the delayed separation of the two curves was inconsistent with an early occurrence of pro‑thrombotic events, which would be expected if the FitzGerald hypothesis were valid. This was one of the main pieces of evidence that gave Prof Celermajer cause to pause before believing that the hypothesis might be valid. However, in the concurrent evidence session Prof Celermajer accepted that the Kaplan‑Meier curves did not give one a basis for saying that the effect of Vioxx emerged only after 18 months. He said: [A] visual inspection of the CV risk hazard curves … suggests that these curves are broadly similar for the first 18 months and diverge after this point, up to the 36 month study point. Statistical analysis of these hazard curves, however, do not suggest that the risk difference between groups progresses differently over time … The study was designed for a 36 month follow‑up period and it is clear that, at the 36 month time point, Rofecoxib was associated with a statistically significant increased risk of serious CV events, as prospectively defined. Prof Vaughan said: [If] you look at the data, and people look at it in all different ways, the rates of myocardial infarction in the Vioxx treated group and the placebo treated group track - they overlap, pretty much, for the first year and a half, for 18 months, and the rates are very similar and what happens after 18 months is the rate continues at the same level for Vioxx and it drops off for the placebo group. Now, I don't doubt that those numbers are real but I don't understand why all of a sudden the placebo group would drop off in terms of their rates of events. So it's a peculiarity. It may be a red herring but it's an oddity of that study. 335 If we move from the visually‑apparent separation of the curves in the Kaplan‑Meier plot at 18 months to the technical means by which the statisticians would measure whether there was any significant difference in the proportional rate of occurrence of events in two arms of the study over time, we come to what Prof Madigan described as the "proportional hazards" assumption. He explained it in the following terms: The "proportional hazards" assumption plays an important role in survival analysis and greatly simplifies many analyses. For confirmed CVT events in APPROVe, it amounts to assuming that the ratio of the "hazard function" for a Vioxx patient to the "hazard function" for a placebo patient does not vary over time. The hazard function is a‑function of time and essentially represents the probability of having a first event at a given moment. So if Vioxx patients have a hazard function that is, say, double that of placebo patients, the proportionality assumption says that this doubling stays constant over time. The assumption presumably is never perfectly true but the general idea is that it is often close enough to being true that it represents a reasonable basis for analysis. It was in relation to this test that Bresalier and colleagues made the mistake to which I have referred above. As to that mistake, Dr Marks said: The original proportionality test reported in the Bresalier publication produced a p value of p 14 days after drug use discontinuation, and (3) non‑serious AEs. The counts also include adding the five Vioxx and seven placebo confirmed CVT SAEs not including in Professor Madigan's original analysis. The last row updates the Merck January 2005 analysis to include confirmed CVT SAEs from protocol 126. Vioxx Placebo n n RR 95% CI Madigan original analysis from Table 1 99 73 1.5 1.1 - 2.0 Madigan analysis excluding events - Not confirmed as CVT 83 72 1.24 0.90 - 1.69 CVT confirmed > 14 days after drug use58 64 0.97 0.68 - 1.39 Non-serious AE 46 49 1.01 0.67 - 1.50 Merck 1-05 analysis adding protocol 126 48 53 1.05 0.71 - 1.54 As the heading to the table indicates, the figure of 1.05 (0.71, 1.54) is derived by adding to the analysis sent by Merck to the FDA in January 2005, which related to Protocols 078 and 091 only, corresponding data from Protocol 126. Any difference between that figure and the one sent to the FDA as part of the pooled analysis in March 2004 - 1.03 (0.70, 1.53) is not presently material. 407 It may be seen from this table that, in the Vioxx arm, 25 of the events were excluded by Dr Marks because, although they had been confirmed as CVT events, they occurred more than 14 days after discontinuation of use. There were only eight such events in the placebo arm. Dr Marks then examined these events by reference to the length of time that each patient had been taking Vioxx and the length of time after discontinuation that his or her CVT event occurred. He produced the following table: Table 5. Summary of Alzheimer's studies Vioxx AEs that occurred off‑drug and were counted by Professor Madigan in his analysis. Results summarize time on drug and time to event after drug discontinuation. Follow‑up Time Off-Drug Until AE Occurs Days 1-90 days 91-365 days 1 2 years TOTAL on Drug 1-90 days 2 4 3 2 11 91-365 days 0 0 3 2 5 1 2 years 0 3 1 0 4 TOTAL 3 8 9 5 25

408 Dr Marks undertook the same exercise with respect to the placebo arms of the Alzheimer's studies: Table 6. Summary of Alzheimer's studies placebo AEs that occurred off‑drug and were counted by Professor Madigan in his analysis. Results summarise time on drug and time to event after drug discontinuation. Follow‑up Time Off-Drug Until AE Occurs Days 1-90 days 91-365 days 1 2 years TOTAL on Drug 1-90 days 1 1 1 0 3 91-365 days 3 0 0 0 3 1 2 years 0 1 0 0 1 TOTAL 4 2 1 1 8

409 With respect to the inclusion by Prof Madigan of events which had occurred more than 14 days after discontinuation, Dr Marks said: Note that for the 25 Vioxx subjects whose CVT event occurred more than 14 days after drug discontinuation, 11 (44%) were on their study drug for no more than three months. In addition, 14 of the events (56%) occurred more than one year after drug discontinuation, with 25% being more than two years after drug discontinuation. Only three Vioxx events (12%) occurred within three months of drug discontinuation. … These results indicate generally little Vioxx exposure in these subjects and resulting CVT events that occurred long after Vioxx exposure ends. There are considerably fewer placebo events, and they generally occurred in subjects with little placebo exposure. Those events, unlike those in the Vioxx group, tended to cluster in the first 90 days after their drug discontinuation. A cardiologist needs to interpret these results and determine if there is any reasonable biological relationship that can be shown between short‑term Vioxx use and long‑term occurrence of CVT events. Generally with respect to Prof Madigan's analysis, Dr Marks said: The end result here is that Professor Madigan has combined numerous categories of events from the Alzheimer's studies, some non‑standard categories (off‑drug and nonserious) and one inappropriate category (not confirmed by adjudication to be CVT) to arrive at a statistically significant result. Indeed, this fragile [relative risk] quickly drops to that of no risk when these categories are scrutinized. Such results are not considered proof of a documented Vioxx CVT risk. While under cross‑examination by counsel for the applicant, Dr Marks was not challenged on this evidence. 410 I generally accept Dr Marks' defence of Merck's use of confirmed rather than investigator‑reported events in the Alzheimer's studies. As the respondents pointed out, if the investigator‑reported data in a study show a higher incidence of the event of interest than do the confirmed data, it follows that some events considered to be of interest by investigators were regarded otherwise by the blinded, specialist, adjudicators. The question remains, however: should the data which Merck did use be regarded as compromised, or of little present utility, by reason of the circumstance that events which had occurred more than 14 days after discontinuation were not counted? In the way this issue was debated by the parties, it had two aspects, one procedural and one substantive. 411 The procedural issue related to the matter dealt with in the passage from the evidence of Prof Madigan set out in para 401 above. It was submitted on behalf of the applicant that Merck had originally specified an ITT approach to the collection of data, but subsequently departed from that stated intention. Indeed, in his final written submissions the applicant contended that the terms of Protocol 078 had been amended so as to convert an ITT study to what was effectively an on-drug study. Although not so alleged in terms, the implicit gravamen of the applicant's submission was that this had been done surreptitiously. The submission related to a passage in the original protocol. In the "Data Analysis" section, under the sub‑heading "Statistical Methods", the following appeared: The primary approach for all efficacy and safety analyses will be the "intention‑to‑treat" approach. All patients will be included in the analysis in the treatment group to which they are randomized, regardless of any protocol violation. The applicant submitted that this passage had been deleted without comment and "the ITT analysis disappeared from the document without a noted deletion". I do not accept that submission. Amendments were made on 8 May 1998, but there was no deletion of the passage quoted above. The applicant submitted that "[n]o future document mentioned these changes, rendering it impossible for anyone who did not look at the original protocol to know that ITT was prespecified for safety." The reason that no future document mentioned the changes was that they had not been made. Likewise, the passage in question was in Protocol 091 and 126 from the outset, and remained there subsequently. 412 How did Merck align the use of its "modified ITT" approach with the statement in the passage set out above that the approach for all safety analyses would be the ITT approach as such? Here Dr Reicin made a distinction between the terms of the protocol and the terms of the data analysis plan for each study, focusing specifically on Protocol 078. She considered that the language of the protocol was "ambiguous". Beneath the contentious passage set out above, the text was divided up according to three sub‑subheadings, namely "Primary Efficacy Analysis", "Interim Analysis" and "Safety". Under "Safety", it was said: "All patients who take study medication will be included in the analysis of safety." By contrast, in the section on safety the data analysis plan contained the following passage: Two approaches will be used for tabulation of adverse experiences ... First, a primary analysis will include all adverse experiences occurring when patients are on treatment and up to 14 days following discontinuation of study drug … Second, a summary based on the ITT approach will include all adverse experiences regardless of whether patients were on or off study drug … Each safety subsection will present the on‑drug results followed by the respective ITT results. Dr Reicin said that it was standard practice at MRL for the data analysis plan to take precedence over the protocol with respect to the statistical analyses that were conducted when analysing the data from a clinical trial. 413 The evidence is not such as would entitle me to decide whether, in some absolute sense, Merck was right or wrong to prefer the data analysis plan over the protocol. However, that was not Dr Reicin's only procedural justification for the 14‑day cut-off system which was used. Under cross‑examination, it was put to her that it was because of the data analysis plan for Protocol 078 that she took the view that "an on‑drug analysis was preferable." She responded: It wasn't an issue of preferable or not. That was the primary stated analysis for safety and for [cardiovascular] safety it specifically referred to our standard operating procedure which was on drug and within 14 days. Here Dr Reicin was referring to the CV SOP. Protocols 078 and 091 both pre‑dated the CV SOP (078 was dated 4 December 1997 and 091 was dated 14 October 1998). Merck established the CV SOP specifically for the purpose of providing a consistent, across‑study, basis for monitoring the association between the consumption of Vioxx and the occurrence of CVT events. Such an association was not a pre‑specified concern of the Alzheimer's protocols as such. Other studies, looked at in isolation, may have taken an approach different to that of those protocols. If, as apparently was contemplated from the outset, there was to be pooling of data across studies, an important consideration would have been consistency in the basis upon which events of interest were recorded. I take the view that it was reasonable of Merck, in relation to the Alzheimer's studies, to treat the 14‑day approach specified in the CV SOP as primary for the purpose of collecting and analysing CVT events. 414 In deciding whether Vioxx in fact led to an increased risk of CVT disease, the essentially procedural issues which I have just been discussing are of less importance than the answer to the question whether an ITT or an on-drug approach to the collection and analysis of data would have been the better calculated to reveal that risk, if there were one. That is the substantive issue to which I earlier referred. Here there are several threads of evidence which bear upon the subject. There is the recognition by Prof Madigan himself, contained in the passage set out at para 401 above, that the use of an ITT approach may have the effect of diluting safety signals that would otherwise arise from the data. That is because, I infer, data (including the number of patient‑years accumulating in the denominator of the risk fraction) ostensibly generated by the experiences of patients taking the drug which is presumptively harmful would in fact be coming from patients who were acting as though they were taking placebo. Much the same point was made by Dr Reicin: Although ITT is considered to be a conservative approach when proving efficacy or superiority of the treatment drug, an on‑drug analysis is more conservative when examining safety issues or proving non‑inferiority because off-drug events will tend to dilute any drug effects. International standards in the design of clinical trials support that position: "Although considered conservative for efficacy, ITT analyses are not conservative for analyzing adverse event data where the results will be biased, on average, towards finding no differences between the groups (in other words, a tendency for the groups to be more similar to each other than they should be)." … [Management of Safety Information from Clinical Trials: Report of … Council for International Organizations of Medical Science Working Group VI, Geneva 2005 at 137]. … 415 Next there is the evidence of Dr Marks, set out at paras 407‑408 above, in which he points to some fairly extreme cases of events which would be counted under a true ITT approach. Although one must accept Prof Madigan's point that to ignore a serious event that occurred on the 15th day after discontinuation might be difficult to justify, nonetheless the line has to be drawn somewhere, and to count an event that occurred a year or more after discontinuation might equally, especially if the patient concerned had been on the drug for a short period only, have the potential to distort the picture conveyed by the study. 416 The biostatisticians also had something to say in their joint report on this subject. They said: 11. We agreed that it is appropriate to conduct per‑protocol (PP) and intention‑to‑treat (ITT) analyses for safety endpoints. 12. We agreed that if there exists no a priori belief that a drug could cause a persistent (ie off‑drug) risk, it is reasonable to perform PP and ITT analyses, with the PP analysis as primary. We agreed that one would expect the PP and ITT analyses to agree and any disagreement would lead to further investigation and analyses. 13. Drs. Madigan and Woodward agree that if there is an a priori belief that a drug could cause a persistent risk, then ITT analyses are primary. Dr. Marks believes both PP and ITT have equal importance. In the case of Vioxx, the nature of the "a priori belief" that guided Merck in the development of the CV SOP was identified by Dr Reicin as follows: It is important to remember that our analyses of cardiovascular safety of Vioxx were conducted against the backdrop of the FitzGerald hypothesis: that COX-2 selection decreases prostacyclin … without affecting thromboxane … in the blood vessels, creating an imbalance leading to an increased risk of blood clotting. This hypothesized pharmacological mechanism, if true, would suggest an acute on‑drug effect rather than long‑term risk. This evidence effectively opens up another question which was considered by the cardiologists, namely, whether the effect of Vioxx in the vasculature (assuming there to be one) was acute only as suggested by Dr Reicin, or endured over the long term, eg by promoting the development of atherosclerosis. I deal with that matter at paras 546‑550 below. 417 Prof Zipes relied on the extended data generated by the APPROVe trial. As I indicate elsewhere in these reasons, Prof Zipes had a view, not shared (in the case of Prof Harper, at least to the same extent) by the other cardiologists, that Vioxx accelerated atherosclerosis. In that sense, its toxic effect might persist well after discontinuation. As Prof Celermajer pointed out, that is not the realm of the FitzGerald hypothesis. Notwithstanding, Prof Zipes said that "the fact that there was continued risk for that one year after stopping Vioxx in the APPROVe data would suggest that some of the changes indeed do remain and the individual is still at risk." 418 It is apparent that there is no bright line between situations in which an ITT approach and situations in which an on-drug approach will be most informative on matters of safety. Neither is it uncontentious whether an ITT or an on-drug approach should have been regarded as the better suited for a study designed to test the cardiovascular risks associated with the consumption of Vioxx. In this part of my reasons, there is no reason why I should not derive assistance from whatever evidence is available. As it happens, Dr Marks has divided the data in a way that makes it possible to put to one side adverse events that had been reported by investigators but not confirmed on adjudication. When that is done, the relative risk of suffering a CVT event from taking Vioxx rather than placebo is seen to be 1.24 (0.90, 1.69), on an ITT approach. 419 The difference between this figure and the one reported to the FDA in January 2005 (as adjusted by the inclusion of Protocol 126 - 1.05 (0.71, 1.54)) is entirely the result of the inclusion of events that occurred more than 14 days after discontinuation (it will be seen from Dr Marks' table that the inclusion of non‑serious events in Prof Madigan's data actually lowered the relative risk figure). Given the direction of this difference, I think it is unlikely that any safety signal would have been "diluted" by the inclusion of events occurring after the 14th day. I think it more likely either that there was in fact something about Vioxx which gave rise to an excess of CVT events over placebo to a strikingly greater extent within this extended period than is observed up to the 14th day after discontinuation, or that, by chance, unrelated circumstances lay behind that excess. Although Profs Zipes and Harper expressed the view that the harmful effect of Vioxx persisted, they did not go to the extent of opining that its relative toxicity actually increased with the passage of time off‑drug. Perhaps regrettably, no party asked the cardiologists to express an opinion about the data referred to by Dr Marks, as set out in para 406 above. Absent such an opinion, I am in no position, guided by the data alone, to conclude that the risk of consuming Vioxx as disclosed by the Alzheimer's studies was any greater than disclosed in the reports in fact submitted by Merck to the FDA. 420 In his report, Prof Madigan also expressed strong reservations as to the rates of compliance amongst participants in the Alzheimer's studies. His point was that, if patients were regarded as taking Vioxx when in fact they were not, any pro‑thrombotic tendency in the drug would be concealed, to an extent at least. He said: Significant compliance problems existed in the Alzheimer's studies generally and in 078 in particular. Only 10.9 percent of the patients on Vioxx and 16.2 percent of patients on placebo remained on their study drug for the entire study period. Only 61 percent of patients on Vioxx took at least 80 percent of their assigned tablets, and 25.8 percent of these patients took the drug less than 60 percent of the time. The study was prematurely terminated 11 months prior to its scheduled end. By contrast, in VIGOR, 99.4% of Vioxx and 99.1 % of naproxen patients had a compliance rate of at least 75%. In APPROVe, 91.9% of Vioxx and 94.9% of placebo patients had a compliance rate of at least 75%, and only 3.9% of Vioxx and 2.8% of placebo patients recorded a compliance rate of less than 60%. Since noncompliance would generally tend to diminish the effect size associated with the active treatment, the results … [set out in Prof Madigan's analysis] are all the more striking in the face of such high levels of noncompliance. 421 Dr Marks responded to these criticisms. He said that the ITT approach had been taken for efficacy in the Alzheimer's studies because they were designed to assess residual drug efficacy for cognition after drug use ended. Thus, patients were treated as still being in a trial even if they had stopped taking the drug. For example, a patient who had discontinued half‑way through the trial would have had a compliance rate of 50%. By contrast, a patient in VIGOR or APPROVe who discontinued half‑way through would have a compliance rate of 100%. Dr Marks said that there was "no problem with the quality of data resulting from the Alzheimer's studies, … but instead [the quality of the data] simply reflects the difference in measuring compliance in an ITT versus [per‑protocol] analysis". In his statement in reply, Prof Madigan accepted the force of Dr Marks' observations, but contended that, while the difference was less pronounced, the compliance rate in Protocol 078 was less than that in APPROVe. In a further statement, Dr Marks set out the compliance rates in APPROVe and in Protocol 078 in a table which, as I understand it, was intended to present the figures on a comparable basis: Table 11. On‑drug compliance rate comparison for APPROVe and Alzheimer's protocol 078. "Mean compliance" refers to the average study drug compliance attained across all subjects, and ">75%" refers to the percentage of subjects having at least 75% study drug compliance ------ APPROVe ----- ----- Alzheimer's 078 ----- Vioxx Placebo Vioxx Placebo Mean compliance 93.1% 94.7% 86.9% 90.0% >75 % 91.9% 94.9% 83.1% 88.3% Dr Marks said: Although the Alzheimer's compliance rates are numerically lower than for APPROVe, these compliance rates are still very good for an RCT. Reported results from protocol 078 should not be questioned based on low compliance. 422 Under cross-examination, Prof Madigan conceded that what Dr Marks said about compliance rates was correct. He described the compliance rates in the Alzheimer's studies as "a bit lower" than those in VIGOR. I do not think that the utility of the Alzheimer's data should be regarded as compromised by reason of low levels of compliance amongst patients taking Vioxx.

VICTOR 423 The applicant submitted that the results of the VICTOR study also showed "a strong signal for CVT risk". That study was, along with APPROVe and ViP, part of Protocol 203. It was terminated early when Vioxx was withdrawn from the market. In the study, 2434 patients with colorectal cancer were randomised to Vioxx 25 mg daily or placebo. It had been intended to enrol 3500 patients for two years', and a further 3500 patients for five years', follow‑up. Prof Celermajer said that "the study's eventual number of patient years follow‑up was less than 10% of that planned". To the time when the study was terminated, the occurrence of CVT events yielded a relative risk figure (for taking Vioxx) of 2.66 (1.03, 6.86). It seems that a disproportionate number of the patients in the Vioxx arm were diabetics and, after adjusting for that circumstance, the figure was 2.41 (0.93, 6.26); p = 0.07. Prof Celermajer took the view that the study was "not particularly informative". Counsel for the respondents submitted that VICTOR did not "replicate the APPROVe results". I consider, however, that counsel for the applicant were closer to the mark when they submitted in reply that "VICTOR showed a RR of CVT events of about 2.5 which is either statistically significant, or just shy of statistical significance, depending on the analysis used". Although the adjusted relative risk figure of 2.41 was not statistically significant, the p figure shows that there would only be 7 chances in 100 that one would be in error to exclude the hypothesis that there was no difference in the incidence of CVT events as between those who took Vioxx and those who did not. Allowing for the statistical limitations on use of the data involved here, although it might be strictly true that those data do not "replicate" APPROVe, they are conspicuously consistent with it.

Other meta analyses 424 The applicant next relied on two meta‑analyses of RCTs which, he submitted, reinforced the conclusion that the consumption of Vioxx increased CVT risks and the risk of myocardial infarction. The first was that of Kearney (2006). In his report, Prof Celermajer provided the following summary of this research: The authors performed a meta‑analysis of published and unpublished tabular data from any randomised trial comparing COX-2 inhibitor use to placebo or traditional NSAIDs; where trials were ≥ 4 weeks duration and vascular event data were available. In the placebo comparisons, they found a [relative risk] of 1.42 (95% CI 1.13‑1.78) for serious vascular events, for any coxib versus placebo. They found no evidence of differences in the [relative risk] associated with different coxibs. The overall result was chiefly driven by a difference in the relative risk of acute [myocardial infarction], at 1.86 (95% CI 1.33‑2.59) with no significant difference in the rates of other vascular events in subjects on COX-2 inhibitors … The applicant relied on the relative risk figures of 1.42 for serious vascular events and 1.86 for myocardial infarction as providing support for his case on risk. 425 Profs Celermajer and Vaughan offered no criticism of Kearney. Indeed, they appeared to regard it as a good study (subject, of course to the caveats conventionally expressed in relation to meta‑analyses by comparison, for example, with RCTs). In the joint report of the cardiologists, they relied upon Kearney for their opinion that the available data disclosed no significant difference between coxibs with respect to cardiovascular outcomes; and for their opinion that that data did not show that Vioxx predisposed to thrombotic stroke. Speaking of Kearney, Prof Vaughan said: I think the Kearney analysis does the most thorough job of giving us a number with regard to the absolute risk related to the administration of a COX-2 inhibitor and that analysis gives us a number of about three events per 1,000 people allocated to a COX-2 inhibitor per year. I think what Prof Vaughan meant when he referred to the "absolute risk" was the increased risk arising from the taking of Vioxx rather than placebo. An examination of the Kearney article shows that the 3 per 1000 per year figure to which Prof Vaughan referred was the excess of events for those on coxibs by comparison with those on placebo. The absolute figures were, for coxibs, 12 per 1000 per year and, for placebo, 9 per 1000 per year. It may also be relevant to note that these figures were for "vascular events" as defined in the study, namely, myocardial infarction, stroke and vascular death. 426 Setting the background for their study, Kearney and colleagues said: The accumulating evidence suggests that selective COX-2 inhibitors are associated with an increased risk of vascular events, but several important questions remain unanswered. Firstly, what is the magnitude of any excess risk of myocardial infarction, stroke, and vascular mortality? Secondly, is the excess risk of vascular events dose related, and is the size of this risk different in people who are also taking aspirin (which chiefly inhibits COX-1 at low doses)? Thirdly, are traditional NSAIDs (which also inhibit COX-2) associated with an increased risk of vascular events? The endpoints of interest were serious vascular events, defined as fatal or non‑fatal myocardial infarction, fatal or non‑fatal stroke and vascular death (including death from myocardial infarction or stroke). It is not clear whether haemorrhagic stroke was included, but no party suggested that the results were not useful on that account. For the sake of simplicity, I shall treat Kearney as dealing with CVT events. 427 Kearney and colleagues presented their placebo‑controlled data in the following form: 428 Although the authors stated the relative risk numerically only when giving the composite results for the five coxibs being studied, it is clear from the numbers that that risk figure, in each case, was strongly influenced by the rofecoxib and celecoxib data. Using the data in the Kearney paper, Prof Woodward calculated the relative risk of myocardial infarction from ingesting rofecoxib rather than placebo. It was 1.74 (1.11, 2.72). He undertook no such calculation for vascular events generally. It was implicit in the cases of both parties, however, that I should accept the composite figure of 1.42 (1.13, 1.78) as broadly applicable to rofecoxib. I consider that the Kearney study provides firm, and relatively uncontroversial, support for the applicant's case on risk. 429 The other meta‑analysis relied on by the applicant was that of Juni (2004). The authors examined the results of 18 RCTs, in which Vioxx had been compared with placebo, with naproxen and with non‑naproxen NSAIDs. Their endpoint of interest was myocardial infarction. They examined the results by reference to the dose of Vioxx being taken. Their broad finding, taking all comparators and all doses into account, was that the relative risk of suffering a myocardial infarction from taking Vioxx rather than a comparator was 2.24 (1.24, 4.02). Their finding in relation to situations in which Vioxx was taken at a daily dose of 25 mg (all comparators) was that the relative risk was 1.37 (0.52, 3.61). When the comparator was placebo (all doses), the figure was 1.04 (0.34, 3.12). 430 The overall risk figure derived by Juni and colleagues was criticised by the respondents as being skewed upwards by the gravitational pull of VIGOR (ie because of the size of the sample in that trial). They made their point by reference to the following figure in the published article: The size of the black squares is an indication of the size of the patient samples in the various studies. Of this figure, Prof Celermajer said: So if one looks at figure 2, until the very biggest black square which is VIGOR, all the dots lie near unity. When VIGOR is introduced, the square moves to the right of unity and when you follow it vertically downwards, the black square moves back towards unity again. So the Juni meta‑analysis is driven entirely by the VIGOR result, which … is flawed because of the comparator dose of naproxen and the high dose of Vioxx. Dr Marks made much the same point. The respondents' submission was that, if the contention that the VIGOR results were largely the result of the cardioprotective work of naproxen is reasonably open, Juni went no further than to beg the question. It did not, at a statistically significant level, establish that Vioxx increased the risk of myocardial infarction. 431 The respondents' experts criticised Juni also for having omitted from the meta‑analysis trials the results of which might have been thought to favour Vioxx. Most obviously in this regard, the Juni analysis did not include the results of the Alzheimer's studies. Prof Woodward defended the authors on this aspect, pointing out that the timing of the publication did not permit them to obtain the safety data from the FDA for those studies. I accept that defence so far as it goes, but, in present context, the exclusion from a meta‑analysis of a significant body of data where the comparator was placebo must compromise the utility of the research. I also accept that the inclusion of a large trial in which naproxen was the comparator is not obviously calculated to address the questions left unanswered by VIGOR. In their final written submissions, counsel for the applicant ignored these contentious aspects of Juni. They contented themselves with drawing attention to the results as such. I accept the respondents' reservations as to this study. I consider that its utility as an indicator of the tendency of Vioxx to cause myocardial infarction is limited. 432 The respondents relied on oral evidence given by Prof Celermajer, the purport of which was to show that the relative risk (point estimate) of about 2 - observed in relation to CVT events in APPROVe - was atypical. Indeed, it was submitted that this figure lay within the 95% confidence interval for the relative risk of taking Vioxx rather than placebo in only a minority of studies. Prof Celermajer drew together what he described as "the best placebo‑controlled data" to put against the relative risk figures yielded by APPROVe. The first study which he mentioned was Konstam (2001) which, as I have indicated, contained the same data as were forwarded to the FDA on 8 January 2001. For APTC endpoints, the relative risk of taking Vioxx as against placebo was 0.84 (0.5, 1.4). The next study was the Juni (2004) meta‑analysis. There, the relative risk for myocardial infarction (although not expressly so limited by Prof Celermajer in his evidence) of taking Vioxx rather than placebo was found to be 1.04 (0.34, 3.12). Prof Celermajer next referred to the Alzheimer's disease studies, in which regard he understood that the biostatisticians had agreed that the relative risk of encountering a CVT event if taking Vioxx rather than placebo was found to be (on‑drug) 0.97 (0.7, 1.4) or (ITT) 1.24 (0.9, 1.7). The next study was APPROVe itself, in which, for CVT events, the risk of taking Vioxx rather than placebo was said to be 1.9 (1.2, 3.1). The next was the Kearney (2006) meta‑analysis, where the relative risk in the case of serious vascular events was 1.4 (1.1, 1.8). The final study referred to by Prof Celermajer was another meta‑analysis, this time relating only to myocardial infarctions, published as Chen (2007), wherein the relative risk of taking rofecoxib rather than placebo was found to be 1.38 (0.87, 2.19). 433 Profs Harper and Zipes each responded to Prof Celermajer's analysis. Prof Harper said: I have not heard of statisticians agreeing that when you have a placebo controlled trial that is the gold standard then lumping that together with lots of meta‑analyses of small studies which in themselves have no power to show an end point. Comparing that data to a placebo controlled randomised study is not appropriate and I do not [resile] from my statement that I think Vioxx at a dose of 25 milligrams has a risk factor of 2. Perhaps even higher. If you look at the APPROVe study … the total thrombotic adverse events, the risk ratio was 1.92 but if you looked at cardio events the risk ratio quoted in that study is actually 2.98 [sic - the correct figure was 2.80]. Prof Celermajer agreed with Prof Harper that a placebo‑controlled randomised clinical trial was the "sine qua non" of evidence, but added that there was a lot of evidence available, and that to throw it all out without regard for how it "contextualises" APPROVe was to risk losing much valuable information. Prof Zipes' response to Prof Celermajer was: I find [Professor Celermajer's] analysis not acceptable. It is combining oranges and apples and whatever else. However, if one were to accept that - which I don't but if one were to - my conclusion is that Professor Celermajer agrees that there is risk associated with Vioxx. It's just a question of how much. 434 I shall consider the studies described by Prof Celermajer as involving the best placebo-controlled data in turn. If one is attempting to find the most informative data, I cannot understand why the pooled analysis of January 2001 (which was the basis for the Konstam article) should be used in preference to the latest such data forwarded by Merck to the FDA (in March 2004). Neither can I understand why the APTC endpoint would be regarded as more valuable in the context of the question of the pro‑thrombotic tendency of Vioxx than the CVT endpoint (although I accept, of course, that the January 2001 data contained only the APTC endpoint). If the March 2004 data and if the CVT endpoint are used, the relative risk of taking Vioxx rather than placebo is seen to be 1.26 (0.89, 1.78). Having said that, Prof Celermajer's point, that a point estimate of 2 does not lie within this confidence interval, remains good (albeit that the interval does overlap with that observed in APPROVe). 435 As set out above, Prof Celermajer's relative risk figure does represent that reported by Juni (2004). It relates to myocardial infarction only. Being confined to the placebo comparison, the utility of the figure is not compromised in the way of Juni's overall risk figure as discussed in para 431 above. However, although the point estimate is close to unity (and for that reason the figure is unhelpful to the applicant), the confidence interval is wide enough to encompass each of the presently relevant point estimates in APPROVe (ie 1.92 for CVT, 2.53 for myocardial infarction and 2.80 for cardiac events generally). 436 I do not understand the biostatisticians in the present case to have agreed that the correct relative risk figures to be derived from Merck's Alzheimer's studies were those stated by Prof Celermajer. Merck's figure - based on confirmed CVT events occurring up to the 14th day after discontinuation - was 1.03 (0.70, 1.53). Prof Madigan's figure (which I have declined to accept) - based upon all investigator‑reported events at any time - was 1.5 (1.1, 2.0). Prof Madigan also supplied a figure which incorporated confirmed events for the "on‑drug" period and investigator‑reported events thereafter: it was 1.27 (0.91, 1.79). Aside from the investigator‑reported analysis of Prof Madigan, it is true that the confidence intervals stated here do not incorporate a risk figure of 2 or thereabouts. 437 Prof Celermajer's figure for the relative risk of a CVT event as shown in Kearney (2006) is correct; and he is correct to say that a relative risk of 2 does not fall within the confidence interval (which was 1.13, 1.78). It might be noted, however, that the myocardial infarction risk figure reported by Kearney was 1.86 (1.33, 2.59), where the confidence interval does cover the point estimate of the relative risk for myocardial infarction yielded by the APPROVe data (2.53), although only just. 438 Curiously perhaps, very little reference was made in the cases of the parties to Chen (2007). In the evidence here under discussion, Prof Celermajer relied on it. He correctly reported the relative risk figure for myocardial infarction where the comparator was placebo. Prof Woodward relied on it in his witness statement in reply. He was evidently impressed with the quality of the data from Chen, based as they were on clinical trials rather than observational studies. He said that the data supported the view that the consumption of Vioxx was associated with myocardial infarction. In the final submissions on behalf of the applicant, there was no reference to this evidence or to Chen. The respondents mentioned Chen, but with little emphasis. For myocardial infarctions, it presents a very different picture from that presented by APPROVe (although, as Prof Woodward said, being "indicative of an effect"). 439 There was a further meta‑analysis upon which Prof Woodward relied: McGettigan (2006). This study involved an examination of the data from 17 case‑controlled and 6 cohort studies, of which 9 and 2 respectively involved a comparison between use of Vioxx and non‑use. Cardiovascular events - predominantly myocardial infarction - were the endpoints of interest. The relative risk of taking Vioxx (all doses) as observed in those 11 studies was 1.31 (1.15, 1.59). Neither party relied on, or referred to, McGettigan in final submissions. Neither was it mentioned in any of the oral evidence. There was something of a technical issue played out in the witness statements of Prof Woodward and Dr Marks which related to this study, Dr Marks contending that, in relation to retrospective studies, it was accepted in the scientific community that nothing less than a statistically significant relative risk of 3 should be regarded as evidence of causation. Only two of the comparisons tabulated by McGettigan (and, as it happens, none of those that go to make up the relative risk figure referred to earlier in this paragraph) satisfied that condition. However, Prof Woodward pointed out that it was a "misconception [to contend] that studies which are, themselves, inaccurate can … not make a valuable contribution to a meta‑analysis". This study, therefore, supports both the applicant's case that Vioxx causes CVT disease and Prof Celermajer's contention that the relative risk as against placebo is somewhat less than that shown in APPROVe.

Other studies 440 The applicant relied also on a study of another coxib, valdecoxib, published as Nussmeier (2005). In that study, 1671 patients who had undergone "CABG" (coronary artery bypass grafting, pronounced "cabbage") were randomised into three arms - the first to be given paracoxib (the analog of valdecoxib) intravenously for three days followed by (oral) valdecoxib for seven days, and the third to be given placebo for 10 days. All were taking prophylactic aspirin. The relative risk of encountering a cardiovascular event (including, but not limited to, myocardial infarction) was found to be 3.7 (1.0, 13.5). Although Prof Zipes referred to this study as evidence in support of the FitzGerald hypothesis, Prof Celermajer said: The situation of cardiopulmonary bypass is a highly unusual one in that a patient's blood is circulated through an extra‑corporeal circuit of plastic tubing and this results in significant perturbations of the coagulation and haemostatic systems. Furthermore, the coronary arteries are physically manipulated and occasionally subjected to surgical trauma, as well as the heart/lung bypass circuit, often resulting in a systemic pro‑inflammatory response. For these reasons, conclusions made about COX-2 inhibitors for the relief of post‑operative pain in patients who have had open heart surgery are certainly valid, but only for that specific clinical situation. For those reasons, and because the study was not concerned with Vioxx as such, I am disposed to think that the work of Nussmeier and colleagues is of little assistance to the applicant in the present case. 441 Prof Zipes referred also to the APC study, to which I have referred at para 343 above. He relied upon the statistically significant relative risk of taking celecoxib rather than placebo with respect to cardiovascular events. Profs Celermajer and Vaughan, however, regarded this study as at least potentially corroborative of their view, expressed primarily in relation to APPROVe, that colon polyp patients may be an atypically susceptible group. Dr Reicin referred to the APC study as tending to indicate that such cardiovascular risk as might arise from the consumption of Vioxx was by way of a "class effect" in which all coxibs were implicated. As with the post‑CABG study, the APC study did not involve Vioxx as such. Since it showed a statistically significant increase in the risk of taking celecoxib rather than placebo, I am prepared to regard it as providing a measure of support for the applicant's case, but it must also be recognised that, to the extent that the respondents have a point about the susceptibility of colon polyp patients, the study likewise gives them a measure of support for treating the results of APPROVe as not generalisable.

The mortality data 442 In my consideration of the data from the various Merck trials and studies, and from published materials, I have followed the parties by focusing upon the events - generally APTC and/or CVT - reported in those sources. Additionally, the parties drew my attention to a particular category of data which, it seems, are commonly if not invariably collected in RCTs and similar studies. They are the mortality data, that is, a record of the deaths occurring amongst participating patients. To a statistician, deaths occurring for any reason will be at least potentially of interest, since the pattern of them may show an association. So too will it be of interest to know the pattern of deaths occurring as between patients taking the drug of interest and patients taking the comparator. To a clinician, of course, the cause and circumstances of each death will be of interest, since they may aid in the determination of a biological, rather than a merely statistical, association between the therapy and the death. 443 In the trials conducted in accordance with the CV SOP, Merck's "modified ITT" approach required a death to be counted if it had occurred while the patient was on study therapy or within 14 days after discontinuation or, where the death was to be ascribed to an adverse experience of interest, whenever it occurred if the adverse experience happened, or began, on therapy or within those 14 days. However, it seems that all deaths were sent for adjudication, even those that were not to be counted in the analysis. This meant that, in general, it was possible to identify how many participants in a particular study had died as a result of, for example, a CVT event, whether the event occurred either before or after the 14th day after discontinuation. 444 Although mortality data were available in respect of all the Merck studies to which the court was referred, the applicant relied only on the data which came from the Alzheimer's studies. As a result, those data, and how the deaths in those studies might have been otherwise reported and analysed, came to occupy an atypically conspicuous place in the forensic controversy. For that reason, I shall commence with them. 445 Although Merck forwarded to the FDA all the raw mortality data from the three Alzheimer's protocols, it carried out statistical analyses only with respect to Protocols 078 and 091 (probably because they were the only studies that had run their course according to the original specification). In a Combined Safety Analysis for those protocols sent to the FDA on 17 December 2003, Merck said that "[t]here were 41 (3.84%) deaths from all causes in the rofecoxib group and 23 (2.14%) in the placebo group." The relative risk (of taking Vioxx) was 2.23 (1.33, 3.73). Of these data, the author of the analysis said: The difference in deaths was due to increases in the "Injury, Poisoning and Procedural Complications," "Infections and Infestations," and "Cardiac Disorders" categories. … There was no apparent pattern in the specific cause of death to suggest an increased risk with rofecoxib. Overall, the number of patients who died during the trials was small and the findings should be interpreted with caution due to the fact that no statistical multiplicity adjustment was performed. Dealing with the subject of CVT mortality, the author said: There were 11 (l.03%) patients in the rofecoxib arm whose deaths were adjudicated as due to a thrombotic cardiovascular event and 5 (0.47%) in the placebo arm. The patient‑year adjusted incidence rates were 0.66 and 0.26 per 100 patient‑years for the rofecoxib and placebo arms, respectively. The relative risk (of CVT death from taking Vioxx) was said to be 2.56 (0.89, 7.35). 446 My attention was not drawn to any such combined analysis which included also the data from Protocol 126. For the record, however, I note from the Clinical Study Report, sent to the FDA on 22 July 2002, that there was one confirmed CVT death in the Vioxx arm and two such deaths in the placebo arm. If these figures are added to those referred to in the Combined Safety Analysis for Protocols 078 and 091, it will be seen that there were 12 CVT deaths in the Vioxx arms of the three studies and seven in the placebo arms. 447 Prof Madigan analysed the CVT mortality data yielded by the Alzheimer's studies, but he did so in two ways that differed from Merck's analysis of December 2003. First, he included the data from Protocol 126. Secondly, he used true ITT data, since all deaths had been sent for adjudication. Although he did not set out the crude numbers on which he based his calculation, his evidence was that, by reference to data available in June 2003, the relative risk of CVT death from taking Vioxx rather than placebo was 3.49 (1.48, 9.68). Dr Marks did not challenge these figures in his statement in reply to Prof Madigan. Although Prof Madigan was cross‑examined on this aspect, there was no suggestion that his figures were wrong, or that his analysis was misconceived. 448 Of the mortality data from the Alzheimer's studies, Dr Reicin said: In the Spring of 2001, medical statisticians at Merck conducted an interim analysis of data from the Alzheimer's studies. An all‑cause mortality analysis revealed that there were statistically significantly more deaths in the Vioxx group than in the placebo group. ... Cardiovascular mortality was not the key driver behind the difference in overall mortality. Cardiovascular mortality showed a small numerical imbalance that did not reach statistical significance. MRL found that there were numerically more accidental deaths and deaths related to infection on Vioxx than on placebo. Two examples include a patient that was electrocuted and an Alzheimer's patient that ingested a bromide tablet that significantly burned his esophagus that led to infections that ultimately caused his death. Dr Reicin made no comment on what was shown by the final figures (as distinct from the "interim analysis") from the Alzheimer's studies. Although she submitted a statement in reply which dealt extensively with the report of Prof Madigan, she did not challenge his mortality figures; neither did she refer to the final mortality data of December 2003. Clearly her reference to deaths arising from irrelevant causes is no answer to Prof Madigan's analysis of the confirmed CVT deaths. While it may be accepted that deaths from non‑CVT causes "drove" the overall mortality figures in one or other, or both, of the arms of the studies, the more relevant question for present purposes relates to the difference in the risk of CVT death as between the two arms. 449 In their final written submissions, the respondents referred to Prof Madigan's CVT mortality figures from the Alzheimer's studies. They submitted that those figures relied on off‑drug events (which I am prepared to assume they did). They cited Dr Reicin's evidence, set out above, that cardiovascular mortality "showed a small numerical imbalance that did not reach statistical significance", describing it as being based on "a more detailed analysis". That was not a satisfactory response to Prof Madigan's point. Dr Reicin's evidence clearly does not bespeak "a more detailed analysis" than that undertaken by Prof Madigan. The respondents relied on Dr Marks' evidence as to cardiovascular events generally which occurred long after discontinuation of study treatment. I have accepted that evidence, but neither Dr Marks nor any other expert applied it in the specific context of confirmed CVT deaths. 450 It is possible that something might have been made of the different patterns of CVT mortality as between Protocol 078 and Protocol 091 with respect to ITT versus on‑drug data collection. The Clinical Study Report for Protocol 091 noted that there was only one death that did not result from an adverse experience that began while the patient concerned was receiving therapy or within 14 days after discontinuation. That patient, an 81 year‑old female from the Vioxx arm, took Vioxx for 35 days, discontinued, and, 148 days later, experienced an adverse event which led to death. By contrast, it appears from the Clinical Study Report for Protocol 078 that, of the total of 24 deaths classified as "cardiac disorders" (a grouping which I accept is not co‑extensive with CVT disorders) (18 in the Vioxx arm and 6 in the placebo arm), 10 (9 in the Vioxx arm and 1 in the placebo arm) resulted from adverse experiences occurring after the 14th day after discontinuation. Prof Zipes referred to follow-up work which had been undertaken by Merck in relation to Protocol 078. Dealing with deaths generally (ie not confining himself to CVT deaths), Prof Zipes said: Of note however, the sponsor continued to accrue data on a significant number of subjects after discontinuation of the study, i.e., 356 in the Vioxx arm and 307 in placebo. Over a median follow up of 29 and 20 weeks respectively, 17 deaths occurred in the Vioxx arm versus only 5 in placebo. The authors do not offer statistical analysis, although it is clearly very significant. Indeed, this is a disturbing signal, consistent with long‑term toxic effects. This evidence, which was given in Prof Zipes' original report, was referred to neither in the answering reports of Profs Celermajer and Vaughan nor in the joint cardiology session. Such evidence as the cardiologists might have been able to give on the differences in the ITT data (compared to the on‑drug data) as between Protocols 078 and 091, and how they might have related to the different study designs involved, could well have thrown light on the potential for Vioxx, if taken over an extended period, to produce harmful effects over the long term. As I have said, however, the issue was not explored. 451 Doubtless because they rejected the ITT approach as such, the respondents made no attempt to reconcile their mortality figures with Prof Madigan's. The applicant too contented himself with relying on Prof Madigan's figures (although, as I have said, by reference to investigator‑reported events). Indeed, his final submissions contained no reference to the analysis of CVT confirmed deaths undertaken by Prof Madigan. The parties' cases do, in these respects, pass each other like ships in the night. It may be that some or all of the CVT confirmed deaths resulting from events which occurred more than 14 days after discontinuation so occurred a very long time thereafter, and did so in circumstances in which it might have been clinically adjudged that they had nothing to do with the treatment received in the studies (such as, possibly, the death of the patient referred to in the previous paragraph). However, the court has the benefit of no such analysis of individual events as Dr Marks provided in relation to adverse events generally. 452 In due course I shall consider whether it was unreasonable for Merck to have taken the 14‑day approach to CVT events leading to death in the Alzheimer's studies. I am here concerned not with that question but with the question whether the data from the studies, viewed in the most informative way, in fact implied the existence of CVT risk from taking Vioxx. Here I have a relative risk figure supplied by Merck to the FDA of 2.56 (0.89, 7.35). In broad terms, whether or not the events from Protocol 126 are included, there were about double the number of relevant deaths in the Vioxx arms as in the placebo arms. To the extent that a relative risk calculation is available (ie for Protocol 078 and 091 only), the difference is not significant. But the direction of the signal is unambiguous. Prof Madigan's analysis tells us that, if CVT events which occurred more than 14 days after discontinuation and which led to death are also counted, the relative risk is substantial and significant: 3.49 (1.48, 9.68). If these mortality data were looked at in isolation from those of the Alzheimer's studies generally, they would have to be regarded as providing some support for the applicant's case on risk. 453 However - and here I turn to the other studies and trials of which evidence was given - I can think of no reason why they should be looked at in isolation. Commencing with VIGOR, there were 22 deaths (0.5%) in the Vioxx arm and 15 deaths (0.4%) in the naproxen arm. Prof Celermajer said that the overall mortality rate was similar in the two arms, and he was not challenged on that evidence. These overall figures would not appear to provide a source of comfort for Merck, but, within them, the most common form of death in the Vioxx arm (four deaths) was pneumonia, while the most common forms of death in the naproxen arm (four deaths each) were pneumonia and myocardial infarction. Perhaps the most interesting statistic is that there were two deaths from myocardial infarction in the Vioxx arm and (as already noted) four deaths from that cause in the naproxen arm. 454 With respect to Merck's arthritis studies, Dr Reicin said: The Phase IIb/III osteoarthritis studies showed statistically significantly fewer deaths in the Vioxx group than in the NSAID group (diclofenac, ibuprofen, and nabumetone). This difference was driven by more cardiovascular deaths in the NSAID group than in the Vioxx group. Dr Reicin was not challenged on that evidence. 455 In the APPROVe trial, there were ten deaths in each arm that either occurred or arose from adverse events which occurred while the patients concerned were on study therapy or within 14 days of discontinuation. Of these, six in the Vioxx arm and four in the placebo arm arose from thrombotic causes. There were a further 21 deaths which occurred, or arose from adverse events which occurred, after the 14th day but during the anticipated three‑year study periods for the patients concerned: 13 in the Vioxx arm and eight in the placebo arm. Of these, three in each arm were thrombotic. 456 The only other analysis to which it is useful to refer in the present context is Kearney (2006). It will be seen that the authors' Figure 1, reproduced in para 427 above, includes an analysis of "vascular death". Although I recognise that that category is not co‑extensive with CVT death, it provides some kind of indication that the excess of deaths in the Vioxx arms of the studies there examined was only slightly above unity at the point estimate and not nearly statistically significant. 457 In the course of the cardiology concurrent session, Prof Celermajer said: [T]here is absolutely no evidence that Vioxx predisposes to fatal cardiac events. … The signal here is for non‑fatal myocardial infarction. There is no signal for fatal heart disease in any of the Vioxx trials, either in meta‑analysis [or] in the APPROVe study. Despite the fact that this evidence (which was given in the course of an exchange with the court) was not later challenged, I am not prepared to accept it at face value, as the respondents invited me to do in their final written submissions. First, as Prof Zipes immediately pointed out, the Alzheimer's data revealed a statistically significant excess of overall mortality in the Vioxx arm. It is true that Prof Celermajer was referring to cardiovascular death specifically, as to which there was no (at least uncontroversial) statistically significant excess in the Vioxx arms of the Alzheimer's studies, but I consider that it did these (non‑significant) data less than justice for Prof Celermajer to have said that "there is no signal for fatal heart disease in any of the Vioxx trials". Secondly, Prof Celermajer's comment that "the signal here is for non‑fatal myocardial infarction" is not quite correct either. Under the CV SOP, fatal and non‑fatal myocardial infarctions were counted. The "signal" in VIGOR, and in APPROVe, related to myocardial infarction, whether or not death resulted. Prof Celermajer would have been more correct to say "the signal here is for myocardial infarction generally, not for fatal myocardial infarction as such". 458 Notwithstanding those qualifications, it is as clear as may be that the only evidence of any conspicuous association between the consumption of Vioxx and CVT death resides in the data from the Alzheimer's studies. That evidence is only slightly less conspicuous when those data are looked at through Merck's 14‑day prism than when Prof Madigan's ITT approach is taken. Ultimately, I consider that the difference between those two approaches is less weighty for present purposes than the difference between the Alzheimer's mortality data, on the one hand, and the like data from other studies and trials, on the other hand. Taking everything into account, I could not conclude that there was most likely something about Vioxx that led to death as a result of a CVT event, as distinct from leading to the event itself. Neither could I conclude that, if the generality of the evidence is not such as to persuade me on the probabilities that the consumption of Vioxx increased the risk of CVT events, the mortality data would make any material difference.

The dose relationship 459 The question whether the dose at which Vioxx was ingested had an impact on the risk of CVT events is presently relevant for two reasons. First, the dose relationship is the sixth Bradford Hill criterion. No party suggested that the observed presence of such a relationship ought not to be taken into account in addressing questions of risk. Secondly, if there is such a relationship, it would go part of the way to explaining the results of VIGOR. In that trial, it will be recalled, the dose of Vioxx taken was 50 mg daily, twice the recommended therapeutic dose. 460 In their joint report, the cardiologists agreed that the data were "variable, consistent with a dose effect but not conclusive". They went beyond that, however, in their separate opinions. Profs Zipes and Harper held the view that the adverse effect of Vioxx was dose‑dependent. They relied upon the study published as Graham (2005), where the authors distinguished between patients taking 25 mg or less and patients taking more than 25 mg. Possibly because this was an observational study of the experiences of contributors to a large health care organisation in California, there was no placebo arm as such. There was, however, an arm described as "remote use" of NSAIDs - where use had ceased more than 60 days before the index date. The relative risk figures - for acute myocardial infarction taking Vioxx rather than remote use of any NSAID - were 1.23 (0.89, 1.71) for the standard dose of Vioxx and 3.00 (1.09, 8.31) for the higher dose. Prof Harper accepted that, ideally, one would not rely on observational studies, but the Graham research was one place where he had been able to find a statistical treatment of the relative risk of taking Vioxx at different doses. Profs Harper and Zipes also contrasted the results of APPROVe (where the dose was 25 mg) with those of VIGOR (where the dose was 50 mg). To them, this comparison (even allowing for some modest effect of naproxen in VIGOR) tended to point to a dose relationship. 461 When looking at the sixth Bradford Hill criterion, it was not in the respondents' interests to submit that there was a dose relationship, but they did submit, and the experts called by them expressed the opinion, that the VIGOR results were at least partly to be explained by the high dose of Vioxx involved there. In his report, Prof Celermajer drew attention to the APC trial (Solomon 2005), where the relative risk of CVT events from taking celecoxib rather than placebo (for colon polyp patients) was 2.3 (0.9, 5.5) at a dose of 200 mg twice daily, but 3.4 (1.4, 7.8) at a dose of 400 mg twice daily. He said: Therefore it is plausible that doubling the dose of rofecoxib above the recommended daily dose may have been a major factor in the observed excess CV risk of rofecoxib, when compared with naproxen in the VIGOR study. Prof Celermajer referred also to the observational study of Ray (Oct 2002), where the relative risk of acute myocardial infarction or fatal coronary heart disease (for current users of Vioxx) was, at doses of or less than 25 mg, 1.03 (0.78, 1.35) and, at doses greater than 25 mg, 1.70 (0.98, 2.95); and (for persons new to the drug during the study) it was, at doses of or less than 25 mg, 1.02 (0.76, 1.37) and, at doses greater than 25 mg, 1.93 (1.09, 3.43). To these data might be added the data of McGettigan (2006), who found that the relative risk of CVT events (mostly myocardial infarction) from taking Vioxx rather than placebo was 1.33 (1.00, 1.79) at doses of or less than 25 mg, but 2.19 (1.64, 2.91) at higher doses. Prof Woodward relied on these data to conclude that the relationship between the consumption of Vioxx and myocardial infarction was dose‑dependent. 462 The data just discussed appear to give a fairly consistent picture of a dose relationship. However, the two major meta‑analyses of RCTs discussed in the evidence - Juni (2004) and Kearney (2006) - are less helpful than one might have hoped. The relative risks yielded by the Juni data were: Dose Relative risk 12.5 mg 2.71 (0.99, 7.44) 25 mg 1.37 (0.52, 3.61) 50 mg 2.83 (1.24, 6.43) The endpoint of interest was myocardial infarction, and the authors commented that they "recorded no evidence to support the notion that rofecoxib's cardiovascular toxicity is dose‑dependent". They did not remark upon the very odd‑looking data set out above. At a dose of 50 mg those data were heavily influenced by the inclusion of the VIGOR results: for about three‑quarters of the patients who took that dose, the comparator was naproxen. For these and other reasons canvassed above, perhaps the Juni study ought to be approached with reserve. No such qualification applies to Kearney, but, unhappily for present purposes, there were too few vascular events amongst patients taking higher or lower doses of Vioxx than 25 mg to enable an evaluation of dose‑dependence. There was a weak trend towards greater risk with higher doses of celecoxib, but that trend was driven by the results of one study (Solomon 2005). 463 Although, as I have said, the Juni and Kearney studies do not confirm the picture conveyed by the other studies to which I have referred, neither do they confound it. Taking everything into account, I am persuaded that there is sufficient to justify the conclusion of Profs Zipes and Harper that such an association as there was between taking Vioxx and encountering CVT events, including myocardial infarction, was dependent, at least to an extent, on dose. This is, of course, an intermediate conclusion based on the epidemiology, and does not take biological factors into account. However, I consider that there is sufficient in the evidence to infer dose‑dependence within the framework of the Bradford Hill criteria.

Consistency of association across studies 464 To assess consistency across a broad range of studies, I have found it convenient to set out a summary of the relative risk figures referred to above in tabular form as follows: CVT Events Myocardial Infarction Lower Point Upper Lower Point Upper VIGOR 1.39 2.38 4.00 1.72 5.00 14.29 APPROVe 1.19 1.92 3.11 1.11 2.53 6.28 APPROVe extend (Baron) 1.18 1.70 2.46 1.09 1.94 3.34 Merck pooled 22 March 04

• Rheumatoid arthritis 0.43 3.57 164.23
• Osteoarthritis 0.97 2.84 8.38
• Alzheimer's disease 0.70 1.03 1.53
• All 0.89 1.26 1.78 Madigan RA/OA 1.30 3.10 9.20 Madigan AD, CV death 1.48 3.49 9.68 VICTOR adjusted 0.93 2.41 6.26 Juni (all doses) 0.34 1.04 3.12 Kearney (all coxibs) 1.13 1.42 1.78 1.33 1.86 2.59 Kearney (Vioxx) per Woodward 1.11 1.74 2.72 McGettigan (mostly MI) 1.15 1.35 1.59 Chen 0.87 1.38 2.19

465 Several things should be said about this table. First, save for VIGOR (where the comparator was naproxen) the comparator in each group of data in the table was placebo. Secondly, I have not included the results reported by Konstam (2001), Reicin (2002) or Weir (2003) as those results are effectively comprehended, and superseded, by the pooled analysis of March 2004. Thirdly, where the data were controversial as between the parties in this case, I have prepared the table in accordance with the findings I have made earlier in these reasons. Fourthly, I have set out the figures in a way that places the point estimate between the lower and upper 95% confidence limits, both to assist in a ready understanding of the table and to emphasise that the statistically correct statement conveyed by a particular set of figures is that the true relative risk would lie, in 95% of the cases, between those limits. Fifthly, I have included the McGettigan data in the CVT column, but, as noted, those data were predominantly made up of myocardial infarctions. 466 As I have said, APPROVe was the primary trial upon which the applicant relied. Are the results of the other studies consistent with it? Commencing with VIGOR, there are two particular circumstances which, I accept, most probably contributed to the higher (and, in the case of myocardial infarction, much higher) rate of events in that trial. The first is that the comparator was naproxen. Although the experts did not express it this way, to recognise that the beneficial effect of naproxen was to an extent responsible for the VIGOR results appears to introduce greater, not less, harmony with the APPROVe results. In the case of myocardial infarctions, if naproxen (taken twice daily consistently) is assumed to reduce the risk by about a third, and possibly by up to a half (ie on the basis that the benefit of naproxen in VIGOR may have been similar to that found in Watson (2002) and Kimmel (2004)), one might suppose that up to about a half of the 5.0 relative risk figure in VIGOR was attributable to the work of naproxen. The second circumstance is the 50 mg dose which was used in the VIGOR trial. Although it is impossible to quantify the dose effect, for reasons given above I accept that there most probably was one. 467 Because of the uncertainties involved, it would, in my view, be going too far to say that VIGOR provided support for the actual risk figures yielded by APPROVe. None of the expert witnesses proposed any scientific means by which the risk figures of VIGOR might be adjusted to allow for naproxen and dose. I would not presume to undertake that task. However, those two factors together clearly had the potential to explain the difference between the data of the two trials. In this sense, I am persuaded that the conclusion, presented primarily by APPROVe, that Vioxx was associated with a higher incidence of CVT disease, and of myocardial infarction in particular, is consistent with the results of VIGOR. 468 Turning to the other data set out in the table above, the first impression one gets is that there is nothing like a uniform picture of the extent of the relative risk involved in consuming Vioxx rather than placebo. Such picture as emerges is patchy. However, certain things can be said. First, wherever a statistically significant relative risk is shown, it is a risk of consuming Vioxx rather than placebo. Secondly, even where the figures are not statistically significant, the point estimate lies above unity. Thirdly, the non‑Merck meta‑analysis which attracted the most conspicuous support in the submissions of the respondents - Kearney - yielded a statistically‑significant positive risk of taking coxibs both for CVT events and for myocardial infarction. As Prof Woodward demonstrated, the same may be said for Vioxx as such in relation to myocardial infarction. Fourthly, as against these considerations, the Merck Alzheimer's disease results were not significant and yielded a point estimate very close to unity. So too are the Juni myocardial infarction figures equivocal, but they were based on early data and are not, in my view, sufficient to qualify the conclusion otherwise proper to be reached from the data in this table. That conclusion, in my view, is that the results of the studies referred to in the table are broadly consistent with APPROVe, at least to the extent of showing a greater risk of CVT events and of myocardial infarction if Vioxx rather than placebo is taken. 469 As problematic as it obviously is, it is also necessary that I attempt at least a broad quantification of the extent to which the studies referred to, taken together, suggest that these risks were increased for patients taking Vioxx. From the perspective of public health authorities and manufacturers such as Merck, it may be enough to conclude that there was an increased risk. Such a conclusion will usually be sufficient to warrant the taking of some kind of corrective action. However, the exercise with which the court is presently concerned involves the ex‑post determination of the cause of an event, or series of events, which has happened. Here the task will be advanced to no small degree if it is possible to identify the extent of the increased risk associated with the activity or substance of interest. 470 Although the simplest approach to this task is to take the point estimate of the relative risk figures yielded at statistically significant levels by various studies, it is important to bear in mind what such figures convey. By stating the point estimate, one does not identify a unique figure which, at the 95% confidence level, represents the relative risk. As made clear earlier in these reasons, the point estimate is only the "best estimate" of the true relative risk. That estimate is not made with 95% confidence. Rather, the statement that can be made with 95% confidence is that the true relative risk lies within the confidence intervals which invariably accompany the point estimate as reported. Subject to that caveat, and being conscious of the limitations involved, it is not inappropriate to use the point estimate as a general indicator of relative risk. The parties and their experts did so in this case, and I propose to do likewise. 471 It was the point estimate for the relative risk figure yielded by the APPROVe results that formed the basis for the conclusion of Profs Zipes and Harper that the risk of encountering a CVT event approximately doubled when a person took Vioxx. As I understood their position, they would say that the risk of myocardial infarction would increase by a factor of about 2.5, also because of the results of APPROVe. Profs Celermajer and Vaughan disagreed. In Prof Celermajer's reading of the studies taken as a whole, the more typical relative risk figure was seen to be about 1.4 (for CVT events) (see para 432 above). 472 In my consideration of this question, I should remember that, although the question must be decided on the balance of probabilities, it is a question of central importance in this case. Here the words of Dixon J in Briginshaw v Briginshaw (1938) 60 CLR 336, 361 have direct application: The truth is that, when the law requires the proof of any fact, the tribunal must feel an actual persuasion of its occurrence or existence before it can be found. It cannot be found as a result of mere mechanical comparison of probabilities independently of any belief in its reality. 473 In this forensic context, I consider that the results of the various studies, trials and analyses referred to above warrant a number of observations. First, notwithstanding the technical quality of APPROVe, for reasons expressed above, the generalisability of its results must be regarded as a matter of some uncertainty. Secondly, the extended analysis of the APPROVe results, to which I was invited to have regard by the applicant, show relative risk figures, both for CVT events and for myocardial infarction, which are lower, and within tighter confidence intervals, than the original figures (notwithstanding that the lower limits of the confidence intervals remained effectively unchanged). Thirdly, the one meta‑analysis on which I was invited to rely by both sides, and of which neither was critical, yielded a relative risk figure for CVT events (within fairly tight confidence limits) in line with Prof Celermajer's figure of 1.4, and for myocardial infarction which was broadly consistent with that yielded by the APPROVe follow‑up data. It is true that the Kearney study related to a number of different coxibs, but it may be noted that Prof Woodward's analysis of the Vioxx‑only myocardial infraction data revealed a relative risk figure that was lower (albeit only slightly) than that yielded by the data generally. Fourthly, despite their limitations, there is nothing in the McGettigan data (which were not drawn exclusively from RCTs) or in the Chen data (which did not yield a statistically significant result) which would tend to contradict any of the observations made above. 474 Turning to the other available data, while I am persuaded that the VIGOR results play an appropriate role in supporting the conclusion that the consumption of Vioxx increased the risk of CVT events and myocardial infarction, I do not think they are useful in the quantification of that risk. I have held that naproxen and dose both most probably contributed to the results, but any attempt on my part to place a figure on the extent of that contribution would be altogether too hazardous, particularly when I have rejected the applicant's evidence that the naproxen effect was no more than about 2%. I am prepared to say that the VIGOR results are not inconsistent with those of APPROVe and the APPROVe follow‑up study, but I could not go to the length of finding that they supported a quantification, say, of something more than 2 rather than of something less than 2. 475 It is Prof Madigan's combined arthritis figures that make a striking contrast with those of APPROVe and the meta‑analyses. What Prof Madigan did, by pooling, was to give statistical significance to the relative risk data of the separate Merck osteoarthritis and rheumatoid arthritis studies. In the case of the original osteoarthritis data, the relative risk figure was very nearly significant and, subject to that qualification, the point estimate for CVT events was substantially greater than the corresponding figure yielded by the other studies to which I have referred. I would say the same about Prof Madigan's relative risk figure for cardiovascular death in patients covered by the Alzheimer's studies. However, Prof Madigan's figures related only to CVT events as a group, and tell us nothing (at least directly) about myocardial infarction. Also, I am here concerned to estimate, so far as possible, the extent to which the consumption of Vioxx increased the relative risk of encountering a CVT event as a general proposition, rather than (at this stage at least) to make such an estimate with respect to patients suffering from a particular condition. In that setting, I can see no reason not to recognise that the (non‑fatal) data yielded by the Alzheimer's disease studies, although non‑significant, conveyed no message of risk, or not to combine those data with those from the arthritis studies. 476 In the result, I am persuaded that, taken as a whole, the data referred to warrant generalisation that, over a population, the consumption of Vioxx increased the risk of CVT events by a factor of about 1.5, and of myocardial infarction by a factor of about 2. I make these findings because of the allegations in the applicant's pleading and because of the questions which I am required to address. Their practical utility, however, must be understood to be subject to two qualifications. First, they are based on the statistical results of the trials and studies referred to. They take no account of issues of mechanism, to which I shall turn next. And secondly, they relate, as I have said, to people generally. The data may have a rather different utility when the circumstances of a particular person, suffering a particular condition, are required to be considered.

The FitzGerald hypothesis 477 Turning to the third Bradford Hill criterion - the existence of a plausible biological explanation - the applicant relied primarily on the FitzGerald hypothesis. It will be convenient to commence by considering the nature of CVT disease. In terms with which the other cardiologists did not disagree, Prof Vaughan laid out the basic steps in the development of CVT disease as follows: 1) injury to the arterial wall; 2) the adherence and migration into the vessel wall of monocytes (a certain type of cell); 3) uptake of oxidized LDL (low‑density, or "bad" cholesterol) into the arterial wall; 4) progression of lipid accumulation within the atherosclerotic plaque and development of a necrotic, lipid core; 5) destabilization and thinning of the plaque's fibrous cap overlying the necrotic, lipid core; 6) rupture or erosion of the fibrous cap exposing the highly prothrombotic contents of the plaque to the circulating blood; and 7) thrombosis and resulting ischemia. 478 Prof Zipes explained that there were "roughly four … main stages" of atherosclerosis: The first stage for the development of atherosclerosis is that of endothelial injury, or damage to the inner cellular lining of the blood vessel wall (by hypertension, shear stress, toxins like nicotine, diabetes, etc.). The damaged inner lining attracts the adherence of white blood cells to its surface… The second stage is one of fatty streak formation. The LDL cholesterol ("bad" cholesterol) penetrates the endothelium … and accumulates in the vessel wall. When this LDL is oxidized as a result of its penetration into the arterial wall … it sets up an inflammatory reaction in the endothelium, attracting more white blood cells that ingest the oxidized LDL. These white blood cells called monocytes become "foam cells" after they ingest the LDL, and are the hallmark of the fatty streak … These cells also elaborate a host of inflammatory mediators … that promote inflammation in the fatty streak, regulate the direction, amplitude and duration of the immune process, and contribute to the progression of the lesion and formation of a plaque. The third stage is one of fibrous cap formation, which is probably the first step in the development of a complex lesion that can cause an acute thrombosis … that can close off an artery. This fibrous cap prevents the lipid core that has accumulated beneath it from contacting the blood pool. But the cap is susceptible to damage from activated white blood cells that secrete enzymes which weaken the collagen in the cap. Inflammation, occurring for reasons that are poorly understood, appears to play an important role in the activation of white blood cells that later undermine the fibrous cap. The final stage is the development of a complicated atheroma, which typically occurs when rupture of the weakened fibrous cap causes the blood to come into contact with the lipid core, causing the formation of a thrombus. Physical disruption of the atherosclerotic plaque, due to fracture of the fibrous cap or superficial erosion of the intima, commonly causes acute thrombosis. Thrombus formation occludes the blood vessel, interrupting blood flow to the perfused organ, in this case the heart. If the thrombus dissolves spontaneously, it may cause a healing response that thickens the fibrous cap, making it bulge into the lumen of the artery and further restricting blood flow by the atheroma. If the thrombus persists and completely occludes the vessel, the downstream myocardium dies due to lack of blood flow, which is the definition of [myocardial infarction]. 479 It is the seventh step in Prof Vaughan's sequence, or the fourth stage referred to by Prof Zipes, where the imbalance hypothesized by Dr FitzGerald and his colleagues is said to have a biological impact, favouring the development of thrombotic material in the vasculature. 480 In the joint report of the cardiologists, Profs Zipes and Harper said that the FitzGerald hypothesis was biologically plausible and provided a reasonable explanation for the observed association between the consumption of Vioxx and adverse cardiovascular events. They would apply that conclusion to all COX-2 inhibitors, but added that Vioxx at a dose of 25 mg daily had a more powerful effect on COX-2 inhibition than Celebrex at a dose of 200 mg daily, and therefore carried a greater risk of adverse cardiovascular events at those doses (ie consistently with the FitzGerald hypothesis). By contrast, Profs Celermajer and Vaughan said that they were "not convinced that the FitzGerald hypothesis is biologically relevant to an understanding of the pathophysiology of plaque rupture and thrombosis." Prof Vaughan said that there was nothing to suggest that the mechanisms proposed in the FitzGerald hypothesis were unique to selective COX-2 inhibition. He said that all COX inhibitors, with the exception of low-dose aspirin and high-dose naproxen, were statistically similar with respect to cardiovascular risk. 481 I have explained the origins, and broadly the content, of the FitzGerald hypothesis at paras 43‑47 above. In final written submissions on his behalf, the applicant put it as follows: The basic premise of the FitzGerald hypothesis is that selective inhibition of COX-2, while sparing COX-1, upsets the critical balance between prostacyclin and thromboxane, thereby increasing the likelihood of thrombosis. That premise was, however, articulated in a rather more sophisticated way in the evidence of the cardiologists called by the applicant. In his witness statement, Prof Zipes relied upon the following passage in Antman (2005): COX-1 is the only isoenzyme expressed in platelets; endothelial cells express both COX-1 and COX-2. In the normal artery, the balance between PGI2 and TXA2 production favors PGI2 and inhibition of platelet‑dependent thrombus formation. In the atherosclerotic artery, both PGI2 and TXA2 production is increased, owing in part to increased platelet activation with compensatory PGI2 formation via both COX-1 and COX-2 in endothelial cells; the net effect is an imbalance favoring TXA2 production and platelet‑dependent thrombus formation. Low‑dose aspirin selectively impairs COX-1‑mediated TXA2 production in platelets restoring the net antithrombotic balance. COXIB use suppresses COX-2 dependent PGI2 production in endothelial cells, which has only a marginal effect on the net antithrombotic balance owing to the importance of COX-1 as a source of PGI2 in the normal state. In the setting of atherosclerosis, however, COX-2 plays a greater role as a source of PGI2 and more TXA2 is produced; thus, inhibiting COX-2 in this setting has a more profound effect on prostanoid balance, favoring TXA2 production and promoting platelet dependent thrombosis. Likewise, Prof Harper said: The drug Vioxx is a selective inhibitor of the [COX-2] enzyme. Inhibition of this enzyme in atherosclerotic arteries has been shown to adversely alter the balance between the production of prosta‑cyclin … which is a protective substance secreted in the lining cells of blood vessels and thromboxane A2 … which is a substance secreted by platelets. TxA2 is a potent vaso‑constricting compound that is highly active in aggregating platelets and acts to promote clot formation. … In contrast, PGI2 is a vaso‑dilator substance which causes dilatation of blood vessels and directly antagonises the constricting and procoagulant effect of TxA2. Vioxx unfavourably alters the balance between these two agents by blocking the production of PGI2 thereby enhancing the effect of TxA2 thus increasing the risk of clot formation on an athero‑sclerotic plaque. Save for standing as explanations of the mechanism hypothesised by Dr FitzGerald, the significance of these statements is that they situated the scientific debate with which the court is presently concerned in the context of the atherosclerotic vasculature. 482 The cardiologists called by the respondents did not accept the FitzGerald hypothesis as a plausible explanation for the relatively greater number of CVT events amongst patients taking Vioxx observed in some trials and studies. Prof Celermajer said that, while he originally considered that the hypothesis "had some potentially attractive features", later publications had "cast significant doubt on its validity". He said that there were problems with the hypothesis and its applicability to humans, namely: (a) The hypothesis reduced a highly complex system to an overly simplistic paradigm. (b) Because prostacyclin acted locally, and was not a circulating hormone, the presence of the urinary metabolite was, or at least might well be, evidence only of prostacyclin production in the kidney and urinary tract. (c) Numerous studies had shown that the selective inhibition of COX-2 - or, more accurately, the sparing of COX-1 - did not, as would have been expected, lead to an increase in the urinary levels of thromboxane metabolites. (d) In the studies that had been conducted, there was no evidence that the supposedly adverse effects of COX-2 inhibition were neutralized by the inhibition of aspirin. (e) A 1979 study found that even a 90% decrease of prostacyclin release by endothelial cells still left enough prostacyclin to prevent platelet aggregation in humans in vivo. (f) In a 1981 article, Dr FitzGerald himself suggested that the vasculature did not produce enough prostacyclin for it to be a systemic antiplatelet agent. (g) There was doubt over whether endothelial cells produced prostacyclin via the COX-2 pathway. (h) Contrary to what one would expect if the FitzGerald hypothesis were valid (an early sign of the increased incidence of CVT events in patients taking Vioxx), in the APPROVe trial the risk of CVT events appeared to emerge only after about 18 months. The data on the time‑relationships involved in the emergence of risk were not consistent between trials, but they did not provide support for the hypothesis. (i) There were multiple, mutually‑compensating, systems which regulated thrombosis and bleeding in the vasculature. It was unlikely that perturbation of any single system would not result in some counter‑balancing compensatory change of another system. (j) Recent studies involving other coxibs - lumiracoxib in 2004 and etoricoxib in 2006 - did not reveal significant differences between groups, on an ITT analysis. (k) Recent studies which showed a possible increase in cardiovascular risk in the case of patients taking non‑selective NSAIDs called into question the "unbalanced inhibition" aspect of the FitzGerald hypothesis. Prof Celermajer found items (d) and (h) on this list most important in raising doubts about the FitzGerald hypothesis. 483 Prof Vaughan said that there were "numerous unresolved questions" which limited the interpretation that could be placed on the findings out of which the FitzGerald hypothesis arose. In his report, he continued: For example, prostacyclin is generally viewed as an autocoid, meaning that it is generated and acts locally. At this time, I am not aware of any studies that have ever been done to define the relevance or magnitude, if any, of COX-2 dependent prostacyclin production in the human coronary circulation. Importantly, there is no evidence to suggest that COX-2 is in fact present in normal human arterial vasculature. Indeed, numerous studies indicate that human arteries exclusively generate COX-1. Furthermore, the studies that suggested that COX-2 inhibition reduced systemic prostacyclin production were based on reductions in the measurement of a stable prostacyclin metabolite in the urine. The precise location of the tissue responsible for this effect and altered prostacyclin synthesis has not been determined. Studies in humans suggest that COX-2 inhibitors do not, however, affect prostacyclin production in the human vasculature … Furthermore, it has been shown that COX-2 inhibition has no effect on endothelial vasodilator function in adults … Taken together, the data from experimental and preclinical studies have thus far failed to generate a consistent picture or understanding of the potential impact that COX-2 inhibitors might or might not have on the progression of human cardiovascular disease. 484 Against this background of contention, it is convenient to turn to the case advanced by the respondents in opposition to the hypothesis. They proposed that there were seven "necessary key assumptions that must apply in both healthy and diseased vasculature for the FitzGerald hypothesis to be operative". They were:

1. Compensatory systems in the vasculature are insufficient to overcome the prothrombotic effect caused by an imbalance between prostacyclin and thromboxane.
2. Reductions in the prostacyclin urinary metabolite (PGI‑M) correspond to actual reductions in prostacyclin in the vasculature.
3. COX-2 is present in the endothelium.
4. COX-2 rather than COX-1 makes endothelial prostacyclin.
5. A partial reduction in prostacyclin will have a clinical effect.
6. COX-2 inhibition has no effect on thromboxane levels.
7. The balance between prostacyclin and thromboxane is critical for preventing thrombosis. I am not at all satisfied that each of these points is apt to be described as an "assumption". As I understand it, the FitzGerald hypothesis is not based on assumptions. It takes as its starting point observed outcomes from pharmacological studies, and hypothesises a biological process consistent with those outcomes. However that may be, these points were used by counsel for the respondents in the cardiology concurrent evidence session to seek to obtain a degree of scientific consensus for the implicit proposition that the FitzGerald hypothesis was in effect unsound. As will be apparent, that endeavour was largely unsuccessful, but the respondents' points will nonetheless provide a convenient framework within which to assess the strength of the applicant's case to the extent that it relies on the hypothesis. I shall, however, deal with these points in what I consider to be a logical sequence, rather than in the order in which they are set out above. 485 I take first the second point, namely, that the FitzGerald hypothesis requires that "reductions in prostacyclin urinary metabolite (PGI‑M) correspond to reductions in prostacyclin in the vasculature". As it seems to me, this was in the nature of a pharmacological premise used in the interpretation of the data on which the hypothesis was based. Profs Zipes and Harper agreed with the proposition that "if the FitzGerald … hypothesis is to be proved to be correct one has to assume that the reduction in the prostacyclin metabolites in the urine necessarily correspond to reductions in prostacyclin in the arterial vasculature". They also agreed that "the measurement of urinary metabolite, … is a systemic rather than a local measurement", that "the FitzGerald studies of themselves don't point to the reduction in prostacyclin in the arterial vasculature" and that the mechanism proposed by the hypothesis was "one possibility but … not demonstrated by the studies". 486 The respondents then moved to the proposition that the reduction in the urinary metabolite observed in the studies on which the hypothesis was based was probably not sourced in the vasculature (item (b) on Prof Celermajer's list if problems). However, they so proposed on the strength of studies from which the operation or non‑operation of COX-2 in the endothelium might be inferred. That aspect was more directly the concern of the third and fourth of the respondents' points, to which I shall turn next. Directly on the question of the source of the metabolite observed in the original studies on which the FitzGerald hypothesis was based, it seemed to be common ground that no direct evidence was available. 487 Turning next to the third of the respondents' points, namely, that COX-2 is present in the endothelium, all the cardiologists agreed that that circumstance was a necessary precondition to the validity of the hypothesis. There was, however, vigorous disagreement as between Profs Zipes and Harper, on the one hand, and Profs Celermajer and Vaughan, on the other hand, as to whether COX-2 was in fact present in the endothelium. In expressing their respective opinions, the cardiologists referred to studies from which the presence or absence of endothelial COX-2 might be inferred, at which point the debate (inevitably as it seemed to me) dealt also with the fourth point, namely, whether COX-2 rather than COX-1 makes endothelial prostacyclin, and under what circumstances. These points address the problem which was item (g) on Prof Celermajer's list. 488 Prof Vaughan dealt with the subject at the level of the normal vasculature. I have set out (at para 309 above) what he said on the matter in his original report. He developed this evidence in his second witness statement: However, the report generally cited to support the proposition that the COX-2 enzyme is present in normal vasculature used cultured endothelial cells. … Furthermore, it is highly debatable that endothelial cells derived from umbilical cords actually display the functional or biological properties of endothelial cells in the human systemic arterial or coronary vasculature. It is well known that endothelial cells functionally transform under the artificial conditions of life outside the body in tissue culture. A more valid and informative way of looking at protein expression and localization in endothelial cells utilizes immunohistochemistry staining of fresh, intact human vasculature. Importantly, these studies demonstrate that COX-2 is not normally present in blood vessels .… 489 As I understood Prof Zipes, however, he regarded it as something of a distraction to focus upon the healthy vasculature. In the healthy, he said, "… [prostacyclin] is not likely to be increased and, therefore, not likely to play an important vasodilator role, so COX-2 inhibition would not be expected to have a major inhibitory effect …." Indeed, it was as good as common ground between the cardiologists that it was the constitutive enzyme COX-1 that synthesises prostacyclin in the normal, healthy, state. Rather, Prof Zipes asserted that the inducible enzyme COX-2 synthesised endothelial prostacyclin under inflammatory conditions: see the extract from his original report at para 481 above. 490 In short, Prof Zipes contended that, in an atherosclerotic or like inflammatory state, the production of prostacyclin is in effect up‑regulated by COX-2. He referred to several studies in support of that conclusion, most notably the one published as McAdam (2005). Since this article was relied on also by the respondents (in respects to which I shall refer presently), it became a significant focus of debate in the cardiology concurrent session. In the study, smokers and non‑smokers received rofecoxib 25 mg twice daily or placebo for one week each in random sequence. The synthesis of systemic thromboxane and prostacyclin was assessed by an analysis of their respective urinary metabolites. Serum TXB2 was measured as an indicator of platelet COX-1 activity. It was found that, at baseline, the excretion of the urinary metabolite of prostacyclin was significantly higher in smokers than in non‑smokers, that both were reduced in the group taking rofecoxib, and that the reduction in the smoking group was significantly greater than the reduction in the non‑smoking group. The study confirmed previous work that thromboxane synthesis was greater in smokers than in non‑smokers. In non‑smokers, there was no significant difference in the synthesis of thromboxane as between the placebo arm and the rofecoxib arm. However, in smokers, the administration of rofecoxib produced a 21% reduction in the synthesis of thromboxane as measured by the urinary metabolite, while there was no reduction in the placebo group. The administration of rofecoxib produced no significant difference in the levels of serum TXB2. In their article in Circulation, McAdam and colleagues expressed the following conclusion: In conclusion, prostacyclin biosynthesis in cigarette smokers was found to be derived largely from COX-2. This major reduction in prostacyclin biosynthesis during COX-2 inhibition in smokers, however, was not accompanied by an increase in the level of the urinary metabolite of TXA2. Indeed, rofecoxib lowered TXA2 metabolite levels in smokers to a greater extent than in nonsmokers, which indicates that TXA2 biosynthesis via COX-2 is increased in cigarette smokers. 491 In his first witness statement, Prof Zipes said of the McAdam study that it supported - … the notion that [prostacyclin] is predominantly derived from endothelial COX-2 because it was increased by smoking, which would not be expected to affect renal [prostacyclin] production, but also suggesting that some non‑platelet TXA2 is also COX-2 derived. In concurrent evidence, Prof Zipes said that the study demonstrated - … [t]hat the smokers and non‑smokers had very different responses, that the inflammatory response from the smoking is interpreted to have increased prostacyclin and hence, their elevated excretion following COX-2 inhibition and [the authors draw] the conclusion from that that it more likely than not is from the endothelium and it has been induced by COX-2. This final proposition - as to the locus of the prostacyclin seen to be elevated in smokers - was not accepted by the respondents. When asked to identify the passages in the article which supported his position, Prof Zipes was offered by counsel for the respondents, and accepted, the opportunity to consider the matter over the course of an adjournment. By the time counsel returned to the point, the McAdam article had been extensively canvassed by the cardiologists in connection with another of the respondents' points. Prof Zipes was then asked to identify the passages to which he had originally intended to refer, and he did so. He was not, at that stage, reminded of the terms of the question, in relation to which he had intended to search the article. Although he did respond by identifying certain passages, they did not, at least on my understanding of them, establish the proposition that the elevated production of prostacyclin observed in smokers had an endothelial source. 492 Prof Vaughan dealt also with the presently controversial issues in the context of the unhealthy vasculature, in which respect he said that "[i]nvestigators have directly measured prostacyclin metabolite levels in the blood of patients with atherosclerosis and failed to see a reduction in patients taking a COX-2 selective inhibitor". Here Prof Vaughan relied on two studies, only one of which was the subject of any observation by Prof Zipes. That one was published as Kuklinska (2005). Prof Zipes agreed with the proposition that this study, involving a cohort of patients with a clinically obvious cardiovascular disease, demonstrated that a low dose of rofecoxib did not diminish prostacyclin synthesis. However, it appeared that patients in both arms of the study were receiving statins. Prof Zipes' comment on the study was that the FitzGerald hypothesis had "nothing to do with statins" and that the study did not, therefore, "in any way disprove that hypothesis". He said that statins were anti‑inflammatory, and "for all we know may preserve prostacyclin". It also appeared that the dose of rofecoxib being taken was 12.5 mg/day, which Prof Harper described as "a very low dose". Prof Zipes argued that it was "an insufficient dose to have reduced the prostacyclin metabolism particularly when combined with a statin". 493 Turning to Prof Celermajer, he said in his report that there was doubt over whether endothelial cells produced prostacyclin via the COX-2 pathway. He said that animal studies had implicated primarily COX-1, and that certain in vitro experiments had found no evidence of COX-2-dependent prostacyclin production by endothelial cells. He referred to a study which had identified the expression of COX-2 in cultured endothelial cells stimulated by being placed under shear stress conditions for 24-48 hours (Topper 1996), but added that more prolonged shear stress (for 7 days) was not associated with an increased expression of COX-2 (Dekker 2002). He observed that there was a difference between isolating and proliferating endothelial cells in a culture dish and the behaviour of such cells in the intact organism. In that respect, Prof Celermajer said that the expression of COX-2 had not been found to be expressed in the endothelial cells of a normal umbilical vein, but that expression of the enzyme appeared only during cell culture. 494 Prof Zipes responded by referring to studies (Hla 1992; Jones 1993) in which "the human nucleic acid sequence of COX-2 was cloned from unstimulated endothelial cells, reflecting the unstimulated expression COX-2". He said that COX-2 had also been found in atherosclerotic lesions, and mentioned a study in which the expression of COX-2 had been found in human and mouse vessel walls, and in which it was stated: "The failure of some studies to report COX-2 expression in endothelial cells ex vivo (outside the body) may reflect the particular experimental circumstances and/or discordance between the offset kinetics of flow‑induced gene expression and the time of sample preparation." Prof Celermajer distinguished the studies relied upon by Prof Zipes, in various ways, as being inapplicable to the question whether COX-2 was present in the endothelium. He concluded (in his oral evidence) that "the totality of evidence provided by Professor Zipes in his report does not demonstrate COX-2 protein in relevant human arteries but it suggests that the prostacyclin in the vessels is thereby coming from COX-1". 495 Ultimately, there was no satisfactory resolution of the disagreement between Prof Zipes, on the one hand, and Profs Celermajer and Vaughan, on the other hand, with respect to the questions whether COX-2 is present in the endothelium and, if so, whether it was responsible for the synthesis of prostacyclin in an atherosclerotic situation. I should not be surprised by that circumstance. The cardiologists' disagreement lies at the centre of the scientific controversy with which this proceeding has been concerned. The results of Protocol 023 were unexpected for the very reason that it had not been previously thought that COX-2 was present in the endothelium: see the views of Dr Morrison and of the authors of Catella-Lawson (1999) set out at paras 44 and 46 above respectively. Dr Fitzgerald and his colleagues thereafter hypothesised that COX-2 was present in the endothelium, and that the inhibition of it would alter the prostacyclin - thromboxane balance with pro-thrombotic consequences. However, to the extent that the synthesis of prostacyclin is seen to be up‑regulated (inferentially by COX-2) in an atherosclerotic or other inflammatory situation, it does not appear to have been scientifically established that that prostacyclin has an endothelial source. On the other hand, to the extent that the respondents' endeavour was to disprove (forensically) the FitzGerald hypothesis by establishing the falsity of the third and fourth points proposed by them to be inherent in the hypothesis, I would have to find that they have not done so. Prof Zipes seemed to have a response - which I could not find to be illegitimate - to each of the pieces of scientific evidence upon which Profs Celermajer and Vaughan relied, whether it be that that evidence related only to healthy subjects, that the study in question involved subjects who were taking statins, or similar. If the FitzGerald hypothesis is otherwise to be regarded as providing a plausible biological explanation for the results of the APPROVe study, I am not persuaded that it should be disqualified by the established fact that COX-2 is not present in the atherosclerotic endothelium. 496 The respondents made another point which might be conveniently mentioned at this stage. It relates to Prof Zipes' disclaimer, in effect, of any claim to the relevance of the healthy vasculature. Profs Celermajer and Vaughan responded by pointing out that the studies on which the FitzGerald hypothesis was originally based involved healthy subjects. As Prof Celermajer put it: "[T]he FitzGerald hypothesis was derived from healthy individuals. I just note that because both Professors Zipes and Harper resile from healthy individual data but that is the data on which the FitzGerald hypothesis is based." Prof Vaughan referred to the McAdam study of celecoxib, which - … was performed in healthy individuals and indeed, COX-2 inhibition reduced the levels of the prostacyclin metabolite. This was the whole basis of the hypothesis using healthy people. In his written submissions in reply, the applicant contended that, in the context of Protocol 023 (Catella‑Lawson 1999), "healthy" should not be regarded as synonymous with "without atherosclerosis". However, during the examination of the cardiologists by counsel for the respondents in concurrent evidence, counsel for the applicant interjected to make a specific point about whether Protocol 023 and the companion study on celecoxib involved healthy adults. Profs Zipes' and Harper's attention was drawn to the point, and they agreed that they did. Counsel for the applicant did not subsequently invite the cardiologists to infer that the study might have involved subjects with atherosclerosis. 497 Because the applicant's experts effectively limited their reliance on the FitzGerald hypothesis to atherosclerotic or other inflammatory situations, the court is spared the task of addressing the question whether the studies of healthy adults upon which the respondents relied, and which were not consistent with the proposition that COX-2 mediated the synthesis of prostacyclin in the endothelium, compromised the hypothesis. On the other hand, the fact that the studies out of which the hypothesis grew involved healthy subjects only does seem substantially to limit the value of the hypothesis itself in the setting of an atherosclerotic vasculature. The position to which the applicant attached himself was that endorsed by Profs Zipes and Harper, namely, that the FitzGerald hypothesis identified a scientifically plausible explanation for the more frequent occurrence of cardiovascular thrombotic events amongst those taking Vioxx in such a setting, whether or not the experimental facts upon which the hypothesis was originally based were seen to be replicated. 498 I propose next to consider the sixth of the respondents' points. Here they proposed that the FitzGerald hypothesis required that "COX-2 inhibition has no effect on platelet thromboxane". In the course of their concurrent evidence, counsel for the respondents had each of the cardiologists agree with that proposition. It became apparent from what followed, however, that the proposition was not understood in the same sense by all present. Prof Zipes made it clear that he understood the proposition to be a reference to the hypothesis itself, rather than to any "assumption" or precondition necessary for its validity. So understood, the proposition was that, conformably with the hypothesis as identified by him, the inhibition of COX-2 would reduce the levels of prostacyclin in the vasculature, while leaving levels of thromboxane unaffected. To confound that proposition, counsel for the respondents first drew Prof Zipes' attention to so much of McAdam (2005) as showed that, in smokers, the urinary metabolite of thromboxane was "significantly reduced" by taking rofecoxib (ie the 21% reduction referred to above). Prof Zipes agreed that the study did show that. In their written submissions, the respondents contended that this reduction "demonstrates that COX-2 can also produce thromboxane", which was said to be "inconsistent with the FitzGerald hypothesis". However, Prof Zipes was not induced to any such concession, and neither Prof Celermajer nor Prof Vaughan so asserted. 499 The scientific purport of this sixth point came to the fore only when Prof Celermajer contributed to the discussion. As will appear, what was apparently intended by the respondents was to propose that, if the FitzGerald hypothesis were sound, one would actually see an increase in the production of thromboxane after the administration of rofecoxib (as suggested by item (c) on Prof Celermajer's list of problems); or, put differently, that the hypothesis was contradicted by the absence of any such increase in the studies upon which it was based. Prof Celermajer explained the biological basis of that proposal. He explained how, if the mechanism proposed by the hypothesis were empirically valid, one would, inescapably, observe an increase in thromboxane upon the inhibition of COX-2. He said that platelet activation and aggregation were mutually positively reinforcing. An active platelet was more likely to aggregate with other active platelets. In turn that released thromboxane, which brought other platelets in and activated them to aggregate as well. He said that prostacyclin was a specific chemical entity that bound to a receptor on the surface of the platelet to render it quiescent. The loss of that "brake", as Prof Celermajer put it, should allow the platelets to be active, and to aggregate, on a larger scale than when the brake was on, and if so, one would expect to see an increase in the production of thromboxane. 500 Agreeing with Prof Celermajer, Prof Vaughan made much the same point as follows: So the platelet is a cellular entity. It has specific receptors for prostacyclin. When prostacyclin is engaged by those receptors it initiates specific signalling inside the platelet that basically increases levels of factors that help keep the platelet quiescent. So as one individual platelet goes bumping around through your vasculature, through your arteries, through your capillaries, through your veins, it's exposed to a variety of situations where it might be predisposed to activate but that prostacyclin that's in the vasculature helps keep the platelets quiet. If you don't have that prostacyclin, then theoretically they are more likely to aggregate - or activate than aggregate in the presence of any factor that stimulates them whether it be collagen or thromboxane or ADP or any other of a variety of noxious factors that stimulate platelets to become activated. Both Profs Celermajer and Vaughan proposed that, if someone were in a potentially thrombotic state, and if the source of prostacyclin were turned off, then, if the FitzGerald hypothesis were valid, one would almost inevitably see an elevated production of thromboxane. 501 Returning to the point being made by counsel for the respondents as to the relationship between the administration of a coxib and the production of platelet thromboxane, Prof Celermajer said: I am sure I see what you are getting at, Mr Garling, which is if there is an imbalance that creates a prothrombotic environment the necessary consequence of a prothrombotic environment is some thrombosis and if thrombosis occurs, platelets will release thromboxane. So you must, if you hypothesise a prothrombotic balance, find thromboxane levels increase because of the thrombus that results from the imbalance, and none of the data that we have seen show urinary thromboxane metabolites going up. So it supports the idea that this is a hypothetical imbalance that actually has no prothrombotic consequence, because if it had a prothrombotic consequence you would have thrombus and you would have thromboxane go up … Prof Celermajer said "in the McAdam study where they have measured very specifically the platelet thromboxane it is unchanged in the presence of Vioxx". Prof Celermajer was here referring to the measurement of serum TxB2 rather than to the urinary metabolite (the latter being a measure of systemic thromboxane only). He clarified his point as follows: I think the paper itself makes this abundantly clear and I will just read two sentences from the abstract … The first sentence is the "Background" section: We further hypothesised that if the overproduction of prostacyclin in smokers were restraining platelet activation, then inhibition of COX-2 would lead to an increase in the activation of platelets with a corresponding increase in the biosynthesis of thromboxane. So their hypothesis is if you have an imbalance then removing the imbalance will activate the platelets. The next sentence I wish to read you is from the end of the methods and results: Levels of serum (TxB2) were not different in smokers and non‑smokers and were unaffected by rofecoxib. So the hypothesis that was set up in sentence one is unproven by the study which suggests that the hypothesis is incorrect. The hypothesis, … is - … if the overproduction of prostacyclin in smokers were restraining platelet activation then rofecoxib would increase platelet activation … … and that is unproven by the study. Prof Vaughan added, on this issue of the response of thromboxane to the administration of a coxib: The first author of this publication, Brendan McAdam, was a fellow in my division in cardiovascular medicine in Vanderbilt when this paper was completed, in fact some of the measures performed in this study were done in my own laboratory. We measured the c‑reactive protein and other markers of platelet activation for Brendan. Brendan's hypothesis was accurately summarised by Professor Celermajer there. They expected to see the presence of an augmented thrombotic state by delivering Vioxx to the individuals in the study and they thought they would [prove] the FitzGerald hypothesis … that prostacyclin would go down and in this higher risk group there would be evidence of platelet activation systemically and that thromboxane levels would go up. In fact, it did nothing and Brendan was astonished that that was the result. 502 Prof Zipes agreed with his colleagues' exposition of the mechanism of the interaction between the activation of platelets and prostacyclin in the non‑medicated vasculature. He continued: However, that interaction between the reduced prostacyclin and elevated thromboxane platelet derived, if it produces a thrombosis, it does it locally and that local event is exactly as my learned colleagues have described in terms of activating the platelets locally. This is not a systemic indication that would increase thromboxane levels to a degree that are easily measured but very importantly for the vessel involved, if it happens locally it could still occlude the vessel but you would not get a measurable increase in thromboxane. It's all in a very tiny area. So I don't see how or why this should be in conflict with the overall FitzGerald hypothesis. Prof Harper, who otherwise was not involved in this aspect of the controversy, added: I just think it's important to emphasise from a broad perspective if someone is taking Vioxx they are not immediately going to clot things off. The process only becomes relevant when a stimulus for platelet aggregation occurs and if the stimulus is great, platelet aggregation will occur irrespective. If the stimulus is small then perhaps it wouldn't have occurred to the same extent, but in the presence of Vioxx, because of the mechanisms described, it occurs to a greater extent than it otherwise would. 503 It does seem to have been accepted by Profs Zipes and Harper that, if the FitzGerald hypothesis were sound, one would expect to see an increase in the generation of platelet thromboxane consequent upon the administration of a COX-2 inhibitor. That such an increase has not, apparently, been seen in any human context that might be considered to be presently relevant does, in my opinion, compromise to an extent the utility of the hypothesis to provide a mechanistic basis for the risks associated with the consumption of Vioxx contended for by the applicant. I could not say that the hypothesis itself must be taken to have been disproven - that would be a scientific rather than a legal judgment, and is beyond the court's role. To the extent that the applicant relies on the hypothesis as part of his legal case, however, I would have to say that the issues discussed in this part of my reasons justify the non‑scientific conclusion that the validity of the hypothesis is a matter of vigorous controversy amongst the experts, and that the rationale relied on by opponents of the hypothesis does seem to be intelligible, coherent and justified by the empirical evidence to which they point. 504 I turn next to the respondents' seventh point, namely, that the balance between prostacyclin and thromboxane is critical for preventing thrombosis. In their written submissions on this point, the respondents referred to the evidence with which I have dealt above under their sixth point (the effect of coxibs on thromboxane levels). This was not, however, the sense in which the point was put to the cardiologists in concurrent evidence. That was confined to a debate as to the consequences - hypothesised and observed - of the concurrent administration of aspirin with a coxib (item (d) on Prof Celermajer's list of problems). 505 All the cardiologists provided an affirmative answer to the following question: I think everyone has agreed that there are multiple systems assisting clotting and haemostasis in the body of which the prostacyclin and thromboxane balance is one but would you agree for FitzGerald as a hypothesis to be scientifically correct that it must be critical for that balance to exist to prevent thrombosis? The cardiologists were then asked whether, if the balance were critical as proposed, the use of aspirin would be expected to neutralise any adverse effect from the selective inhibition of COX-2. Prof Harper's answer was to say that there was "evidence that aspirin does not protect against the deleterious effects of COX-2 inhibitors". Prof Zipes accepted that there was such evidence, but he considered that there were explanations for it, not inconsistent with the FitzGerald hypothesis. Before coming to those explanations, I should refer to the material upon which the respondents relevantly relied. 506 In his evidence, Prof Celermajer had previously (ie previously to counsel for the respondents articulating their seven assumptions) pointed to what he described as "two key pieces of data" to demonstrate that, contrary to what one would expect if the FitzGerald hypothesis were valid, the administration of low‑dose aspirin did not appear to have any effect on the occurrence of cardiovascular adverse events in patients taking a COX-2 inhibitor. The first was the meta‑analysis published as Kearney (2006). Included in the trials for which data were available were 84 placebo-controlled trials that allowed concomitant use of aspirin. The authors stated that they "found no significant heterogeneity of the summary rate ratios for vascular events among aspirin users and non‑users … [and] a similar lack of heterogeneity for myocardial infarction, stroke, and vascular death .…" Profs Zipes and Harper indicated that they were aware of the meta‑analysis by Kearney and others. It was then put to Prof Zipes that, if aspirin were not providing that protection, "that tells against the scientific validity of the FitzGerald hypothesis". He agreed that it might, but he said that it was "[known] from from well done studies that aspirin may not always protect and there are good explanations as to why it may not work." He provided four reasons why aspirin might not neutralise the harmful effect of COX-2 inhibition without disproving the FitzGerald hypothesis. They were that (1) the dose of aspirin taken may not have been sufficient in the trials which demonstrated that the administration of aspirin made no difference, (2) there may, in such trials, have been concomitant administration of ibuprofen or naproxen, (3) the coxib itself may biochemically interfere with the beneficial work of aspirin, and (4) to some extent thromboxane may be synthesised by COX-2 in inflammatory cells, additionally to the normal course of synthesis by COX-1 in the platelets (and, implicitly, in such a situation the acetylation of platelet COX-1 by aspirin would not mean the end of thromboxane production). 507 Prof Celermajer's other piece of data was the study of Nussmeier (2005) in the context of patients who had had CABG. As I have indicated, all patients were taking aspirin, but the relative risk of encountering a cardiovascular event as between continuous coxib use and placebo was 3.7 notwithstanding. In their published article, Nussmeier and colleagues said: Cardiopulmonary bypass increases the levels of both prostacyclin and thromboxane A2. … However, administration of aspirin, as in our study, theoretically inhibits the formation of thromboxane by platelets. Low‑dose aspirin prevents myocardial infarction and stroke, … and Mangano … has shown that postoperative administration of aspirin is associated with a reduced risk of death and cardiovascular and cerebrovascular ischemic complications after CABG requiring cardiopulmonary bypass. Although our study protocol required the administration of 75 to 325 mg of aspirin daily, resistance of platelets to aspirin is known to occur after CABG. … These aspirin doses, administered concurrently with a selective COX-2 inhibitor after CABG, may have been insufficient to block the formation of thromboxane by platelets in some patients. … Also, 7 of the 20 thromboembolic events (35.0 percent) occurred at least two days after all study medications had been discontinued. Another factor may be thrombocytosis, which is common within two weeks after surgery. … In clinical conditions of enhanced platelet regeneration, the prevalence of COX-2‑dependent synthesis of thromboxane may be increased .... I have set out this lengthy passage because, as I understood him, Prof Zipes would wish to associate himself with the authors' explanations of why, in this particular study, the administration of aspirin did not apparently mitigate the adverse impact of the coxib and of why, therefore, the result of the study was not necessarily inconsistent with acceptance of the FitzGerald hypothesis. 508 Of Prof Zipes' explanations for the apparent lack of impact by aspirin, Prof Celermajer said: … it seems to me [that] both Professor Zipes and Professor Harper … are using the results of outcome studies to justify an interpretation of mechanistic data, whereas in fact what I think you are trying to ask is if one assumes the mechanistic data are correct, that aspirin inhibits COX-1 and so co‑administration of aspirin removes the imbalance postulated by the FitzGerald hypothesis, then you would expect certain outcomes that weren't observed in Kearney and Nussmeier, for example. So my view is that the answers that Professors Zipes and Harper have given have used the outcomes to justify the mechanism rather than predicting what the mechanism should show and then examining if the outcomes of the study support that. Specifically in connection with Prof Zipes's fourth reason (in para 506 above), Prof Celermajer said: [T]hat in no way invalidates my argument because in someone on aspirin and Vioxx, COX-1 is gone and COX-2 is gone so prostacyclin is gone and thromboxane is gone, from whatever source. It's predominantly from platelets and it's gone because of COX-1 inhibition and a little bit comes from macrophages but that's gone with COX-2 inhibition. So if you are taking aspirin with Vioxx, the imbalance is gone and if the imbalance is gone and there is no difference in observed events the FitzGerald hypothesis is untenable. Prof Vaughan stated his opinion as follows: I think Kearney's analysis really points to a very important issue. I mean, if anything, you would expect to see a beneficial effect of aspirin in the setting of COX-2 inhibition because theoretically, at least according to the FitzGerald hypothesis, prostacyclin production is reduced, therefore those patients would be exquisitely sensitive or there would be a therapeutic effect of aspirin. The fact that aspirin doesn't make any difference says again that the hypothesis is non‑operational. 509 Finally on this question, Prof Zipes relied on the following passage in Grosser (2006): Finally, the issue of a mitigating effect of low‑dose aspirin has not been addressed in the RCTs [randomized controlled trials]. This seems biologically plausible as COX-l knockdown in mice which genetically mimics the impact of low‑dose aspirin … attenuates the prothrombotic and hypertensive effect of COX-2 inhibition .… However, aspirin use was only prespecified in one of the RCTs in humans: TARGET. As mentioned, this was under‑powered to address the cardiovascular question. However, the available evidence is compatible with risk attenuation; the relative risk of myocardial infarction was reduced from 2.37 in nonusers to 1.36 in those patients taking aspirin when lumiracoxib was compared with naproxen. However, this might also reflect a differential capacity of naproxen versus lumiracoxib to interact with and undermine the antiplatelet effect of low‑dose aspirin …. Counsel for the respondents made the point, which Prof Zipes accepted, that the authors of this article noted that the study referred to (TARGET) was underpowered in relevant respects. Notwithstanding that, Prof Zipes contended that there were indications, contrary to what appeared from the meta‑analysis by Kearney and others, that low‑dose aspirin might be mitigatory. 510 The respondents invited me to find that the FitzGerald hypothesis could not be sound for reasons which involved the demonstrated absence of mitigation by the administration of low‑dose aspirin. However, that is itself an issue upon which I could not find that there was a scientific consensus. It is not just that Prof Zipes resisted the conclusion drawn by Profs Celermajer and Vaughan, it is also that he derived support in that resistance from the observations (albeit guarded and qualified) of the authors of the Nussmeier and Grosser papers. Notwithstanding that, there appear to be quite solid empirical data (ie those referred to by Kearney and colleagues) that are inconsistent with the hypothesis that coxibs are pro‑thrombotic because they leave thromboxane unaffected while suppressing prostacyclin. In this state of scientific uncertainty, I take the view that the absence of demonstrated mitigatory impact of low‑dose aspirin stands in the way of an unqualified acceptance of the FitzGerald hypothesis as a mechanistic explanation for the empirical data on which the applicant relies. 511 The next of the respondents' points to which I propose to turn is that the FitzGerald hypothesis required that a partial reduction in prostacyclin would have a clinical effect. Each of the cardiologists agreed with that as a proposition. Counsel for the respondents then put the following question to Prof Zipes: Isn't it the fact that even a 90 per cent decrease of prostacyclin released by endothelial cells still leaves sufficient prostacyclin to prevent platelet aggregations in humans? It was put to Prof Zipes that, if that statement (which corresponds with item (e) on Prof Celermajer's list of problems) were correct, it would stand "as a large demonstrative barrier to a successful demonstration of the FitzGerald hypothesis". Prof Zipes did not agree. He said: "It's going to depend upon where the prostacyclin is as to its interaction with thromboxane". When asked if he supported the proposition that a 90% decrease of prostacyclin still left enough prostacyclin to prevent platelet aggregation in humans, Prof Celermajer said: "In the circumstance where that study was performed, yes". Prof Vaughan agreed. 512 The study to which Prof Celermajer referred was that published as Jaffe (1979). Of that study, Prof Celermajer said: Jaffe and Weksler … noted that even a 90% decrease of prostacyclin release by endothelial cells still left enough prostacyclin to prevent platelet aggregation in humans in vivo. Thus one would have to postulate a very profound inhibition of prostacyclin indeed, and establish that no compensatory mechanisms through other enzyme systems such as [nitric oxide] synthase were invoked, for the FitzGerald hypothesis to hold true. Prof Zipes' response to this statement was as follows: What [Prof Celermajer] does not include is that this statement, taken from a 30‑year old study, was based on projected (not measured) PGI2 levels calculated from the assumed surface:volume ratio of the normal human vascular system. Jaffe and Weksler published no experiments in this study to prove that statement. Further, the calculations were computed from estimates in a theoretical normal individual and, therefore, with normal TXA2 levels. Obviously, if TXA2 levels were elevated in an atherosclerotic individual, the assumptions would not hold. 513 Exactly what Prof Celermajer meant by "the circumstance where that study was performed" was not clarified. Some light is thrown on the subject by a consideration of the (previous) evidence of Prof Cleland given in the rheumatology concurrent session. The following passage from the Jaffe article was referred to by counsel for the respondents: Thus in vivo production of PGI2 at 10% of maximum could theoretically yield a peak blood PGI2 concentration of [about] 830 nM (2.8 nM x 2.86 x 103/9.6). In vitro, such levels of PGI2have a profound inhibitory effect on platelet behavior. For example, 1.4 nM PGI2 fully inhibited thrombus formation, and 57 nM PGI2 inhibited platelet adhesion by 56% when human blood was exposed to rabbit aorta subendothelium [reference given]. Furthermore, 47 nM PGI2 caused a half‑maximal increase in platelet cyclic AMP to a level of [about] 12 times basal level [reference given] when only a doubling of cyclic AMP was needed to inhibit platelet aggregation [reference given]. Similarly, we have reported that 0.1 nM PGI2 completely inhibited platelet aggregation in platelet‑rich plasma induced by threshold levels of arachidonic acid [reference given]. Thus, in man and experimental animals even a small fraction of the productive capacity for PGI2 in normal blood vessels should result in more than enough PGI2 to inhibit platelet function. Prof Cleland responded by pointing out that, in their comment about the ability of rather low levels of endothelial prostacyclin to inhibit platelet aggregation, the authors were referring to studies other than that as to which the article was directly written. He said that it would be more informative to look at those other studies. He continued: The issue about in vitro studies is they help you to explore mechanism and show you what's possible. They don't allow you to predict accurately what happens in the whole body. They certainly give you a guide as to what to look for and what might happen but there are a lot of uncertainties here. Here we have early methods based on endothelial cell culture in artificial culture media. There's no issues of COX selectivity addressed here. Pressed to respond to the conclusion by Jaffe and Weksler that "the ability of endothelial cells in normal blood vessels to produce PGI2 seems to be far in excess of that needed to inhibit platelet function", Prof Cleland said: I don't think that's necessarily correct. These studies were undertaken in the era when they were trying to sort out optimal doses for low dose aspirin and really, what they are arguing is even though aspirin has some systemic effect on prostacyclin production it's not sufficient to override a possible beneficial effect of taking low dose aspirin on the platelet. The issue as to whether sustained long term inhibition of systemic prostacyclin production via COX-2 has adverse cardiovascular effects in a minority of patients, a minority to those affected, isn't excluded by these studies. Profs Celermajer and Vaughan were not taken to this evidence, and said nothing more about the Jaffe article than I have indicated above. 514 I must say that the respondents' final written submissions dealt with this point as to the clinical effect of a partial reduction in prostacyclin in a way that, to put it most charitably, did not reflect the thrust of the questions put to the cardiologists or to Prof Cleland. Those submissions referred to the evidence given by Profs Celermajer, Vaughan and Zipes, but contained no argument as to why I should accept the proposition implicit in the respondents' reliance on the Jaffe article. The submissions merely asserted, without elaboration, that Prof Zipes had "relie[d] on weak criticisms to argue that the study is flawed". I did not understand Prof Zipes so to contend. 515 The respondents' submissions proposed that their experts had "concluded that a vascular prostacyclin reduction of greater than 90% would be required to prevent platelet aggregation". As I understood the position with which Profs Celermajer and Vaughan implicitly agreed in concurrent evidence, however, it was that a vascular prostacyclin reduction of greater than 90% would be required to permit platelet aggregation. The submissions then argued that Prof Celermajer had "put it most succinctly" when he said: It's fanciful, in my view, to suggest that ... the relatively modest inhibition of prostacyclin production by Vioxx - which even if you believe Catella‑Lawson is only around 60 per cent - would sway the balance. The submissions relied also on Prof Vaughan: "… to think prostacyclin has to do all that work on its own against an infinite excess of thromboxane is really almost - it's unimaginable"; and "… if you inhibit prostacyclin production it doesn't really matter because there's so much thromboxane there in the first place. Even if you didn't inhibit it, it can't really counteract what's happening specifically at the site of a clot …". 516 Thus, as it seems to me, the respondents are simultaneously tying themselves to two contradictory positions in proposing that a partial reduction in prostacyclin will not have a clinical effect. Ironically perhaps, either position, if valid, may well justify such a proposition. The first position (the one put to the cardiologists in concurrent evidence) is that even a reduction of 90% would not have a clinical effect in the sense that the remaining 10% would be sufficient to inactivate platelets. The second position (that most clearly relied on in the respondents' written submissions) is that, even in the absence of any reduction, endothelial prostacyclin is unlikely to be sufficient to cope with what Prof Vaughan described as "an infinite excess of thromboxane". That position appears to be consistent with Prof Harper's evidence that there is a distinction between great and small stimuli to platelet aggregation. As he said (see para 502 above) if the stimulus is great "platelet aggregation will occur irrespective". This is, I consider, an important point, and I shall return to it. For present purposes, however, my conclusion is that the mechanism proposed by the FitzGerald hypothesis, if otherwise consistent with the science, is likely, at least in some circumstances, to have a clinical effect. 517 I turn finally to the first of the respondents' points, namely, that the FitzGerald hypothesis implies that compensatory systems in the vasculature are insufficient to overcome the prothrombotic effect caused by an imbalance between prostacyclin and thromboxane (item (i) on Prof Celermajer's list of problems). Prof Celermajer's position was effectively that upon which this point was based, and was set out in his report: In addition to the prostacyclin/thromboxane system, the classical coagulation pathway, platelets, the [nitric oxide] system and the plasminogen activation/activation inhibition systems are all relevant components to a delicately balanced homeostasis for humans, which has the vital function of preventing excessive bleeding and excessive thrombosis. It is unlikely that perturbation of any single system would not result in some counter‑balancing compensatory change of another system and there are extensive data to suggest a degree of cross talk between several of these systems, especially the prostaglandin and [nitric oxide] systems. Prof Vaughan's position was as follows: It's rather interesting to look at important clinical trials that have examined the relative relationship between arterial or vasodilator capacity - arterial vasodilator capacity which is mediated by nitric oxide. For example, if you have an impairment in flow mediated vasodilation that is a predictor of cardiovascular events over time. The nitric oxide system is one of the systems that helps protect against thrombosis. So not only does it plausibly impact upon things like platelet aggregation, there's clinical data to indicate that impairments in flow mediated vasodilation project risk. … There is another system that contributes to our ability to protect ourselves against intervascular thrombosis, that's the plasminogen activator system. It involves the release of [tissue plasminogen activator] from our endothelial cells which facilitates the dissolution of clots. Impairments in arterial [tissue plasminogen activator] release are associated with increased cardiovascular events over time. As the respondents pointed out in their written submissions, Prof Vaughan resisted the proposition that the different vascular systems here under discussion were, as proposed by Prof Celermajer, "delicately balanced". 518 Profs Zipes and Harper accepted that the regulation of thrombosis and bleeding involved a complex interaction in the human system and that "in the classical coagulation pathway there [were] a number of relevant components" including the platelet system, the nitric oxide system, the plasminogen activation systems and the activation inhibition systems. They accepted that that each of those pathways had extensive "cross‑talking or cross‑connection between them with one system leading to compensatory changes in the others" and that there were "multiple lines of defence to clotting in an artery". However, Prof Zipes did not accept the next proposition put to him by counsel for the respondents, namely, that "the FitzGerald hypothesis assumes that by altering but one of the multiple systems for clotting the others will not undertake any compensatory effect". He said that "the FitzGerald hypothesis could clearly be operative and overpower whatever compensatory mechanisms are there or interact with those mechanisms in some fashion". When asked if he knew of any study that established that the compensatory mechanisms were insufficient to overcome the imbalance proposed in the FitzGerald hypothesis, Prof Zipes said that "when you have a myocardial infarction you have completed the essential experiment and that imbalance has led to a thrombus that [oc]cluded a vessel". 519 Prof Harper's response was more lengthy, and, because of its importance, should be set out in full. He said: In any system there is always [a] compensatory system but if an outcome occurs such as a thrombus then clearly the compensatory system hasn't been sufficient. I think in the setting that we are describing a plaque rupture is a very strong stimulus to clot formation and therefore you need - the compensatory system has to be strong to overcome it. But the degree of stimulus depends on - not all plaque ruptures are the same so in some plaque ruptures the stimulus is so strong because of exposure of collagen, et cetera, that nothing can overcome it, and irrespective of whether a patient is or isn't on Vioxx some plaque ruptures will clearly lead to a heart attack. But it's possible that some plaques are ruptures that would otherwise not lead to an event. If the stimulus for thrombosis is slightly more, is slightly greater, then in that particular case the thrombus will occur, and my concept is that Vioxx does increase the risk of thrombosis. I am not convinced that it's necessarily the FitzGerald hypothesis, and that that sometimes leads to an event that otherwise wouldn't occur. The sense of what Prof Harper most recently said in this passage would have been more accurately rendered in transcript as "… my concept is that Vioxx does increase the risk of thrombosis (I am not convinced that it's necessarily the FitzGerald hypothesis) and that that sometimes leads to an event that otherwise wouldn't occur." 520 There was no resolution of the disagreement amongst the cardiologists on this point, most probably because it effectively lies at the core of the FitzGerald hypothesis itself. That is to say, whereas Profs Zipes and Harper, following FitzGerald, hypothesised that a disturbance of the balance between endothelial prostacyclin and platelet thromboxane might well lead to thrombotic consequences, Profs Celermajer and Vaughan proposed a number of reasons why it need not. Profs Zipes and Harper accepted the existence of the compensatory systems to which the others referred, but adhered to their position that the inhibition of COX-2 was nonetheless a factor - albeit one amongst several - that would have an impact in a certain direction. They were never likely to concede that the existence of the other systems to which Profs Celermajer and Vaughan referred would eliminate the potential for that impact, and they did not. 521 Overall, the burden of the evidence of Profs Celermajer and Vaughan was that the FitzGerald hypothesis was, as an explanation of the consequences of the inhibition of COX-2 in the vasculature, still no more than a hypothesis. It had not been scientifically validated. Profs Zipes and Harper accepted that, but contended that, as such, it was a biologically plausible explanation for what was observed in APPROVe and elsewhere. Prof Harper's position was that the data yielded by APPROVe established that the consumption of Vioxx increased the risk of CVT events, and that it did not matter greatly whether Dr FitzGerald's hypothesis was the explanation. He did, however, consider the hypothesis to be plausible. Prof Zipes' position was somewhat more categorical, in that he regarded the hypothesis as the only plausible explanation for the data currently known to science and, in the absence of a better explanation, he considered that the hypothesis should be accepted. 522 In assessing the plausibility of the FitzGerald hypothesis as an explanation for what was observed in APPROVe, one must, in my view, keep in mind that we are here concerned to identify an explanation for adverse events which occurred in a small minority of the patients who took Vioxx. Even taking account of the extended range of data looked at in Baron (2008), of the 1287 patients in the Vioxx arm, only 59 suffered CVT events (of which 34 were myocardial infarctions) in the period under review. On any view, therefore, it could not be said that taking Vioxx "caused" these endpoints in the sense of giving rise to them as a direct and inevitable consequence. That is not a complete answer to the applicant's case, of course, but it provides a context for assessing questions of plausibility. It is not surprising that, under certain conditions and in certain study settings, outcomes which might reasonably be expected if the FitzGerald hypothesis were valid are not consistently observed. 523 Summarising the position reached after consideration of the respondents' seven points which were said to confound the FitzGerald hypothesis, I would commence by noting that there is no scientific consensus as to the presence of COX-2 in the endothelium or as to its activity in a situation of atherosclerosis. As noted earlier in these reasons, prostacyclin acts only in the immediate vicinity of its synthesis, which means that, if it were to have an effective anti‑aggregatory role in the platelets, it would need to be synthesised in the endothelium at, or closely adjacent to, the point of interest. It seems that, scientifically, whether this is so remains a matter of hypothesis. 524 One piece of pharmacological evidence that would at least have pointed to the validity of the FitzGerald hypothesis would, it seems, have been an increase in the production of platelet thromboxane in response to the inhibition of COX-2 in the context of an inflamed vasculature. However, the researchers who studied this aspect found no such consequence. Profs Zipes and Harper pointed out that that was not conclusive, a proposition which I accept. But the result does add to, rather than reduce, the uncertainty associated with the consequences in the vasculature of inhibiting COX-2 while sparing COX-1. 525 The mitigation of the hypothesised pro‑aggregatory effect of selectively inhibiting COX-2 by the administration of low‑dose aspirin would be another mark of consistency between the FitzGerald hypothesis and the empirical experience. No such mitigation, however, has been observed. Again, there may be reasons for this which do not involve the rejection of the hypothesis, but neither can we mark down the aspirin effect as a sign of consistency of the hypothesis with actual experience. 526 That brings me to the final two points raised by the respondents as to the FitzGerald hypothesis. They concern the linkages between the mechanism proposed by the hypothesis and the clinical outcomes potentially produced. Here there are, it seems, two aspects to consider. The first relates to the characteristics of the event or events in the vasculature which give rise to the presumptive thrombus. The second relates to the system's biological response to those events. Both are, I consider, important to an assessment of the hypothesis generally and to the attribution of a causal relationship between COX-2 inhibition and a CVT event in a particular case. 527 As to the first aspect, I refer to the evidence of Prof Harper which I have set out at paras 502 and 519 above. Of all the cardiologists, Prof Harper had, if I may observe without disrespect to his colleagues, perhaps the most conspicuous focus upon clinical, as distinct from experimental, circumstances. He made it clear that, whether or not the FitzGerald hypothesis is valid, we are not here talking about absolutes. In the unmedicated vasculature, the stimulus to platelet aggregation following plaque rupture may be weak, or it may be strong. A small or large thrombus may result. It may lead to an occlusion of an artery more or less immediately, or it may do so later, possibly in conjunction with other prothrombotic circumstances then existing. However these factors may work out in the normal case, when the selective inhibition of COX-2 is added to the mix, in Prof Harper's view there is now another pro‑aggregatory factor which, in all cases, makes it that much more likely that what would not otherwise have been a CVT event becomes one and that a CVT event that would in any event have occurred occurs sooner. 528 As to the second aspect, all the cardiologists were agreed that the vasculature has a number of systems which tend to protect it against the consequences of platelet aggregation. If the FitzGerald hypothesis is valid, the up‑regulation of endothelial COX-2, resulting in the production of prostacyclin, is one of them. In that event, the selective inhibition of COX-2 would leave the vasculature with one less defensive mechanism than it has in the unmedicated state. That was the position for which Profs Zipes and Harper (and, indeed Prof Cleland) contended. But the continued existence (and importance) of the other defensive mechanisms - together with the heterogeneous nature of aggregatory stimuli -means that the inhibition of COX-2 will not necessarily render thrombotic all events or circumstances which otherwise would not have been so. If the FitzGerald hypothesis is valid, it may be supposed that, over a population of patients, there will be some for whom the inhibition of COX-2 will make a difference, but it seems that there may not be a way of knowing before the event who those patients will be or of diagnosing after the event who those patients were. 529 Starting from the position that, if the FitzGerald hypothesis is valid, it makes a statement about the course of thrombus formation after plaque rupture, the position, therefore, seems to be more or less as follows. In the unmedicated vasculature, some ruptures generate strong stimuli which lead to thrombi, even with prostacyclin doing its presumptively compensating work. In the context of selective COX-2 inhibition, some ruptures generate weak stimuli which do not have thrombotic outcomes because of the compensatory work of the other systems to which Profs Celermajer and Vaughan referred, notwithstanding the absence of prostacyclin. Between these extremes, it is postulated that there are some stimuli which are of a strength, and which occur in cardiovascular settings generally, as would be effectively counteracted by the compensatory systems as they exist in the unmedicated vasculature, but where the removal of prostacyclin would make a clinical difference. If I am correct in supposing that there are these various combinations and permutations, it is not surprising that the studies that have looked at the cardiovascular consequences of COX-2 inhibition have produced varying results. 530 Does the FitzGerald hypothesis provide a plausible biological explanation for the excess of CVT events observed in the results of APPROVe and the other studies to which I have referred? Before answering that question, I propose to consider the remainder of the applicant's submissions on the biological issues, as a consideration of them has the potential to throw light on the relationship between the results of the trials and studies in which Vioxx was involved and the mechanism on which the applicant relies.

Other aspects of a biological explanation 531 The applicant submitted that Vioxx "contributed" to each of the four stages of atherosclerosis identified by Prof Zipes. In this respect, he relied first upon the following statement by Dr FitzGerald himself in what Prof Zipes called an "opinion piece" written in 2004: Thus, a single mechanism, depression of prostaglandin I2 formation, might be expected to elevate blood pressure, accelerate atherogenesis, and predispose patients receiving coxibs to an exaggerated thrombotic response to the rupture of an atherosclerotic plaque. A reading of Dr FitzGerald's piece, however, shows that he used the expression "might be expected to …" as an indication of what his research group hypothesised in 1999. Be that as it may, the passage above refers to three respects in which Vioxx might have harmful effects: the elevation of blood pressure, the acceleration of atherogenesis and the exaggeration of the thrombotic response to plaque rupture. The third is the concern of the FitzGerald hypothesis itself. The other two were also the subject of direct evidence by the cardiologists in this case. 532 The cardiologists were asked for their opinion on the question whether Vioxx affected blood pressure. In their joint report, they said that Vioxx did increase blood pressure in some subjects, adding that they did not believe - … that the blood pressure raising effect of Vioxx is significantly different from that of other NSAIDs. As these drugs affect salt and water handling by the kidney, their effects on [blood pressure] are broadly similar. Profs Zipes and Harper, however, added that they considered that the effect of Vioxx on blood pressure was greater than that of Celebrex, and in another part of the joint report they expressed the view that Vioxx had a more pronounced hypertensive effect than either Celebrex or other NSAIDs. Profs Celermajer and Vaughan disagreed, adhering to the view that Vioxx did not cause more hypertension than other NSAIDs. 533 For his view that Vioxx contributed to hypertension, Prof Zipes relied on a meta‑analysis of 19 RCTs involving coxibs published as Aw (2005). The relative risk of developing hypertension from taking Vioxx rather than placebo was found to be 2.63 (1.42, 4.85) and the corresponding figure where the comparator was the non‑selective NSAIDs combined was 1.78 (1.17, 2.69). In his statement in reply, Prof Vaughan said that the Aw study contained "several methodological limitations", most importantly the inclusion of RCTs in which Vioxx had been taken at doses higher than any that would be recommended to be used chronically. When limited to studies that involved Vioxx at 25 mg per day, the picture that emerged was of "a modest association with increases in blood pressure" only. In their final submissions, counsel for the applicant made no reference to this evidence by Prof Vaughan, and he was not cross‑examined on it. 534 In her statement in reply, Dr Reicin addressed Prof Zipes' conclusion that Vioxx increased blood pressure in some detail. She said that it had long been well‑known that NSAIDs increased blood pressure in some patients, and that the effect was dose‑related. Even when dose was taken into account, NSAIDs appeared to have a range of blood pressure effects, with naproxen "at one end of the spectrum", ibuprofen at the other end and diclofenac "somewhere in the middle". (Dr Reicin did not say which end was which.) Dr Reicin referred to data contained in Merck's Integrated Summary of Safety that accompanied its New Drug Application to the FDA in November 1998. According to Dr Reicin, those data - … showed that the incidence of hypertension‑related adverse experiences in patients taking 25 mg Vioxx was comparable to the incidence seen in patients taking other NSAIDs, and not unexpectedly higher than the incidence seen in patients taking placebo.… …. The data also showed that Vioxx use was associated with small increases of systolic blood pressure…[of] the magnitude of 0.2) …, or in adjudicated confirmed thrombotic events (9 [0.3%] vs. 12 [0.4%]; P > 0.2). Five myocardial infarctions occurred in the rofecoxib group, and 1 occurred in the naproxen group (P > 0.2). No strokes occurred in the rofecoxib group and 6, all thrombotic, occurred in the naproxen group (P = 0.015). Prof Zipes pointed out that the 5/1 myocardial infarction ratio seen in advantage was the same as, and therefore was consistent with, the like ratio in VIGOR; and there were 15 patients in the Vioxx arm who discontinued on account of hypertension, and only six in the naproxen arm who did so. Prof Zipes also went to a review of the advantage data written in December 2001 by two medical officers within the FDA. In a passage cited by Prof Zipes, they said: Consistent with VIGOR, there was a trend of excess in serious cardiac thrombotic events in the rofecoxib 25 mg group, compared to the naproxen group (ten and three events, respectively, as per FDA review). There were five myocardial infarction …, two anginal events and three sudden deaths in the rofecoxib 25 mg group and one [myocardial infarction] and two angina (no sudden deaths) in the naproxen group. There were also two and five ischemic cerebrovascular events in the rofecoxib and naproxen groups, respectively. 656 The FDA reviewers were clearly dissatisfied with the adjudication process undertaken in relation to advantage. Because this aspect was not mentioned by the parties and neither Prof Zipes nor Dr Reicin was cross‑examined about it, I shall not deal with the causes of their dissatisfaction. However, they "re‑adjudicated" the data and presented the results in the following table: Table 16. ADVANTAGE: Summary CV Thrombotic events as presented by the sponsor (adjudicated by CV Adjudication Committee) and FDA re‑adjudicated events. Number of patients with CV Committee adjudicated serious CV‑thrombotic events Number of patients with FDA re‑adjudicated serious CV‑thrombotic events Rofecoxib Naproxen Rofecoxib Naproxen (N=2785) (N=2772) (N=2785) (N=2772) 9 12 12 9 Cardiac 8 3 10 3 Sudden death 2 0 3 0 MI 5 1 5 1 Angina 1 2 2 2 Cerebrovascular 1 7 2 5 CVA 0 6 1 4 TIA 1 1 1 1 Peripheral 0 2 0 1 DVT/thromboflebit 0 2 0 1

657 In her statement in reply, Dr Reicin referred to Prof Zipes' opinion that advantage provided an important signal of cardiovascular risk, and said that it was "not supported by the data". She referred to the passage from Lisse (2003) which I have set out above. Quite clearly, the data referred to in the Lisse article and the FDA data referred to by Prof Zipes cannot both be right. In their submissions, the respondents ignored the FDA review (which was their own exhibit) and its manifest inconsistency with Lisse (2003). The review does, perhaps, throw a little light on the "terrible situation" into which, according to Dr Scolnick, the marketers had placed MRL as a result of insisting that the ADVANTAGE trial should be conducted. 658 Dr Reicin was cross‑examined about an email she received in April 2000 in the context of then preliminary results of advantage to which she was blinded, but responded by relying on the final data as reported in Lisse (2003). She relied particularly upon the fact that there were six strokes, all ischaemic, in the naproxen arm and none in the Vioxx arm, adding "if Vioxx had been prothrombotic I certainly wouldn't have expected to see statistically fewer strokes on Vioxx compared with naproxen." She was not cross‑examined about the inconsistency between the figures on which she relied and those on which Prof Zipes relied. Neither was she challenged on the following evidence given in her statement in reply: Finally, ADVANTAGE compared Vioxx to naproxen. Even if we had observed a meaningful difference between Vioxx and naproxen, it would not have materially changed my belief about Vioxx's cardiovascular safety - we had already seen a statistically significant difference between Vioxx and naproxen in the VIGOR study. 659 In the result with respect to advantage, I am not prepared to hold that it put Merck on any greater notice as to the potential cardiovascular risk of Vioxx than it already had as a result of the VIGOR trial. The comparator in both cases was naproxen, and the highest the applicant can put it is that advantage was consistent with VIGOR. If there were some sound scientific basis upon the strength of which Merck ought reasonably to have viewed the advantage results as taking the matter further, it was put neither to Dr Reicin in cross‑examination nor by the applicant in his final submissions. I could not find, therefore, that there was. 660 The only other series of events in 2001, to which I should refer is the exchange of correspondence involving Dr Scolnick in September and again in November of that year (see paras 172‑174 above). I propose to deal with the timeliness, and with the circumstances generally, of the cardiovascular outcomes study later, but I mention here the applicant's submission that the correspondence demonstrated that Dr Scolnick was far from satisfied with the safety of Vioxx and most reluctant to accept it as self‑evident that the VIGOR results could be explained by the naproxen effect. It was submitted on behalf of the applicant that - Dr Scolnick was conspicuous by his absence from the witness box. He was head of [MRL], he was the most senior person involved; he was consistent in his concern to conduct a large study directed to [cardiovascular] outcomes from the moment the VIGOR results were unblinded. It should be assumed that his evidence would not have helped Merck's case. The difficulty with this submission is that it omits any identification of the additional evidence that Dr Scolnick would have given had he been called. I accept that, on the evidence as it stands, Dr Scolnick was consistent in his concern to conduct a large study directed to cardiovascular outcomes, although I think that to add "from the moment the VIGOR results were unblinded" somewhat overreaches on the part of the applicant. I accept that it is proper to infer from the correspondence that Dr Scolnick had ongoing concerns in the second half of 2001. It was consistent with the data then available to him that he should have had those concerns. I would not, however, regard the existence of his concerns as bespeaking the existence of facts additional to those given in evidence in the case or as altering the conclusion otherwise proper to be reached on the strength of all the information then available to Merck. 661 In the context of the correspondence of November 2001, it was submitted on behalf of the applicant that Dr Scolnick proposed the conduct of a trial that would test the cardiovascular benefits of naproxen. I have rejected that as an interpretation of his email of 21 November 2001, but on any view he did propose a trial in which Vioxx plus a known or hypothesised cardioprotective agent was set against naproxen alone (plus a pump inhibitor in each arm) in a sample of patients known to have some level of cardiovascular risk. It was put to Dr Reicin in cross‑examination that such a trial could and should have been conducted. She rejected the idea, and pointed out that she had done so in her email of 28 November 2001. In her evidence, she said: Naproxen versus aspirin, no, that was the point. That was exactly the point. If you are taking patients who need to be on aspirin and you put them into a study evaluating naproxen versus aspirin, those patients who are on aspirin who get put on to naproxen will be taken off their aspirin. So they will instead of getting aspirin which they could forget to take … and still have the antiplatelet effects, they will be given naproxen which they have to remember to take twice a day. They will have greater [gastrointestinal] toxicity because of the naproxen and we didn't think that that was a study that physicians would be anxious to do or to put their patients in. The matter was not taken further by counsel for the applicant. Notwithstanding Dr Reicin's explanation, it was submitted on behalf of the applicant that there was "no evidence that Merck ever determined whether such a study was possible". If this submission is intended to imply dereliction, I could not accept it. The feasibility of taking patients off aspirin in order to assess the effect of naproxen was rejected on ethical grounds by Dr Reicin, and inferentially her approach held sway at MRL during the period in question. There was, in my view, nothing in that approach that departed from those reasonable standards of prudence and care that the law would expect of Merck in the circumstances then confronting it. 662 Taking all the events of 2001 into consideration, I am of the view that the conclusion expressed in para 634 above with respect to the end of 2000 would need to be amended in some respects only. That relates to the data showing the confirmed CVT mortality from the Alzheimer's studies (see para 640 above). I refer here to my conclusion that those data ought to have been seen as a conspicuous signal of CVT risk. They gave emphasis to the view which Merck ought to have taken as a result of VIGOR - that there was a worrisome signal of potential cardiovascular risk. They ought to have been regarded as an element in the overall fabric of data then available to Merck which tended to make that signal a realistic one. However, they still did not stand as the whole of that data. In the context of all the information, I do not consider that the position occupied by Merck at the end of 2001 was one in which it ought to have known - ie to have concluded - that the consumption of Vioxx caused or contributed to CVT events generally.

2002 663 Subsequently to about the end of 2001, it appeared that a deal of effort went into the design of the proposed VALOR trial. In his final written submissions, the applicant contended that Merck had designed "but failed to conduct" the VALOR study. Without saying so in terms, the sense of the submission was that Merck was derelict in its abandonment of VALOR. However, Prof Celermajer and Dr Reicin were not cross‑examined on their evidence to which I referred in para 176 above. It was not put to Dr Reicin that she and others at MRL were remiss in not having pursued the VALOR option, or that the reasons for the abandonment of that option articulated by Prof Celermajer were not reasonable ones. In the circumstances, I cannot accept the applicant's implicit criticism of Merck as to the abandonment of VALOR. 664 There was nothing in the third pooled analysis of May 2002 that had the potential materially to change the position confronting Merck from that which existed in 2001. The new data which were included in that analysis, limited though they were, continued to justify Merck's contention that no signal of CVT risk appeared. I consider that the thinking reflected in the discussion section of the analysis (see para 183 above) was justified by the data. 665 Weir (2003), which was substantially the work of scientists at MRL, was submitted for publication in the same time‑frame as that in which the third pooled analysis was being prepared. Prof Woodward's comment on this article included the following: The enlarged data add support to Reicin et al's conclusion of no effect but still do not approach the critical size to rule out a chance finding of no effect due to an insufficient sample size. Save to rely on Prof Woodward's evidence, and to reiterate his reliance on Prof Madigan's approach to the arthritis and Alzheimer's data (which I have rejected), the applicant's submissions made no point about Weir (2003). 666 2002 was a significant year in Prof Harper's assessment of the information by reference to which a scientific conclusion that Vioxx was most likely pro‑thrombotic could, and should, have been made. As mentioned in para 594 above, Prof Harper joined in the opinions of Profs Celermajer and Vaughan that the VIGOR results were "hypothesis generating". By the end of 2002, however, he considered that there were sufficient data for Merck to have realised that Vioxx "had significant cardiovascular toxicity". This opinion was based substantially upon emerging evidence as to the cardioprotective effect of naproxen. Prior to 2002, Prof Harper held the view that naproxen might, in an extreme case, have had a cardioprotective benefit something akin to that of aspirin - about 30%. However, the myocardial infarction relative risk figure of 5 revealed by the VIGOR data meant that, to stand as a complete explanation for that result, the cardioprotective benefit of naproxen would have had to have been in the vicinity of 70%. Prof Harper continued: I think there were seven studies, some observational, some case control studies of naproxen, which clearly showed that naproxen was not having that sort of beneficial effect. So that's why I have said at the very least, by the end of 2002, it should have been known that the initial explanation of the VIGOR study was incorrect and that there was an important signal that Vioxx had … a cardiac toxicity. Prof Harper here referred to studies which had been published as separate entities in 2002, but which were brought together in Juni (2004). The analysis was similar to that undertaken by Prof Woodward and mentioned at paras 351‑353 above. 667 Prof Harper accepted that the studies mentioned by Juni and colleagues were observational ones, and that none of the published works contained any statement about the levels of compliance achieved in them. Neither they could, of course, since the researchers concerned were not in a position either to influence or (contemporaneously) to monitor compliance. I have referred (at para 366 above) to Prof Woodward's acceptance of the proposition that, standing alone, Watson (2002) would "shine a light that said naproxen was cardioprotective". I consider, therefore, that, had Merck looked at all the published naproxen studies as at the end of 2002, it would have noted that they were observational ones, it would have concluded that rates of compliance could well have been variable, it would have been aware that two of them (Watson and Schlienger) contained relative risk intervals that were consistent with there being as much as about a 60% cardiovascular benefit from the consumption of naproxen, and it would not reasonably have been driven from the view which it then took that the cardioprotective effect of naproxen was responsible at least for a major part of the myocardial infarction differential in VIGOR. 668 The position as at the end of 2002 was, in my view, no different from that which confronted Merck a year earlier, and as to which I expressed my conclusion in para 662 above.

2003 669 Prof Carlo Patrono, described by the applicant in his submissions as "an Italian pharmacologist widely regarded as a leading expert in the field of prostacyclin‑thromboxane effects", was a co‑author of Baigent (2003), published in January 2003, and tendered by the applicant. It contained a section headed "Coxibs and cardiovascular disease". The authors referred to VIGOR, and identified the cardioprotective effect of naproxen and the promotion of thrombosis by Vioxx as the two mechanistic explanations which had been proposed for the myocardial infarction results of that trial. I have set out (at para 375 above) what they said about the former. As to the latter, they considered first the possibility that the result might be explained by an alteration of the ratio of endothelial prostacyclin to platelet‑derived thromboxane. This was, of course, the FitzGerald hypothesis. Their conclusion on this aspect was: It seems unlikely, therefore, that alteration of the homeostatic balance of endothelial PGI2 and platelet‑derived TXA2 could explain the higher risk of myocardial infarction among patients allocated to receive rofecoxib in the VIGOR trial. The authors then considered the possibility of a blood pressure effect, noting that the non-selective NSAIDs and coxibs were "known to induce an increase in blood pressure through their effects on renal prostaglandins". They concluded that differences in blood pressure could not explain much of the excess of myocardial infarctions observed in the Vioxx arm of VIGOR. Their general conclusion was: Therefore, although the cause of the apparent excess risk of myocardial infarction in the VIGOR trial cannot be conclusively established, a combination of some cardioprotective effect of naproxen and chance does seem to offer a plausible explanation for these unexpected findings. Although other mechanisms cannot be discounted, there is currently little evidence in humans to support a prothrombotic effect of coxibs. There is, in this passage, no support for the contention that, at about the start of 2003, the state of scientific understanding was such that Merck ought reasonably to have concluded that Vioxx caused or contributed to CVT disease. Quite the contrary. 670 Protocol 078 was completed in April 2003. My attention was not drawn to evidence of the final CVT or APTC relative risk figure arising from this study as such (ie apart from the overall figures for the three Alzheimer's disease protocols), but there were 38 CVT events within 1361 patient‑years in the Vioxx arm (a rate of 2.79 events per 100 patient‑years) and 36 such events within 1551 patient‑years in the placebo arm (a rate of 2.32 events per 100 patient‑years). Of these data, the members of the study group for the protocol said in Thal (2005): Elderly patients are at increased risk for serious vascular events. Rofecoxib did not appear to increase the risk in this study, since the number of confirmed serious thrombotic vascular events was similar in each treatment group. The authors used the expression "elderly patients" because the median age of the patients in the study was 75 years. The completion of Protocol 078 in 2003 also gave final form to the Alzheimer's disease mortality data. As mentioned in para 446 above, over the three studies there were 12 CVT deaths in the Vioxx arms and seven in the placebo arms. Relevantly, these results were broadly in line with the 2001 interim data to which I referred in para 642 above. The conclusion I expressed on that occasion remains valid for 2003. 671 It was not until 25 July 2003 that Merck submitted the final version of Protocol 203 to the FDA. That was the cardiovascular outcomes study that began to be the subject of consideration within MRL in late 2001. Although the applicant made a number of criticisms of Merck in relevant respects, tardiness between March 2000 and late 2001 to commence planning for a cardiovascular outcomes study was not one of them. Dr Reicin did not, in chief, explain how that delay (if delay it be) came about, and she was not cross‑examined on the point. Subsequently, there was seemingly some time spent on the design of the proposed VALOR study, which was abandoned in March 2002, and then upon the design of the study which became Protocol 203. The first version of that study was submitted to the FDA in October 2002, and consultations apparently followed as outlined by Dr Reicin in her evidence referred to at para 176 above. Although the time intervals seemingly tolerated by this process of consultation with the FDA may perhaps be viewed as inconsistent with a perception of the pressing importance of testing the hypothesis of cardiovascular safety, Dr Reicin was not challenged on this aspect under cross‑examination and I think that nothing ultimately turns on it. 672 I express the latter view because, assuming always that the design of Protocol 203, even if completed much earlier than it was, would have included APPROVe, VICTOR and ViP, it was not the conclusion of Protocol 203 itself that ultimately caused Merck to withdraw Vioxx from the market. It was the emergence of the statistically significant excess of CVT events in the Vioxx arm of APPROVe. That trial commenced in early 2000, before the VIGOR results were available. If the applicant intended to propose that there was some way of conducting a large placebo‑controlled cardiovascular outcomes study that would have yielded a meaningful result before September 2004, he articulated the details and architecture of such a study neither in his submissions nor in the cross‑examination of Dr Reicin. It must be remembered that placebo‑controlled studies are problematic in populations of patients that require drugs for therapy. Dr Marks said that a placebo‑controlled RCT was preferable both for sponsors and for regulatory agencies, but added that - … if the study were to run for two years, the use of a placebo group might be unreasonable for ethical reasons because all subjects would require an active drug for their condition, so would require a positive control as the comparator. Similarly, Prof Celermajer said: [The] area of trials in arthritis does not lend itself easily to placebo‑controlled trials, as patients with arthritis require some medication for pain relief and the use of placebo, especially for long durations, may therefore be considered unethical. There is, in the circumstances, no basis in the evidence for me to second‑guess Merck about the design of Protocol 203, the result of which is that, whatever tardiness might have been evident in developing and implementing that design, it was the duration and data of APPROVe as an entity within the study that ultimately provided to Merck the evidence of cardiovascular risk that was decisive. 673 In his written submissions, the applicant sought to give relevance to certain circumstances which existed in May and November 2003. The point related to the APTC relative risk figures as they appeared to the unblinded External Safety Monitoring Board for the APPROVe trial in those months. The applicant pointed to the following passage in the minutes of the Board's meeting on 17 September 2004: The trend for excess risk for treatment B for confirmed APTC events has continued to grow at each meeting over the last 1‑2 years. In May 2003, the hazard ratio was 1.2; in November 2003 it was 1.4; last February it [sic] 1.8; and currently it is 2.2. Whereas there was an excess of 2 events on treatment B in May 2003, there are now 17. While the applicant acknowledged that Merck did not have access to the figure as it existed in May and November 2003, he submitted that, if Merck had taken reasonable action to increase the sensitivity for CVT events in its studies, or advised its monitoring boards to change their protocols, Merck would have had this information. I must say that I have no idea what the applicant meant by either of these suggestions. The subject was not canvassed with Dr Reicin while she was giving evidence. Neither was it put to her that at some unspecified point during the conduct of the APPROVe trial, Merck should have arranged for "interim unblinding" with respect to the emerging data, as it had done, in a limited way, with respect to the emerging Alzheimer's disease data in the aftermath of the VIGOR results. Accordingly, I have no idea how Dr Reicin would have reacted to such a suggestion, nor what it would have involved in the context of Protocol 203 generally. Absent the assistance of Dr Reicin's evidence in relevant respects, I do not consider that I am in any position to uphold these essentially technical criticisms of Merck in relation to the APPROVe data as they were known only to the Board before September 2004. 674 I do not believe that Merck's position as at the end of 2003 was materially different from that which had obtained a year (and two years) earlier. The conclusion I expressed in para 662 remains valid for December 2003

2004 675 In March 2004, Capone (2004) was published in Circulation. The passage from it which I have set out above at para 367 provided some independent scientific support for the view which Merck then took as to the role of naproxen in the VIGOR results. I should not, however, leave the article without setting out the authors' closing paragraph: In conclusion, the present study demonstrates the pharmacodynamic plausibility of a COX-1-dependent cardioprotective effect of naproxen and contributes to the interpretation of the VIGOR cardiovascular findings. Although our results are mechanistically informative of what may happen under the best‑case scenario of a randomized clinical trial of regular, prolonged use of a high‑dose reversible COX inhibitor, practicing physicians should not assume that the same holds true in the less‑than‑ideal circumstances of real‑life use of these drugs, which is neither regular nor continuous nor necessarily at high doses. I read this as suggesting not that naproxen in fact explained the VIGOR results, but rather than it plausibly contributed to an explanation of them. 676 Also, in March 2004, Merck forwarded the fourth pooled analysis to the FDA. Although the relative risk was not significant, and the text accompanying the analysis contained the view that "the data continue to support the lack of a prothrombotic effect with rofecoxib", the point estimate of the relative risk was now 1.26. It had risen from 1.04 in May 2002. The lower point of the 95% confidence interval had risen from 0.72 to 0.89. This drift, which accompanied the addition of more data in the analysis, ought to have been of some concern to Merck. However, I do not believe I could put it higher than that, and the applicant did not base his case on the pooled analysis of March 2004. As I have said, his case was based (in relevant respects) on different data altogether - those derived by Prof Madigan which I have declined to accept. 677 A final event of interest was the publication in September 2004 of Patrono (2004). I have, at para 385 above, set out a view which the authors of that study expressed as to the explanation for the VIGOR results, on which Prof Celermajer relied. It will be seen that it was very nearly the same sentiment as expressed by Prof Patrono in Baigent (2003), cited at para 669 above. As I did with that article, I am disposed to view Patrono (2004) as implying the absence of any established scientific consensus that Vioxx was pro‑thrombotic. 678 All things considered, the applicant's case against Merck relies heavily upon two co‑operating propositions: first, that Merck should have regarded the FitzGerald hypothesis, rather than the naproxen hypothesis, as the "correct" mechanistic explanation for the results of VIGOR; and secondly, that Merck should have viewed the data from its own arthritis and Alzheimer's disease studies as Prof Madigan did rather than as it actually did at the time. For reasons which I have attempted to explain, I am not persuaded that it was unreasonable of Merck not to have acted consistently with these propositions. Once it be accepted that it was reasonable for Merck to have regarded naproxen as a potential contributor of some significance to the VIGOR results, to have applied the CV SOP to the collection and analysis of data from its clinical trials, to have pooled those data as it did, and to have regarded the FitzGerald hypothesis as itself as the subject of some uncertainty, as I do, I could not hold that there was any time before September 2004 when Merck ought reasonably to have taken the view that Vioxx was - as distinct from might be - pro‑thrombotic.

Summary 679 That brings me back to the opinions of the cardiologists, which have been of central importance in this aspect of the litigation. Here I return to para 594 above, which dealt with the position immediately after the release of the VIGOR results. Commencing with Prof Zipes, for reasons already given I do not accept so much of his opinion as was based on the re‑analysis of the arthritis data carried out by Prof Madigan. The analysis by Dr Chen to which Prof Zipes referred was that mentioned in para 637 above: it related to all‑cause mortality. I have dealt with that aspect by accepting Merck's close investigation of the circumstances surrounding the deaths in question. The Juni study mentioned by Prof Zipes was in fact published in November 2004, after Vioxx had been recalled. And the internal memorandum of Dr Shapiro was, as I have said, wholly consistent with the approach which Merck took to its data generally, and of which I have not been critical. In the result, I am unable to accept Prof Zipes' opinion that Merck ought, in 2000, to have accepted that Vioxx had significant cardiovascular toxicity. 680 Prof Harper would have regarded the VIGOR trial as no more than hypothesis‑generating until, by about the end of 2002, there was sufficient published research to permit the conclusion that the results of VIGOR could not be explained by the effect of naproxen - see para 666 above. However, for reasons I have given, I take the view that, looking at the matter as at the end of 2002, Merck would reasonably have concluded that naproxen had the potential to be as cardioprotective as aspirin, if taken regularly. There was no time, subsequent to that but before September 2004, when Merck ought to have taken a different view. 681 That leaves Profs Celermajer and Vaughan. They joined in the opinion that the VIGOR results presented a worrisome and important signal of potential cardiovascular risk that mandated comprehensive analysis and investigation. I accept that evidence of the cardiologists. I also accept that Merck did give the problem the analysis and investigation that was reasonably required in the circumstances. For reasons I have given, I consider that Merck was entitled to regard the generality of the placebo‑controlled data available to it as providing little or no confirmation of the VIGOR results. Neither, however, did they remove the cause for concern to which the cardiologists unanimously referred. That was recognised by the scientists at MRL, most conspicuously by Dr Scolnick himself. He was amongst a number of those scientists who keenly felt that underlying sense of concern, notwithstanding those data. Thus the origins of Protocol 203. It was, I consider with respect (and here I speak with the considerable advantage of hindsight), both prudent and wise to include APPROVe in that study. It meant that, to an extent at least, the time which had passed since the VIGOR results became available was not wasted. APPROVe was a major placebo‑controlled RCT which had the obvious potential to be about as informative as any individual study could be, given the constraints applying to such trials in populations of patients experiencing pain. 682 Thus I reject the applicant's case that, before late September 2004, the respondents knew or ought to have known that Vioxx caused or contributed to the pleaded cardiovascular conditions. I accept his alternative case that the respondents should have regarded the VIGOR results as a worrisome and important signal of potential cardiovascular risk. I reject the applicant's case that Merck proceeded as though no such signal existed. It recognised the signal and sought, within the constraints to which I have referred, to confirm or deny, as a matter of reality rather than of potentiality, the existence of the risk implied thereby.

The applicant 683 The applicant was born on 28 June 1950. He played sport regularly as a boy. He and his brother were keen cyclists, and were members of the Northcote Cycling Club. At the age of 13, he contracted hepatitis A after swimming in the Merri Creek. He suffered from migraines in his youth, and continues to do so today. 684 The applicant left school in 1965 at the age of 15. He applied to join the Navy, but was not then accepted. For the next three years, he had a series of jobs including as a projectionist at the Curzon Theatre in Melbourne, at Maxwell's Radio in Elizabeth Street, and as a typewriter mechanic. 685 When the applicant turned 18 he again applied to join the Navy, and was accepted on 11 January 1969 as a medic. He worked as a Navy medic for about 3‑4 years, during part of which time he also attended St Lucia's University in Queensland to study pathology. He worked in medical and surgical wards at HMAS Cerberus and on various other ships as a sick berth attendant. He did a 9‑10 month medics' course at HMAS Cerberus, and later worked as an instructor at the Navy medical training school. His work mainly involved studying areas such as trauma, recognition of diseases, tropical diseases, hygiene, anatomy and physiology. He was then classified as an Able Seaman - Medic. 686 The applicant was chosen to work in a pathology laboratory, doing haematology. He learned how to perform blood tests and other pathology tests. In the course of performing this work, he gained an awareness of cardiovascular issues and came to understand the signs of heart problems. 687 In the applicant's last couple of years with the Navy there was a focus on the dietary content of the meals. He had earlier developed a habit of eating healthily (after suffering from hepatitis A), so dietary focus was not a major issue for him, but, together with his training as a medic, it reinforced the importance of good diet and health. The applicant was a regular smoker when he was in the Navy. He usually smoked a pipe (a pouch of tobacco would last for about a week), but, when he used cigarettes, it was at a rate of about 15‑20 per day. He progressively reduced his use of tobacco between 1975 and 1980, when he stopped smoking. 688 The applicant left the Navy on 20 January 1974 (although he continued serving in the Navy Reserve until 20 January 1979). He then worked for the Board of Works in Melbourne as a driver and trades assistant for a crew that performed maintenance on pumping stations in the south‑eastern suburbs. There is no evidence as to when the applicant left the Board of Works, but his next job was as National Scientific Representative for Terumo Australia, a company which manufactured medical disposables. He was involved in the training of hospital staff in the use of equipment. His employer was the first to introduce portable foetal heart monitors in Australia, and he assisted in training hospital staff in their use. After working for Terumo for about three years, he left that job because it required too much travel. 689 The applicant worked for himself until about 1980, researching the commercial fishing of sea urchins. He obtained an experimental permit to harvest sea urchins for the Japanese and Korean markets. He entered into a contract with a Japanese corporation, Mitsubishi, worth about $4 million annually to catch and process sea urchins and export them to Japan. The permit was due for renewal in November 1985, but the applicant was advised that the Victorian government intended to undertake a three‑year study into the effect of sea urchin harvesting, and the permit was not renewed. As a result, the applicant lost his business and had to sell his boat and refinance his house to survive. 690 Then, which was 1985, the applicant did casual work as a chemical formulator for a friend at a company named Soltech. Soltech was later bought by Ensign Laboratories, at which the applicant became Safety Manager and Manager of Special Gases. Most of his work with Ensign involved dangerous and highly explosive gases, including propane, butane and ethylene oxide. He became very aware of safety issues, and was the company's first Safety Manager. He remained with Ensign until about 1997, developing a good relationship with the Managing Director. He completed an Associate Diploma in Applied Science and Occupational Health and Safety at the Holmesglen College of TAFE, and a Diploma of Applied Science in Environmental Management at Holmesglen and Dandenong TAFE. These were his first formal qualifications. 691 The applicant left Ensign because he was offered a job as a safety officer at the Williamstown Naval Dockyard with Transfield Defence Systems, later called Tenix Defence Systems. After three months he was promoted to the position of Safety Coordinator. His work for Tenix required him to start before 6.00 am, to inspect all the ships in the yard prior to 7.00 am, to conduct compartment inspections of the ANZAC frigates, and to carry out safety audits and accident investigations. While at Tenix, the applicant significantly improved the safety record on the ships and in the dockyard, reducing the accident rate quite considerably. When he started, there were about 18‑20 lost‑time injuries per month; by the time he left, these had been reduced to 2‑3 per month. He had a medical check‑up performed while employed at Tenix. This did not identify any particular problems. He was told to keep an eye on his blood pressure, but he did not believe that his blood pressure was a significant problem. He was not prescribed any medication for it. He also had cholesterol and triglycerides tests performed on his blood. He believed the results were normal. In 1999, the ANZAC frigate construction program on which the applicant had been working was winding down, and he left with a redundancy package. 692 Some months later, the applicant was offered a job with BHP as global safety manager of its marine fleet of 26 ships. To obtain this job, the applicant was required to pass a medical test. The job paid about $75,000 per year. The applicant was based in Melbourne, but the job involved a lot of travel. This meant that he could not keep up with his regular cycling, although he made a point of using the hotel gyms and the exercise equipment on the ships when he was away from home. Every twelve months when he was with BHP, the applicant had a "cardiac workup", which involved undertaking exercise to get his heart rate up to 180 beats per minute for fifteen minutes, and then timing how long it took for it to return to normal. The applicant remembers a doctor telling him that his cardiac recovery was excellent. In 2001, BHP's marine fleet was put into a joint venture with Teekay Shipping, and the applicant transferred to the new company. However, Teekay closed its Melbourne office about a year later, and the applicant was offered the choice of transferring to Vancouver or to Sydney. He agreed to work in Sydney, but he felt that Teekay's commitment to safety was not as good as BHP's and, after giving approximately 12 months' notice, he left Teekay on 2 October 2003, intending to set up his own consultancy. 693 On 3 October 2003, the applicant caused a company called "Graeme Peterson & Associates Pty Ltd" ("GPA") to be incorporated. This was to have been the vehicle through which he would conduct his consultancy business, namely, the provision of occupational health and safety solutions, especially for the maritime industry. An aspect of the business was to have been the undertaking of safety audits, inspections and training. 694 While working in maritime safety at BHP and Teekay, it became apparent to the applicant that there was no way safely to shut down the energy systems in some parts of a ship, such as would be required during maintenance, for example. He developed a system to identify, isolate and lock down a particular system or piece of equipment, which he called "Lockout". In his evidence, the applicant described this system as follows: The basis of Lockout was to enable securing of all isolators in any mechanical, electrical, hydraulic or any other energy system, to be able to secure those isolators with a device, whatever was necessary - a clamp or whatever it took - secure that with a lock. The lock is then placed in a keyboard that has a clear front on it. The keys and the locks are all engraved with identifying numbers. There's tags that are attached to the lock and a part of the tag is also left where the lock has been drawn from, so there is a double-check of where the lock is. They are serial numbered to give it a traceability. The person in charge of the job then, once all those devices are locked and secured and tested, he then locks the door of the board, the clear door, so all the keys are visible and he has locked it with another lock. They are colour-coded, all the isolation locks are yellow. His key for securing the board is green. It is also engraved and he is the custodian of that key. Everybody that then comes to work within what we call the isolation barrier, within the area that has been isolated, has their own personal lock which has another engraved identifier and key and they also place them on the door of this board so if you have six people working on the job you have there six red locks, you have the isolation coordinator's green lock and they are all - the whole seven of those locks - securing the keys to the isolation yellow locks inside there. So until everybody has left the job, left the isolated area or the barrier nobody can get to the keys without physically breaking open the board. So once people are finished their jobs, they remove their lock, take it with them. When the isolation coordinator is satisfied that everybody is finished he checks that the personal safety locks have been removed, that the area is clear. He opens the board, takes the keys for the isolators and de-isolates …. In 2003 the applicant won the "SEACARE" award for the best solution to an occupational health and safety problem in the maritime industry for his "Lockout" system. The system is now fitted to 180 ships worldwide.

The applicant's back pain 695 While in the Navy, the applicant commenced to experience back pain. That has remained with him ever since then, to a greater or lesser extent. At least by 1983, he had commenced taking anti‑inflammatory drugs for this condition (he thought it may have been earlier than that). In that year, he was prescribed a medication called Indocid. Under cross‑examination, he accepted that he had subsequently taken that and other drugs called Clinoril, Voltaren, Feldene and Orudis SR200, in each case to obtain pain relief with respect to his back. He accepted a series of propositions put to him by counsel for the respondents: that the sort of jobs he was doing in the '80s and '90s required him to bend, to climb ladders, to get into confined areas and to walk around ships and other like areas and spaces; that that caused him to spend a lot of time on his feet, it involved a lot of bending and twisting as he went about his duties, and those activities exacerbated his back pain; and that the reason he took the drugs was to enable him to keep working without pain. The applicant said that, in the 20 years before he commenced taking Vioxx, he had been taking NSAIDs regularly. 696 The applicant said that he experienced some very bad gastrointestinal effects from his anti‑inflammatory medication. He suffered from very painful gastric reflux which sometimes caused him to vomit. He would take Mylanta and Maalox, and peppermint, to prevent or to reduce the gastric pain caused by the anti‑inflammatory drugs which he took. The applicant also agreed with counsel for the respondents (who was cross‑examining by reference to medical records) that he had had a number of investigative procedures in this regard. In 1985 he had a barium meal examination. In the same year he had a gastroduodenoscopy, which found a degree of inflammation in his stomach. He continued to suffer from indigestion, and was prescribed a drug called Pepcidine. In 1995 he was prescribed a drug called Losec, which he has taken regularly ever since. That was, and is, principally because of gastrointestinal problems. In 1993 he had a gastroscopy, which demonstrated some mild to moderate inflammation of the oesophagus. He had a further gastroscopy in 1994. In 1997 he had both a gastroscopy and a colonoscopy, which showed some abnormality in his gastric area. He had another colonoscopy in 2002 because of the possibility of bleeding. 697 It was explained to the applicant at the time, and he understood it to be the case, that these gastrointestinal problems were associated with the anti‑inflammatory medication that he was taking. Over the 20 years that he took NSAIDs, that period, the applicant was balancing in his own mind the issues of being able to work without pain and of putting up with such symptoms as he had. He said that, in consulting with his doctor about a drug, he would try to find a balance between a good anti‑inflammatory effect and a low level of gastric discomfort. 698 The applicant referred to some alternative medications that he was taking - fish oil, glucosamine sulphate and "extract"‑type medications, such as shark cartilage and green‑lip mussel extract, for example. He said that he would always read up on these kinds of medications, and would not take them if he was concerned about their contents or side‑effects. He had a practice of taking care to ask about the effects of taking new drugs, and, he said, would always weigh up these effects against joint pain and stomach upsets. The applicant said that he considered himself to be a fairly stubborn person who preferred to reach his own "conclusions about things", rather than accepting someone else's word. He considered himself a cautious and safety‑conscious person.

Dr Dickman 699 Dr John Dickman is a general practitioner of considerable experience. He graduated from the University of Melbourne in 1966, and has been in general practice since 1972. He is a member of the Royal Australian College of General Practitioners. He practises at the Tower Hill Medical Centre in Frankston, and has done so at all times which are presently material. He sees about 200‑250 patients a week on average. He first met the applicant in 1970, when they were in the Navy together, and has known him since then. He commenced treating the applicant in 1999. 700 Dr Dickman said that, as a general practitioner with a busy and varied practice, in an average week he would prescribe over a hundred different drugs. Consequently, he had limited time to research the effect of each drug. There were, however, some drugs that he prescribed more regularly than others - they made up his "formulary", as put to him by counsel for the respondents. He said that, between 2001 and 2004, Vioxx was one of those. He prescribed it "fairly frequently". 701 From many years of practice, Dr Dickman was aware that a prescription medicine differed from an over‑the‑counter medicine in that it required a medical practitioner's authority for a patient to obtain it. This was because of the nature of the medication. He knew that every prescription medication had effects ranging from good ones through to serious adverse ones. He accepted what was put to him by counsel for the respondents that he proceeded on the basis that no prescription medicine was absolutely safe for every patient. In the case of every patient, he had to consider the good and bad effects and make a judgment about whether the medicine should be prescribed for that patient. 702 Often, Dr Dickman became aware of a drug's side-effects by witnessing them in his patients or by hearing about them in the media. If a side-effect actually occurred in a particular patient, he may have moved the patient on to a different drug, or changed the regime or dosage of the existing drug. If the risk of a side‑effect arose, Dr Dickman would weigh up the risk against the benefit provided by the drug to determine whether it was appropriate to continue prescribing it. If he were to continue to prescribe the drug, he would need to be able to advise the patient of the seriousness of the risk posed by the side‑effect, and of the likelihood of the risk coming to pass. He accepted that this was a process through which he went each time he prescribed the drug. On each occasion, he accepted that, in effect, he went through a process that involved asking himself whether anything had changed since he first prescribed the drug. In some situations, he would carry out a more complete risk benefit analysis, such as when the patient's condition had changed, or when the drug profile had changed. 703 Dr Dickman accepted that, as time went by, he would build up a picture, across his patients, of the tolerability and effectiveness of a particular drug, and as to its tendency to cause side-effects. That would have applied as much to Vioxx as to any other prescription medication. He accepted that, with respect to prescription medicines generally, he was collecting information all the time, and constantly factoring that information into his decision‑making process. Subject to those qualifications, once Dr Dickman had commenced a patient on a long‑term regimen of a particular drug, he tended not to switch the patient to a different drug unless there were a specific reason to do so. Because he prescribed Vioxx frequently, Dr Dickman was accumulating information on it regularly, and scanning, so far as he could, information that he received to see if there were any reason why he should change his prescribing habits. 704 The sources of information about new and existing drugs upon which Dr Dickman relied included specialists, sales representatives, journal articles and the medical press, other general practitioners, product information and patient feedback. Specialists were a particularly powerful source of information about new drugs. He regarded them as more knowledgeable in their areas of specialisation, and better informed about new drugs, than he could be as a general practitioner. 705 Dr Dickman said that it was usual, when a drug was being launched, for the manufacturer to host a number of educational meetings at which the uses and benefits of the medication were discussed. These usually took the form of an expert in the field talking about the drug or the class to which it belonged. Often, the meeting was over dinner at a local restaurant. Dr Dickman regarded dinners sponsored by pharmaceutical companies as attractive because they tended to be informative, they involved dinner and they offered CME points, which were required to maintain a doctor's licence to practise medicine. He recognised that specialists who spoke at sponsored dinners were compensated by the pharmaceutical company concerned, and he assumed that they provided unbiased and truthful information about the drug. Such dinners were also the occasion for interaction with his colleagues about the speaker's subject, and for a free-flowing professional discussion generally. 706 Specialists influenced Dr Dickman's prescribing habits also through his patients. When a patient returned from a specialist with a prescription for a certain drug, Dr Dickman would take note of the prescription, and generally continue to prescribe that drug to that patient. He would often prescribe the drug to other patients in similar situations. 707 Dr Dickman said that information provided by sales representatives about drugs was "sometimes useful". He saw sales representatives once a week, on a Thursday morning. He recognised that a sales representative's job was to increase prescriptions of the drugs they represented, but he assumed that the information given by them was truthful. In his witness statement, Dr Dickman said that, when representatives told him that a drug was safe, he assumed that they were telling the truth. However, under cross‑examination, he accepted that, if a representative said to him, "Here is a prescription medicine - I can guarantee you that it's absolutely safe", he would be likely to have regarded it as an overstatement. He accepted that he would not take the representative's word for it, but would think to himself, "I had better go and have a look at what I can find out about this drug to see what the safety of it is". He would know that a comment by a sales representative about the safety of a drug had to be placed in the context of all of the information that was available about the drug. 708 Sometimes a sales representative would tell Dr Dickman that a drug was now approved for a different indication, such as when Vioxx was approved for the indication of rheumatoid arthritis. In such a case, when he next came to prescribe the drug, particularly (in this example) if it were for someone with rheumatoid arthritis, he would go back to the Product Information to see what the relevant information was with respect to that indication. 709 When a new drug was marketed, there was usually information about it in the medical press. For Dr Dickman, the most prominent publications were the Medical Observer, Australian Doctor and Family Physician. He read these journals when he was able, consistent with the time demands of his practice. 710 Dr Dickman talked to other general practitioners about their prescribing habits and the results they achieved with drugs. At Tower Hill Medical Centre, the general practitioners tried to hold practice meetings about every month or so. One of the subjects discussed at these meetings was prescribing habits and results with different pharmaceuticals. 711 Dr Dickman used a computerised version of the Monthly Index of Medical Specialties ("MIMS") to look up a drug's Product Information. In his witness statement, he said that, as the Product Information could be very lengthy, his practice was not to "read it from start to finish". Instead, he would call up the sections that were of particular relevance, for example on drug interactions. He also agreed with counsel for the respondents that there were some aspects of the Product Information that were more important than others. He accepted, by way of example, that the indication for a drug was important, as were the contraindications, the appropriate dosage and administration, the precautions and the adverse reactions. He agreed that they were important because they related to why he might prescribe the drug, and what might happen if he did. He accepted that he needed to weigh them up as part of his information about the drug. Thus, although he did not read the Product Information from start to finish, he accepted that he looked at the sections that were of particular relevance. 712 Dr Dickman said that he would not be aware of a change to a drug's Product Information unless notified about the change. However, under cross‑examination, Dr Dickman accepted that, in his practice, he used a computer program called "Medical Director", which contained a prescribing module, part of which was information about the drug being prescribed. That enabled him, with the click of a mouse button, to access information instantly about a particular product by reference to headings such as "Indication", "Contraindications", "Precautions", etc. He could do this without having to read the whole of the Product Information. He agreed that this was one of the more easily available sources of information. Indeed, Dr Dickman said that he more commonly used the Medical Director software to have access to the electronic version of the Product Information. He agreed that Medical Director was electronically updated four times a year, but said that it did not give him a note of what drugs had changed; nor of an indication that had changed. The paper version of MIMS, which Dr Dickman still received, was updated three or four times a year. The updating version would contain only those drugs that needed to be updated. 713 Dr Dickman obtained information about Vioxx from the various sources mentioned above, and used this information to assess Vioxx's appropriateness for the applicant and his other patients. There was a great deal of attention paid to the launch of Vioxx (as there had been with Celebrex) because of the perception that the drug would provide good pain relief for arthritis without the risk of the gastrointestinal effects associated with the traditional NSAIDs. As a general practitioner, that is what attracted Dr Dickman's interest. The gastrointestinal complications of long‑term NSAID consumption could be quite serious. Dr Dickman mentioned one patient - an older lady - who was taking an NSAID and who had a haemorrhage, as a result of which her blood pressure dropped and she suffered a stroke. 714 In late 1999 or early 2000, Dr Dickman attended a dinner meeting about Vioxx hosted by MSDA. A local rheumatologist - of whom Dr Dickman had a good opinion - spoke of the COX-2 specific inhibitors and of Vioxx in particular, which he endorsed. Dr Dickman learned that this new class of drug had the same or a similar overall profile to NSAIDs in terms of effectiveness and safety, but had also the particular gastrointestinal safety benefit. The rheumatologist said that Vioxx was safer than traditional NSAIDs. His opinion about Vioxx was probably the most significant factor in Dr Dickman's decision to prescribe it to his patients. 715 Dr Dickman's clear impression at the time was that the new class of COX-2 specific inhibitors, including Vioxx and Celebrex, had a similar profile of effects to that of the NSAIDs, but had the identified gastrointestinal benefits. He considered that it would have been almost negligent not to have prescribed them. In discussions between Dr Dickman and his colleagues, there was a very real fear that they would have been exposing themselves to negligence claims if they prescribed "an older type of NSAID" to a patient who later experienced a gastrointestinal bleed. Save for the treatment of acute gout, Dr Dickman could not think of any situation in which he would have prescribed a traditional NSAID once the coxibs were on the market. 716 Although Dr Dickman did not recall the specifics of the meetings which he had with Merck sales representatives about Vioxx, he did meet them frequently. He said that there was "intense competition" between sales representatives for Vioxx and Celebrex. He recognised their respective activities as amounting (in the words of counsel for the respondents) to a "sales pitch". The only real difference between the two which he was able to recall being raised by the representatives was that Celebrex was "a sulphide", whereas Vioxx was not. Dr Dickman later explained that this was a reference to the sulphonamide chain in Celebrex. It seems that some patients were allergic to sulphonamides, and in such cases he would have chosen Vioxx. Otherwise, he prescribed Vioxx and Celebrex about "50/50". 717 Dr Dickman did not recall any MSDA representatives mentioning cardiovascular risks in relation to Vioxx. Under cross‑examination, he accepted that this was because he had no recollection of any specific interaction at any meeting with a representative. He also accepted that he gave that evidence without the benefit of knowing of the conversation he possibly had with a representative on 13 September 2001, as set out in the list below. He said that, if a sales representative had mentioned the possibility of cardiovascular risks from Vioxx, he would have discussed the issue with other doctors and specialists, and would have raised the matter with the applicant. Indeed, Dr Dickman said that meetings with MSDA representatives left him confident about the safety of Vioxx. In his witness statement, he said: During meetings with Merck sales representatives about VIOXX, the sales representatives' emphasis was primarily on VIOXX's safety. Under cross‑examination, he was not challenged on this statement, but acceded to the proposition that a regular theme with the representatives was that Vioxx had a real benefit for his patients because it had a better gastrointestinal safety profile than traditional NSAIDs. The other theme was that Vioxx needed to be taken only once a day, which meant that the patient would not get "breakthrough pain". 718 In evidence was a schedule of the interactions between MSDA sales representatives and practitioners at the Tower Hill medical centre over the period to which this proceeding relates. It reveals that representatives saw Dr Dickman as follows: · On 9 January 2001 − Christopher Brown · On 30 January 2001 − Christopher Brown, noting that Dr Dickman was "very happy with Vioxx" · On 15 February 2001 − Christopher Brown, noting that Vioxx was "going great guns" · On 8 March 2001 −Christopher Brown and Kieran McAuley, noting that Dr Dickman used Vioxx · On 20 April 2001 − Christopher Brown, noting "good push for Vioxx as number 1 choice before other Cox 2 …" · On 2 May 2001 − Christopher Brown · On 11 May 2001 − Christopher Brown · On 14 May 2001 − Marcus Daddo · On 15 May 2001 − Marcus Daddo · On 16 May 2001 − Marcus Daddo, noting that Dr Dickman "has used Vioxx but usually @ 25mg" and (as I interpret the document) that Mr Daddo "went through the types of patients best suited to Vioxx" · On 5 July 2001 − Marcus Daddo, noting "quick otc about the benefits of Vioxx … aware of and using" · On 8 August 2001 − Christopher Brown, noting "benefits agreed now Vioxx is running 50/50 no real cardio issues yet" · On 12 September 2001 − Christopher Brown · On 13 September 2001 − Marcus Daddo, noting that Dr Dickman had "some problems patients querying use of Vioxx with HF and MI's etc, clarified concerns and moved on to Vioxx promo" · On 14 November 2001 − Christopher Brown, noting that Vioxx was "getting good grounding but with hearty debate" · On 21 December 2001 − Christopher Brown · On 10 January 2002 − Kym McCarthy, noting as follows: Vioxx key messages, CV competitor issues addressed. All prefer decreased side effect profile of Cox 2's … ID reasons to choose Vioxx 1st line based on SSS. · On 27 March 2002 − Christopher Brown, noting that Vioxx was going "ok but still high Nsaids" · On 23 April 2002 − Kym McCarthy, noting "Vioxx efficacy" · On 14 May 2002 − Kym McCarthy, noting "Vioxx OTC efficacy" · On 13 June 2002 −Kym McCarthy · On 23 August 2002 − Kym McCarthy · On 12 September 2002 −Kym McCarthy · On 29 October 2002 − Kym McCarthy, noting "Vioxx med info follow up …" · On 5 December 2002 − Kym McCarthy, noting "Vioxx key messages" · On 16 January 2003 − Kym McCarthy · On 20 March 2003 −Kym McCarthy · On 25 June 2003 − Kym McCarthy · On 27 June 2003 − Kym McCarthy · On 22 July 2003 − Kym McCarthy · On 18 August 2003 − Kym McCarthy, noting "Vioxx … full detail − reminder benefits over others in class". 719 Save for Mr McAuley, none of the representatives mentioned above was called. I believe I am able to infer that none of them would have been in a position to deny Dr Dickman's evidence that their emphasis, in their meetings with him, was on the safety of Vioxx. As for Mr McAuley, he proffered no such denial and provided no elaboration on the meeting which, apparently, he had with Dr Dickman on 8 March 2001. 720 Dr Dickman said that, at the time that he prescribed Vioxx to the applicant, he was not aware that use of the drug was associated with increased cardiovascular risk. He first became aware of a possible increased cardiovascular risk associated with Vioxx at an educational meeting, about a couple of months before it was withdrawn, addressed by a local cardiologist. Before then, he had felt confident in the safety of Vioxx, but the implication from the cardiologist was that there was a greater cardiac risk than he had imagined previously. In his witness statement, he said that, had he been aware of an increased cardiovascular risk from Vioxx, this would have affected his risk/benefit analysis in prescribing the drug. He would have urged caution in the use of Vioxx and, in particular, would have recommended use for brief periods only. When it was put to him that he gave this evidence with the benefit of hindsight, he responded: "I certainly think that my current knowledge can't be eradicated" from the evidence. He said that he would have warned his patients about any known risks to enable them to make informed decisions about their medication, and would have respected their decisions. He said that the increased cardiovascular risk that he now knows to be connected with Vioxx would certainly have warranted a warning to patients who had been taking the drug. 721 Dr Dickman was shown a copy of the October 2001 newsletter of the National Prescribing Service, which he accepted was an independent body largely if not entirely funded by government, the purpose of which was to provide information to doctors about prescribing habits, drugs and the like. Dr Dickman received this publication. His attention was drawn to the following extract: Do COX-2 selective NSAIDs carry a risk of thrombosis? Evidence is accumulating that selective inhibition of the COX-2 enzyme may be associated with prothrombotic effects. The VIGOR study showed a small but statistically significant difference in the incidence of myocardial infarction between the groups treated with naproxen and rofecoxib (0.1% vs 0.4%)…. This trend has also been observed in a review of rofecoxib studies which includes as yet unpublished data. [Reference given to an FDA publication available online.] … It is uncertain whether the observed increase in cardiac adverse events with rofecoxib is valid, whether it is specific to rofecoxib only or COX-2 selective NSAIDs in general, or whether some NSAIDs have an aspirin‑like cardioprotective effect and actually reduce the risk of thrombosis. The practical implications of these observations are: - those who require low‑dose aspirin for cardiovascular prophylaxis should receive it [Reference given to Cleland (2001)] - consider low‑dose aspirin as an additional risk factor when assessing the overall risk of serious gastrointestinal toxicity with NSAID use in an individual - low‑dose aspirin may offset any potential gastrointestinal protective effect of COX-2 selective NSAIDs [Reference given to Lichtenstein (2000)] - the possible increased risk of myocardial infarction, together with known side‑effects such as oedema and hypertension, indicates that COX-2 selective NSAIDs should be used cautiously in persons with cardiac disease (as with conventional NSAIDs). Asked whether the statement that evidence was accumulating that selective inhibition of the COX-2 enzyme might be associated with prothrombotic effects reflected his state of knowledge at the time, Dr Dickman said that his feelings were "coloured by what I know now but I think I was probably in a state of naďveté and still believing that this class of drug had lesser risk". He said that he had no recollection of reading this newsletter, but accepted that it was the type of publication that he would have read. As to the statement contained in the last bullet point set out above, Dr Dickman agreed that, if he had in fact read the newsletter, it was something that would have stuck out as an important piece of information. But he added: "… but again, it's coloured with today's [information]". In this and similar respects, Dr Dickman acknowledged that it was difficult, knowing what he now does, to recall his state of mind before September 2004 about the cardiovascular risks of Vioxx. 722 Dr Dickman was also shown a copy of the June 2003 newsletter of the National Prescribing Service. He accepted that the evidence which he gave about the October 2001 newsletter - as to his receipt of the publication and his tendency to read it - was likewise applicable to this one distributed in June 2003. His attention was drawn to the following: Thrombotic concerns with COX-2s remain unresolved We are no closer to adequately explaining why more myocardial infarctions occurred in the rofecoxib‑treated subjects during the VIGOR trial than those taking naproxen. An epidemiological study has suggested that rofecoxib doses greater than 25 mg (such as those used in VIGOR) are more likely to be associated with serious coronary heart disease [Reference given to Ray (2002) "COX-2 selective non-steroidal…"] although this conclusion needs to be confirmed. Until an appropriate study is performed focusing on cardiovascular outcomes in patients taking COX-2 selective NSAIDs, caution should be exercised when prescribing these drugs in patients at risk of cardiovascular events. What is accepted is that patients who require low‑dose aspirin for cardiovascular prophylaxis should receive it as the benefits are established. [References given to Cleland (2001) and to FitzGerald (2001)] If such patients require an anti‑inflammatory agent, prescribing COX-2 selective NSAIDs preferentially over conventional NSAIDs is not justified on current evidence. [Reference given] Using more than one NSAID concurrently increases the risk of gastrointestinal adverse effects. Again, with the benefit of hindsight, Dr Dickman acknowledged that it was difficult to say whether this passage represented his state of mind in 2003. He said that he was "still feeling quite comfortable with Vioxx and Celebrex in the patients [for whom he] was using it". He accepted that his position at the time was that, to the extent that there were side-effects with these drugs, they were not causing him to refrain from prescribing them. 723 A passage from the Australian Adverse Drug Reactions Bulletin, published in October 2003 by the Australian Adverse Drug Reaction Advisory Committee, was put to Dr Dickman, but he was unfamiliar with it. The passage dealt with the then learning as to the link between the consumption of coxibs and cardiovascular disease, and at one point contained a statement to the effect that the evidence for an association between rofecoxib and a risk of cardiovascular events was "inconclusive and indirect". Dr Dickman said that, if he were aware at the time of information broadly to that effect, it was not sufficient to influence his prescribing, adding, "we are all coloured by our own experiences and I didn't have any unpleasant experiences with my prescribing of Vioxx or Celebrex." 724 Dr Dickman was shown the fourth version of the Vioxx Product Information, approved by the TGA on 14 December 2000 (although identified by counsel as the original version approved on 23 December 1999). He agreed that the "Precautions" section was the sort of topic with which he would have made himself familiar; and that the "Adverse Reactions" section was also something with which he would have had some familiarity at the time he commenced to prescribe Vioxx. It was established that Dr Dickman understood the structure and meaning of the tables and other representations of data in this section. When he first started prescribing Vioxx, he was aware of the range of adverse reactions there set out. 725 In 2001, Dr Dickman had occasion, clinical condition requiring it, to advise patients to take aspirin in a low dose as a prophylactic against cardiovascular risk. Aspirin was understood by him to have some antithrombotic tendencies. His attention was drawn to the statement in the "Precautions" section of the version of the Product Information that was approved on 16 November 2001 that Vioxx was not a substitute for aspirin for cardiovascular prophylaxis because of its lack of effect on platelets. He agreed that, when he was prescribing Vioxx between 2001 and 2004, he understood that it was not a substitute for aspirin because it lacked any effect on platelets. 726 Dr Dickman's attention was drawn to the paragraph headed "Cardiovascular Effects" in the same section of the November 2001 Product Information (see para 258 above). Although he could not put a specific time on it, at some time between December 2001 and September 2004 he knew the ideas encapsulated by this paragraph. That knowledge was not, however, sufficient to make him "unconfident" in the use of the drug. When asked by the court to reconcile that evidence with his evidence in chief that, at the time that he prescribed Vioxx to the applicant, he was not aware that use of the drug was associated with increased cardiovascular risk, Dr Dickman said that he did not regard the risk mentioned in the "Precautions" section of the Product Information - 1.67 events per 100 patient years - as a particularly large risk in the applicant's case because he regarded him as a "mild to moderate" cardiac risk. Asked in re‑examination to explain what the "Precautions" section conveyed to him, he answered: The rate of serious cardiovascular thromboembolic adverse events were significantly lower in patients receiving [naproxen] than in the rofecoxib group. So that it indicates [naproxen] to be a safer drug in terms of cardiovascular events but the overall rate, I would think, with Vioxx is still relatively low. Asked by the court whether, had he had the relevant text on his computer screen at the time he was prescribing Vioxx, and was conspicuously conscious of it, he most likely would still have prescribed it, Dr Dickman said that he would have discussed it with the patient concerned, explained the risk, balanced it against the patient's cardiovascular risk, and left the final decision to him or her.

The applicant's experience with Vioxx 727 The applicant was first prescribed Vioxx by Dr Dickman on 10 May 2001. Dr Dickman had no recollection of any discussion between himself and the applicant at that time about the prescription of Vioxx. From a perusal of the records of his practice, however, he was able to say that the applicant had been complaining of increasing pain in his neck. Some radiological investigations were undertaken, and these confirmed osteoarthritis in the neck. Dr Dickman accepted that the applicant had a long history of back pain, which he (Dr Dickman) associated with osteoarthritis. In May 2001, the applicant was suffering from osteoarthritis from the neck down to the low back. He accepted that, although the applicant's acute presenting problem was pain in the neck, the prescription of Vioxx would have addressed all osteoarthritic pain in his back and spine. Dr Dickman also accepted that, in the circumstances then existing, had he not prescribed Vioxx or one of the other coxibs, he would have prescribed a non‑selective NSAID. The pain being experienced by the applicant had to be treated by something. Dr Dickman chose Vioxx because "it was attractive from the point of view of [the applicant's] gastro‑oesophageal reflux". The dose prescribed was 25 mg daily. 728 According to the applicant, Dr Dickman told him that Vioxx gave good pain relief without causing stomach upsets. Dr Dickman recommended Vioxx, the applicant did not request it. Having known Dr Dickman since his time in the Navy, the applicant regarded him as the kind of doctor who asked questions about new products. He considered Dr Dickman's judgment to be very sound. The applicant said that he always asked his doctors about the side‑effects of any medications they prescribed. The side-effects that Dr Dickman and he discussed in relation to Vioxx were the gastric side-effects of the NSAIDs, which Dr Dickman did not expect to see with Vioxx. Dr Dickman explained that Vioxx worked differently to other anti‑inflammatory drugs. The applicant recalled that Dr Dickman looked through the MIMS entry for Vioxx on his screen, and he indicated that he and others had looked at and discussed Vioxx at length, and "they did not consider it had any major downsides." 729 The applicant said that he tended "to try to look into" the medications which he was supposed to take, as he was a safety‑conscious person who did not believe in taking actions without knowing the risks involved. He said that he read "the Vioxx label or product information" when he was first put on Vioxx. By "product information", he was referring not to the "Product Information" as such, but to the folded sheet of information that was included in the pack in which the Vioxx tablets were supplied. In the lexicon of the TGA, that is the "Consumer Medicine Information". The applicant did not recall reading anything that suggested or implied that Vioxx would increase his risk of suffering a heart attack. There was nothing which indicated a concern about cardiovascular safety. He said that, had he read anything suggesting that there would be a serious side‑effect like that, he would have "headed straight back to Dr Dickman to ask more about it". In his witness statement, the applicant said that he did not read the Vioxx product information (ie the Consumer Medicine Information) or MIMS entry each time he received a new Vioxx prescription, but his discussions with Dr Dickman at such times would always include questions (from Dr Dickman) about how he was tolerating the drugs he was on, and questions from him (the applicant) about whether Dr Dickman thought that he should continue using those drugs, and whether anything had changed since the last time they were discussed between them. He said that he "probably would have gone back to re‑read the Vioxx MIMS entry once or twice during this period", but he mostly relied on his conversations with Dr Dickman and his initial reading of the Consumer Medicine Information to satisfy himself that the pills "were OK to consume". The applicant was never alerted to any concern about cardiovascular risks involved in Vioxx use until the drug was recalled. 730 While using Vioxx, the applicant did not experience any gastrointestinal effects. He was "feeling quite good for most of the time" he was on Vioxx. He was "even able to go for 20 km walks with our dogs on Sunday mornings". After he had been using Vioxx for a while, he told Dr Dickman that it was "a great drug". 731 The applicant was cross‑examined extensively as to his knowledge about Vioxx, and as to his readiness to take Vioxx, notwithstanding being aware of a range of side‑effects, in May 2001 when he was first prescribed the drug. He was shown two documents, neither of which he identified as something he had read at that time. The only familiar aspect of one of them was that it contained a structural representation of the rofecoxib molecule, which the applicant thought he may have seen. 732 The first document shown to the applicant was one which was not tendered, in which circumstances I shall refer only to the applicant's oral evidence about it. Asked about a "mild" side-effect referred to in the document as "high blood pressure", the applicant said that, had he read the document, he would not have associated that with a heart attack, since he would not have taken a "mild" side-effect as being indicative of a heart attack. Had he read the document, he would also have noticed that another side-effect mentioned was "pain or tightness in the chest", which he understood to be a sign associated with the occurrence of a heart attack. He accepted that that would have been a serious side-effect of which he would have been aware had he read the document, but he added that he would also have read a notation to the effect that this side-effect was amongst those "reported rarely in people taking Vioxx and not knowing whether they are definitely caused by Vioxx. Don't be alarmed by this list of possible side-effects. You may not experience any of them." However, he accepted that, if that was the document that he read in May 2001, the information in it did not deter him from taking Vioxx. As I have said, it was not established what this document was, nor whether the applicant ever saw it. 733 The other document was the Vioxx Product Information approved by the TGA on 16 May 2001. The applicant was cross‑examined on the basis that this was current at the time that he was first prescribed Vioxx. That was not strictly accurate, since that prescription was written on 10 May 2001, but probably nothing turns on any differences. In the section headed "Adverse Reactions" (which the applicant understood to be the same as "side‑effects"), there was a table listing all adverse experiences, regardless of causality, befalling people who had taken Vioxx in clinical trials of patients with osteoarthritis in which the comparators had been placebo, ibuprofen or diclofenac. Only events occurring in at least 2% of patients receiving Vioxx were included. The applicant's attention was drawn to the entry for hypertension, in which the figures were 3.5% for Vioxx and 1.3% for placebo. He did not recall seeing these figures at the time. He accepted that, had he seen it, it was not sufficient to give him concern about taking Vioxx, but he added: "… given that hypertension isn't a heart attack". 734 The applicant's attention was then drawn to the adverse events which had occurred in more than 0.1%, but fewer than 2.0%, of patients taking Vioxx (see para 225 above). Under cross‑examination, the applicant was induced to accept that he had a general understanding of the meaning of most of these terms, but only one of which (venous insufficiency) he accepted as being associated with having heart attacks (or, he added, migraines). 735 The applicant was then taken to a passage in the Product Information that dealt with serious adverse reactions that occurred in fewer that 0.1% of patients taking Vioxx (see para 225 above). It was established that the applicant understood these terms. It was put to him that, had he read the document, it would have been immediately apparent to him that there were serious adverse reactions with Vioxx which included strokes, heart attacks and other like conditions. He responded that he would have taken into account the statement that these reactions occurred at a patient‑rate of less than 0.1% in patients taking Vioxx. He said that, had he read this passage, he would have discussed it with his doctor. It was put to him that, given that these events occurred in less than 0.1% of the population studied in the studies concerned, it would not have caused him to refrain from taking Vioxx. His response was that he would have spoken about it with his doctor. 736 The applicant was not shown the new cardiovascular paragraph in the "Precautions" section of the Product Information, as introduced in the November 2001, nor asked how he would have reacted to that paragraph. 737 In his witness statement, the applicant said that, if Dr Dickman had told him of the cardiovascular risk involved with the consumption of Vioxx, he would have "weighed up the positives and negatives about the drug before deciding to take it". He would have been "pretty wary of it, as joint pain and gastric upsets would not kill me, but a heart attack could". He said that he would have wanted to know the exact risks involved before making a decision. At the very least, had he known of any risk, he would have discussed it much more with Dr Dickman. If Dr Dickman had given him the impression that there was a cardiovascular risk, he would not have taken Vioxx, even if told that it would also get rid of his gastric pain. The applicant said that, had he understood, before taking Vioxx, what he now understands, he would not have taken Vioxx; that, had he been told that a clinical trial of Vioxx against naproxen had shown that there was a substantially greater risk of adverse cardiovascular events with Vioxx than there was with naproxen, he would not have taken Vioxx; and that, had he been told that taking Vioxx would approximately double his risk of having a heart attack, he would not have taken Vioxx. 738 I allowed the evidence referred to in the previous paragraph to stand only once the applicant had been examined in chief on the subject, as I was concerned about the imprecision, and tendentiousness, of statements based upon the assumed existence of a certain "cardiovascular risk" without the court knowing the extent of the risk, or the increase in risk, which the applicant had in mind as being enough, hypothetically, to have caused him to act differently. In that examination, the applicant said that he would not have taken Vioxx if Dr Dickman had said to him that his risk of a heart attack, whatever it happened to be, would double, or would increase by 40% or 50%. Asked to state the percentage increase in risk of heart attack or equivalent cardiovascular problems which he would have regarded as acceptable, and consistent with which he would still have taken Vioxx with the gastric benefits that it offered, he responded: "I would have had to discuss that with my doctor at the time. As a balance it would have to be a very low risk and it would have to have the other benefits that I was taking the medication for but I certainly would have relied on his advice." If it came to a choice between naproxen and Vioxx, and the applicant were told that "the risk of a heart attack was two or three or four times as high on Vioxx as on naproxen", the applicant said: I would have wanted to know where the figures came from because I wasn't comparing it with anything else other than if my doctor had told me it was a greater risk than not taking it purely as not taking it. Not taking something else but just not taking Vioxx as against taking Vioxx. I can't speculate what I would have said about anything else. The applicant said that his present understanding was that the consumption of Vioxx at least doubled his risk of having a heart attack, "and possibly [made] it 500 per cent more likely". 739 Under cross‑examination, the applicant accepted that his evidence that he would not have taken Vioxx if informed that it would have doubled his risk of having a heart attack was, or at least may have been, affected by "hindsight bias", a concept with which the applicant, from his area of work, was well familiar. Indeed, because of the applicant's training and experience, he was able to respond intelligently to questions put to him in cross‑examination which, to another witness, might have been too technical. It was put to him, in effect, that there was a world of difference between a doubling of risk from 1/10 to 2/10 on the one hand and from 1/100,000 to 2/100,000 on the other hand. He denied that he would, if told that taking Vioxx would double his risk of a heart attack, only have asked himself what the absolute risk was. He accepted that he knew, over many years of taking NSAIDs for his back pain, that such drugs carried with them some risk of quite serious gastrointestinal problems, even to the extent of requiring hospitalization and, in very serious cases, death. Notwithstanding that knowledge, he said that he had never asked his doctor what was the actual the rate of serious gastrointestinal effects involved in the taking of an NSAID. Cross‑examination then proceeded as follows: In other words, your consumption of that range of medication was without any knowledge of what the actual rate was?---General rate, no, but as far as my risk, I was satisfied that my doctor had considered that. So you relied on your doctor to consider whether the side-effects of the various NSAIDs that you took were appropriately balanced in your case?---Yes. Against the benefits?---Yes. If your doctor thought it was an appropriate balance and prescribed it for you, you took it?---Generally. 740 The applicant was next taken to so much of his evidence in chief as involved evidence that he would not have taken Vioxx if told that it would increase his risk of having a heart attack by 40% or 50%. It was put to him that, for him to have immediately acted on a suggestion that his risk, whatever it was and without knowing what it was, would be increased to that extent would have been contrary to the way in which he practised his business of safety and risk management. While the applicant accepted that, in his line of work, he did usually want to know the absolute level of a particular risk, he rejected the suggestion that, in 2001, he would have taken such an approach to deciding whether or not to take Vioxx. 741 The applicant was asked about his answer in chief that, for him to have been persuaded to take Vioxx against the knowledge that there was some risk, the estimate of the risk would have had to be a low risk, and he would have discussed it with his doctor. He accepted that the decision whether to take Vioxx involved more than a straight comparison of two situations, one in which there was a risk and the other in which there was not. Rather, it was a more complex picture, one in which "a weighing process" was involved, because the hypothetical situation related to a drug which might have increased his risk of heart attack, but reduced the risk of serious gastrointestinal effects. The applicant said that, in such a situation, he would have sought his doctor's guidance. The cross‑examination continued: And you feel quite unable now to say what your reaction would have been to the information you got in the course of such a complex process in May 2001. Isn't that right?---To a certain extent, taking into account, as you say, the bias of hindsight. It's not a question you would be prepared to answer now, is it?---I would still attempt to answer it but I would have to weigh what I know now as against what I knew then. You would accept that if one was attempting to get a snapshot of your mind in May 2001 that snapshot would not be represented by what you could say today?---No, I would say that I would have to try and remember what I was aware of, what I knew, what my impressions of the risk of heart attack and things were then. That's not an exercise you have ever done?---Yes, I have. You have done that?---Yes. Was that the exercise you were doing when you answered these questions with Mr Burnside yes[terday]?---Yes, I was trying to apply what my state of mind and what my thinking was then. Hence, in answer to the question about which I am now asking you which was a weighing up of different risks and benefits you said that you would have had to have discussed it and that you would have sought advice from your doctor and relied on his advice?---Correct.

Continuity of the applicant's use of Vioxx 742 The applicant said that, between May 2001 and September 2004, to the best of his recollection he took a Vioxx tablet every day. There may have been some days during this period when he did not take a tablet, for example, if he forgot (which he said would have been "very rare") or if he had run out of tablets (which he also said occurred only rarely). If he omitted to take his tablets "for a day or two", the pain would return and remind him to take Vioxx again. He used a seven‑day pill box, which he would take with him when travelling away from home and, when at home, which he would leave under his toothbrush or glasses in order to remind him to take his tablet each day. 743 Notwithstanding this evidence, the respondents submitted that I should find that the applicant failed to take Vioxx tablets for a period of about two months between the first week in October, and the first week in December 2003. That submission was based upon records obtained from Medicare of prescriptions obtained, and filled, under the PBS. It was the applicant's consistent practice to obtain prescriptions and repeats from Dr Dickman (or from Dr Anderson − one of Dr Dickman's colleagues at Tower Hill − on one occasion when Dr Dickman was not available). Relevantly to the present question at least, a prescription and three repeats were written each time, each providing for 30 days of medication. The records show that the applicant was prescribed a 30‑day course of Vioxx, and three 30‑day repeats, on each of 10 April 2002, 19 July 2002, 20 December 2002, 30 May 2003 and 2 December 2003. He had a prescription filled on or soon after each of those dates. He also had tablets dispensed under his repeats at approximately 30‑day intervals. Thus, after his prescription written (by Dr Anderson, as it happens) on 30 May 2003, the applicant was dispensed Vioxx on 1 June, 7 July, 3 August and 8 September 2003. The PBS records disclosed no prescription of Vioxx after that written on 30 May 2003 until 2 December 2003. If the records are complete and the applicant was acting consistently with what appeared to be his previous invariable practice, he would have visited Dr Dickman in about the first week of October 2003, to obtain a further prescription and repeats. There is no evidence that he did so. The respondents asked me to find that the applicant took no Vioxx tablets between his completion of the repeat which was dispensed on 8 September 2003, which would have occurred in early October 2003, and 2 December 2003, when the prescription which he obtained that day was filled. 744 According to the applicant, he became aware only in the course of preparation of the evidence for this proceeding that the PBS records showed the apparent gap in the dispensation of Vioxx tablets for him. Notwithstanding the PBS records, the applicant maintained his evidence that he took Vioxx every day. He could not explain the PBS records. While not objecting to the admission into evidence of the records as such, the applicant submitted that it could not be assumed that they accurately set out all of the prescriptions that had been written for him. It was submitted, correctly, that there was no evidence as to the nature or reliability of the systems used at the pharmacies to which the applicant had resort to record information about PBS prescriptions filled. Neither was there any evidence as to the nature or reliability of the systems used by Medicare to collect and record such information. It was submitted that some deficiency in the records themselves was at least as likely to be the explanation for the gap in the prescription of Vioxx which the records disclose. Although not stated in terms, the submission involves the proposition that I should find that the applicant did in fact obtain a prescription, and at least one repeat, in about the first week of October 2003. Previously, Dr Dickman's practice had been to write a prescription with three repeats. Accepting the applicant's submission would seem to involve the proposition that, on one occasion, Dr Dickman departed from his erstwhile practice, and gave the applicant one repeat only. I say that because a further prescription, with three repeats, was written for the applicant on 2 December 2003. What the applicant invites me to do is to base my inference upon the prospect that the PBS records, on this one occasion, failed to include any reference to a prescription which was in fact written, and to tablets which were in fact dispensed, and upon the further proposition that Dr Dickman's previous, and subsequent, practice of giving the applicant three repeats was not followed. That is to say, in two separate and unrelated respects, the applicant asked me to base an inference upon a departure from normality. Unless other indications pointed quite strongly to the facts claimed to be inferred, I would be reluctant to do so. 745 It was put to the applicant that there was a good reason why he might have discontinued taking Vioxx in October 2003, namely, that it was at the start of that month that he gave up his employment with Teekay, thus removing the necessity for him to perform work which involved walking around ships, bending, climbing, getting into confined spaces and the like. The applicant rejected the suggestion that that circumstance made any difference to the regularity of his consumption of Vioxx. In closing submissions, his counsel pointed out that the PBS records showed that he continued to take Vioxx regularly after the beginning of December 2003, notwithstanding that, because of his heart attack, he was presumably taking things very easily at that time. As I shall demonstrate in a moment, however, if only the applicant's PBS records are looked at, this submission is wrong in point of fact: after having had a prescription filled on 2 December 2003, the applicant next obtained Vioxx (on his own repeat) on 11 February 2004, an interval of 71 days. 746 That leaves the question: if the applicant took Vioxx in October and November 2003, how did he come by the tablets? After both the applicant and his wife, Mrs Julia Peterson, had given evidence, the applicant's PBS records had been tendered and the applicant had been cross‑examined by reference to them, the PBS records which related to Mrs Peterson were tendered. Both she and her husband were then recalled for further cross‑examination. The focus of the debate then shifted to the question whether, if there were no Vioxx tablets available to the applicant after early October 2003 as a result of his own prescriptions and repeats, there were tablets available that had been prescribed for, but had not been taken by, his wife. 747 In her witness statement, Mrs Peterson had originally said that she took Vioxx once herself. She could not recall exactly when, but said that it would have been in about 2001 or 2002. Her doctor (not Dr Dickman or anyone from Tower Hill) prescribed Vioxx for her back pain, and gave her a sample pack. She thought that the sample pack was a week's worth of tablets. However, medical and PBS records disclosed that she saw her doctor on 28 August 2003 with pain in the fifth finger on her right hand. Her doctor gave her a sample pack of Vioxx, which was 10 tablets. She accepted that she was mistaken to have supposed that her doctor prescribed Vioxx in about 2001 or 2002. Mrs Peterson saw her doctor again on 3 November 2003, because of a rash on her face and neck, which she was advised to treat with some cream available over the counter. At that time she obtained a prescription for Vioxx, with three repeats. She accepted that it was most likely that she had intimated to her doctor that the Vioxx which she had taken (the sample pack) had eased the pain in her finger, and that the doctor probably said, "well, I will give you a script for that medication". 748 Mrs Peterson filled the prescription on the same day as she had obtained it, 3 November 2003. A repeat was filled on 23 November 2003. In each case, 30 tablets of Vioxx were dispensed. However, she rejected the suggestion that this sequence of events suggested that she then commenced to take the Vioxx for her own pain. She was firm in her denial that, although she had been prescribed a course of Vioxx, she never took any tablets. She said that this was because of a concern, which she first had about 30 years previously when speaking to another doctor, of becoming dependent upon medication. It was submitted on behalf of the applicant that I should accept Mrs Peterson's evidence that, having obtained 30 tablets of Vioxx on 3 November 2003, she took none of them. If so, these 30 tablets would have been in the Peterson household at that time, and available to the applicant, had he run out of his own supply of Vioxx. 749 The respondents did not challenge the credibility of the applicant or his wife, save in the sense that they were mistaken as to the events of late 2003 of which they had little actual recollection. It was submitted that the most likely explanation for those events was that the applicant in fact took no Vioxx tablets between early October and early December (or at least early November) 2003. The respondents relied upon the fact that the explanation ultimately offered by the applicant was not originally advanced by him, before his wife's PBS records for 2003 became available. They submitted that Mrs Peterson's explanation was a most unlikely one. Her evidence involved the proposition that she had been given, and had taken, a sample pack of Vioxx tablets, and had found them effective in the relief of her pain; that she had returned to her doctor and obtained a prescription of Vioxx; that she had, on the same day, filled the prescription at a pharmacy; yet that she had failed to take any of the tablets so obtained, not through oversight or inadvertence, but by reason of a firm conviction that she ought not to take drugs because of the possibility of becoming dependent on them. The respondents also relied on Mrs Peterson's evidence that she had never had a prescription in her own name filled with the intention of giving the tablets to her husband for him to take. Indeed, it was submitted on behalf of the respondents that neither the applicant nor his wife was the kind of person who would engage "in that sort of subterfuge and probably illegality without reason" and "there was no reason why they would engage in that sort of conduct". 750 Mrs Peterson said that she had no specific recollection of her doctor having prescribed Vioxx on 3 November 2003, or thereabouts, but she was adamant that the only Vioxx tablets which she ever consumed were those from the sample pack. When the strangeness of her behaviour was put to her in cross‑examination, she said (speaking of the prescription written on 3 November 2003): I would have perhaps filled it thinking that I would try them and then not gone on with taking the medication itself. I had the prescription, thought, 'well, I will fill the prescription but whether or not I take it is up to me', and I definitely did not take it. This was, of course, ex post facto rationalisation on the part of Mrs Peterson, but it was not put to her that that explanation was a conscious untruth, or had been crafted purely for the purpose of supporting her husband's claim. The sense I had of Mrs Peterson when she was giving this evidence was that she was conscientiously attempting to provide a viable explanation for what the PBS records showed, against her own clear recollection that she did not take any of the tablets which had been prescribed for her. I would also add that what might otherwise be viewed as the implausibility of Mrs Peterson's evidence is rendered the less so when it is recognised that her appointment with her doctor on 3 November 2003 was not, apparently, for the purpose of obtaining Vioxx, nor even for purposes related to the pain in her finger. As noted above, she agreed with the inference proffered by counsel for the respondents that it was the doctor who had volunteered the proposal that more Vioxx should be prescribed. It is not the evidence that, on 3 November 2003, Mrs Peterson needed Vioxx for her own purposes. 751 To resolve these questions, I have found it useful to set out in a table the dates upon which the applicant had Vioxx prescribed for himself, the corresponding dates, commencing with 30 May 2003 (upon which a prescription was written), upon which he had each prescription, or a repeat, filled, the date of the 30th day after the date of each dispensation of Vioxx (ie the day upon which the applicant ought to have filled his next repeat, or new prescription, had he been taking Vioxx every day) and the numbers of days that he was, notionally, "late" in each case. I have prepared a second table, but this time including the dispensations of Vioxx done under the prescription written for Mrs Peterson on 3 November 2003. 752 The tables referred to are the following: Timeliness of purchase of Vioxx - Applicant's records only Patient Date of Pres Date of Disp Prev +30 days Days "late" GP 30-May-03 01-Jun-03 GP 30-May-03 07-Jul-03 01-Jul-03 6 GP 30-May-03 03-Aug-03 06-Aug-03 -3 GP 30-May-03 08-Sep-03 02-Sep-03 6 GP 02-Dec-03 02-Dec-03 08-Oct-03 55 GP 02-Dec-03 11-Feb-04 01-Jan-04 41 GP 02-Dec-03 15-Mar-04 12-Mar-04 3 GP 02-Dec-03 08-Apr-04 14-Apr-04 -6 GP 01-Jun-04 15-Jul-04 08-May-04 68 GP 01-Jun-04 14-Aug-04 14-Aug-04 0 GP 01-Jun-04 05-Sep-04 13-Sep-04 -8

Timeliness of purchase of Vioxx - Applicant's & Mrs Peterson's records Patient Date of Pres Date of Disp Prev +30 days Days "late" GP 30-May-03 01-Jun-03 GP 30-May-03 07-Jul-03 01-Jul-03 6 GP 30-May-03 03-Aug-03 06-Aug-03 -3 GP 30-May-03 08-Sep-03 02-Sep-03 6 JP 03-Nov-03 03-Nov-03 08-Oct-03 26 JP 03-Nov-03 23-Nov-03 03-Dec-03 -10 GP 02-Dec-03 02-Dec-03 23-Dec-03 -21 JP 03-Nov-03 12-Jan-04 01-Jan-04 11 GP 02-Dec-03 11-Feb-04 11-Feb-04 0 GP 02-Dec-03 15-Mar-04 12-Mar-04 3 GP 02-Dec-03 08-Apr-04 14-Apr-04 -6 JP 03-Nov-03 13-May-04 08-May-04 5 GP 01-Jun-04 15-Jul-04 12-Jun-04 33 GP 01-Jun-04 14-Aug-04 14-Aug-04 0 GP 01-Jun-04 05-Sep-04 13-Sep-04 -8

753 Looking at the first table, there were three occasions (shaded in the table) upon which the applicant would have been significantly late in obtaining further supplies of Vioxx if he were relying on his own prescriptions and repeats only: 2 December 2003, 11 February 2004 and 15 July 2004. However, if one assumes that he had available to him also his wife's prescriptions and repeats, one of the delays (11 February 2004) is eliminated, and the others are about halved. It is not only the gap between 8 September 2003 and 2 December 2003 that may (in part) be accounted for by Mrs Peterson's tablets: it is also the gap between 2 December 2003 and 11 February 2004 and that between 8 April 2004 and 15 July 2004. The apparent oddity that the applicant was - if he were taking his wife's tablets - 21 days "early" when he obtained a prescription in his own name on 2 December 2003 is not seen to be so odd when it is realised that he visited Dr Dickman on that occasion not to obtain Vioxx but, as mentioned below, because of his chest pain. 754 The applicant and his wife frankly admitted that they had no recollection of the actual events with which I am here concerned. Mrs Peterson denied having obtained a prescription in her own name with a view to obtaining tablets for the applicant. For his part, the applicant denied "hoarding" (counsel for the respondents' word) tablets. However, they both regularly took prescription drugs, and had the practice of keeping all the outstanding prescriptions and repeats together in a particular place. They thought it quite possible that the applicant (or his wife on his behalf) might have occasionally taken a prescription in Mrs Peterson's name to the pharmacy with a view to obtaining Vioxx for himself. This was conjecture on their part, of course, but it strikes me as an explanation, as likely as any other, for the fact that repeats were filled on Mrs Peterson's prescription on 23 November 2003, 12 January 2004 and 13 May 2004. It may be one thing to reject Mrs Peterson's evidence that she did not take any of the tablets obtained by her on 3 November 2003, but it would be another thing altogether to find, in the face of her denials, that she consumed all of the tablets, the purchase of which is implied by those further repeats. 755 The applicant struck me as a credible witness who had a clear recollection of having followed a system which involved, more or less, the daily consumption of Vioxx. He was a systematic and careful man by nature and training, and brought to the taking of medication a degree of organisation which reflected that. He readily conceded that there were days when he omitted to take Vioxx, but I consider it unlikely that he would have allowed matters to lapse to the extent reflected in the first table set out above. A ready explanation for the gaps shown in that table not reflecting reality is provided by the pattern of dispensations under Mrs Peterson's prescription. I am disposed to accept that explanation. Objectively, it introduces greater sense into what would otherwise be a less than credible pattern of consumption. An aspect of this conclusion is that I should find, as I do, that the tablets prescribed and dispensed on 3 November 2003 were most probably taken by the applicant rather than by his wife. 756 But the respondents next submitted that, on any view, there was a gap between about 8 October and 3 November 2003 in which the applicant had no Vioxx tablets to take, his own repeats having been exhausted and his wife's prescription not yet having been written. It was suggested on behalf of the applicant that he might have been provided with a sample pack (or two) himself, but, given the previous regularity of prescriptions written for him, I think that unlikely. The applicant was not, at that time, in the position of someone contemplating taking a new drug. He had been on Vioxx for about 2˝ years. I do not think there is any satisfactory explanation for how the applicant might have had Vioxx tablets available to him in this period. It would be speculation on my part to attempt to answer the question why the applicant did not visit his doctor and obtain another prescription (the only seemingly plausible explanation - that he had recently discontinued employment which required physical work - having been rejected by him). In the circumstances, I am not satisfied that the applicant had available to him more Vioxx tablets in the second half of 2003 than is implied by the second table above. 757 I should stress that the preparation of these tables had the purpose only of providing a base for the inference which I drew as to the applicant's access to tablets obtained under his wife's prescription. I do not infer that the actual daily pattern of consumption was as set out in the second table. I do not infer, for example, that the applicant took Vioxx religiously every day until 8 October 2003, after which there was a period of exactly 26 days when no tablets were taken. I think it much more likely that the days (occasional though they were) when the applicant overlooked taking his tablets were scattered randomly over the periods when he had tablets to take. Thus, for example, I think it likely that he did not "run out" of tablets on 8 October 2003 exactly, but had some tablets which probably carried him into the next few days. 758 On any view, however, there was a period of three weeks or thereabouts leading up to 3 November 2003 when the applicant did not take Vioxx. I do not accept his evidence to the contrary. I am not, however, disposed to use that circumstance to qualify my acceptance of the applicant's evidence that, generally, he took Vioxx every day. Specifically, I find that the applicant took Vioxx between 3 November 2003 and his heart attack about five weeks later.

The applicant's heart attack 759 In early December 2003, the applicant began to experience an ache or pain in his chest, which would last for 10‑15 minutes and then go away. On 2 December 2003, he saw Dr Dickman, who noted that the applicant's blood pressure was 155/90. Dr Dickman's working diagnosis was reflux oesophagitis and hypertension. Dr Dickman was concerned that the applicant's chest pain may have been angina, so he prescribed Atenolol, a drug to lower blood pressure and to stabilise any cardiac rhythm disturbance. Various pathology tests were arranged, including an electrocardiogram ("ECG") which was done on 3 December 2003. After the ECG test, the nurse told the applicant that he could go, which he took as an indication that his results were normal. As it happened, however, the ECG showed T‑wave inversion in leads I and aVL with a comment that this was possibly due to sub‑endocardial ischaemia or left heart strain. The cardiologists agreed that the applicant "definitely had obstructive atherosclerotic coronary disease with an acute coronary syndrome" at this time. Profs Harper and Celermajer added, in their oral evidence (the latter noting that all the cardiologists were agreed on the point), that what caused the applicant's pain in early December 2003 was plaque rupture. However, the applicant did not know of the ECG results. 760 On 4 December 2003, the applicant drove to Canberra with his wife for a work commitment. Dr Dickman telephoned him on that day (inferentially to inform him of the results of the ECG), but the applicant missed the call. After completing his commitment in Canberra, the applicant and his wife continued on to NSW for a friend's birthday. They returned to Melbourne on Sunday 7 December 2003. On the morning of that day, the applicant experienced another episode of chest pain for about ten minutes. Mrs Peterson gave evidence that her husband was not feeling well, as a result of which she drove the car. They arrived home at about 9.30 or 10.00 pm and retired. 761 In the early hours of 8 December 2003, the applicant experienced another episode of chest pain which was worse than the previous ones. The pain was severe, and radiated down both his arms. Soon after it began, he started losing his peripheral vision. He felt as though he had been hit very hard in the solar plexus. He said he was "stunned and almost choking, and couldn't regain my breath no matter how hard I tried". He was doubled over and gasping. He described the pain as "a crushing type of pain, like I was suffering a massive cramp across all of my upper body". Realising that something was very seriously wrong, the applicant took some aspirin (this was at about 1.00 am) and had a lukewarm shower. Then he and his wife went to the Frankston Hospital, where he arrived at about 3.00 am. 762 What occurred thereafter, as derived from hospital records, was described by Prof Vaughan as follows: [The applicant] was found to have acute electrocardiographic changes including ST elevation in multiple contiguous leads and was diagnosed with an anterior myocardial infarction. … He was admitted and treated with nitroglycerine and thrombolytic therapy. … His initial cardiac enzymes drawn at 3.47 am were not elevated; however, by 7.00 am he had elevated markers of myocardial injury, including elevated troponin and CK‑MB. [The applicant] underwent cardiac catheterization on December 11, 2003. At the time of coronary angiography, [he] was found to have significant coronary artery disease, including a 90% stenosis in his proximal left anterior descending artery (LAD), a tight ostial stenosis in his LADD1 (first diagonal artery off of the LAD), and minor disease in his right coronary artery (RCA). … His left main and left circumflex arteries were noted to be free of disease. … His ejection fraction was calculated at 40%. … He underwent successful PTCA and stenting to his proximal LAD without complication. … Final angiographic result was noted to be excellent with 0% residual stenosis. Prof Harper gave evidence to much the same effect. 763 Prof Harper examined the applicant in October 2008. He gave evidence that, since the applicant's heart attack, he has been given lifestyle modification and has been treated with a standard cardioprotective pharmacological regime. As part of the cardiac catheterisation which the applicant underwent on 11 December 2003 he had a left ventriculogram which showed antero-apical and apical wall hypokinesia. This meant there was reduced contraction as a result of the heart attack in a large portion of the left ventricle. The ejection fraction - a measure of overall cardiac strength - was 40%. A normal ejection fraction is greater than 50%. Prof Harper said that, when heart muscle is damaged by a heart attack, the ejection fraction does not necessarily fall unless the extent of damage has been large. This was because the undamaged heart muscle would compensate for the damaged muscle by contracting more strongly. The fact that the applicant's ejection fraction was significantly below normal indicated that he had had a large heart attack. Subsequent echocardiograms confirmed that the applicant's heart attack was a large one.

Did Vioxx cause or contribute to the applicant's heart attack? 764 The cardiologists said that the applicant's risk factors for myocardial infarction in 2001 were hypertension, hyperlipidemia, obesity and the presence of left ventricular hypertrophy. He was, the cardiologists agreed, "highly likely to have had coronary atherosclerosis that was clinically silent at the time". In addition, he was a former smoker, of male gender and aged 51 years. He was at moderate to high risk of a cardiovascular event over the next 5 years. Prof Harper estimated that risk at 20‑25%, and the other cardiologists took no issue with that. 765 Putting aside the possibility of the consumption of Vioxx as such increasing the risk, the cardiologists agreed that, by December 2003, the applicant's risk factors were "slightly improved". They noted that the applicant had lost weight and that his lipid profile had improved, although still abnormal. They considered that the other risk factors were essentially unchanged. The cardiologists were unable to say whether the consumption of Vioxx had affected the applicant's blood pressure, as there were insufficient data (only three blood pressure readings having been taken since the applicant commenced to take Vioxx). I should add that, although counsel for the applicant made the general submission that the consumption of Vioxx did lead to elevated blood pressure (a subject which I addressed at paras 532‑535 above), they did not submit that this occurred in the case of the applicant himself. In any event, the evidence would be insufficient to sustain any such finding. Neither, in the applicant's case, was there any attention given to the question whether it was elevated blood pressure that led to his atherosclerosis as it existed in December 2003, and thus indirectly contributed to his heart attack. 766 The cardiologists were agreed that, in December 2003, the applicant had a large acute anterior ST segment elevation myocardial infarction. The aetiology of that heart attack was thrombosis consequent upon a ruptured atherosclerotic plaque in his proximal left arterial descending coronary artery. In terms which, while not referred to by the other cardiologists, were not the subject of any challenge by the respondents, Prof Harper explained what most likely happened to the applicant. The … findings at coronary angiography are consistent with the hypothesis that Mr Peterson had developed a significant athero-sclerotic plaque in his left anterior descending artery on which a thrombus, or blood clot, formed, thus completely obstructing the artery producing a ST segment elevation myocardial infarction. Most likely the surface of the athero-sclerotic plaque had ulcerated in the week prior to the actual heart attack, causing intermittent thrombus formation and partial obstruction resulting in the paroxysmal episodes of chest pain Mr Peterson experienced. Eventually the thrombus completely obstructed the artery, thus producing the anterior ST segment elevation infarction on 8 December 2003. The thrombolytic therapy that he was given that day presumably dissolved the clot leaving the residual atherosclerotic plaque, which was subsequently treated by angioplasty and stenting on 11 December 2003. 767 The more difficult part of the task confronting the cardiologists was to form a view, so far as possible, about the contribution of Vioxx to the events in the vasculature as described by Prof Harper. They agreed that, in a patient with multiple risk factors such as the applicant, there was no way definitively to determine which risk factor caused the heart attack. Neither was there any specific feature of the applicant's condition that established whether Vioxx did, or did not, cause or contribute to the heart attack. Prof Celermajer put the matter as follows: There are many 53 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. That is to say, the applicant may have had the very heart attack which he did have, at the same time and of the same level of seriousness, had he not been taking Vioxx. 768 In this state of things, it is perhaps unsurprising that the cardiologists were not agreed on the question whether Vioxx contributed to the applicant's heart attack. Earlier in these reasons, I have set out their respective views on the general question whether Vioxx increased the risk of CVT events, and of myocardial infarctions, occurring. As to the applicant specifically, Profs Zipes and Harper expressed the view that the consumption of Vioxx increased the risk of him having his heart attack by a factor of about two. They were asked whether that was the same thing as saying that they believed it twice as likely that the applicant's consumption of Vioxx in fact caused, or in some material way contributed to, the heart attack which in fact took place. Prof Zipes answered as follows: That number comes primarily from the APPROVe trial where the relative risk was around 2. When an individual has multiple risk factors 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. Prof Harper reiterated that, in his view, Vioxx doubled the applicant's risk of having a heart attack. When asked to look at the matter ex‑post and to express a view as to whether Vioxx in fact contributed to the applicant's heart attack, Prof Harper said that it was a difficult question, "but if it is more than two times then it's more likely than not that Vioxx contributed to the heart attack". Later in his evidence, Prof Harper revised upwards his estimate of the extent to which Vioxx increased the applicant's risk of heart attack. Looking at the data from APPROVe, he said: There were 21 myocardial infarctions in the rofecoxib group and nine in the placebo group; slightly more than 2:1. That is the data that I would rely on over and above any other data that's been presented. 769 When Prof Harper said that a risk of "more than two times" meant that it was more likely than not that Vioxx contributed to the applicant's heart attack, he was implicitly invoking a rule of thumb that says that if, for example, in two otherwise identical groups of people, the events of interest are twice as numerous in the group taking a particular drug as in the placebo group, we may infer that half of those in the former group who experienced an event would have done so anyway. From this it is said that a relative risk of 2.0 goes no further than to imply that an event which occurred in the drug‑taking group is equally likely to have done so as a result of the work of the drug as it is to have occurred in any event. This subject is explained in the judgment of Spigelman CJ in Seltsam Pty Ltd v McGuiness (2000) 49 NSWLR 262, 280‑285. Concluding, his Honour said (at 285 [137]): In Australian law, the test of actual persuasion does not require epidemiological studies to reach the level of a relative risk of 2.0, even where that is the only evidence available to a court. Nevertheless, the closer the ratio approaches 2.0, the greater the significance that can be attached to the studies for the purposes of drawing an inference of causation in an individual case. The "strands in the cable" must be capable of bearing the weight of the ultimate inference. 770 The attribution of a contributory role to Vioxx in the applicant's heart attack, then, came down to an interpretation of the risk data yielded by the various trials and studies and to an opinion as to the relevance of those data to the circumstances of the applicant particularly. Inescapably, this required the cardiologists to form a view as to the validity of the FitzGerald hypothesis. Despite what appeared to be a certain agnosticism about the hypothesis, Prof Harper expressed the opinion that the observed riskiness of Vioxx was due to its effect in the post‑plaque rupture vasculature. This was, I consider, an implicit endorsement of FitzGerald. He and Prof Zipes considered that the applicant's consumption of Vioxx increased his risk of having a heart attack by approximately a factor of two (which they derived from APPROVe). Profs Celermajer and Vaughan did not agree. They expressed their conclusion thus: "We do not believe, with a reasonable degree of scientific certainty, that Vioxx played a role in causing [the applicant's] heart attack." When asked by the court what was meant by "reasonable degree of scientific certainty", Prof Celermajer said: We were presented with a binary outcome - it contributed or it didn't. We were not invited to say with what degree of possibility might it have contributed. So when asked to make a binary outcome decision we responded to that by saying we did not. We simply wished to acknowledge that we are not absolutely certain of that because the data themselves are [uncertain] …. 771 Unlike Prof Celermajer, I am required to make an assessment of the probability that Vioxx caused or contributed to the applicant's heart attack. Here the actual circumstances of the applicant on 8 December 2003 are important. I accept the evidence of Prof Vaughan that Vioxx did not cause atherosclerosis and did not cause plaque rupture. However, the cardiologists are agreed that the applicant had clinically silent atherosclerosis in and subsequent to 2001, and that he experienced plaque rupture in early December 2003. It seems highly probable that this would have been a clinical diagnosis positively made had the applicant's interstate trip not caused him to miss Dr Dickman's phone call. However that may be, the fact is that, after plaque rupture, the applicant was in the high risk group referred to in the APPROVe results - he had symptomatic atherosclerotic cardiovascular disease. He may have been in that situation earlier, but on 2 December 2003 he unquestionably was. 772 As the respondents and their experts pointed out, if valid, the FitzGerald hypothesis proposes an acute risk of thrombotic outcomes from the consumption of Vioxx. That there should be such a risk, however, requires first that there be a potentially thrombotic environment in the vasculature. That environment was, in the applicant's case, present in December 2003. I think it likely that the applicant's was a case in which the absence of prostacyclin in the immediate vicinity of his injured artery made some contribution to the formation of the thrombus or thrombi that caused the occlusion which gave him his heart attack. I do not find that the heart attack would not otherwise have occurred: there is no way of knowing whether it would have. But I am satisfied that some material contribution was played by the brake on the synthesis of prostacyclin applied by the inhibition of COX-2, and therefore by the consumption of Vioxx. 773 It is a necessary premise of this finding that the applicant was taking Vioxx, more or less daily, in the weeks leading immediately to early December 2003. As I have found earlier, he was doing so because he had access to Vioxx obtained under his wife's prescription. Had that not been the case, I would not have been able to find, on the probabilities, that Vioxx made a material contribution to the applicant's heart attack. Here I refer to my treatment of the cardiologists' evidence as to the relevance of the pattern of use of Vioxx at paras 548‑550 above. While I recognise the force of Prof Harper's evidence as set out in para 519 (which provided a measure of support for Prof Zipes' more categorical evidence on the same subject), in the light of my reasons on mechanism, and given the absence of any trial data with respect to risk in a situation of discontinuous administration of the drug, I could not be satisfied that Vioxx would, merely by having been taken by the applicant continuously down to about (say) the middle of October 2003, have contributed to what happened on 8 December 2003. In the words of Spigelman CJ in Seltsam, there would then have been insufficient "strands in the cable" to support such a finding.

Consequences of the applicant's heart attack 774 I have referred (at para 763 above) to the evidence given by Prof Harper as to the damage done to the applicant's heart muscle as a result of his myocardial infarction on 8 December 2003. Prof Harper said that this damage was permanent. He said that, at present, the applicant has only mild overall impairment of heart function, but he has a significantly diminished cardiac reserve. If he were to suffer a further heart attack and sustain further damage to his heart, his ejection fraction would fall further, putting him at significant risk of developing cardiac failure and increasing his susceptibility to death. 775 Prof Harper referred also to a number of matters of which he was apparently informed by the applicant, namely, that he continues to work as a self-employed marine consultant but by choice does less work than previously; that he avoids locations which lack immediate high quality cardiac care if needed; that he no longer scuba dives or undertakes heavy physical activity; that he tires more easily; and that he feels short of breath on exertion much more readily than prior to his heart attack. The applicant informed Prof Harper that he experienced intermittent episodes of chest pain. In Prof Harper's view, these were not necessarily related to exertion. A negative result to an exercise test recently undertaken by the applicant indicated to Prof Harper that the chest pain was not due to recurrent myocardial ischaemia, but was probably anxiety-related; nonetheless it caused the applicant great concern. Prof Harper said that the applicant consistently had symptoms which corresponded to activities which required 5-6 METS of energy. Taking these physical and psychological factors into account, Prof Harper considered that the applicant's level of "whole person impairment" as a result of his heart attack was in the order of 25-30%. 776 In Prof Harper's view, the applicant's current risk of having a further heart attack has been significantly reduced by the facts that he is no longer taking Vioxx, that he has an improved lifestyle and that he is currently on a strong pharmacological cardioprotective regime. Prof Harper estimates the applicant's current risk of suffering a further heart attack in the next five years to be in the order of 5-10%. 777 As a result of the applicant's heart attack, he was not able to continue with so much of his plans as involved GPA providing safety consultancy services directly to industry. Instead, through GPA, he has undertaken work for another safety consultancy company, Safety Wise Solutions Pty Ltd ("SWS"). There he does the same kind of work as he would have done had GPA provided such services directly, that is, he runs training courses, he undertakes safety audits, he performs safety inspections and he carries out accident and incident investigations. He also does some work as a consultant for P & O Maritime Services. 778 In the small team of consultants used by SWS, the applicant is the only one with substantial experience in the maritime industry. The managing director of SWS, Mr Gerry Gibb, holds the applicant in high regard. In the kind of work that the applicant does, it is often a requirement to be on a site for ten or more consecutive days before taking a break. However, the applicant finds that he is able to work for about six days straight at most. He tends to get too tired to work much more than that. The applicant told Mr Gibb that he did not really want to work more than 8-10 days each month. According to Mr Gibb, if the applicant wanted to work more, he could have as much work as he wanted. SWS is always very busy, and always has work available for the applicant. 779 Before he allocates work to the applicant, Mr Gibb assesses whether the particular assignment would be suitable for the applicant, having regard to his heart condition. About 20% of the applicant's work is undertaken outside Australia, in relation to which Mr Gibb considers the availability and standard of medical facilities at the location in question, and the length and arduousness of the travel required to get there. Thus, for example, Mr Gibb perceived that there would be no difficulty with the applicant being sent to Dubai, where the medical facilities are excellent and the site in question was reasonably accessible, but chose not to send the applicant to a particular job in South Africa because travel to the site required a very long journey by car. This latter consideration is also taken into account by Mr Gibb when allocating work to Mr Peterson to remote sites within Australia. I rather gather from Mr Gibb's evidence, however, that it is the applicant's self-imposed limitation of 8 − 10 days per month, rather than any of these considerations, that ultimately provides the practical restraint upon the amount of work that he performs for SWS. 780 The applicant did not suggest that the operation of his "Lockout" business had been affected by heart attack. Indeed, in the financial year to 30 June 2008, sales from that business (which is also conducted through GPA) exceeded $550,000. 781 Recreationally, the applicant's heart attack has obliged him to give up diving, which he used to enjoy.

The existence and content of a duty of care 782 The applicant submitted that "[a] manufacturer of a product intended for human consumption owes a duty to intended ultimate consumers to take reasonable care to prevent the product from causing injury or loss to those consumers …". At the general level, the respondents' articulation of this proposition was, if anything, even broader. They referred to the principle as stated by McHugh J in Dovuro Pty Ltd v Wilkins (2003) 215 CLR 317, 328 [29]: It is beyond doubt that a manufacturer of any product owes a duty to a consumer to take reasonable care to prevent the product causing injury or loss to the consumer. His Honour said much the same thing in Graham Barclay Oysters Pty Ltd v Ryan (2002) 211 CLR 540, 585 [106]. The respondents added − and I have little doubt but that the applicant would agree − that "[a] manufacturer's duty includes responsibility for ensuring that appropriate and necessary information about the product is communicated to persons who will use or consume the product, and who it can be foreseen may suffer loss or damage …". 783 In the applicant's written submissions, it was contended that: c. The scope and content of the duty of care owed by the manufacturer of a product to a consumer will be limited to taking reasonable steps to avoid injuries which are reasonably foreseeable … d. The particular injury suffered need not be foreseeable. It is sufficient if the injury suffered is of a general type or kind which is foreseeable … e. A risk of injury is foreseeable if it is real and not far‑fetched or fanciful, even if remote and extremely unlikely to occur … f. In order for a duty to extend to a particular risk, it must be one that is "not insignificant": Wrongs Act 1958 (Vic), s 48(1)(b). "Insignificant risk" includes risk which is far‑fetched or fanciful, and a "not insignificant risk" is a risk other than an insignificant risk, and includes a significant risk: Wrongs Act 1958 (Vic), s 48(1)(b). The first three of these propositions were supported by references to authority. All four of them are uncontroversial at the general level. Only in one respect did the respondents take issue with the applicant's articulation of the law in these terms. They made the following submission: [T]he Respondents' duty must be informed by, and not inconsistent with, the peculiar regulatory regimes which regulated all of their actions in bringing Vioxx to market, and also in light of the fact that Vioxx could only be obtained on prescription from an appropriately qualified healthcare professional. … Accordingly, … any such duty is discharged by the provision of information to the TGA in accordance with the applicable legislation and in satisfaction of the TGA's requirements and the provision of information to prescribers in a way which is limited by and complies with the relevant legislation and the conditions of the medicine's registration on the ARTG. It will be apparent, however, that this submission is essentially concerned not with the content of the duty of care, but with its discharge. Indeed, in a passage in Ryan immediately following that on which the respondents relied, McHugh J said: To formulate the duty in more specific terms invites error because it is likely to mix a question of law (whether a duty existed) with a question of fact (whether a breach occurred). If the duty is formulated in specific terms, the issue on breach is whether the duty has been performed in accordance with the terms of the duty as formulated. But, as Wyong Shire Council v Shirt ([146 CLR 40 at 47‑48, per Mason J, Stephen and Aickin JJ agreeing]) shows, the question of breach is far more complex than an affirmative or negative answer to the question whether the defendant carried out the duty as formulated. It involves evaluating and weighing a number of competing considerations. I shall deal with the respondents' point as to the sufficiency of their compliance with the regulatory regime for which the TG Act provides below, as part of my consideration of the steps which MSDA took in the discharge of the duty of care. 784 The applicant also submitted as follows: A duty of care will only arise in respect of risks that are "material". A risk will be "material" if a reasonable person in the consumer's position would be likely to attach significance to it or the manufacturer was or should have been aware that the consumer would be likely to attach significance to it: see Rosenberg v Percival (2001) 205 CLR 434 at [75]; Rogers v Whitaker (1992) 175 CLR 479 at 490 [16]. In order to satisfy the "materiality" requirement it is not necessary to establish that the patient would have acted upon a warning if given - this is a question of causation. The test is "somewhat lower than that" and materiality will be established if the reasonable or particular person "would have been likely seriously to consider and weigh up the risk before reaching a decision": Rosenberg v Percival (2001) 205 CLR 434 at [79], [80]. Rogers v Whitaker was a medical negligence case. In the course of their joint reasons, Mason CJ, Brennan, Dawson, Toohey and McHugh JJ considered the judgment of King CJ in F v R (1983) 33 SASR 189, noting that his Honour had been of the view that − … the amount of information or advice which a careful and responsible doctor would disclose depended upon a complex of factors: the nature of the matter to be disclosed; the nature of the treatment; the desire of the patient for information; the temperament and health of the patient; and the general surrounding circumstances. (175 CLR at 488). In a paragraph which contains a passage relied on by the respondents in the present case, their Honours in Rogers v Whitaker said (175 CLR at 490): We agree that the factors referred to in F. v R.. by King C.J…. must all be considered by a medical practitioner in deciding whether to disclose or advise of some risk in a proposed procedure. The law should recognize that a doctor has a duty to warn a patient of a material risk inherent in the proposed treatment; a risk is material if, in the circumstances of the particular case, a reasonable person in the patient's position, if warned of the risk, would be likely to attach significance to it or if the medical practitioner is or should reasonably be aware that the particular patient, if warned of the risk, would be likely to attach significance to it. This duty is subject to the therapeutic privilege. This appears to be the supposed jurisprudential basis for the applicant's submission that a duty of care will only arise in respect of risks that are "material". 785 In Rogers v Whitaker, however, the existence of a duty of care was not controversial: see 175 CLR at 483. Neither was it controversial in Rosenberg v Percival. The test of materiality was formulated (in both cases) in the context of the question whether the discharge of the duty of care required a medical practitioner to warn his or her patient of risks − even very unlikely risks − known to be involved in a procedure under contemplation. In such a context, that test has, if I may so observe with respect, a particular relevance, as it provides a framework for applying the general law of negligence to the circumstances of a doctor‑patient relationship where the doctor has a duty to advise but the patient has the ultimate decision. 786 By contrast, the present is a product liability case. The notion of materiality finds no express mention in the classic formulation of Lord Atkin in Donoghue v Stevenson [1932] AC 562, 599 that − … a manufacturer of products, which he sells in such a form as to show that he intends them to reach the ultimate consumer in the form in which they left him with no reasonable possibility of intermediate examination, and with the knowledge that the absence of reasonable care in the preparation or putting up of the products will result in an injury to the consumer's life or property, owes a duty to the consumer to take that reasonable care. Indeed, as noted above, the parties in the present case accepted such a proposition. I consider, in the circumstances, that the applicant was wrong to submit that a duty of care arises only in respects of risks which are "material". In my view, on the facts of the present case, the duty of care was a general and universal one arising from the proximity between the respondents and all who fell within the class of persons for whom Vioxx was intended − and to whom it was conventionally prescribed − as a packaged product for human consumption. 787 Before completing this section of my reasons, I should refer to the potential relevance of one aspect of the applicant's evidentiary case to the question whether MSDA owed a duty of care to him. I have found that the Vioxx tablets which the applicant consumed between 3 November and 2 December 2003 had been, as a matter of probability, obtained under a prescription written for his wife. The respondents did not submit that, should I make a finding in those terms, they did not owe the applicant a duty of care, or their duty of care was somehow qualified, by reason of that circumstance. Subject to their other points to which I refer, the respondents approached the matter as though the applicant were within the class of persons to whom they owed the duty.

Discharge of the duty of care 788 In the course of their written submissions, the respondents advanced three general propositions on the subject of the discharge of their duty of care. It is convenient to deal with them at the outset. 789 The first proposition was that compliance with the requirements of the regulatory regime for which the TG Act provided constituted, as a matter of law, a sufficient discharge of the duty of care which fell upon the manufacturer of prescription medicines such as MSDA. The respondents submitted that the TGA was the "independent expert evaluator of prescription medicines" and that - (a) one of the means by which the TG Act does this is a system of registration and listing of medicines which requires the TGA to be satisfied of the quality, efficacy and safety of a prescription medicine for its intended purposes before that medicine can be marketed in Australia. The TGA also has the power (delegated to it by the Secretary of the Department of Health & Ageing) to impose conditions on its approval of a medicine: ss 25(1) and 28 of the TG Act; (b) the TGA's review of a medicine involves a detailed consideration of the data submitted by the sponsor (in this case MSDA), including review by expert evaluators and consideration by a committee of expert advisors (ADEC); (c) TGA review continues throughout the life of the medicine; (d) in the case of Vioxx, the TGA reviewed three Category 1 applications: the original application for approval, the application to incorporate the VIGOR data into the PI, and the application for approval of an indication for symptomatic treatment of rheumatoid arthritis; (e) in addition, the TGA received Periodic Safety Update Reports from MSDA throughout the time Vioxx was on the market. 790 The respondents submitted that the system of evaluation of prescription medicines established by the TG Act was comprehensive. Implicit in it was a recognition that prescription medicines carried with them inherent risks. The system struck a balance between the need to protect the public from the harmful, and the public's need for the beneficial, effects of medicines. The Act did this by providing for a detailed review regime, and "a system for the provision of information and warnings to doctors in a prescribed form". The regime sought to strike a balance between the need to test prescription medicines before they were marketed so as to understand their risks and the interest of the public in obtaining access to medicines sooner rather than later. The respondents submitted that it would be inconsistent for the law of negligence to impose a duty of care upon manufacturers of prescription pharmaceuticals beyond the duty to participate in this regulatory scheme in a bona fide manner, and to fulfil their statutory obligations under the scheme. 791 The objects of the TG Act were set out in s 4(1) as follows: The objects of this Act are to do the following, so far as the Constitution permits: (a) provide for the establishment and maintenance of a national system of controls relating to the quality, safety, efficacy and timely availability of therapeutic goods that are: (i) used in Australia, whether produced in Australia or elsewhere; or (ii) exported from Australia; (b) to provide a framework for the States and Territories to adopt a uniform approach to control the availability and accessibility, and ensure the safe handling, of poisons in Australia. Consistently with these objects, the system established by the TG Act was essentially a regulatory one, such as legislation might regulate, for example, the driving of cars on public roads, the standards of construction of new buildings or the guarding of dangerous machines. There was nothing that I could find in the TG Act - and there was no provision to which the respondents drew my attention - that purported to confine what would otherwise be required in the reasonable discharge of the duty of care owed by a drug manufacturer to those who consumed it. Notwithstanding the absence of any such provision, was it a matter of necessary implication that the TG Act operated in the way proposed by the respondents? 792 The respondents' submissions fell a good distance short of persuading me that any such implication should be made. They contained no such rigorous examination of the terms of the TG Act as would be necessary to make good the point. In one respect at least, the submissions overreached the actual terms of the Act. I refer to the proposition that the TG Act provided for "a system for the provision of information and warnings to doctors in a prescribed form". The respondents did not identify where the Act so provided. For my own part, I have been able to find nothing in the TG Act which either mandated or regulated the terms in which a drug manufacturer such as MSDA provided information and warnings to doctors. 793 The effect of accepting the respondents' submission would be that, so long as the manufacturer of a prescription medicine complied in good faith with the system for which the TGA provided, it could never be held to have fallen short in the discharge of its duty of care to consumers. The manufacturer, could, it seems, engage in all manner of negligent promotion, communication or presentation without being exposed to claims of the kind that the applicant now brings. A careless error in the preparation of a particular production batch (ie a snail‑in‑the‑bottle problem) could never be held to constitute a failure to discharge the duty of care. I highlight here, of course, the circumstance that the respondents' point fails to address quite egregious negligent acts of commission. I do not know how the respondents might respond to these criticisms: their written submissions proceeded more by way of manifesto than by way of analysis. They were not developed orally. 794 By placing on the market a product to be consumed by end users, the manufacturer of a prescription medicine, no less than the manufacturer of any other product intended for human consumption, establishes the setting for the creation of the relationship of proximity from which the common law duty of care arises. I would be slow to hold that a law which did not in terms deal with that very subject implicitly qualified the manufacturer's obligation - as it would otherwise be defined by the common law - so as to permit it, in effect, to act less than reasonably in the discharge of the duty, and to act in a way that produced loss or damage, yet to be shielded from claims by injured parties. There is, in my view, nothing unworkable or anomalous about such a manufacturer remaining under an obligation to take reasonable steps to avoid loss or injury to the end user at the same time as being required to comply with the regulatory system for which the TGA provided. The manufacturer's obligation is not, in my view, exhausted upon compliance with the statute - no more so than the motorist's obligation to take care in the driving of his or her vehicle is exhausted upon compliance with road traffic regulations: see Sibley v Kais (1967) 118 CLR 424, 427. 795 For the above reasons, I reject the respondents' point that the steps required in the discharge of their duty of care went no further, as a matter of law, than to participate in the system of regulation for which the TG Act provided. That conclusion does not, of a course, exclude the prospect that, in identifying the steps required in the discharge of the respondents' duty of care, the requirements of that system, and MSDA's compliance with them, might not be relevant under the general law. To the extent relevant, this is a matter to which I shall turn in due course. 796 The respondents' second general proposition was that the court should recognise the existence of the "learned intermediary" defence which is available in many jurisdictions in the United States in product liability proceedings involving prescription drugs. The nature of the defence was explained by the Fifth Circuit Court of Appeals in Reyes v Wyeth Laboratories 498 F 2d 1264 (1974) at 1276: We cannot quarrel with the general proposition that where prescription drugs are concerned, the manufacturer's duty to warn is limited to an obligation to advise the prescribing physician of any potential dangers that may result from the drug's use. This special standard for prescription drugs is an understandable exception to the Restatement's general rule that one who markets goods must warn foreseeable ultimate users of dangers inherent in his products. See Restatement (Second) of Torts, Section 388 (1965). Prescription drugs are likely to be complex medicines, esoteric in formula and varied in effect. As a medical expert, the prescribing physician can take into account the propensities of the drug as well as the susceptibilities of his patient. His is the task of weighing the benefits of any medication against its potential dangers. The choice he makes is an informed one, and individualized medical judgment bottomed on a knowledge of both patient and palliative. Pharmaceutical companies then, who must warn ultimate purchasers of dangers inherent in patent drugs sold over the counter, in selling prescription drugs are required to warn only the prescribing physician, who acts as a "learned intermediary" between manufacturer and consumer. The defence was referred to by Kiefel J in Carey‑Hazell v Getz Bros & Co (Aust) Pty Ltd [2004] FCA 853 at [219]. In a passage relied on by the respondents, her Honour said: The effect of a "learned intermediary" upon a manufacturer's duty has been the subject of considerable case law in the United States. In Sterling Drug, Inc. v Cornish 370 F.2d 82 (8th Cir 1966) the term was used in relation to a physician who acted as a liaison between patient and drug manufacturer. The content of the manufacturer's duty was to warn prescribing physicians. … It has been explained that the reason for describing the duty in this way is because it is a physician's duty to remain abreast of product characteristics and to decide which facts should be told to the patient. Once adequate warnings are given to the physician, the choice of treatment and the duty to disclose properly fall upon the doctor. With respect, as I understand the defence, it is not based on the assumption that a physician will "remain abreast of product characteristics". Quite the contrary: the duty to warn the physician seems clearly to be based on the silent proposition that, absent warnings, the physician may know little about the characteristics of a product alleged to be harmful. However, the defence does involve the assumption that a physician, with his or her training and understanding, will be best equipped to receive a warning from the drug supplier (which may well be quite technical and unintelligible to many patients) and to factor that into the many considerations taken into account when making prescribing decisions. 797 The learned intermediary defence was not resorted to by the court in Carey‑Hazell, and has not been the subject of any authoritative judgment in Australia. I consider that, expressed as it was in the extract from Reyes set out above, it may be too categorical an articulation of the duty of a manufacturer of a product intended for human consumption. As so expressed, the test almost defies one to contemplate situations in which the broad duty deriving from Donoghue v Stevenson may not be sufficiently discharged, even in cases of prescription medicines, by warnings given to physicians. There may, for example, be unusual lifestyle choices made in the future by the consumer which, being beyond the range of matters reasonably inquired about by the physician, might later lead to adverse reactions. However, nothing further needs to be said about such speculations, or about the defence generally, since I consider that the present case can and should be decided without reference to the learned intermediary defence as such. As will appear, I consider that the general principles adumbrated in the cases to which I have referred provide a sufficient framework for the making of the judgments necessary to resolve the issues presented here. 798 The respondents' third general proposition was that any identification of the steps required of them in the discharge of their duty of care had to proceed on a case‑by‑case basis and could not be done generally, that is to say, so as to produce an answer that was applicable to all group members. They founded the point upon the applicant's allegation in his Further Amended Statement of Claim that the consumption of Vioxx materially increased the risk of suffering the pleaded cardiovascular conditions. In response to a request for particulars of his pleading, the applicant gave the following meaning to his allegation of a material increase in risk: The increased risk is said to be material in that: (i) the consumption of Vioxx elevated the chance of a person who consumed Vioxx experiencing one or more of the cardiovascular conditions; and (ii) a reasonable person would be likely to attach significance to it. The respondents took the applicant here to be invoking the test propounded in the joint judgment in Rogers v Whitaker (175 CLR at 490 − see para 784 above). They then went to that judgment, and noted that the hypothetical person referred to in subpara (ii) of the applicant's response was not just any reasonable person but such a person in the patient's position. From this it followed, according to the respondents, that the "ascertainment of the materiality of a risk involves an individual element". Therefore, whether the respondents ought to have regarded a risk as material was not susceptible of a single answer across all group members, but would have to be determined on a case‑by‑case basis. It followed again from that that the only group member with respect to whom the court could now reach a conclusion as to the nature of the response reasonably required of the respondents to the circumstance (if it were a circumstance) that Vioxx increased the risk of suffering the pleaded cardiovascular conditions was the applicant himself. 799 I do not accept the respondents' analysis of the law relating to the steps required of them in the discharge of their duty of care. Here one must start with the circumstances from which the group members' cause of action arises. This is a case in which the product in question has been manufactured as intended, without the intrusion of a foreign substance, without any miscalculation in the mix of ingredients and without any deterioration in the course of wholesale or retail supply. The kind of considerations which, in such a case, should inform the inquiry were referred to by the UK Court of Appeal in Wright v Dunlop Rubber Co Ltd (1972) 13 KIR 255, 272, in a passage cited with apparent endorsement in the Appeal Division of the Supreme Court of Victoria in Thompson v Johnson and Johnson Pty Ltd [1991]2 VR 449, 490: It is obvious that the answer to the question: 'What are reasonable steps?' must depend upon the particular facts. It is obvious, also, that the duty is not necessarily confined to the period before the product is first produced or put on the market. Thus, if, when a product is first marketed, there is no reason to suppose that it is carcinogenic, but thereafter information shows, or gives reason to suspect, that it may be carcinogenic, the manufacturer has failed in his duty if he has failed to do whatever may have been reasonable in the circumstances in keeping up to date with knowledge of such developments and acting with whatever promptness fairly reflects the nature of the information and the seriousness of the possible consequences. If the manufacturer discovers that the product is unsafe, or has reason to believe that it may be unsafe, his duty may be to cease forthwith to manufacture or supply the product in its unsafe form. It may be that in some circumstances the duty would be fulfilled by less drastic action: by, for example, giving proper warning to persons to whom the product is supplied of the relevant facts, as known or suspected, giving rise to the actual or potential risk. Factors which would be relevant would be the gravity of the consequences if the risk should become a reality, and the gravity of the consequences which would arise from the withdrawal of the product. 800 The applicant does not allege that, as a direct and inevitable result, the consumption of Vioxx gave rise to any one or more of the pleaded cardiovascular conditions. Rather, his case is concerned with an activity by the respondents which is said to have given rise to a risk to him, and to the other group members, of which they knew or ought to have known. As reasonable manufacturers and suppliers of Vioxx, what ought the respondents have done in such circumstances? The answer, I consider, is to be found in the judgment of Mason J in Wyong Shire Council v Shirt (1980) 146 CLR 40, 47−48: In deciding whether there has been a breach of the duty of care the tribunal of fact must first ask itself whether a reasonable man in the defendant's position would have foreseen that his conduct involved a risk of injury to the plaintiff or to a class of persons including the plaintiff. If the answer be in the affirmative, it is then for the tribunal of fact to determine what a reasonable man would do by way of response to the risk. The perception of the reasonable man's response calls for a consideration of the magnitude of the risk and the degree of the probability of its occurrence, along with the expense, difficulty and inconvenience of taking alleviating action and any other conflicting responsibilities which the defendant may have. It is only when these matters are balanced out that the tribunal of fact can confidently assert what is the standard of response to be ascribed to the reasonable man placed in the defendant's position. This was not a product liability case, of course, but the principles laid out by Mason J are, in my view, universal. 801 Conformably with the passage from Wyong v Shirt referred to above, the question in the present case is: what would the reasonable manufacturer and supplier do by way of response to the risk identified? I consider it to be a distraction to attempt to equate the position of the respondents with that of a surgeon advising a patient about the risks involved in undertaking a particular procedure. The respondents were not in a one‑on‑one relationship with the consumers of Vioxx. They were manufacturers and suppliers of a mass‑produced product, packaged and labelled by them without discrimination as between those consumers. Any decision they made about continuing to supply Vioxx, or about providing a warning, would have to be made generally (although, I accept, a warning may in its terms have made such a discrimination). They did not pretend to understand the circumstances of particular patients. Quite the contrary: by relying on the "learned intermediary" defence, they implicitly disclaimed any such understanding. The so‑called subjective limb of the two‑part test in Rogers v Whitaker can, therefore, have no relevance to the circumstances of the respondents in the present case. 802 In the particulars which he provided (as mentioned in para 798 above), the applicant confined himself to a modified version of the objective element of the test in Rogers v Whitaker. He contended that the risk in the present case should be regarded as material if a reasonable person would be likely to attach significance to it. I say "modified version" because, as will be noted, the applicant omitted the qualifier "in the patient's position". In so doing the applicant was proceeding consistently with the distinction I have made above between the circumstances of a surgeon advising an individual patient about the risks involved in a contemplated procedure and those of the respondents as manufacturers and suppliers of a product intended for general distribution. I consider that it would be quite artificial to impose upon the respondents an obligation to consider the individual situation of every consumer who did or might purchase Vioxx and to make individual decisions about whether to supply the drug to him or her, or whether to warn, and if so in what terms. Even an objective test, if posited on the "patient's position", would, in my view, be quite unworkable where those presumptively making an informed response to the risk as they reasonably perceived it were manufacturers and suppliers such as the respondents. 803 I consider that the matter should be approached in a much less complicated way than was proposed by the respondents. That approach should be as stated by Mason J in Wyong v Shirt: confronted with the existence, or the prospect, of a risk of which he or she knew or should have known, what would a reasonable person in the position of the respondents have done by way of response? The object of the reasonable person would be, of course, to eliminate or to minimize the scope for the risk coming home, or at least to warn the consumer, or to provide information or advice in the nature of a warning, so that he or she might weigh the size and nature of the risk, or the prospect of a risk, against the benefit of taking the drug, and make his or her own decision. If the reasonable person would have perceived that there were, or might be, differences as between consumers that would militate against a "one size fits all" approach, then no doubt an appropriate discrimination would be made in the terms in which any warning was expressed. However, as will appear, I do not accept that the nature of the response required of the respondents cannot be identified without assuming to them a knowledge of the individual circumstances of all consumers. Indeed, when a response to the results of the VIGOR trial was called for, MSDA took a single step upon which it now relies as constituting the discharge of its duty of care to all consumers (the amendment of the Product Information in November 2001). Likewise, the response of the respondents to the results of the APPROVe trial was a single one which applied across all patient groups (the withdrawal of Vioxx). 804 I turn now to the facts of the case, and to the question whether, in the circumstances obtaining, the respondents discharged their duty of care to consumers of Vioxx. I have held that there was no time before the withdrawal of Vioxx from the market when the respondents knew or ought to have known, as a matter of established scientific fact, that the consumption of rofecoxib materially increased the risk of suffering the pleaded cardiovascular conditions. However, I have also held that the results of the VIGOR trial ought to have been regarded by them as a worrisome signal of potential cardiovascular risk. As manufacturers with a duty of care, how ought the respondents reasonably have responded to that circumstance? I do not think - and the respondents did not submit - that doing nothing would have been a reasonable response. 805 What Merck ought to have done was the subject of an allegation in the Further Amended Statement of Claim, as follows: At all material times after 30 June 1999, in manufacturing the rofecoxib from which Vioxx tablets were manufactured by Merck Australia, Merck Inc: (a) failed to undertake or cause to be undertaken any or any adequate research, investigations, clinical trials or observational studies in order to ascertain the adverse side effects and health risks that may be associated with the consumption of rofecoxib including a material increase in the risk of suffering the [pleaded] cardiovascular conditions; (b) failed to have adequate regard to the results of any research, investigations, clinical trials or observational studies undertaken or caused to be undertaken by Merck Inc or others suggesting that the consumption of rofecoxib materially increased the risk of suffering the [pleaded] cardiovascular conditions; (c) failed to await the results of any research, investigations, clinical trials or observational studies being undertaken or planned by Merck Inc or others to ascertain whether the consumption of rofecoxib materially increased the risk of suffering the [pleaded] cardiovascular conditions; (d) withheld from and failed to publish in medical publications or otherwise reveal data and information of which it was aware concerning adverse cardiovascular risks associated with the consumption of rofecoxib. It follows from my reasons above that I reject the allegations set out in subparas (a) and (b) of this pleading. 806 The allegation in subpara (d) was the subject of little elaboration in the applicant's final submissions, or in his case generally. No attempt was made to establish the proposition that the discharge of the duty of care which lay upon Merck involved a positive obligation to "publish" data and information. However that may be, on no view (subject only to what I mention in the next paragraph) did Merck fail "otherwise to reveal" all the data and information about the cardiovascular results of the various trials and studies of Vioxx with which it was associated. There were no relevant data to which the applicant could point in the present case which had not been provided to the FDA and TGA. In the way he conducted his case, the applicant put in issue not the failure to publish the data and information, but Merck's interpretation of the data and information which was available to it. 807 The one instance where Merck's omission to publish something was controversial related to the three additional myocardial infarctions which were not included in Bombardier (2000) as submitted to the New England Journal of Medicine (see paras 138‑142 above). While the applicant was critical of that, and used to some forensic effect the expression of concern by the editors of the Journal, ultimately it is hard to see how these circumstances bear upon the question whether Merck (or, for that matter, MSDA) discharged its duty of care. As pointed out in the correspondence which followed the expression of concern, whether with or without the three myocardial infarctions, the data revealed that there was a statistically significant difference between the risk of taking Vioxx and the risk of taking naproxen. Further, however disputable as a matter of publishing ethics, the authors of Bombardier (2000) had a credible explanation for the non-inclusion of these events that I am in no position to hold to be unreasonable (ie that they were reported after the cut-off date). Neither was it as though Merck made any secret of the full extent of the relevant data: they were included in the safety update report to the FDA of 13 October 2000. 808 I would also note that the applicant's allegation in relevant respects is that Merck's dereliction was in substance one of commission, notwithstanding his use of the familiar formula "failed to …". I say this because there could be no suggestion that Merck would have fallen short in the discharge of its duty of care to group members in this proceeding had Bombardier (2000) not been published at all. The vice, to the extent that there was one, is that a misleading impression of the extent of cardiovascular risk was conveyed. Although I am in a sense anticipating an aspect of the applicant's negligence case to which I shall turn below (causation), I consider it unlikely in the extreme that any difference would have been made to the clinical judgments made by the cohort of medical practitioners whose decisions are presently relevant if the three additional myocardial infarctions had been used as a basis for the rates set out in the article (particularly given the very small impact which that would have made thereby, as pointed out by Drs Reicin and Shapiro − see para 141 above). 809 The kernel of the applicant's pleading is, of course, the allegation in subpara (c) in the extract from the Further Amended Statement of Claim set out in para 805 above. Expressed in a positive way, here the applicant is alleging that Merck ought not to have made rofecoxib available for incorporation into Vioxx until the completion of any relevant research, investigations, clinical trials or observational studies. This aspect was stressed by counsel for the applicant in their closing submissions. While recognising that, until September 2004, it had not been established that Vioxx caused or contributed to CVT events, they submitted that Merck ought nonetheless to have recognised that there was a risk that Vioxx was working in that way, and that such a cause or contribution would ultimately be scientifically established. They submitted that, in the meantime, Merck ought not to have continued to supply rofecoxib to MSDA for incorporation into Vioxx tablets. 810 I accept so much of the applicant's submission as involves the proposition that Merck ought to have recognised that it might ultimately be found that the consumption of Vioxx caused or contributed to CVT events. In the state of the science as it existed until September 2004, however, I am not persuaded that the only course reasonably open to the respondents was to have withdrawn Vioxx from the market altogether; or that the only course reasonably open to Merck was to have made rofecoxib unavailable to MSDA. Rofecoxib was not a drug which, as a direct and inevitable consequence, caused CVT events in all cases. Indeed, the occurrence of CVT events in the Vioxx arm of the VIGOR trial (including those which presumably were not caused or contributed to by Vioxx) was only 1.67 such events for every 100 patient‑years. As against this, I must recognise that Vioxx was a drug which worked a lot of good: for many people (including the applicant) it brought relief from the pain and discomfort associated with arthritis without gastrointestinal side‑effects. As a prescription drug, it required the judgment of a medical practitioner before any person could consume it. For rofecoxib to have been withdrawn upon nothing more than the signal of potential risk generated by VIGOR would have been to deny a great many arthritis sufferers a means of securing comfort which they may freely have chosen, even if fully informed. It is notorious that many drugs carry side‑effects, yet resort is had to them as the result of the balancing by patients of the risks and benefits to be derived, informed and assisted by the professional judgments of their medical practitioners. 811 In the circumstances as they existed until September 2004, the present was a case in which Merck's duty of care as manufacturer and supplier of rofecoxib could be discharged by the provision to its subsidiaries - in the present case, MSDA - of information necessary to enable the latter to formulate and to disseminate adequate instructions and warnings about the possibility of the drug causing or contributing to CVT events. In the present case, MSDA did not suggest that it was unable, by reason of lack of information from Merck, to provide the appropriate instructions and warnings. Indeed, the respondents' case was based upon the silent proposition that MSDA should be fixed with the whole of Merck's relevant scientific knowledge at each point in time. On all of the evidence in the case, I am satisfied that that was a realistic position to take, and one which reflected the facts as they existed. That being the case, I think that Merck had done everything that might reasonably be expected of it in the discharge of its duty of care. 812 The applicant did allege that Merck failed to provide to pharmacists, to medical practitioners and to other health care professionals, and to the Australian public, any or any adequate information, advice or warning to the effect that the consumption of rofecoxib materially increased the risk of suffering the pleaded cardiovascular conditions. However, the obligation to provide information, advice or warning of the kind referred to fell upon MSDA as the manufacturer and supplier of Vioxx in Australia. Merck would, in my view, have discharged its duty of care by ensuring that MSDA was fully informed about the nature and biological operation of rofecoxib, and about the existing state of the science with respect to the consequences, in the vasculature, of consuming it. I am satisfied that it did so. 813 For the above reasons, I propose to dismiss the applicant's case in negligence against Merck. 814 The applicant's negligence case against MSDA commences with allegations that MSDA − (a) utilised a non‑steroidal anti‑inflammatory drug, namely rofecoxib, the consumption of which materially increased the risk of suffering the [pleaded] cardiovascular conditions; (b) failed to utilise a non‑steroidal anti‑inflammatory drug the consumption of which did not materially increase the risk of suffering the [pleaded] cardiovascular conditions; (c) failed to make any or any adequate inquiries of Merck … regarding the adverse side effects and health risks that may be associated with the consumption of rofecoxib including a material increase in the risk of suffering the [pleaded] cardiovascular conditions. The applicant then makes substantially the same allegations against MSDA as those set out in subparas (a), (b) and (c) of his allegations against Merck as set out in para 805 above. With respect to those allegations, I find, for the same reasons as I have given above in relation to Merck, that MSDA did not breach its duty of care merely by using rofecoxib in Vioxx rather than some other NSAID. As to (c) in the extract above, very little attention was paid to this aspect in the applicant's case. As I have said, I infer that MSDA was as well‑informed about the potential side‑effects and health risks of Vioxx as was Merck itself. The resources and research of MRL were available to MSDA, whose management were in regular contact with Merck. I do not think there is anything in the applicant's "failure to inquire" case.

Failure to warn 815 The next part − and a very significant part − of the applicant's case is centred on his "failure to warn" allegations. He alleges that MSDA failed to provide any or any adequate information, advice or warning to the effect that the consumption of rofecoxib or of Vioxx tablets materially increased the risk of suffering the pleaded cardiovascular conditions. He so alleges in a number of contexts. He says that no such information etc was set out on the packets in which Vioxx was sold, or on the labelling associated therewith. He says that no such information etc was provided to pharmacists, medical practitioners and other health care professionals, either in the marketing, or in the distribution and supply, of Vioxx. And he says that no such information etc was provided to the general public (being the consumers or potential consumers of Vioxx tablets) or to pharmacists, medical practitioners and other health care professionals who might have advised or treated members of the public. He also alleges that Merck failed to provide such information etc to MSDA, to pharmacists, medical practitioners and other health care professionals, or to the public. All these allegations are denied. 816 The applicant's "failure to warn" case implicitly calls up the following questions: first, did a duty to warn arise, and if so when, and by reference to what circumstances; secondly, of what risk ought the warning to have been given, to whom and in what terms; and thirdly, did MSDA provide a warning which, in its timing, content and communication ought to be regarded as having discharged the duty of care which was owed to consumers of Vioxx? 817 As to the first question, it was not seriously suggested on behalf of the applicant that a duty to warn arose until the preliminary results of the VIGOR trial were available in March 2000. Other aspects of the alleged tendency of Vioxx to be associated with cardiovascular disease did not feature in the applicant's failure to warn case. It was not suggested, for example, that MSDA was derelict in not having issued a warning that Vioxx was associated with hypertension. Had it been, it is difficult to see how such a case might have been sustained, given the terms of the original Product Information (see para 225 above) that was sent to doctors by correspondence in October 2000 (see para 226 above). These possibilities, however, do not have to be considered further, as they were not elements of the applicant's case. To the extent that it is necessary to do so explicitly, I hold that no duty to warn arose before the arrival of the preliminary VIGOR results in March 2000. 818 Did the results of the VIGOR trial give rise to a duty to warn? There are, in my view, two reasons why it should be held that they did. First, as noted elsewhere in these reasons, those results represented a worrisome and important signal of potential cardiovascular risk, and ought reasonably to have been so viewed by the respondents. As I have held, Merck did so view them. The respondents' case was conducted without discrimination as between Merck and MSDA on matters of scientific knowledge and understanding. They called no member of the medical or scientific staff of MSDA, in which event I would be prepared to infer that MSDA viewed the VIGOR results in the same way as did Merck. However that may be, I would hold that MSDA ought, viewing the matter reasonably and prudently (as is appropriate in matters of safety), to have taken the same view as expressed by the cardiologists, namely, that the results were a worrisome and important signal of potential cardiovascular risk. 819 That view reasonably mandated, in my opinion, the giving of a warning. It was, as I have held, a reasonable course for Merck to have undertaken a cardiovascular outcomes study, and MSDA was entitled to rely on the ongoing work of MRL in that regard. Neither was it necessary that Vioxx be withdrawn from the matter pending the results of such a study. However, in the meantime it was, I consider, incumbent on MSDA (ie consistently with the discharge of its duty of care) to issue a warning − or some information or advice in the nature of a warning − which reflected the state of understanding which arose from the VIGOR results. 820 Secondly, it was ultimately accepted by MSDA that a warning in appropriate terms was necessary to be introduced into the "Precautions" section of the Vioxx Product Information. It is true that the revised Product Information that was originally submitted by MSDA in January 2001 did not contain any such warning, but the clinical evaluator was - it seems quite emphatically - of the view that one was necessary in the circumstances. The then delegate agreed. So do I. Ultimately, MSDA itself accepted that there had to be a warning in the Product Information. In the light of this history of events, it could hardly be suggested that no warning at all was called for in consequence of the results of the VIGOR trial. 821 As I have set out at paras 721‑723 above, Dr Dickman was cross‑examined about his knowledge of the general subject of Vioxx and cardiovascular risk as derived from sources other than MSDA. I do not understand the respondents presently to be proposing, however, that such sources as I there referred to should be regarded as satisfactory substitutes for an appropriate warning from MSDA itself. I would certainly not so regard them. They may be relevant to the matter of causation, but they do not, in my view, bear upon the question whether MSDA took such steps as would be sufficient to discharge its duty of care. 822 When should a warning have been given? When the VIGOR preliminary results became available in March 2000, Vioxx had secured registration on the ARTG, but was not yet formally on the market in Australia. Vioxx was announced to the medical profession, and a copy of the Product Information provided, by way of Ms Paterson's letter of October 2000 (see para 226 above). By then, the VIGOR Clinical Study Report had been forwarded to the FDA (on 29 June 2000). Indeed, what were effectively the final cardiovascular results of VIGOR were forwarded to the FDA in the safety update report of 13 October 2000. MSDA was, therefore, possessed of sufficient information to provide the necessary warning no later than its letter of October 2000 formally announcing the availability of Vioxx. In my opinion it should have done so. 823 Turning to the second question identified in para 816 above, quite obviously it was with cardiovascular risk that a warning should have been concerned. However, as the respondents pointed out, at no stage did the applicant formulate the actual terms of a warning that should have been given. Rather, he contended that "MSDA … [was] negligent in failing to provide any adequate information, advice or warning to the effect that the consumption of Vioxx materially increased the risk of suffering the [pleaded] cardiovascular conditions". I am prepared to work on the basis that the kind of warning which the applicant proposed should have been incorporated into the Product Information in 2000 would have been along these lines. 824 The imposition on MSDA of a duty to warn in such terms would be problematic in a number of respects. First, the "signal" given by VIGOR was not a consistent one over all of the pleaded cardiovascular conditions. To say that the consumption of Vioxx might have increased the risk of suffering each of those conditions would have been to overreach the results of VIGOR on any view. Secondly, the VIGOR results did not speak at all along the Vioxx‑placebo axis. The only sense in which they justified a statement about increased risk was with reference to a situation in which the notional comparator was naproxen. Thirdly, the trial was not concerned with, and (as the cardiologists in the present proceeding agreed) said nothing about, a situation in which Vioxx was taken at the recommended maximum therapeutic dose in Australia − 25 mg daily. Fourthly, a warning in such terms as proposed by the applicant would have gone beyond what, as would reasonably have appeared to the respondents, was the prudent scientific consensus in 2000/2001. Here I refer to the views of the FDA Arthritis Advisory Committee expressed on 8 February 2001 − see para 156 above. And fifthly − and perhaps most importantly for present purposes − a warning in the terms proposed by the applicant would have gone beyond what I have held the respondents either knew or ought to have known about the consequences of consuming Vioxx until September 2004. I take the view, therefore, that the availability of the VIGOR results did not oblige MSDA to issue a warranty in the categorical terms proposed by the applicant. 825 Does that conclusion mean that there was no warning that MSDA could have issued, and acting reasonably should have issued, that would have fairly reflected the results of the VIGOR trial? I do not think so. Here it is convenient to commence with the warning which did ultimately find its way into the "Precautions" section of the Vioxx Product Information in November 2001 (see para 258 above). Would that have been a sufficient warning if given in October 2000? The applicant submitted that the relevant paragraph in the Product Information was inadequate as a warning. To provide an opinion about that paragraph (and other things), he led the following evidence from Prof Donovan: In my opinion, the language used in this product information does not convey a warning that Vioxx causes, or could cause, an increased risk of cardiovascular thrombotic events. The framing of the results is consistent with the reduction framing method described above and employed elsewhere in Merck marketing messages. Although the "naproxen theory" is not explicitly propounded, the reference to the difference in antiplatelet activity between some COX-I inhibitors and COX-2 selective inhibitors provides an explanation for the VIGOR cardiovascular events that exonerates Vioxx as a cause of increased CVT events. … The explicit statement that "In other controlled clinical trials spontaneous reports of these cardiovascular events are similar between Vioxx and nonselective NSAID comparators" precludes any interpretation of an increased risk with Vioxx. The statement then appears to minimize the clinical significance of any adverse findings by simply providing generic advice to doctors to "assess the importance of these data" when prescribing for patients at CV risk. 826 Prof Donovan was cross‑examined on this evidence. He accepted that he had not undertaken any specific study on the subject of how a prescribing practitioner would interpret the paragraph. He agreed that whether or not the paragraph conveyed a warning would depend partly upon the knowledge and expertise of the person reading it. When it was put to him that the statement that "the difference in antiplatelet activity between some COX-l inhibiting NSAIDs and COX-2 selective inhibitors may be of clinical significance in patients at risk of thrombo‑embolic events" stood as a clear warning that the difference in antiplatelet activity as between Vioxx and some NSAIDs might have a consequence in the particular clinical situation with which a doctor was confronted, he said: "I don't know that it's a clear warning but it's certainly a clear statement of the data." When it was suggested that the words stood as a clear signal to doctors to proceed with caution, Prof Donovan said: Well, I don't know how doctors would interpret this. I have an opinion of whether or not it sends a message of increased cardiovascular risk but I can't say what an individual doctor - how they would interpret that. 827 Dr James Lynch was a very experienced general practitioner called by the applicant as an expert. In his witness statement, he said that he had been asked to provide an opinion, based on his training, knowledge and experience in general practice, about the Product Information that accompanied Vioxx. He referred to the Product Information that was approved by the TGA in November 2001, and to the passage in it to the effect that Vioxx was not a substitute for aspirin for cardiovascular prophylaxis because of its lack of platelet effects. He interpreted this to mean that, if patients were taking aspirin, they should continue to do so after commencing Vioxx, not as a warning that Vioxx might have given rise to a cardiovascular risk. He referred to part of the section headed "Cardiovascular Effects", but made no (admissible) comment about it. 828 Dr Dickman did not express an opinion about the adequacy of the warning in that section of the Vioxx Product Information. Neither did Dr Anderson. 829 In his witness statement, Dr Bertouch said that the paragraph contained "an appropriate cautionary note regarding the difference in cardiovascular thrombo‑embolic events between VIOXX and naproxen". Save by way of drawing attention to the circumstance that patients do not normally view the Product Information, Dr Bertouch was not challenged on this evidence. 830 As a communication addressed to a professional audience, I consider that the new paragraph inserted into the Vioxx Product Information in November 2001 was a reasonable warning of the potential cardiovascular risk disclosed by the VIGOR results. It drew attention to difference in CVT events as between the two arms of the study, and to the fact that the comparator was naproxen. It accurately identified the cohort of patients that had been involved in the trial, and the dose that had been used. It referred to other clinical data where no difference had been disclosed as between Vioxx arms and (non‑naproxen) NSAID arms. And it drew attention to the critical biochemical difference between coxibs and non‑selective NSAIDs, namely, the absence of any antiplatelet activity in the case of the former. As to this last aspect, it is important to note that the clinical context in which Vioxx might be under consideration was one in which the patient was presumptively suffering from osteoarthritis and would, normally, be in need of an anti‑inflammatory drug. The paragraph in the Product Information was such as would draw the prescriber's attention to the difference between coxibs and at least some other NSAIDs, most obviously naproxen, with respect to antiplatelet activity. Whereas all NSAIDs inhibit COX-2 (and, as Prof Celemajer said, are given in doses that achieve that purpose wholly or very substantially), traditional NSAIDs also inhibit COX-1, thereby suppressing, to an extent at least, the aggregation of platelets. Vioxx did not. This was the essence of the distinction between Vioxx and the traditional NSAIDs. It was the distinction which would have been relevant to the clinician; and it was the distinction to which the new paragraph in the Product Information pointed. 831 The other consideration is that the Product Information was a medical document intended to be read by medical practitioners. It is, therefore, substantially by reference to the evidence of the medical witnesses that the court should attempt to assess the sufficiency of the Product Information as a warning of such risks as ought reasonably to have been apparent to MSDA in the period subsequent to VIGOR. As will be apparent from what I have said above, no medical witness expressed the view that the terms of the paragraph inserted in November 2001 were less than sufficient for that purpose. Dr Bertouch considered that the paragraph sounded "an appropriate cautionary note". In these circumstances, unless it was, as a matter of ordinary language, palpably inadequate as a warning, I would be most reluctant to hold that the paragraph, in the reading of it through professional eyes, did not fairly raise the prospect that the consumption of Vioxx might be associated with the onset of CVT events. For reasons stated earlier, I do not think it was palpably inadequate. 832 Finally with respect to the reasonableness of the paragraph in the Product Information that was introduced in November 2001, I note that that paragraph was approved by the TGA. It is true that its wording owed much to the input of MSDA, and I accept the applicant's point that MSDA made every effort to render inconspicuous the message that Vioxx might well be pro‑thrombotic. However, the differences between the paragraph which came to be included in the Product Information, and that recommended by the clinical evaluator on 3 July 2001 (save with respect to the co‑administration of aspirin) are, to my reading of them, essentially matters of emphasis and balance. The original delegate, Dr Anantharajah, recommended that the Product Information should contain a statement that "long‑term therapy is not recommended for those with a history cardiovascular disease", which would not, in my estimation, have been much different in point of substance from that ultimately adopted: "Physicians should assess the importance of these data for an individual patient at risk for cardiovascular thrombo‑embolic events, if considering long‑term therapy with a COX-2 selective inhibitor". I make this comparison because the applicant was not critical of the evaluator or of Dr Anantharajah. 833 To whom should such a warning have been communicated? If, as I have held above, a warning in the terms of the new paragraph inserted into the Product Information in November 2001 should be regarded as sufficient, clearly such a warning should have been communicated at least to general and other medical practitioners who might reasonably be supposed to have had cause to treat or to advise patients suffering from osteoarthritis (and, subsequently to 17 January 2002, from rheumatoid arthritis). Had this been done, I do not consider that a warning to pharmacists would have been required in addition. The nature of such a warning would have implied the making of the necessary professional judgments by the prescribing practitioner. Once a decision to prescribe Vioxx had been made, I do not think that MSDA ought reasonably to have contemplated a further monitoring role for the dispensing pharmacist. MSDA should not be regarded as having fallen short in the discharge of its duty of care by not putting the pharmacist in possession of a warning in the same or similar terms as those provided to the prescriber. 834 The applicant's case as pleaded proposed that the warning ought also to have been communicated to "other healthcare professionals". This proposal was, however, developed neither in the evidence nor in the applicant's final submissions. I do not know who these other professionals might have been. I do not think that the applicant has made good his case in this regard. 835 The applicant also alleged that MSDA ought to have placed a warning (or "information" or "advice" as to cardiovascular risk) on the Vioxx packets and labels. One of the oddities of this case is that, despite the mountain of evidence that was tendered, neither a Vioxx packet nor any example of the labelling used on Vioxx was placed into evidence. The applicant submitted that the packet and label contained no warning, but the only evidence as to that aspect was the applicant's, that he read the label or product information when he was first put on Vioxx, but did not recall reading anything that suggested or implied that Vioxx would increase his risk of suffering a heart attack. He was not challenged on this evidence (although, as noted elsewhere, he clarified that the "product information" to which he referred was the package insert, or "Consumer Medicine Information"). I regard it as having been established in the applicant's own case, therefore (but not otherwise), that MSDA did not include any presently relevant warning on the packets in which Vioxx was sold, on the labelling associated therewith or as part of the Consumer Medicine Information. 836 If an appropriate warning had been provided to medical practitioners, however, I do not think that MSDA fell under any duty additionally to warn the patient, or consumer. Once a professional judgment had been made to prescribe Vioxx, with all of the balancing and compromises that that implied, I consider that the addition of a warning to which the patient would first be exposed when he or she obtained Vioxx from the pharmacist would be both inappropriate and unnecessary − not to mention somewhat confusing. The contradictions involved in allowing for Vioxx to be prescribed by a doctor and then recommending that the patient himself or herself make a further judgment based on his or her own assessment of underlying cardiovascular risk were not addressed by the applicant. Had he been serious about his submission that MSDA fell short in the discharge of its duty of care by not providing such a warning, they should have been. 837 To date in this section of my reasons, I have held that MSDA ought to have warned medical practitioners of the signal yielded by the VIGOR results at the time when Vioxx was introduced on to the Australian market in October 2000. A warning in the terms set out in the new paragraph in the "Precautions" section of the Product Information in November 2001 would have been sufficient. I do not hold that, to be effective, a warning had to be in those terms. I mention them because they represent a formulation with which MSDA was content and which would have gone no further than the state of the science justified. Was such a warning, or any equivalent warning, ever given? 838 On no view was any warning given to medical practitioners by MSDA before November 2001. In its final submissions, MSDA did not directly confront this omission. Indeed, it is implicit in its submissions that there was no such warning. However, it is also implicit that the Product Information was a sufficient warning to doctors of the signal of cardiovascular risk presented by the VIGOR trial. This is a question which arises only upon consideration of the situation as at November 2001, and I shall return to it. Before then, there was nothing in the Product Information which would have put doctors on notice of that signal. MSDA justified the absence of any reference to the VIGOR results by the need to obtain the approval of the TGA for the terms of an amendment to the Product Information. The applicant submitted, however, that a safety‑related amendment could have been made at any time. This submission was well‑founded (see paras 205 and 207 above), but the respondents rejoined that the amendment which was in fact (finally) approved by the TGA would not have been permissible as a safety‑related one because it was based upon, and involved an explanation of the results of, a clinical trial which compared Vioxx with another therapeutic good (naproxen). The respondents submitted that this would not have come within the terms of s 9D(2) of the TG Act. In this they were mistaken, since s 9D was not part of the TG Act until October 2002. However, the provision that became s 9D(2) was s 32(4) of the TG Act before then (see para 205 above). 839 As pointed out elsewhere in these reasons, the effect of s 32(4) was to require the Secretary to vary the terms of a Product Information where (amongst other things) the only effect of the variation would have been to add a warning or precaution that did not include a comparison with other therapeutic goods. But the provision did not prohibit the Secretary from allowing a variation even where such a comparison was involved. According to Mr Back, when he first informed Dr Chipman of the results of VIGOR in March 2000, the latter said that MSDA should immediately consider a safety‑related notification, and that the TGA would be happy to include important safety information in the current Product Information, no matter what the patient group. MSDA did not so proceed, for which omission there was not, I consider, a satisfactory explanation. However, since the making of an approved amendment to the Product Information which reported on the signal of risk yielded by the VIGOR results in a way which did not overreach, and which did not do unnecessary injustice to Vioxx, would have required the approval of the TGA, an organisation which MSDA did not control, I am not prepared to hold that MSDA might, by confining its amendment to matters of safety, have procured such an amendment very promptly in mid‑2000 or thereabouts. 840 However, the Product Information was not the only means by which MSDA might have communicated with medical practitioners. The evidence justifies the conclusion that it often communicated by way of "Dear Doctor" letters which, I infer, could readily have been sent to all relevant practitioners at any time. Indeed, it was such a letter that formally announced the availability of Vioxx in October 2000. That letter − which is reproduced in para 226 above − contained a warning about possible interactions with warfarin, methotextrate and lithium. If there is any reason why that letter − or another letter sent out at about the same time − might not have conveyed an appropriate warning about the signal of cardiovascular risk yielded by VIGOR, none was suggested either in the evidence or in the respondents' submissions. I do not, therefore, accept that MSDA's inability to procure an amendment to the Vioxx Product Information before November 2001 is a sufficient explanation for its failure until then to provide medical practitioners with an appropriate notification of the VIGOR cardiovascular risk signal. 841 When the Vioxx Product Information was eventually amended to reflect the results of the VIGOR trial − in November 2001 − did that constitute a sufficient warning of the cardiovascular risk signal? I have held that it was sufficient in its terms. But was the manner of its communication such that MSDA was reasonably entitled to assume that all medical practitioners would see it and take note of it? This is a difficult and finely‑balanced question. There were certain propositions which, expressly or implicitly, informed the respondents' case on negligence: that the Product Information was the, or at least the most important, means by which MSDA communicated with the medical profession; that the Product Information was controlled by the TGA (in the sense that, as the respondents put it, the TGA was the "final arbiter" of the terms thereof); that (for that reason) it could not be said that MSDA itself was free to communicate with doctors (or others) in terms of its own choosing; and that knowledge of the Product Information by doctors (as amended from time to time) should be presumed, much as one would presume knowledge of the terms of statutes, for instance. Upon analysis, however, these propositions are at best problematic and in some respects unfounded. 842 As I have mentioned elsewhere in these reasons, the TG Act did not give the Product Information any such status as the respondents' submissions implied. Indeed, it did not treat product information as, or as the subject of, a document which would have a discrete existence. The term "product information" was used once only (in s 32) as a shorthand reference to "information relating to the safe and effective use of the goods, including information regarding the usefulness and limitations of the goods" included in the entry in the ARTG that related to the goods in question. Even then, the term was used only in a provision which identified the circumstances in which the Secretary was obliged to vary certain details in the ARTG. It was the 1994 guidelines, approved for the purpose of s 23(2), which gave the "Product Information" its identity as a discrete document and which required it to contain the full range of details set out in para 208 above. That requirement of the TGA, together with conditions established under s 28(2), gave the Product Information its important place in the regulatory scheme for therapeutic goods in Australia. 843 I was not referred to any provision − and for my own part I have found none − which required the Product Information to be published or disseminated, either to medical practitioners or at all. It seems, however, that the Product Information for any drug on the ARTG was accessible by doctors, at least by way of MIMS and such software as "Medical Director". Although I was not told about it, I infer that that was a computer program available to doctors by private acquisition, much as, for example, they might obtain accounting software for their practices. Merely by providing Product Information to the TGA (and by amending it as appropriate) and by having it approved, however, a manufacturer in the position of MSDA did not either communicate with doctors or initiate a process of publication by which such a communication would occur in the inevitable course. 844 However, was the Product Information so firmly established as a resource readily available to medical practitioners that MSDA, acting reasonably and prudently in the discharge of its duty of care, was entitled to assume that, by doing no more than obtaining the TGA's approval to an amendment thereof, it effectively communicated the terms of such an amendment to all such practitioners? It is clear that the Product Information, as it existed from time to time, was in fact readily available to all such practitioners. It may be that MSDA was entitled to assume that practitioners who contemplated the prescription of a new drug for the first time would, as a matter of course, look up the Product Information. However, Vioxx had been on the market in Australia for nearly a year in November 2001, and practitioners had presumptively read Ms Paterson's letter of December 2000, in which some precautionary notes were sounded, but nothing was said about cardiovascular effects. Was such an assumption warranted in the circumstances of November 2001? 845 In his witness statement, Dr Dickman said that he would not be aware of a change to a drug's Product Information unless notified about the change. He was cross‑examined about the updating of Product Information, but not specifically about this evidence. I should set out in terms what I perceive to be the relevant aspects of that cross‑examination: So far as you know, is it the position that Medical Director is updated via some electronic means four times a year?---Yes. And such new information as is necessary to be fitted into the program is sent down about four times a year?---Yes. So far as the drugs are concerned, does it give you a note of what drugs have changed?---No, it doesn't. Give you a note if an indication has changed?---No, I don't think so. Prior to having MIMS over the Medical Director software, MIMS would be updated in paper three or four times a year, wouldn't it?---Yes. The updating version of MIMS would only contain those drugs that needed to be updated. Is that right?---Yes. So you would know three or four times a year from your paper copy of MIMS what drugs were being updated, is that right?---Yes. Do you still keep a paper copy of MIMS in your surgery?---Yes. Is that updated four times a year still?---Some of the copies are slower to get to us but I think, yes. But there is a regular updating process which by looking at the index you can see what the drugs are that have been updated, is that right?---Yes. That's one way in which you would be notified about a change, isn't it?---Yes. Another way in which you would be notified about a change would be if a drug representative told you that the drug was now approved for a different indication?---Yes. So, as an example, with Vioxx, it was initially approved for osteoarthritis, it was later approved as an indication for rheumatoid arthritis; that would be made known to you?---Yes. When you came next to prescribe the drug, particularly if it was for someone with rheumatoid arthritis, you would go back to the product information and look to see with respect to that indication what the relevant information was, wouldn't you?---Yes. Of course, you may hear about a change from one of your colleagues. Is that right?---Yes. Or you may get it from one of your other sources of information; a specialist noting that something has changed by changing a prescription, is that right?---Yes. Or through one of the other sources that you have spoken about. Is that right?---That's right. 846 I do not think that Dr Dickman's evidence travels the distance necessary to justify the conclusion that MSDA was entitled to assume that, as a matter of inevitable course, general practitioners would read the Vioxx Product Information amendment of November 2001. First, he was not challenged directly on the evidence in his witness statement to which I have referred. Secondly, the furthest he was pressed in cross‑examination was to accept that resources were readily available to him from which he could ascertain which drugs had recently had their Product Information updated: he was not induced to give evidence to the effect that he did keep abreast of such changes as a matter of course. And thirdly, it may be one thing to know which drug's Product Information had recently changed: it would be quite another to be alerted to those changes that involved new precautions on potentially serious side‑effects. 847 Dr Lynch referred to, and was cross‑examined about, the Product Information (both generally and for Vioxx), but not in any way that was presently useful. Dr Anderson, a colleague of Dr Dickman's at Tower Hill who was called by the applicant because one of the applicant's prescriptions for Vioxx was written by him, also gave no presently useful evidence. 848 It follows that Dr Dickman's was the only evidence that usefully dealt with the question of how a general practitioner would respond, as a matter of normal practice, to changes in the Product Information for a particular drug. As appears from what I have written above, I do not think it has been established that MSDA was reasonably entitled to assume that a practitioner would, without specific prompting, necessarily have taken note of the fact that the Vioxx Product Information had been amended, or of the content of the amendment. It was never suggested to Dr Dickman that he had been remiss in not having done so, or was thereby acting inconsistently with the accepted norms of his profession. In the result, his evidence in chief that he would not be aware of a change to a drug's Product Information unless notified about the change stands unchallenged, and is not inconsistent with any oral evidence which he gave. 849 Clearly the making of an amendment to the Product Information should be regarded as a necessary response by a drug manufacturer to the results of a clinical trial which conveyed a signal of risk. However, I do not consider that such an amendment should of itself be regarded as a sufficient response − that is to say, as a sufficient discharge of the manufacturer's duty of care. Absent the manufacturer taking steps directly to inform medical practitioners of the amendments, I do not accept that the manufacturer would be entitled to assume that every such practitioner − including the one directly involved in prescribing the drug for the putative applicant − would inevitably become aware thereof. Thus I would hold that, by doing no more than amending the Vioxx Product Information in November 2001, MSDA had not taken reasonable steps to warn medical practitioners of the cardiovascular risk signal thrown up by the VIGOR results. 850 Did MSDA in fact do more than that? It led no evidence of a direct communication to doctors on the subject. I have found that the pro forma "Dear Doctor" letter dated December 2001 was not sent (see para 267 above). I make these findings generally (ie not merely in the applicant's case). Whether, apart from them, a particular doctor was warned (advised, informed etc) is a question upon which it will be open to the respondents to lead evidence in that part of the proceeding which relates to his or her patient. In the remaining sections of this part of my reasons, I deal with the applicant's own circumstances. 851 Did Dr Dickman in fact come to read, or otherwise to learn of, the new paragraph in the "Precautions" section of the Vioxx Product Information of November 2001? I would find not. Against his evidence in chief that he would not, unless notified, be aware of a change to a drug's Product Information, he was cross‑examined, if I may so observe with respect, rather tangentially to the important question whether he read the new paragraph in the Product Information. He was not asked that question directly. Counsel appeared to be more concerned to discover whether Dr Dickman knew "the ideas encapsulated" by the paragraph (which he did, at some time between 2001 and 2004 − see para 726 above). However that may be, I could not discern in any evidence given by Dr Dickman that, in November 2001 or thereabouts, the amendment to the Product Information came to his attention. 852 I would hold, therefore, that the applicant has made good his case that MSDA failed to warn his treating practitioner of the cardiovascular risk signal from VIGOR of which it had been aware since March 2000. 853 For the sake of completeness, I would add that it was part of the applicant's pleaded case that MSDA failed to provide, to the general public, any (or any adequate) information, advice or warning to the effect that the consumption of Vioxx materially increased the risk of suffering the pleaded cardiovascular conditions. That allegation was denied by the respondents. A submission which went little further than the allegation in his pleading was made by the applicant in his final written submissions. The respondents made no response to that submission. Neither did they deal with the allegation in their own final written submissions. The matter was dealt with barely, tangentially and indirectly in the applicant's case. Save to refer to a media release of 16 November 2001 announcing the publication, and generally the findings, of Konstam (2001), the applicant referred me to no evidence by reference to which I might uphold this allegation. It was as though, having made the allegation of a failure to act, it then lay upon the respondents to prove the contrary. Clearly it was not. The allegation was part of the applicant's case, and, save in the context of his own personal claim (as to which see para 729 above), it has not been made good. That is not to say that I could find that MSDA did provide any such warning to the general public as the applicant alleged it failed to do: there is just no evidence about it one way or the other.

MSDA's marketing representations 854 The applicant alleges that MSDA developed and implemented a marketing strategy or campaign, by which it formulated and disseminated to pharmacists, medical practitioners and other health care professionals the following "information about Vioxx": (a) Vioxx has an excellent gastrointestinal safety profile compared with other … NSAIDs …; (b) Vioxx has an excellent overall safety profile compared with other NSAIDs; (c) Vioxx does not increase the incidence of adverse cardiovascular events; (d) higher rates of myocardial infarction and other cardiovascular events among persons taking Vioxx relative to persons taking other traditional NSAIDs (in particular naproxen) did not indicate that Vioxx increased the risk of suffering adverse cardiovascular events but were attributable to the fact that the consumption of naproxen produced a lower incidence of cardiovascular events because naproxen inhibits platelet aggregation in a manner similar to aspirin while Vioxx does not; (e) the higher rates of myocardial infarction among persons taking Vioxx relative to persons taking naproxen observed in the Vioxx Gastrointestinal Outcomes Research trial … did not indicate that Vioxx increased the risk of suffering adverse cardiovascular events; (f) any information to the effect that Vioxx was not as safe as other NSAIDs because the consumption of rofecoxib or Vioxx tablets materially increased the risk of suffering the [pleasded] cardiovascular conditions was incorrect, misleading, exaggerated and/or unreliable. The applicant describes these things as "the Vioxx representations". 855 In support of these allegations, the applicant relied upon the evidence to which I have referred briefly at paras 259‑296 above, and much more. I have not rehearsed the whole of the extensive (largely documentary) evidence on which the applicant relied, because central to its utility in the applicant's case is the allegation that the Vioxx representations were disseminated to pharmacists, medical practitioners and other health care professionals. Quite obviously, only if it were proven that a particular representation was made to, or came to the attention of, a doctor (etc) whose position was relevant to the decision of a particular group member to take, or to continue taking, Vioxx would that representation have the potential to perform service in the applicant's negligence case. By the concept of "relevance" here I include, of course, both direct and indirect relevance, allowing for the possibility, for example, of a directly relevant doctor having been influenced by more senior members of the profession and the like. However, the mere fact of marketing "messages" in various terms having been formulated within the MSDA marketing department would not be sufficient to provide the evidentiary link that such messages came to the attention of, and influenced, the practitioners who ultimately made the decision, or gave the advice, which led to Vioxx being prescribed for a particular patient. 856 It is also important to make a discrimination between different kinds of promotional material and means of communication. In relation to the "Dear Doctor" and "Dear Pharmacist" letters, I refer to what I have written at para 273 above. They constitute evidence of communications which were specific in the terms in which, and general in the addressees to whom, they were sent. Another class of document was the publication of an entry in a journal or periodical circulating generally in the medical profession, such as the "advertorials". A publication of that kind would represent an objectively observable communication which may be presumed to have been accessible to the profession as a whole, and, to the extent that it was read by practitioners, would amount to a single communication made in the same terms to each of them. But I could not infer that every such publication was necessarily read by every practitioner. Next in order would be documents which may be assumed to have informed the general approach of sales representatives, most obviously the "detail aids". However, I could not find that the mere existence of such a document justified the inference that its terms were represented, as such, to every practitioner. The particular use to which such documents were put would depend upon choices made by individual representatives from situation to situation. Next again would be documents the use of which was, seemingly, entirely contingent, most obviously the "objection handling modules". By definition, the use of these documents depended on a particular doctor, for example, raising some query or the like about Vioxx. 857 These considerations show that it is not possible, at this stage of the case, to find that every document produced by MSDA with an ostensible marketing purpose represented a communication made in the terms indicated to every member of the class of apparent addressees. That is not to say that I reject the applicant's case that MSDA, having devoted considerable funds to the promotion of Vioxx in Australia, would be unlikely not to have ensured that its marketing message had the intended impact at the level of prescribers and other relevant health care professionals. But an impressionistic conclusion at that level would clearly be insufficient, standing alone, to provide a basis for a positive finding that a particular representation or communication had been made to and perceived by every relevant practitioner in Australia. At that level, I shall have to receive evidence which is specific to the circumstances of the individual group members, as I have in the case of the applicant himself. 858 Likewise, the practical utility of the evidence led by the applicant about MSDA's marketing campaign and strategy would seem to depend upon the extent to which the message − effectively the contents of documents developed internally to MSDA − was communicated externally in a material context, or possibly because it enabled an inference to be drawn in support of some otherwise contested evidence about such a communication. By the second possibility, I have in mind, for example, that there may be conflicting evidence about what a representative said to a doctor on a particular occasion. It might then be possible to infer that the representative was more likely to have been speaking consistently with some recent internal instruction or memorandum issued by MSDA. However, absent any primary evidence of a representation that would advance the case of a particular group member, it is not easy to see how the court could infer that a certain conversation was had simply on the ground that to have had such a conversation would have been consistent with a the marketing campaign as developed internally. 859 Turning then to the applicant's own case, it is established that, in their meetings with Dr Dickman, the MSDA representatives emphasised the safety of Vioxx (see paras 717‑719 above). That emphasis was not consistent with the cardiovascular risk signal given by the VIGOR trial, which was known to MSDA at all times when Dr Dickman was prescribing Vioxx to the applicant. Neither, for that matter, was it consistent with MSDA's own detail aids, which confined the claims made about safety to gastrointestinal safety. I accept the applicant's case that the emphasis given to safety in those unqualified terms was inconsistent with the proper discharge by MSDA of the duty of care which it owed to the consumers of Vioxx. 860 There is, however, no evidence that any other promotional representation (other than the "Dear Doctor" letters to which I have referred) made by or on behalf of MSDA came to the attention of Dr Dickman (or, for that matter, of Dr Anderson). For example, neither Dr Dickman nor Dr Anderson gave evidence that he queried an MSDA representative in any circumstances that might make any of the objection handling modules relevant to the circumstances of the applicant. Neither of them gave evidence that they read, or had read to them, the contents of a detail aid, or ever saw a "leave‑behind card".

Causation 861 I have decided the matter of biological causation favourably to the applicant, but I have also held that the proper discharge of the respondents' duty of care did not require them to withdraw Vioxx from the market sooner than they did. The legally relevant causation questions, therefore, are whether MSDA's failure to warn, and/or its emphasis upon safety, caused Dr Dickman to prescribe, and to continue to prescribe, Vioxx to the applicant, and caused the applicant to continue to consume it. Before turning to those questions as such, however, I should deal with an aspect of the respondents' submissions which is appropriately dealt with in this section on causation. 862 The respondents submitted that, regardless of any steps taken or omitted by MSDA, Dr Dickman and the applicant were aware that the consumption of Vioxx was associated with a potential cardiovascular risk. There was, however, nothing in the evidence that would sustain such a conclusion in the case of the applicant himself. As to Dr Dickman, the respondents' submissions were based upon the evidence to which I have referred in summary at paras 721‑723 above. It is not established, on that evidence, that Dr Dickman had in fact read the October 2001 newsletter of the National Prescribing Service, the June 2003 newsletter from the same source or the October 2003 bulletin published by the Australian Adverse Drug Reaction Advisory Committee. Such evidence on the subject as he was induced to give under cross‑examination was both hypothetical and tentative. I am not satisfied that Dr Dickman was in fact aware, at any time which is presently relevant, of the risk that the consumption of Vioxx might be associated with the occurrence of cardiovascular events, or of the results of the VIGOR trial. 863 On the other hand, I do accept that, at some time between December 2001 and September 2004, Dr Dickman came to be aware of the "ideas encapsulated" in the new paragraph introduced into the Vioxx Product Information in November 2001. He was not aware of those ideas before that month. Further, it has not been established when, within the 33‑month period referred to by cross‑examining counsel, he first became aware of those ideas. Relevantly to the circumstances of the applicant, it has not been established that Dr Dickman became so aware before December 2003. I accept that, in the light of the evidence to which I have referred, there should be some qualification to Dr Dickman's evidence in chief that he was not aware of an increased cardiovascular risk associated with Vioxx at the time that he prescribed it to the applicant. However, I do not accept that that evidence has been undermined to the extent necessary to justify the conclusion that, at some time before December 2003, Dr Dickman became aware either of an increased cardiovascular risk as such or of the kind of worrisome signal of potential risk that ought to have been notified to him by MSDA. 864 What would have happened had an appropriate warning been given to Dr Dickman? That is a crucial aspect of causation in a negligence case based on failure to warn: see eg Rosenberg v Percival. There is a certain artificiality about the task thus presented to the court in a product liability (as distinct from a professional liability) case, particularly where the product was consumed consistently over a period. However, I consider it is necessary to look at the matter as at the time when the duty first arose, and by reference to a hypothetical warning no more categorical than has been held to be the minimum necessary to discharge the manufacturer's duty of care in the circumstances obtaining. I have held that a warning should have been given no later than October 2000, but had it been given to Dr Dickman at any time before 10 May 2001 it would presumably have had the same relevance to his decision to prescribe Vioxx to the applicant on that day. As to the terms of the warning, I have held that the terms of the new paragraph in the Vioxx Product Information inserted in November 2001 would have been sufficient. 865 How would Dr Dickman have responded to a warning in those terms, if given to him by correspondence at some time before 10 May 2001? By then, although Vioxx had been on the PBS for about four months only, Dr Dickman's experience with it had been very positive: see the entries for 30 January, 15 February, 8 March and 20 April 2001 in the list in para 718 above. In the balancing of the considerations that he would have undertaken had he been aware that Vioxx involved an increase in cardiovascular risk (see para 720 above), I consider that this positive experience would have made a contribution of some substance. Further, it seems that Dr Dickman regarded the absolute risk rate of CVT events for patients taking Vioxx as disclosed in VIGOR − 1.67 events per 100 patient‑years − to be low in the circumstances of the applicant, whom he regarded as a "mild to moderate" cardiac risk. With all the problems that the making of a judgment about a hypothetical situation involves, I am persuaded that the most likely response of Dr Dickman to a warning in the terms that I have held to be sufficient would have been to advise the applicant that the increased risk of a cardiovascular event was relatively low. While Dr Dickman would have left the final decision to the applicant, my impression is that he would have placed rather more emphasis upon the benefits of Vioxx and rather less upon the cardiovascular risk. 866 As Dr Dickman made clear in his evidence, the choice facing the applicant was whether to take a coxib or a conventional NSAID. To have left his back pain untreated was not a realistic option. Dr Dickman well understood the sense of the "Cardiovascular Effects" paragraph in the Product Information of November 2001. He understood that, relevantly for a patient who needed a drug for his arthritis, the difference between naproxen and Vioxx was that the former had an antiplatelet action while the latter did not. He is likely to have explained this to the applicant, and also to have pointed out that the other side of the coin was that naproxen would be likely to be associated with a greater risk of gastrointestinal side‑effects. 867 How would the applicant have responded to the kind of advice from Dr Dickman that I have found would most likely have been given? The applicant described himself as a fairly stubborn person who preferred to reach his own conclusions, rather than accepting someone else's word; and as cautious and safety‑conscious. He said that he was "wary of medication". While he was in the Navy, he experienced a bad reaction from having omitted to read the label on some migraine tablets that had been prescribed at twice the strength of those that he had previously taken. This taught him a lesson about reading labels and checking carefully what he was taking. He regarded himself as risk‑averse, and would "tend to evaluate the pros and cons before making any important decision". 868 I refer also to the applicant's evidence as I have referred to it at paras 737‑741 above. The applicant respected Dr Dickman and placed store by his advice. He was not in terms asked how he would have responded to news that patients on Vioxx in the VIGOR trial experienced CVT events at a rate of 1.67 per 100 patient‑years, but he was asked in chief how he would have reacted to advice that the risk of a heart attack was two, three or four times as high on Vioxx as on naproxen. He said that he would have wanted to know where the figures came from, beyond which he declined to speculate: see para 738 above. Had he asked Dr Dickman where the figures came from, I consider that Dr Dickman would have told him that VIGOR was a trial involving patients with rheumatoid arthritis, that the dose of Vioxx in the trial was double what was then proposed, and, as mentioned above, that naproxen had an antiplatelet action whereas Vioxx did not. As I have said, I consider that Dr Dickman's advice would have been generally favourable towards Vioxx. There was, additionally, the applicant's long and unhappy experience with the gastrointestinal side‑effects of NSAIDs, which would have provided him with an incentive to opt for a coxib. 869 The present question is one on which the applicant carries the onus of proof. Having regard to the matters referred to above, I am not persuaded that, had the applicant been advised by Dr Dickman in terms which reflected the warning which would have been a reasonable and sufficient response to the VIGOR results, he would have declined to take Vioxx. He may have done so, but he has not established that such a course should now be regarded as more likely than the course which he did adopt, which was to take Vioxx. Since the applicant's experience with Vioxx was entirely positive, neither am I persuaded that, if such advice had been given to him at some point between May 2001 and December 2003, he would have discontinued taking Vioxx. Thus I am not satisfied that MSDA's failure to warn was a contributing cause to the applicant's consumption of Vioxx or (therefore) to his heart attack in December 2003. 870 I deal next with causation in the context of the MSDA sales representatives' emphasis upon the safety of Vioxx in their conversations with Dr Dickman (see para 717 above). To what extent did Dr Dickman rely upon that emphasis? Had the representatives said nothing at all about general safety (ie had they confined their promotional talk to the matter of gastrointestinal safety, where MSDA was on surer ground), would he nonetheless have prescribed, and continued prescribing, Vioxx for the applicant? 871 Dr Dickman was an unambiguous supporter of coxibs. He prescribed Vioxx and Celebrex about equally, and considered that it would have been almost negligent of him to have prescribed a conventional NSAID for a patient with a complaint for which a coxib was indicated. In the case of Vioxx, this derived originally from his attendance at the dinner in late 1999 or early 2000 at which the specialist rheumatologist spoke. His experience with Vioxx was universally positive, the applicant himself being an example of a patient for whom Vioxx had brought relief from pain without gastrointestinal side‑effects. He was a very experienced general practitioner who made his own judgments about drugs. 872 Dr Dickman was cross‑examined as follows: It's fair to say that you from at least 2000 onwards proceeded on the basis that no prescription medicine was absolutely safe for every patient?---That's correct. One couldn't proceed that [way], could you?---No. [What] you had to do was to learn about the range of effects of the drug, ranging from good through to serious adverse effects or possible serious adverse effects, and then make a judgment about whether it should be prescribed for the particular patient?---Yes. If a drug representative came to you and said, "Here is a prescription medicine. I can guarantee you that it's absolutely safe", you would shake your head and think, "I think that's an overstatement", wouldn't you?---Yes. Because that doesn't accord with your experience of prescription medications?---No. You would think to yourself, "I had better go and have a look at what I can find out about this drug to see what the safety of it is", wouldn't you?---Yes. You certainly wouldn't just take the rep's word for it, would you?---No. Indeed, whenever a rep made a comment about safety of a drug you knew that it had to be placed in the context of all of the information that was available about the drug?---Yes. These answers were entirely consistent with the impression I had of Dr Dickman generally. In short, I do not think he relied on the emphasis given by MSDA sales representatives as to the safety of Vioxx. Had these statements not been made to him, I am satisfied that he would in any event have prescribed, and continued to prescribe, Vioxx for the applicant. 873 Counsel for the applicant stressed that MSDA's failure to discharge its duty of care should be recognised for the overall impression created by its acts and omissions generally, rather than by addressing each element of that failure in isolation from each other element (as arguably I have done above). They submitted that the court should consider the impact on general practitioners such as Dr Dickman of MSDA's failure to warn in an environment in which inappropriately positive marketing messages were being conveyed by sales representatives. I accept those submissions. However, even by reference to a hypothetical situation in which a warning in terms which I have held to be sufficient had been given to Dr Dickman, and in which there were no marketing representations about the "safety" of Vioxx, I am not persuaded that he would have withheld from prescribing Vioxx for the applicant, or that the applicant would have declined to take Vioxx. 874 For the above reasons, I propose to dismiss the applicant's case in negligence against MSDA.

part viii − the applicant's case under the trade practices act

Implied repeal 875 I have briefly, and very broadly, introduced the applicant's claims under the Trade Practices Act at para 17 above. Before turning to those claims as such, I should mention a sweeping, and potentially decisive, submission made by the respondents with respect to all of the provisions of the Trade Practices Act on which the applicant relies. They submitted that these provisions had been implicitly repealed by the TG Act. This contention was the subject of no mention in the final oral submissions made on behalf of the respondents. I suppose it was covered by the safety‑net submission made at the outset by counsel for the respondents that they adopted their written submissions, and ought not to be taken to have abandoned any part of them just because they did not mention them in the course of their oral address. The subject of implied repeal was dealt with in a cursory and, I would have to say, quite unsophisticated, way in the respondents' written submissions. However, the submission was technically made, and must be dealt with. 876 When two different statutes made by the same legislature deal with the same general subject‑matter, the presumption is that the legislature intended that both provisions should operate: Ferdinands v Commissioner for Public Employment (2006) 225 CLR 130, 138 [18] and 146 [49]. In that case, Gummow and Hayne JJ said that, in deciding whether there was inconsistency (or "contrariety" or "repugnancy"), what was required was "the construction of, and, close attention to, the particular provisions in question": Ferdinands at 138 [18]. Sadly, the respondents' submissions overlooked that requirement. They provided no close attention either to the provisions of the Trade Practices Act upon which the applicant sues, or to the provisions of the TG Act which were said to be inconsistent with them. They confined themselves to a reference generally to the provisions of Pt 5‑1, and of Div 3 thereof, in that Act, and drew particular attention to s 42DL(1)(f). 877 Section 42DL(1)(f) of the TG Act provided, in 2004, as follows: A person must not publish or broadcast an advertisement about therapeutic goods: … (f) that refers to goods, or substances or preparations containing goods, included in Schedule 3, 4 or 8 to the Poisons Standard …. Relevantly to the present circumstances, the "Poisons Standard" was defined to mean - … the latest edition at the commencement of this Part of the document known as the Standard for the Uniform Scheduling of Drugs and Poisons published by the Australian Health Ministers' Advisory Council. The document described as the "Standard for the Uniform Scheduling of Drugs and Poisons" was not in evidence. It was not referred to by any witness. It was not referred to in the submissions of the respondents. On this ground alone, I would have to reject the respondents' point on implied repeal. 878 I would add that s 42DL(1)(f) of the TG Act was, according to the submissions of the respondents, added to the TG Act only in 2003. Those submissions gave me no assistance as to how I should understand the point about inconsistency to the extent that it was said to render inoperative the provisions of the Trade Practices Act before that amendment. 879 In final oral submissions made on his behalf, the applicant pointed out that Pt 5‑1 of the TG Act (on which the respondents relied) does not apply to advertisements directed exclusively to medical practitioners, pharmacists and other identified health care professionals. There was no response to this submission in the reply submissions made on behalf of the respondents. Neither did the respondents' written submissions advert to this exclusion. To the extent that the applicant's allegations under the Trade Practices Act involve the interface between MSDA and medical practitioners or pharmacists, and to the extent that the provisions broadly relied upon by the respondents under the TG Act might otherwise be thought to provide some sustenance for their argument on implied repeal, this provision would appear to be a complete answer. 880 It was also submitted on behalf of the respondents that part of the system implemented by the TG Act involved the regulation of the type of information provided to the public and to prescribers by the power to impose conditions on the approval of Product Information. Section 28 of the TG Act was referred to, and it does, as I have noted elsewhere, contain a power to impose conditions. However, the respondents submitted that this power was used to "require the sponsor to publish the Product Information in an approved form". No example of the s 28 power being used to impose such a condition was cited and, for my own part, I have found none in the evidence. The s 28 conditions imposed on MSDA in the case of Vioxx were in evidence, and I have referred to a number of them. Nowhere was MSDA required to publish the Product Information. Neither does the TG Act itself − or the regulations made under it - impose such a requirement. As I have indicated, the Act contemplated that there would be "product information", and the 1994 guidelines required that information to be provided to the TGA, upon the making of an application for registration, in a particular form. It was also a condition of the registration of Vioxx that the Product Information not be changed without the approval of the TGA. However, I can find nothing, either in the Act or elsewhere, which imposed upon MSDA an obligation to publish the Product Information. 881 It will be apparent that I think very little of the respondents' argument on implied repeal, and I do not propose to occupy further time giving it the content or the attention which the respondents themselves failed to do.

Section 52 882 Section 52(1) of the Trade Practices Act provides as follows: (1) A corporation shall not, in trade or commerce, engage in conduct that is misleading or deceptive or is likely to mislead or deceive. 883 The applicant's case under this provision was based first upon what he described as "the Vioxx circumstances" and "the "Vioxx conduct". He defined the Vioxx circumstances as: (a) rofecoxib was a prescription only non‑steroidal anti‑inflammatory drug; (b) [MSDA] marketed in Australia Vioxx tablets to pharmacists, medical practitioners and other health care professionals as a non-steroidal anti‑inflammatory drug for the treatment of arthritis that was safer than other non‑steroidal anti‑inflammatory drugs in that it was less likely to cause adverse gastrointestinal conditions and reactions; (c) [MSDA] knew that medical practitioners and other health care professionals in Australia would prescribe, and pharmacists in Australia would supply under prescription, Vioxx tablets as a non‑steroidal anti-inflammatory drug for the treatment of arthritis; (d) [MSDA] knew that persons who were prescribed by a medical practitioner or other health care professional in Australia and obtained from a pharmacist in Australia Vioxx tablets would consume the Vioxx tablets as a non‑steroidal anti‑inflammatory drug for the treatment of arthritis; (e) [MSDA] knew that many persons who were prescribed by a medical practitioner or other health care professional in Australia and obtained from a pharmacist in Australia Vioxx tablets and who consumed the Vioxx tablets as a non‑steroidal anti‑inflammatory drug for the treatment of arthritis were likely to be elderly and, accordingly, at particular risk of suffering the [pleaded] cardiovascular conditions; (f) [MSDA] provided to pharmacists, medical practitioners and other health care professionals in Australia product information with respect to Vioxx tablets ("the Vioxx product information") setting out warnings and precautions with respect to the consumption of rofecoxib or Vioxx tablets and adverse reactions that may be associated with the consumption of rofecoxib or Vioxx tablets; (g) the Vioxx product information did not contain any adequate information, advice or warning to the effect that the consumption of rofecoxib or Vioxx tablets materially increased the risk of suffering the [pleaded] cardiovascular conditions; (h) [MSDA] knew or ought reasonably to have known that the consumption of rofecoxib or Vioxx tablets materially increased the risk of suffering the [pleaded] cardiovascular conditions. He defined the Vioxx conduct as: (a) in packaging and labelling Vioxx tablets, [MSDA] failed to provide any adequate information, advice or warning on packets of Vioxx tablets or the labelling thereon to the effect that the consumption of rofecoxib or Vioxx tablets materially increased the risk of suffering the [pleaded] cardiovascular conditions; and/or (b) in marketing in Australia Vioxx tablets, [MSDA] failed to provide pharmacists, medical practitioners and other health care professionals to whom Vioxx tablets were marketed in Australia any adequate, information, advice or warning to the effect that the consumption of rofecoxib or Vioxx tablets materially increased the risk of suffering the [pleaded] cardiovascular conditions; and/or (c) in distributing and/or supplying for sale in Australia Vioxx tablets, [MSDA] failed to provide to pharmacists, medical practitioners or other health care professionals to whom Vioxx tablets were distributed and/or supplied any adequate information, advice or warning to the effect that the consumption of rofecoxib or Vioxx tablets materially increased the risk of suffering the [pleaded] cardiovascular conditions. He alleged that the Vioxx conduct was engaged in in trade and commerce, and that it was misleading or deceptive, or likely to mislead or to deceive. As is apparent, here the applicant's case is that MSDA's conduct was constituted by its failure to do something. 884 The other aspect of the applicant's s 52 case is based upon the "Vioxx representations" to which I have referred in para 854 above. He alleged that those representations (and the marketing campaign out of which they arose) amounted to conduct in trade and commerce which was misleading or deceptive, or likely to mislead or to deceive, in that the consumption of Vioxx materially increased the risk of suffering the pleaded cardiovascular conditions, and in that Vioxx was not safer in that respect than other NSAIDs. 885 The respondents submitted that the conduct upon which the applicant relied for the purpose of s 52 was not in trade or commerce. They relied upon Concrete Constructions (NSW) Pty Ltd v Nelson (1990) 169 CLR 594, 604: What the section is concerned with is the conduct of a corporation towards persons, be they consumers or not, with whom it (or those whose interests it represents or is seeking to promote) has or may have dealings in the course of those activities or transactions which, of their nature, bear a trading or commercial character. The respondents then submitted that the conduct of which the applicant complained was "conduct which occurred in relation the prescription of Vioxx to him (and to the Group Members)" and "involved reliance by MSDA on the [Product Information] as the primary vehicle by which information and warnings about Vioxx were conveyed to medical practitioners". The first aspect of this defence is correct so far as it goes, but the second, to the extent that it makes any clear proposition about the applicant's case, is not. It was no part of that case to suggest that the Product Information was conduct in trade or commerce, or was misleading. Rather, the existence of the Product Information, lacking an adequate warning as it did, was said to provide the "circumstances" against which MSDA's failure to warn should be understood. Or so the applicant alleged. 886 In its Defence, MSDA alleged that it packaged and made available Vioxx tablets for use, on the prescription of permitted prescribers; that it knew that permitted prescribers would prescribe Vioxx tablets and pharmacists in Australia would sell Vioxx tablets under prescription; and that it knew that persons who were prescribed, and who purchased, Vioxx tablets would consume them in accordance with the instructions of their permitted prescribers. These allegations are, relevantly to the present point, tendentiously expressed. They turn a Nelsonian eye to the undoubted fact that Vioxx was sold by MSDA to pharmacists (either directly or through wholesalers - see eg the "Dear Pharmacist" letters to which I have referred at paras 228 and 270 above) by way of conventional (though subsidised) wholesale exchange. The details of that transaction were not the subject of evidence, doubtless because the fact was so obvious as not to require emphasis. MSDA did, of course, operate in a very specialised industry, in which the products it made could be sold only by way of prescription. Thus the end consumer was required to hold a prescription which gave the supplying pharmacist the authority to make the sale. This meant that MSDA's promotional activities to a large extent were directed to the prescribers. As Ms Dobson said of the MSDA marketing team: The role of MSDA's marketing team is to make prescribers aware of the features of its prescription medicines so that they will prescribe them to the broadest group of suitable patients. This is good for patients and good for MSDA, which is a for‑profit company. This was our objective with Vioxx. Within this specialised framework, MSDA was in the conventional position of a company that manufactured a product for supply to retailers in the expectation that those retailers would sell the product to consumers in need of it. 887 Returning to the Product Information, the respondents submitted that it was "not provided in trade or commerce". Whether that submission is well‑founded depends not on the content (or original purpose) of the Product Information, but upon the use to which it was relevantly put. In other words, it depends on what one means by "provided". I am disposed to think that the respondents may be correct to the extent that they submitted that the provision of the Product Information to the TGA for approval was not a transaction of a trading or commercial character. But I do not need to decide that point, since the applicant does not rely upon any such transaction. On the other hand, the evidence is that every time an MSDA sales representative called upon a medical practitioner, he or she would have a copy of the Product Information for every drug then being promoted. The purpose, quite clearly, was to provide the representative with an approved, accurate, source of information to be used at his or her discretion for the purpose of answering questions that might be put by the practitioner. If the Product Information were thus used in the course of what counsel for the respondents described (in his cross‑examination of Dr Dickman) as a "sales pitch", manifestly there would be conduct in trade or commerce of which the Product Information was an element. 888 It does not matter that the MSDA sales representatives did not themselves take orders, or transact any sales. As the High Court said in Concrete Constructions (immediately after the passage referred to in para 885 above) (169 CLR at 604): Such conduct includes, of course, promotional activities in relation to, or for the purposes of, the supply of goods or services to actual or potential consumers, be they identified persons or merely an unidentifiable section of the public. And what I have said about sales representatives applies to the whole range of promotional interactions, or potential interactions, between MSDA and prescribers. A "Dear Doctor" letter, for example, the purpose of which was to promote the prescription of Vioxx, should be regarded as conduct in trade or commerce 889 The respondents relied on R v Small Claims Tribunal; ex parte Gibson [1973] Qd R 490, 493 in support of the proposition that the medical profession did not prescribe medicines in trade or commerce. It was, however, no part of the applicant's case to contend that it did so. That judgment of the Queensland Full Court was concerned to make the traditional distinction between engaging in trade or commerce and carrying on a profession, in which respect see also Holman v Deol [1979] 1 NSWLR 640. But that is not this case. In no sense was MSDA engaged in a professional, as distinct from a trading, activity. 890 The respondents also submitted that so much of MSDA's activities as were constituted by the (internal) development of its marketing campaign did not amount to conduct "in trade or commerce" because such activities did not occur "in the marketplace". Such a proposition is too sweeping. It is clear from Concrete Constructions that things said and done (and, for that matter, omissions) internally to a trading organisation may, in appropriate circumstances, amount to conduct in trade or commerce within the meaning of s 52. All will depend on context. However, the limits of such a proposition do not need to be tested in the present case. To the extent that it was based on what was said to be MSDA's marketing campaign for Vioxx, the applicant's case required that the "Vioxx representations" be disseminated to pharmacists, medical practitioners and other health care professionals. His s 52 case did not involve the contention that, merely by internally developing that campaign or an associated strategy, MSDA would contravene the section. In one aspect of the way the applicant developed his case, he did submit that an inference of external dissemination should be drawn from the internal development of the marketing campaign. That is an evidentiary question to which I shall turn, but in no sense was the applicant contending that the internal development of the campaign was, as such, the conduct in trade or commerce on which he relied. 891 It was likewise with so much of the s 52 case as was based on an allegation in effect, of misleading conduct by failure to warn. The "Vioxx conduct" (see para 9 above) essentially involved failures to communicate. The applicant was here concerned with the interface between MSDA and others, be they consumers, pharmacists, doctors or other health care professionals. 892 I turn then to the primary elements of the applicant's case under s 52. Because of the degree of overlap between the applicant's case in negligence and his case under the statute, I shall assume a familiarity with what I have written in Part VII above, and shall attempt to keep repetition to a minimum. 893 The applicant's case of misleading conduct by commission was based, as I have said, on an allegation that the "Vioxx representations" were disseminated to doctors and others. In the case of any particular group member, however, the question will be whether MSDA engaged in such conduct in a way that was relevant to him or her. Save for the circumstances of the applicant himself, I could not make a finding that MSDA did engage in such conduct purely on the evidence led to date. Assuming a paradigm in which the representations involved in the conduct were made to, and relied upon by, the prescribing practitioner of a particular group member, such a finding will need to await the calling of evidence on that subject. 894 In the case of the applicant, Dr Dickman could not recall the specifics of any particular interaction with MSDA sales representatives, and he gave no evidence about ever having seen any written promotional material for Vioxx. 895 Of the "Vioxx representations" (see para 854 above), I could not find that those referred to in (c)‑(f) were ever made to Dr Dickman. The broad accuracy of that referred to in (a) is not seriously controversial, and I do not understand the respondents to have resisted the suggestion that it was made to Dr Dickman. It is the representation referred to in (b) − that Vioxx has an excellent overall safety profile compared with other NSAIDs − that corresponds broadly with Dr Dickman's evidence that the MSDA sales representatives' emphasis was primarily on Vioxx's safety. For reasons explained elsewhere, I accept that evidence. That message was, in my view, misleading. Even against the scientific knowledge known to MSDA before September 2004, it would have been misleadingly categorical to say that Vioxx was safe. I would hold, therefore, that MSDA contravened s 52 when its sales representatives conveyed this broad safety message to Dr Dickman. 896 I turn next to so much of the applicant's case as involved the proposition that the court should infer, from the size, nature, sophistication and cost of the internal marketing campaign developed by MSDA, that the "Vioxx representations" were in fact made externally. This inference was said to be open because (1) it was MSDA's purpose to disseminate those representations; (2) MSDA spent very large sums on its marketing campaign; and (3) the campaign was successful, in that, soon after its launch, Vioxx "rapidly penetrated the competitive target market". These very high‑level submissions do not, however, come to grips with the very low‑level evidentiary task which confronted the applicant: to prove, either by direct evidence or by necessary inference, what was said or otherwise communicated by MSDA about Vioxx, to whom, when, and in what context. The "Vioxx representations" themselves are in the nature of a catalogue of statements (or paraphrases of statements) to be found in various documents discovered by MSDA. In his final submissions, however, the applicant did not link the evidence as called to each of these representations. In the circumstances, he has left too many dots unjoined in the proof of what representation was made to whom, and when. On the evidence in the case, I could not hold that a particular representation about Vioxx was made to every general practitioner in Australia. 897 The problem is presented in sharp relief by the evidence of the general practitioners whom the applicant did call, Drs Dickman, Anderson and Lynch. Save with respect to the "safety" emphasis of which Dr Dickman gave evidence, none of these doctors said that the Vioxx representations had been made to him. The best evidence of the making of the Vioxx representations would have come from these witnesses, based on their own experiences. Had there been some infirmity of recollection at the point of detail, the timing and content of the marketing campaign as developed internally might have provided some corroboration and, possibly, some assistance by way of inference. But, these doctors having given no evidence about the subject at all, it would be going too far to infer, merely from what MSDA did internally, that they were all most probably addressees of the "Vioxx representations". 898 The applicant contended also that MSDA effectively marketed Vioxx by having opinion leaders in the profession, such as specialists, talk up the benefits of the drug at conferences, dinners and the like. The only evidence of a prescribing practitioner having been affected by such representatives, however, was of Dr Dickman's attendance at a dinner addressed by a rheumatologist in late 1999 or early 2000. This was, of course, before the VIGOR results were available. However that may be, I could not hold MSDA accountable for what the rheumatologist said. I also note Dr Dickman's oral evidence that what he learnt at that dinner was that Vioxx had the same or a similar overall effectiveness and safety profile to NSAIDs, but that it had a particular gastrointestinal safety benefit. 899 Turning next to the applicant's case on misleading and deceptive conduct by omission, under the Trade Practices Act one may engage in conduct by refraining (other than inadvertently) from doing an act: s 4(2)(a) and (c). To the extent that MSDA's failure to warn amounted to refraining from warning, it was not submitted by the respondents that it was inadvertent. From the evidence in the case, it is clear that the relationship between the consumption of Vioxx and adverse CVT events, and the medical profession's perception of that relationship, was very much part of the conscious thoughts of those responsible for marketing and selling Vioxx. 900 As with their response to the applicant's negligence case on failure to warn, the respondents never really came to grips with the corresponding aspect of his case under s 52. They tended to deal with the problem of "silence" (as they described it) in terms of generalities. In opening, their counsel said: Silence is a circumstance on the authorities like any other which needs to be considered in the context in which it occurs and … in our respectful submission will ultimately prove to be an individual matter. In their final written submissions, they said that courts had "expressed a reluctance to set down exhaustive principles by which cases involving allegedly misleading or deceptive conduct by silence may be characterised". They adverted to what was said by Black CJ in Demagogue Pty Ltd v Ramensky (1992) 39 FCR 31, 32: Silence is to be assessed as a circumstance like any other. To say this is certainly not to impose any general duty of disclosure; the question is simply whether, having regard to all the relevant circumstances, there has been conduct that is misleading or deceptive or that is likely to mislead or deceive. To speak of "mere silence" or of a duty of disclosure can divert attention from that primary question. Although "mere silence" is a convenient way of describing some fact situations, there is in truth no such thing as "mere silence" because the significance of silence always falls to be considered in the context in which it occurs. That context may or may not include facts giving rise to a reasonable expectation, in the circumstances of the case, that if particular matters exist they will be disclosed. See also 41 (Gummow J). The respondents referred also to Johnson Tiles Pty Ltd v Esso Australia Pty Ltd (2000) 104 FCR 564, 591−592 [67] and to E v Australian Red Cross Society (1991) 27 FCR 310, 350. These were, with respect to the respondents, submissions at a very high level which engaged little with the actual facts of the present case. 901 Where the respondents did touch upon the facts of the case was in their submission that the applicant's allegation of silence "is made despite the PI, which was the principle [sic] vehicle by which precautions and warnings were conveyed, having been approved by the TGA". This submission does, of course, beg the question, and it does so in two respects. First, it assumes that use of the Product Information as the "principal vehicle" by which precautions and warnings were conveyed legitimises the absence of other forms of communication for such purposes; and secondly, it assumes either that the Product Information at all times said everything that needed to be said by way of warning or, to the extent that it did not, that it was not open (or at least not required as a matter of reasonable response to the emerging science) for MSDA to go beyond it. Each of these propositions is, of course, highly contentious. 902 However that may be, the respondents' submission leaves no doubt about their position in the litigation. It was that all relevant medical practitioners might be assumed to have ready and convenient access to the Product Information. They cross‑examined Drs Lynch and Dickman by reference to such a proposition. That makes the "Vioxx circumstances" alleged by the applicant significant, particularly the following: (f) [MSDA] provided to pharmacists, medical practitioners and other health care professionals in Australia product information with respect to Vioxx tablets ("the Vioxx product information") setting out warnings and precautions with respect to the consumption of rofecoxib or Vioxx tablets and adverse reactions that may be associated with the consumption of rofecoxib or Vioxx tablets; (g) the Vioxx product information did not contain any adequate information, advice or warning to the effect that the consumption of rofecoxib or Vioxx tablets materially increased the risk of suffering the [pleaded] cardiovascular conditions … MSDA denied that it "provided" the Product Information to pharmacists etc, alleging instead that it "made Product Information … available", which I consider to be a more accurate statement of the situation. Subject to that qualification, the respondents' position clearly was that doctors and pharmacists might be expected to have regular reference to the Product Information as an accurate, complete and TGA‑approved source of information about Vioxx, including its potential risks and side‑effects, to the extent that there were any. 903 At all times until November 2001, the Vioxx Product Information lacked any warning which conveyed the results of the VIGOR trial. Was this misleading conduct by silence? I think it was. A practitioner reading the Product Information would, in my view, reasonably have assumed that what was said about the cardiovascular side‑effects was what MSDA knew on the subject. It was said, for instance, that myocardial infarction had been observed in less that 0.1% of patients taking Vioxx in osteoarthritis studies. That was literally true, but in mid‑2000 and thereafter it was misleading since MSDA was then in possession of the VIGOR results which contained a figure of 0.5% based on patient‑years. There were, of course, all manner of qualifications that could, and perhaps should, have been made with respect to a direct comparison between the osteoarthritis studies data and the VIGOR data (eg different patient population, different dose), but these would have been understood by practitioners and given such weight as was appropriate in the making of their professional judgments. As the respondents stressed, the Product Information was written for a professional readership. I also note that, from very soon after the release of the VIGOR results, MSDA took the view that some amendments were required thereby, notwithstanding that Vioxx was then registered in relation to osteoarthritis only (and notwithstanding also that MSDA itself initially proposed that the gastrointestinal results only be the subject of an amendment to the Product Information). However the matter is looked at, to have given medical practitioners no advice of the results of the VIGOR trial when the unamended Product Information was at large amounted to misleading conduct. 904 I stress that it is no part of my reasoning to hold that the Product Information was itself misleading. The applicant did not so contend. Rather, the misleading conduct was constituted by the failure to draw to the attention of doctors and other health care professionals the cardiovascular risk message that emerged from VIGOR. The respondents criticised the applicant for not having articulated the terms that any such advice would embody. Not having done anything, however, they are in no position to make that criticism. Ultimately, they did come up with a form of advice which I have held to be sufficient for the purposes of the applicant's negligence case. But before that occurred, MSDA's failure to provide any qualification to what was then contained in the Product Information did, for the reasons I have given, amount to misleading conduct. 905 For the same reasons, a different conclusion must be reached once the Product Information was amended in November 2001. No longer could it be said that the existence of the original Product Information made MSDA's failure to warn misleading. This is a different point from my earlier conclusion that merely to cause an amended Product Information to be approved by the TGA was not a sufficient warning to doctors. Here the question is not whether MSDA warned: it is whether it misled. It is quite possible to refrain from warning without misleading. Given that the amended Product Information was at large from November 2001, and that it fairly − albeit compendiously − referred to the cardiovascular results of VIGOR, it could no longer, in my view, be said that merely by remaining silent MSDA had engaged in misleading conduct. It is true that the new paragraph in the "Precautions" section did not advert to the myocardial infarction figure from VIGOR as such, but it did refer to the CVT rate as a whole. The 0.5% myocardial infarction figure was part of the CVT figure of 1.67%. The citation of the latter was, in my view, sufficient to absolve MSDA of the charge, made by the applicant, that its failure to advise doctors directly of the myocardial infarction risk signal given by VIGOR was misleading. 906 I would add two riders to what I have just written. The first is to emphasize that I have held that it was misleading for MSDA not to have made any communication to doctors (etc) of the cardiovascular results of the VIGOR trial while the pre‑November 2001 Product Information was abroad. I do not hold as a matter of fact that it did not do so, save in the case of Dr Dickman. Although there is no evidence of any such communication, I allow for the possibility that the practitioner treating a group member other than the applicant might have been addressed by a representative, or otherwise have received a communication from MSDA, in terms which would have rendered MSDA's conduct, viewed in the overall context, non‑misleading. The second rider is to make clear, lest there should otherwise be any misunderstanding, that I do not reach the conclusion expressed in the previous paragraph with respect to the positively misleading representations that Vioxx was safe. I do not consider that the amendment made to the Product Information in November 2001 rendered such representations − to the extent that they were made thereafter to Dr Dickman − non‑misleading. 907 That brings me to s 82 of the Trade Practices Act. By that provision, the applicant would be entitled to recover from MSDA the amount of any loss or damage which he suffered "by" the conduct which was in contravention of s 52. It was submitted on his behalf that the consumption of Vioxx caused (or contributed to) his heart attack, and that the misleading conduct of MSDA caused him to be prescribed Vioxx by Dr Dickman. The respondents accepted that, in a case under ss 52 and 82, it was not necessary for the injured party to have directly relied on the presumptively misleading representation but submitted that the evidence in the present case did not sustain the conclusion that Dr Dickman relied on any misleading representation (either active or silent) by MSDA in his decision to prescribe Vioxx to the applicant. 908 With respect to the period before November 2001, each misleading element of MSDA's conduct - its broad "safety" message and its failure to report the cardiovascular risk signal given by the VIGOR results - was part of the environment to which Dr Dickman was exposed. Were it necessary to do so, I would reach the same conclusion about this conduct as I did in Part VII above with respect to causation in the applicant's negligence case. That is to say, I would not be satisfied that, had MSDA's conduct not contained those elements, or had it contained one only of them, Dr Dickman's prescribing decisions would have been any different. I would not be satisfied that, in prescribing Vioxx to the applicant before November 2001, Dr Dickman relied either on the broad "safety" message conveyed by MSDA sales representatives or on MSDA's omission to report the VIGOR risk signal. 909 As it happens, however, I could not be satisfied that there was a biological association between the consumption of Vioxx in and before November 2001 and the applicant's heart attack in December 2003. That is to say, while I have found in Part VI above that the consumption of Vioxx biologically contributed to the applicant's heart attack, that finding relied on an earlier finding that the applicant consumed Vioxx more or less continuously in the weeks and months leading up to his heart attack. It follows that it is to the prescribing decisions of Dr Dickman well subsequent to November 2001 that regard should be had for the purposes of the question whether the misleading conduct of MSDA contributed to the applicant's heart attack in December 2003. 910 The evidence before the court shows that Dr Dickman prescribed Vioxx for the applicant on 10 April, 19 July and 20 December 2002 and 2 December 2003, and that Dr Anderson did so on 30 May 2003. Over the whole of the period when these decisions were being made, MSDA was not engaging in misleading conduct by omission. Its only misleading conduct was constituted by the broad "safety" message conveyed to Dr Dickman by its sales representatives. For reasons given at para 872 above, I am not persuaded that Dr Dickman relied on that message in the decisions he made to prescribe Vioxx for the applicant. 911 It follows that the applicant's claim for damages under s 82 of the Trade Practices Act with respect to MSDA's conduct in contravention of s 52 thereof must be dismissed.

Section 75AD 912 Section 75AD of the Trade Practices Act relevantly provides as follows: If: (a) a corporation, in trade or commerce, supplies goods manufactured by it; and (b) they have a defect; and (c) because of the defect, an individual suffers injuries; then: (d) the corporation is liable to compensate the individual for the amount of the individual's loss suffered as a result of the injuries; and (e) the individual may recover that amount by action against the corporation; Under this provision, it should be noted that the defect must exist in the particular goods which presumptively caused injury to the individual. The section is not concerned with the question whether other or similar goods ─ even goods which, as a matter of branding or commercial practice, are "the same" ─ have or had a defect. Thus, although it may be accepted that the Vioxx tablets consumed by all of the group members in the present case were, as a matter of composition, identical (subject, of course, to variations in strength), as will be apparent, the applicant's allegations of defect travel beyond the matter of composition into areas in which it cannot be assumed that the circumstances which were relevant to himself were also present and relevant for all group members. 913 The "circumstances" to which I refer are the concern of s 75AC of the Trade Practices Act. Subsections (1) and (2) of s 75AC provide as follows: (1) For the purposes of this Part, goods have a defect if their safety is not such as persons generally are entitled to expect. (2) In determining the extent of the safety of goods, regard is to be given to all relevant circumstances including: (a) the manner in which, and the purposes for which, they have been marketed; and (b) their packaging; and (c) the use of any mark in relation to them; and (d) any instructions for, or warnings with respect to, doing, or refraining from doing, anything with or in relation to them; and (e) what might reasonably be expected to be done with or in relation to them; and (f) the time when they were supplied by their manufacturer. These provisions posit two questions for the court: (1) what is the safety of the goods; and (2) is that safety such as persons generally are entitled to expect? It is the first question with which subs (2) is concerned. The second question is to be addressed by an objective approach, rather than, for example, by inquiring what level of safety the relevant individual did in fact expect: Carey‑Hazell at [186]. 914 The circumstances to which the applicant pointed for the purposes of s 75AC(2) were the following: (a) rofecoxib was a prescription only non‑steroidal anti‑inflammatory drug; (b) [MSDA] marketed in Australia Vioxx tablets to pharmacists, medical practitioners and other health care professionals as a non‑steroidal anti‑inflammatory drug for the treatment of arthritis that was safer than other non‑steroidal anti‑inflammatory drugs in that it was less likely to cause adverse gastrointestinal conditions and reactions; (c) it was reasonable to expect that medical practitioners and other health care professionals would prescribe and pharmacists would supply under prescription Vioxx tablets as a non‑steroidal anti‑inflammatory drug for the treatment of arthritis; (d) it was reasonable to expect that persons who were prescribed by a medical practitioner or other health care professional and obtained from a pharmacist Vioxx tablets would consume the Vioxx tablets as a non‑steroidal anti‑inflammatory drug for the treatment of arthritis; (e) it was reasonable to expect that many persons who were prescribed by a medical practitioner or other health care professional and obtained from a pharmacist Vioxx tablets and who consumed the Vioxx tablets as a non‑steroidal anti‑inflammatory drug for the treatment of arthritis were likely to be elderly and, accordingly, at particular risk of suffering the [pleaded] cardiovascular conditions; (f) in marketing, distributing and/or supplying for sale in Australia Vioxx tablets [MSDA] failed to provide pharmacists, medical practitioners and other health care professionals any adequate information, advice or warning to the effect that the consumption of rofecoxib or Vioxx tablets materially increased the risk of suffering the [pleaded] cardiovascular conditions; (g) the packaging and labelling of Vioxx tablets did not contain or carry any adequate information, advice or warning to the effect that the consumption of rofecoxib or Vioxx tablets materially increased the risk of suffering the [pleaded] cardiovascular conditions; (h) the Vioxx product information did not contain any adequate information, advice or warning to the effect that the consumption of rofecoxib or Vioxx tablets materially increased the risk of suffering the [pleaded] cardiovascular conditions …. 915 Items (a)-(d) on the applicant's list are relatively uncontroversial, and I would have little hesitation in finding that they did exist as circumstances in the present case. Item (e) is not so clear‑cut, but, particularly with respect to the period during which Vioxx was indicated only for osteoarthritis, it finds support in the evidence. Criticising the design of the VIGOR trial, Prof Cleland said that the demographic most likely to take Vioxx was that of elderly patients who tended to have greater pre‑existing cardiovascular risks. He was cross‑examined on that evidence, but from a standpoint that accepted that the elderly were at greater risk of cardiovascular disease. In discussing the Merck Alzheimer's disease studies, Prof Vaughan referred to the elderly as "a population that was at higher risk for cardiovascular disease". Prof Celemajer said that "the major risk factor for atherosclerosis bar none is increasing age". As to the typical profile of osteoarthritis patients, counsel for the respondents confirmed my impression that (in his words) osteoarthritis was "a wear and tear type disease [which] will affect people as they get older". 916 Items (f)‑(h) on the applicant's list assume, without alleging in terms, the existence of a further circumstance that was alleged by the applicant elsewhere in his pleading: that the consumption of Vioxx did materially increase the risk of suffering the pleaded cardiovascular conditions. I have rejected that allegation for all of those conditions save myocardial infarction. In the case of that condition, I have held that, across a population, the consumption of Vioxx did involve an increase in risk, but that the extent of the risk in a particular case would depend on the conditions presumptively existing in the patient's vasculature. For a patient in a reasonably advanced state of atherosclerosis, the risk was more pronounced. Whether there was a risk in the case of a particular patient, and how troubling that risk was, were matters which involved a professional judgment by his or her practitioner. 917 Absent the provision of any information, advice or warning, I consider that the risk to which I have referred made the safety of Vioxx less than what persons generally were entitled to expect. Indeed, the withdrawal of Vioxx from the market on 30 September 2004 implied as much. The respondents stressed, and I accept, that many prescription drugs have side‑effects, sometimes quite serious ones. Conventional NSAIDs, with their gastrointestinal issues, are a presently conspicuous example. I could not hold, therefore, that persons generally are entitled to expect that all drugs will be free of side‑effects. However, (and this reflects the broad position adopted by both sides in this case) the ingestion of prescription drugs occurs only after the making of a professional judgment by a medical practitioner, informed by his or her diagnosis of the condition of the patient concerned. Persons generally are, in my view, entitled to expect that, to the extent that a drug is known or believed to have side‑effects, or to carry the potential for side‑effects (particularly of a serious nature), practitioners will, in whatever terms, and by whatever means, are appropriate, be furnished by the drug supplier with information or warnings sufficient to permit a balanced, cautious and informed judgment to be made. 918 As I have held elsewhere, nothing in the nature of a warning, and no information about the cardiovascular results of the VIGOR trial, were communicated by MSDA to Dr Dickman before at least November 2001. Until then, therefore, the safety of Vioxx (as purchased and consumed by the applicant) was not such as persons generally were entitled to expect. 919 Did the safety of Vioxx become such as persons generally were entitled to expect upon the amendment of the Product Information in November 2001? I consider that the existence thereafter of the Product Information in its amended form was an instruction or warning within the meaning of para (d) of s 75AC(2), but the question remains whether, having regard to that and all other relevant circumstances, the safety of Vioxx was not such as persons generally were entitled to expect. 920 In October 2000, MSDA had chosen to correspond with doctors generally in terms which included advice about various side‑effects which might be associated with the consumption of Vioxx, and various precautions which ought to be observed in that regard. An aspect of that advice was that, in certain osteoarthritis studies, the myocardial infarction rate amongst those taking Vioxx had been less than 0.1%. At all times that Vioxx was on the market in Australia, MSDA had available information to the effect that, in the VIGOR trial, the myocardial infarction rate had been 0.5%. Although there may have been a number of legitimate bases upon which MSDA might have proposed that this level of risk was not generally applicable, or was not applicable to osteoarthritis patients, I consider that persons generally were entitled to expect that an advice or a warning that conveyed the outcome of the VIGOR trial would have been communicated to medical practitioners by a means no less likely to capture their attention than the means employed in October 2000. 921 For the above reasons, I am of the view that the mere amendment of the Vioxx Product Information in November 2001 was, in the context of all the relevant circumstances, insufficient to make the safety of Vioxx such as persons generally were entitled to expect. It follows that, when (after that month) MSDA supplied the Vioxx tablets that were ultimately consumed by the applicant, those tablets had a defect within the meaning of s 75AD of the Trade Practices Act. 922 MSDA advances two defences to the applicant's s 75AD case under s 75AK(1) of the Trade Practices Act. Relevantly to those defences, the subsection provides as follows: (1) In a liability action, it is a defence if it is established that: … (b) [the goods] had that defect only because there was compliance with a mandatory standard for them; or (c) the state of scientific or technical knowledge at the time when [the goods] were supplied by their actual manufacturer was not such as to enable that defect to be discovered; or… MSDA relies upon what it describes as the "mandatory standards defence" (para (b)) and upon the "state of the art defence" (para (c)). 923 In s 75AA of the Trade Practices Act, the term "mandatory standard" in relation to goods, is defined as a standard ─ (a) for the goods or anything relating to the goods; and (b) that, under a law of the Commonwealth, a State or a Territory, must be complied with when the goods are supplied by their manufacturer, being a law creating an offence or liability where there is such non‑compliance; but does not include a standard which may be complied with by meeting a higher standard. MSDA submitted that the conditions of the registration of Vioxx on the ARTG did not permit it to manufacture Vioxx outside "the approved specifications", and did not permit it to add information to the Product Information, except in accordance with the processes for amendment established by the TGA. It submitted that the chemical composition of Vioxx, and the form of the Product Information, existed by reason of its compliance with the conditions imposed by the TGA. It submitted that, where the TGA asked it to include a warning in relation to cardiovascular events in the Product Information, and where there were discussions between it and the TGA in relation to the form of words to be used in that warning, any defect in Vioxx existed only because of compliance with a mandatory standard within the meaning of s 75AA. 924 It will be apparent from what I have written elsewhere in these reasons that I consider these submissions to be quite misconceived. Reading s 75AK(1)(b) with ss 75AC and 75AD, the question is whether the safety of Vioxx was not what persons generally were entitled to expect only because of compliance with a mandatory standard as defined in s 75AA. I have held that the safety of Vioxx was less than what persons generally were entitled to expect because, as a matter of composition, the consumption of Vioxx had the potential to increase the risk of suffering a myocardial infarction, in circumstances which included the absence of any relevant information or warning communicated to the applicant's doctor. It was not because of a mandatory standard that the composition of Vioxx was as it was. Nor was it because of such a standard that Dr Dickman was not warned. It may have been because of a mandatory standard that MSDA could not change the composition of Vioxx without amending the Product Information, and that the Product Information could not be amended without the approval the TGA. But those circumstances were not what made the safety of Vioxx less than persons generally were entitled to expect. Neither did they have any relevance to the failure of MSDA to warn Dr Dickman, even without amending the Product Information. As I have held, the existence of the Product Information (whether in its amended or unamended form) provided no impediment to MSDA giving such a warning to Dr Dickman or to any other general practitioner. 925 For these reasons, I reject MSDA's reliance on s 75AK(1)(b) of the Trade Practices Act. 926 With respect to the state of the art defence advanced by MSDA, it submitted that the defect alleged to have existed in Vioxx was that "Vioxx tablets materially increased the risk of suffering the [pleaded] cardiovascular conditions". MSDA submitted that, while it was not in dispute that there was an hypothesis to this effect during the whole of the period that Vioxx was on the market in Australia, the totality of the scientific evidence did not take the matter further, and "it never rose to the level of scientific knowledge required to enable a defect to be discovered during the relevant period." In Part V of these reasons, I have concluded that it was not until the unblinding of Merck to the cardiovascular data from the APPROVe study in September 2004 that the respondents knew or ought to have known that the consumption of Vioxx increased the risk of the occurrence of cardiovascular events. To that extent, the respondents' submission is well‑founded. However, the present question is whether that is one and the same thing as concluding that the defect which I have identified could not have been discovered by reference to the state of scientific or technical knowledge at the time. 927 At the scientific or technical level as such, I would hold that the defect could not have been so discovered. The defect, of course, is the inadequate safety of the goods themselves. Vioxx was unsafe in that sense because it increased the risk of myocardial infarction. However, it was not until September 2004 that that increase in risk could be "discovered" in the sense of established at the scientific level. Merck was at the forefront of research in this regard (understandably, since rofecoxib was its own molecule). Merck's own knowledge was the state of scientific knowledge to which s 75AK(1)(c) refers. I consider that my conclusion in Part V of these reasons carries the consequence that it was not until September 2004 that the state of scientific knowledge was such as to enable the discovery of the fact that the consumption of Vioxx increased the risk of myocardial infarction. 928 Does that conclusion take the respondents the full distance they need to travel under s 75AK(1)(c)? I ask that question because, on one view at least, by the terms of s 75AC a defect is a situation rather than a particular aspect of the composition of the goods in question. And it is a situation the existence of which must be determined as a matter of judgment only after consideration of all relevant circumstances. In the present case, I have effectively held that persons generally were entitled to expect that MSDA would have given to medical practitioners a warning (etc) which would have conveyed some idea of the signal of risk yielded by the VIGOR trial. The state of scientific knowledge was such as would have enabled such a warning to be given. It was such as enabled MSDA to know of that element of the situational defect as was constituted by the risk signal coming from VIGOR. 929 I do not, however, think that the relevant provisions of Pt VA of the Trade Practices Act should be so construed. Section 75AK(1)(c) contemplates the existence of a defect capable of being discovered by reference to the current state of scientific or technical knowledge. It is not concerned with the kind of contextual circumstances referred to in s 75AC(2). My conclusion that the respondents ought to have acted consistently with the cardiovascular risk signal yielded by VIGOR is in the nature of a judgment as to how persons generally were entitled to expect that MSDA would act. By all means it informed my determination that there was a defect, but the content of persons' expectations did not constitute the defect itself. The defect was something inherent in Vioxx as a matter of composition. I consider that the intent of s 75AK(1)(c) is that if that defect could not be discovered according to the state of scientific or technical knowledge, the defence should be available, notwithstanding that enough was suspected about the product to activate an implied obligation to give warnings of the kind mentioned in s 75AC(2)(d). 930 For the above reasons, I propose to uphold MSDA's defence under s 75AK(1)(c) of the Trade Practices Act.

Section 74B 931 Relevantly to the present case, s 74B of the Trade Practices Act provides as follows: (1) Where: (a) a corporation, in trade or commerce, supplies goods manufactured by the corporation to another person who acquires the goods for re‑supply; (b) a person (whether or not the person who acquired the goods from the corporation) supplies the goods (otherwise than by way of sale by auction) to a consumer; (c) the goods are acquired by the consumer for a particular purpose that was, expressly or by implication, made known to the corporation, either directly, or through the person from whom the consumer acquired the goods or a person by whom any antecedent negotiations in connexion with the acquisition of the goods were conducted; (d) the goods are not reasonably fit for that purpose, whether or not that is a purpose for which such goods are commonly supplied; and (e) the consumer or a person who acquires the goods from, or derives title to the goods through or under, the consumer suffers loss or damage by reason that the goods are not reasonably fit for that purpose; the corporation is liable to compensate the consumer or that other person for the loss or damage and the consumer or that other person may recover the amount of the compensation by action against the corporation in a court of competent jurisdiction. (2) Subsection (1) does not apply: (a) … (b) where the circumstances show that the consumer did not rely, or that it was unreasonable for the consumer to rely, on the skill or judgment of the corporation. 932 The applicant's submissions under this section were brief. He submitted as follows: · MSDA supplied Vioxx to pharmacies which acquired it for re‑supply; · Vioxx was supplied to group members including the applicant by pharmacies; · Vioxx was acquired by the applicant for the particular purpose of consumption as a non‑steroidal anti‑inflammatory drug the consumption of which would not lead to a material increase in the risk of suffering life‑threatening conditions …; · the purpose of acquisition of Vioxx by the applicant (and all group members) was known to MSDA - the very purpose for which Vioxx was developed was to provide an arthritis medication without the potentially serious gastrointestinal side effects of traditional NSAIDs and MSDA's marketing campaign promoted Vioxx as having a gastrointestinal and overall safety profile which was superior to traditional NSAIDS; · because Vioxx materially increased the risk of experiencing life‑threatening cardiovascular conditions, Vioxx tablets were not reasonably fit for their purpose of acquisition; · the applicant suffered his heart attack because Vioxx materially increased the risk of suffering that cardiovascular condition. 933 The respondents' first submission in response to the applicant's case under s 74B was one which they made also in relation to s 74D. They submitted that neither section applied to prescription medicines. They submitted that the remedies created by ss 74B and 74D were not "apt to be applied to circumstances [which] are quite remote from the ordinary supply and acquisition of consumer goods". According to the respondents, the sections imposed norms of conduct which were not "apt to be applied to a case about the inherent properties of a prescription medicine". That was said to be so because "such goods carry with them inherent risks of side‑effects" and because "their supply is mediated by learned intermediaries, that is, the prescribing doctor and the dispensing pharmacist". If these general submissions were intended to be anything more than an introduction to the respondents' case under ss 74B and 74D, they were not developed for that purpose. Indeed, at that general level, the respondents made no submission in addition to those which I have briefly summarised in this paragraph. However, the fact that the goods in question may only be supplied on prescription has the potential to be an important consideration, both under s 74B and under s 74D. I shall return to that consideration in due course. 934 The respondents' first point under s 74B specifically related to what was said to be the intrinsic inappropriateness of the section to the context of a representative proceeding. The respondents referred to the "individualised nature of the inquiry involved", relying in this respect on the judgment of Wilcox J in Ryan v Great Lakes Council [1999] FCA 177. That case concerned oysters which had been contaminated by the presence of a foreign substance in the water in which they were grown. In a representative proceeding, the applicant succeeded under both s 74B and s 74D in relation to his personal claims, but Wilcox J held over the claims of the represented parties. As to the application of s 74B in the circumstances, his Honour said (at [368]): The applicant is entitled to succeed under s 74B as against Barclay Oysters in respect of his personal claim. I cannot make any concluded finding in relation to the applicant's representative claim under s 74B against Barclay Oysters; it is conceivable - although, perhaps, unlikely - that something was said or done, at the time of the supply of oysters to a particular consumer, to make it unreasonable for that consumer to rely on the skill or judgment of Barclay Oysters. The application of s 74B to group members must be left for future determination, if that should prove necessary. It will be noted that Wilcox J's reservation as expressed related to the question whether it was unreasonable for a particular consumer to have relied on the skill or judgment of the manufacturer. That is the second aspect of the defence arising under para (b) of s 74B(2). In the present case, MSDA pleaded that aspect of the paragraph in its Defence, but made no submission about it (in relation to the applicant). The particular respect in which Wilcox J held that the claims of the group members in Ryan were heterogeneous does not, therefore, arise on the applicant's own claim in the present case. 935 Notwithstanding that point of distinction, I accept that the claims of all group members cannot be fully resolved by reference to the case as it has been conducted to date. By the orders made on 30 March 2009 set out in Appendix A to these reasons, the court is presently confined to the resolution of questions which clearly stop a good distance short of dealing with the claims of group members other than the applicant. It is sufficient to say that, for any one group member to succeed under s 74B, he or she must establish what was his or her purpose in acquiring Vioxx and facts sufficient to show, or to give rise to an implication, that that purpose was made known to MSDA. Although, intuitively, the applicant's own circumstances look as though they might be typical, the claims of the other group members cannot be decided by intuition. Thus I accept that it will be necessary to stand those claims over to a later hearing of the proceeding. 936 The respondents then submitted that, in the context of prescription medicines, there is no "supply" of goods within the terms of s 74B(1)(b). They contended: Rather, what has occurred is a supply of professional services with the provision of Vioxx as ancillary for these services. That is, there was a trilateral transaction whereby a doctor has prescribed and a pharmacist has dispensed a prescription medicine to a consumer. There are indeed three parties involved in the transactions out of which a liability presumptively arises under s 74B. However, they are not the parties referred to in the respondents' submissions: they are MSDA, the pharmacist and the consumer. That a pharmacist supplied Vioxx tablets to the applicant within the meaning of para (b) of s 74B(1) does, with respect to the respondents, appear rather obvious. 937 The respondents relied on E v Australian Red Cross Society (1991) 31 FCR 299, in which the appellant was given infected blood in the course of a transfusion carried out while he was a patient in hospital. Relevantly to the present point, the question was whether the hospital had supplied goods within the meaning of s 71(1) of the Trade Practices Act. With the agreement of Sheppard and Pincus JJ, Lockhart J said (31 FCR 299 at 306): In my opinion his Honour correctly found that there was no contract with the CSAHS for the supply of blood plasma to the appellant. The essence of the contract between the appellant and the CSAHS was one for services, namely, the provision of hospital, medical and nursing services for the purpose of treating the appellant for his medical problem and restoring him to health. To the extent that goods were provided to him such as food, sleeping tablets, antibiotics, dressings and things of this nature, they were provided as an incident to the contract for the provision of services. There was no contract for the supply of goods. The contract between the CSAHS and the appellant was one for services and is not divisible into a contract for services and for the supply of goods. I leave open, however, the question whether in an appropriate case a contract between a patient and a hospital may be divisible in other circumstances. But the provision on the facts of this case of medicines, drugs and blood cannot be severed into concepts of the provision of services on the one hand and of purchase and sale of goods on the other. This authority is of no assistance to the respondents in the present case. The transactions with which Lockhart J was concerned related to undifferentiated treatment - which included the supply of blood - given to an inpatient in hospital. A transaction of that character, in my view, is in no sense analogous to that in which a consumer purchases medicines from a pharmacist, albeit that he or she does so on the authority of his or her prescribing doctor. I consider that the Vioxx tablets consumed by the applicant were supplied to him as goods within the meaning of s 74B(1)(b) of the Trade Practices Act. 938 The respondents next submitted that prescription medicines were not "acquired" within the meaning of s 74B(1)(c). Here the presumptive acquisition of goods was that by which the applicant, for example, obtained his Vioxx tablets from a pharmacist. The respondents invoked s 4C(a) of the Trade Practices Act, which provides that "a reference to the acquisition of goods includes a reference to the acquisition of property in, or rights in relation to, goods in pursuance of a supply of the goods". The respondents submitted that this "definition" (as s 4C(a) was described) was not satisfied because, first, there was no "acquisition of property in or rights in relation to Vioxx" and, secondly, there had been no "supply" of Vioxx as contemplated by the Trade Practices Act. I need say nothing further about the second of these points, as I have already held that the transaction by which the applicant obtained Vioxx tablets from his pharmacist was a "supply" in the relevant sense. 939 The provisions of s 4C(a) of the Trade Practices Act do not affect the ordinary meaning of the word "acquire". Their only effect is to incorporate into the connotation of that word, where used in the Act, the additional meanings referred to. In the facts of the present case, it is as clear as may be that the applicant acquired Vioxx tablets from his pharmacist, according to the ordinary sense of the word "acquire". In the circumstances, the applicant has no need to rely (and, indeed, does not seek to rely) on s 4C(a). The respondents' submissions about that paragraph are, therefore, no answer to the applicant's case to the extent that it relies upon the provisions of para (c) of s 74B(1). 940 The respondents' next point was that the purpose for which the applicant alleges that he acquired Vioxx tablets does not reflect his actual purpose at the time, as disclosed by the evidence. As to the latter, the respondents referred to the following passage in the applicant's witness statement: I would always take anti‑inflammatory drugs as directed. In consulting with my doctor about taking a drug, I would try to find a balance between a good anti‑inflammatory effect and a low level of gastric discomfort. They referred also to the following evidence given by the applicant under cross‑examination: Can I suggest to you that as you over time took anti‑inflammatory drugs you saw yourself as really engaging in a process of taking the drugs because the benefit of them outweighed the identified and known disadvantages to you?---Yes. Can you tell me this. Did any of the range of doctors who prescribed to you an anti‑inflammatory drug ever tell you, either because they volunteered it or because you asked, what risk, if any, these drugs had with respect to your cardiovascular system?---No. None at all?---Not that I can remember, no. If it was said it didn't cause you to retain it?---I can't remember it being said. And the issue of whether there was any cardiovascular risk with respect to your taking of these anti‑inflammatories was therefore never an issue for you to weigh up?---I can't remember ever having that as a consideration, no. So you were weighing up pain on the one hand as against no pain and gastrointestinal difficulties on the other?---Basically, yes. And of course ability to work and do your work without interruption. Is that right?---Yes. Notwithstanding their reference to these passages, the respondents did not identify the "particular purpose" for which, in their submission, the applicant did acquire Vioxx. 941 The terms of s 74B(1)(c) of the Trade Practices Act allow for a situation in which the acquirer makes known his or her purpose by implication. The implied purpose may be so made known either directly or through the intermediaries referred to in para (c) of subs (1). That such possibilities are allowed under the section introduces scope for the ex‑post formulation of purpose by reference to the needs of the particular litigation in which the remedy is being pursued. According to the respondents, that is exactly what the applicant is attempting to do in the present case. They submit that he has crafted an allegation of his own purpose tendentiously with an astute eye upon the outcome which he seeks in the case. They point out that the identification of purpose in s 74B(1)(c) is necessarily a subjective matter (see Rasell v Cavalier Marketing (Australia) Pty Ltd [1991] 2 Qd R 323, 330), and the applicant's evidence, set out above, provides no support for the notion that he had in his conscious thoughts the need to obtain a drug "the consumption of which would not lead to a material increase in the risk of suffering life‑threatening conditions". 942 The authorities show, however, that the putative acquirer does not need to have freedom from the particular defect consciously in his or her mind at the time of acquisition. Thus, for example, Dr Grant was not required to prove that he had in mind purchasing a pair of underpants that would not give him dermatitis: see Grant v Australian Knitting Mills Ltd [1936] AC 85. The fact that he contracted dermatitis from a chemical contained in the material of the garment which he wore justified the conclusion that the garment was not fit for the purpose of being worn as intended (ie against the skin). In the present case, if the applicant's purpose were no more than to obtain relief from the pain associated with arthritis (and for present purposes it does not matter whether it be osteo or rheumatoid), he need not also demonstrate that he had it in mind that Vioxx would not cause heart attacks. The debate would then move to the question whether, by reason of the association of Vioxx with heart attacks, Vioxx was unfit for the applicant's purpose. I consider that it is as clear, and as uncontroversial, as may be that the applicant's purpose in taking Vioxx was to obtain relief from his back pain without (so far as possible) gastrointestinal side‑effects. I am satisfied that his pleading fairly reflected the case which he ran in this regard, and that the respondents were left in no doubt as to the purpose for which he would contend (in his final submissions) that he consumed Vioxx. 943 On the other hand, I do accept the respondents' submissions that the applicant's allegation that his purpose was to consume Vioxx as an anti‑inflammatory drug the consumption of which would not lead to a material increase in the risk of suffering life‑threatening conditions is altogether too tendentious an identification of his purpose in taking Vioxx. He gave no evidence that he had such a purpose in that period. It may be said, I suppose, that the purpose of avoiding life‑threatening conditions may be assumed, but this would be, in my view, to make a statement about the applicant's unstated assumptions, rather than about his purpose. In point of fact, therefore, I reject the applicant's case that his purpose was to have a drug that did not give rise to a material increase in the risk of suffering life‑threatening conditions. 944 In my view, in a case such as the present where there is no express or clearly implicit expression of purpose that the consumer requires a product that is free of risk (or of increased risk, or materially increased risk, etc), the point at which the absence of risk becomes relevant is where the existence of the presumptively dangerous tendency of the goods in question compromises their fitness for the purpose in fact made known to the manufacturer. For example, a sunscreen lotion that was coincidentally attractive to wasps would be unfit for purpose as a sunscreen lotion. It would be quite artificial to enquire whether the consumer made it implicitly known to the manufacturer that he or she entertained the purpose of using a wasp‑free lotion. On the facts of the present case, the applicant's point must be that the tendency of Vioxx to contribute to the onset of cardiovascular disease justifies the conclusion that it was not reasonably fit for the purpose of providing relief from arthritic pain. 945 The respondents also submitted that the applicant's purpose was not "made known" to MSDA, as required by s 74B(1)(c). However, the only submission directly made on this subject was the following: In these proceedings, there is no evidence that the Applicant's particular purpose for obtaining Vioxx (let along any Group Member's) was made known to the First Respondent. For example, Vioxx was at various times approved for the treatment of two indications, the symptomatic treatment of osteoarthritis and rheumatoid arthritis in December 1999 and January 2002 and there is no evidence whatsoever that it was ever made known to MSDA, in respect of any Group Member, for which approved indication Vioxx was prescribed. This submission, contained in the respondents' final written submissions, was the subject of neither elaboration nor comment in oral submissions made on their behalf. If the respondents are to be understood as proposing that the applicant's purpose could not have been made known to MSDA under s 74B(1)(c) unless it knew that he was suffering from osteoarthritis or rheumatoid arthritis, I would have no hesitation in rejecting it. Relevantly to the context of the present case, the particular form of inflammatory disease for which the applicant required Vioxx was quite irrelevant to the kind of unfitness for purpose which he alleges. Vioxx was sold as a product to be consumed with a view to obtaining relief from the pain associated with arthritis. That purpose was inherent and self‑evident. It could not but have been made known implicitly to MSDA that the purpose of every person who was prescribed, and subsequently purchased, Vioxx was that purpose, much as the purpose of a householder who purchases milk is to consume it: Frost v Aylesbury Dairy Company Ltd [1905] 1 KB 608, 612, 614. It is true that (at least after January 2002) it may not have been known to MSDA whether a particular patient was suffering from osteoarthritis or rheumatoid arthritis but, for the reasons I have attempted to explain, that would be neither here nor there (much as the defendant in Frost need not have known the particular purpose to which the contaminated milk was to be put - drinking, cooking etc). 946 At this point it is convenient to return to the circumstance that Vioxx was a prescription‑only medicine upon which the respondents rely. In my view, this does put a particular complexion on the matter of "purpose" under s 74B(1)(c). In a case in which the consumer's purpose is to be implied by reason of the nature of the goods, the implication must, in my view, take account of the prescription which authorises supply of the goods, and of the fact that it has been written by a medical practitioner. The consumer's implicit purpose, in such a case, is not merely the achievement of the beneficial effect of the medicine. It is the achievement of that effect in accordance with the terms of the prescription and any advice or instructions that may be assumed to have been given by the doctor, consistently with the prescription. In a clear case, for example, if the doctor had informed the patient that the consumption of a particular medicine carried the real risk of stomach cramp, and if the patient nonetheless decided to take the medicine, his or her implied purpose would be to achieve the conventional beneficial effect of the medicine subject to that risk. It could not then be said that the medicine was not reasonably fit for the purpose as implicitly made known by the consumer. 947 The next point of significance in this respect is that it is the manufacturer to whom the consumer's purpose must be made known under s 74B(1)(c). In most cases, there will be no direct transaction as between the consumer and the manufacturer, and therefore no communication of the consumer's actual purpose. Such purpose as is implicit in the nature of the goods will, therefore, be the basis of the consumer's case. The question will be: considering all relevant circumstances, what communication of purpose as between the consumer and the manufacturer should be implied? In the case of a prescription medicine, those circumstances include those to which I referred in the previous paragraph. So far as the manufacturer's implied understanding of the consumer's purpose is concerned, it would, in my opinion, be wrong to omit consideration of any communication made by it to the doctor with respect to the purpose for which the medicine might be fit, or with respect to any adverse consequences of taking the medicine. Again to take a clear case, if the manufacturer had informed the doctor that the medicine carried the real risk of stomach cramp, it could not be implied as between the manufacturer and one of the doctor's patients (for whom a prescription had been written) that the latter's purpose was not qualified by reference to that risk. 948 As a matter of principle, it seems that what I have just said should be applicable as much in a case in which the doctor had not in fact advised the patient of the risk that would compromise the medicine's fitness for purpose as in a case where such advice had been given. That is because we are here concerned with the matter of implication. The question is not what the consumer said to the doctor, but what he or she implicitly "made known" to the manufacturer. It could not, in my view, be held that a manufacturer implicitly received a communication from a consumer save by reference to facts actually or constructively known to the manufacturer at the time. If the manufacturer had advised the doctor of the risk involved in the taking of a particular medicine, that the consumer's purpose was to derive the beneficial effect of the medicine unaffected by that risk could not, in my view, be implied by the circumstance that the consumer presented the doctor's prescription to a pharmacist in order to acquire the medicine. 949 The approach which I take to this question is, I think, similar to that taken by Kiefel J in Carey‑Hazell. In that case, a mechanical valve had been surgically inserted into the heart of the patient concerned. It was known that mechanical valves gave rise to the risk of thromboembolisms. Notwithstanding the administration of anti‑coagulants to counter that tendency, the patient did suffer thromboembolic events, and sued the Australian importer of the valve. Kiefel J rejected her case under s 74B. Her Honour said: 212 … The … valve cannot however be regarded as unfit for that purpose because there was a known risk that thromboembolisms might develop and cause injury of the kind the applicant suffered. The applicant has identified only that she fell within the category of persons who develop such a complication. The question whether goods which have a use are reasonably fit for it must be assessed not only by reference to the fact that they failed to accomplish their purpose, but also by reference to what a consumer could reasonably expect from the goods. 213 The evidence here clearly establishes that the risk in question was well known to medical practitioners. The applicant was advised of this risk, as I later discuss. In my view, for the reasons I give later it could not therefore have been reasonable for the applicant to expect that there was no prospect that the valve would cause the development of thrombi. This claim is not made out. The essence of this passage, in my respectful view, is that the purpose which the consumer implicitly makes known to the manufacturer will necessarily take account of risks that were known to medical practitioners generally. 950 That brings me to the question whether the increased risk of myocardial infarction which I have held to be associated with the consumption of Vioxx was known to medical practitioners generally, or was known to Dr Dickman, either actually or by reference to communications made by MSDA to them or to him. The literal answer to all these questions must be no. MSDA did not know that Vioxx increased the risk of myocardial infarction by a factor of about 2, and it conveyed no information to Dr Dickman, or to the profession generally, about a risk of that order or of anything like that order. 951 The respondents, however, rely on the terms of the Product Information in this context. As to the situation before November 2001 (when the Product Information was amended), there was a note in the "Precautions" section to the effect that, in some trials, myocardial infarctions had been observed to occur (from any cause) in fewer than 0.1% of the patients taking Vioxx. This was not, in my view, the equivalent of a statement that Vioxx should be regarded as itself associated with a risk of myocardial infarction. The respondents did not submit otherwise. Down to November 2001, therefore, there is no way that the purpose implicitly made known to MSDA by the applicant could be regarded as subject to a proviso that a doubling of the risk of heart attack was acceptable. 952 The Product Information as amended in November 2001 provided two further, arguably relevant, pieces of information to medical practitioners who read it: (1) that a trial of Vioxx had shown a lower rate of serious cardiovascular thromboembolic adverse events for patients taking naproxen than for those taking Vioxx; and (2) that, in other trials, spontaneous reports of such events were similar as between Vioxx and non‑selective NSAIDs. The reader was advised to give consideration to those data in the case of an individual patient at risk for such events. Nothing was said here about the risks associated with the consumption of Vioxx as such (ie by reference to a situation in which the notional comparator was placebo). There was nothing to suggest that the consumption of Vioxx, as such, almost doubled the risk of myocardial infarction. Indeed, the earlier reference to which I have referred in the previous paragraph remained in the Product Information. I do not consider that the amended Product Information provided any basis for saying that the purpose of acquiring Vioxx implicitly made known by the applicant to MSDA was subject to a qualification that a doubling of that risk was acceptable. 953 Thus, although I reject the applicant's point that the purpose which he implicitly made known to MSDA was the consumption of a drug which did not lead to a material increase in the risk of suffering life‑threatening conditions, I also reject the respondents' point that his purpose, as so communicated, was qualified to an extent that made acceptable anything like a twofold increase in the risk of suffering a myocardial infarction. 954 The respondents' next point under s 74B called up the defence arising under para (b) of subs (2). They submitted that the applicant did not rely on MSDA's skill or judgment. Rather, he was said to have relied wholly on the skill or judgment of his treating practitioner, Dr Dickman. I note in this context that MSDA did not advance a defence under the second limb of subs (2)(b) (ie that it was unreasonable of the applicant to have relied on its skill or judgment). 955 Undoubtedly the applicant relied on the skill or judgment of Dr Dickman. But that is not the end of the matter. Neither is it the question posited by para (b) of subs (2). A consumer will often rely on the skill or judgment of a specialised retailer in deciding, for example, which brand or model of particular goods to purchase, but that circumstance is not inconsistent with the consumer at the same time implicitly relying on the skill or judgment of the manufacturer. 956 The requirement of s 74B(2)(b) is not that the consumer did not rely on the skill or judgment of the manufacturer, but that the circumstances show that he or she did not so rely. This proposes a highly objective approach to the matter of reliance. It is almost as though the legislature contemplated that a consumer might, ex‑post, give very self‑serving evidence about the matter. However, the paragraph operates by way of a defence. The applicant does not have to establish that he relied on MSDA's skill or judgment: see Vines v Djordjevitch (1955) 91 CLR 512, 519‑520; Chugg v Pacific Dunlop Ltd (1990) 170 CLR 249. At the core of the defence is the consumer's own state of mind at the relevant time. It would, in my view, be an unusual case in which a court would uphold the defence by reference to a matrix of circumstances which had not been put to the consumer in cross‑examination, or where it had not been put to the consumer that he or she did not in fact rely on the manufacturer's skill or judgment. 957 In the present case, the applicant was not, in cross‑examination, confronted with the circumstances said to justify the conclusion that he did not rely on MSDA's skill or judgment. Neither was it put to him that he did not so rely. Indeed, it is hard to see how the defence now sought to be advanced by MSDA is consistent with the flow of the following cross‑examination of the applicant: It's right to say, isn't it, that as you understood it in May 2001 that Vioxx was a prescription medication that would, just like your anti‑inflammatories, relieve the pain from which you were suffering?---Correct. But it would have an added benefit of addressing your gastrointestinal difficulties?---Correct. You understood that it didn't have at that time - at that time your understanding was that such side effects as they had, whatever they were, would be no different to the anti‑inflammatoriesthat you had been taking?---Nodifferentotherthannogastric--- Correct but the disadvantageous side effects were no different than the anti‑inflammatory medications you had been taking and would have a particular benefit?---Yes. As I have said, the applicant left no doubt but that he relied on the skill or judgment of Dr Dickman. If it were the respondents' case that the applicant did not, therefore, also rely on the skill or judgment of MSDA, I consider that such a proposition ought to have been put to the applicant directly; or at least the "circumstances" that would later be relied on to show that he did not so rely should have been put to him. Neither was done. 958 For the above reasons, I reject MSDA's reliance on s 74B(2)(b) of the Trade Practices Act. 959 For the sake of completeness, I observe that the respondents approached the question arising under s 74B(2)(b) as though the "consumer" there referred to was the applicant. No submission was advanced in the alternative against the prospect that I might find that the Vioxx tablets which the applicant consumed in the period immediately preceding his heart attack in December 2003 were obtained on a prescription written for his wife and that she, therefore, was, or may have been, the relevant "consumer". If so, to the extent that the applicant suffered loss or damage as a result of consuming the tablets, he would be the "other person" referred to in subs (1). The respondents did not deal with the question whether Mrs Peterson relied on the skill or judgment of MSDA. 960 Finally under s 74B, the respondents took issue with the applicant's submission that Vioxx was not reasonably fit for the purpose which he implicitly communicated to MSDA. Specifically, they proposed that, since prescription medicines notoriously had the potential to involve side-effects, Vioxx should not be regarded as unfit for purpose merely by reason of such a circumstance. 961 The applicant's case is that Vioxx was not fit for purpose because it gave rise to an increase in the risk of encountering potentially life‑threatening conditions. Objectively, I have found that Vioxx did give rise to about a doubling of the risk of suffering myocardial infarction, across a population. At the simplest level, there could be little dispute about the proposition that a drug for the relief of arthritic pain is not fit for that purpose if the consumption of it will cause the patient concerned to have a heart attack. That is not the present case, of course, but it serves as a base line for a consideration of the position of a drug which gives rise to a risk, or which increases a pre‑existing risk, of heart attack. 962 Section 74B is concerned with the objective fitness of goods for purpose, whether or not the circumstance presumptively preventing them from qualifying for that description was known at the time of supply. In Medtel Pty Ltd v Courtney (2003) 130 FCR 182, 206, [70], Branson J said (with assent of Jacobson J): Section 74D, … calls for the quality, or fitness for purpose, of the goods to be measured against what it was reasonable to expect in that regard at the time of the supply of the goods to the consumer. That measurement must be undertaken, in my view, in the light of information concerning the goods available at the time of trial. However, the issue remains whether the goods were as fit for the relevant purpose as it was reasonable to expect at the time of their supply to the consumer. Mutatis mutandis, the same approach is, in my view, required under s 74B. In the context of the present case, this means that the fitness of Vioxx for purpose must be assessed against the fact that it gave rise to an increase in the risk of myocardial infarction by a factor of about 2: see para 570 above. 963 I did not understand the respondents to contend that goods could not be regarded as unfit for purpose where all that was known was that they involved the risk of an adverse outcome (or an increase in a pre‑existing risk of such an outcome). Any such contention, in my view, could not stand alongside the judgment of the Full Court in Medtel, where a pacemaker which had not failed, and which was regarded by the primary judge as unlikely to fail, was held to be unfit for purpose because it had been made by a production process which was associated with an increased risk of failure. The respondents make the point, which I accept so far as it goes, that Medtel concerned a faulty product (or at least a potentially faulty product), whereas Vioxx tablets in the present case contained no manufacturing or like fault. This is, however, a distinction without a difference with respect to the point now under consideration. What Medtel demonstrates, in my view, is that the fact that goods give rise to a risk of an outcome of a seriously adverse nature is sufficient, other circumstances permitting, to justify the conclusion that the goods are not fit for purpose. 964 It seems clear that Vioxx was efficacious in the relief of arthritic pain, and would remain so notwithstanding that there might be substance in the applicant's allegation of increased risk. If the notion of purpose is viewed through a narrow prism, there is a sense in which it might be said that Vioxx was fitted for purpose because it provided that relief, whatever might have been the risks associated with its consumption. That is not, however, in my view, an appropriate way to view the concepts arising under s 74B(1)(d). In each case, the basic inquiry is whether the reasonable person would regard the fitness for purpose of Vioxx as compromised by its tendency to produce the unwanted secondary adverse effect. Or, put another way, would the reasonable person reject Vioxx as a suitable drug for the relief of pain if he or she were informed that consumption of it had been found, across a population of persons not shown to be obviously atypical, to double the risk of heart attack? Subject to the other matters with which I deal in these reasons, an inquiry such as this could yield only one answer: an affirmative one. 965 As I have indicated, the respondents submitted that a medicine is not unfit for purpose merely because it carries the risk of side-effects. It was said to be notorious (and the applicant himself accepted) that prescription drugs often carry such risks, yet they are regularly used to beneficial effect without any suggestion they are unfit for purpose or the like. According to the respondents, if Vioxx did carry a cardiovascular risk, that was in the nature of a side‑effect, and it did not mean that the drug was not reasonably fit for the purpose for which it was both prescribed and acquired. The respondents relied particularly on the judgment of Kiefel J in Carey-Hazell. Here I refer to the passages from her Honour's reasons set out in para 949 above. I do not think that her Honour's words stand as any authority for the sweeping proposition that the presence of adverse side-effects associated with an otherwise efficacious drug could never be such as to render the drug less than fit for the purpose within the meaning of s 74B(1)(d). It was an essential aspect of her Honour's reasoning that the risk which came home to the patient in question was the subject of broad knowledge within the medical profession. In the present case, the increase in risk which is alleged to have been associated with the consumption of Vioxx was not generally known. 966 That does not, however, dispose of the respondents' point that Vioxx should not be regarded as unfit for purpose merely because it had, or potentially had, a side‑effect. In my view, the point is not susceptible of a categorical resolution across all possible cases by reference to the characterisation of the unwanted tendency associated with Vioxx as a "side‑effect". The question will always be whether that tendency made Vioxx less than reasonably fit for purpose. As stated earlier, the applicant alleged that Vioxx was not reasonably fit for purpose because consumption of it led to an increase in the risk of suffering life-threatening conditions. I consider that it would be no answer to a case presumptively established under s 74B to say that the risk, or the increase in risk, was proper to be regarded as a side-effect. I think it quite improbable that any reasonable person, at the time of supply, would regard as satisfactory a response from the hypothetical pharmacist to the effect, "Don't worry, it's only a side‑effect such as most medicines have". 967 Related to the reasonableness of an expectation that prescription drugs often carry side-effects is, of course, the extent of information or warnings about the side-effect in question which are brought to the attention of the consumer or of his or her doctor. While I accept that the reasonable person in the street would be unsurprised to learn that a particular medicine − any medicine − has, or has the potential for, side-effects, I likewise consider that he or she would assume that such information or warnings would be so provided. The respondents did not tie this part of their submissions, however, to the provision by MSDA of any such information or warnings. They did make a submission about the present relevance of the Vioxx Product Information, and I have dealt with that aspect above. 968 For the above reasons, I am satisfied that, because it approximately doubled the risk of heart attack, Vioxx was not reasonably fit for the purpose implicitly made known to MSDA by the applicant. I express this conclusion without regard to the base-line risk of heart attack which the applicant had at the relevant times. Whatever that risk, in my view a doubling of it would disqualify Vioxx from reasonably meeting the applicant's implicit purpose. It follows that I shall uphold the applicant's case under s 74B of the Trade Practices Act, and turn presently to a consideration of compensation as is his entitlement under subs (1) of that provision.

Section 74D 969 Section 74D of the Trade Practices Act provides as follows: (1) Where: (a) a corporation, in trade or commerce, supplies goods manufactured by the corporation to another person who acquires the goods for re‑supply; (b) a person (whether or not the person who acquired the goods from the corporation) supplies the goods (otherwise than by way of sale by auction) to a consumer; (c) the goods are not of merchantable quality; and (d) the consumer or a person who acquires the goods from, or derives title to the goods through or under, the consumer suffers loss or damage by reason that the goods are not of merchantable quality; the corporation is liable to compensate the consumer or that other person for the loss or damage and the consumer or that other person may recover the amount of the compensation by action against the corporation in a court of competent jurisdiction. (2) Subsection (1) does not apply: (a) if the goods are not of merchantable quality by reason of: (i) an act or default of any person (not being the corporation or a servant or agent of the corporation); or (ii) a cause independent of human control; occurring after the goods have left the control of the corporation; (b) as regards defects specifically drawn to the consumer's attention before the making of the contract for the supply of the goods to the consumer; or (c) if the consumer examines the goods before that contract is made, as regards defects that the examination ought to reveal. (3) Goods of any kind are of merchantable quality within the meaning of this section if they are as fit for the purpose or purposes for which goods of that kind are commonly bought as it is reasonable to expect having regard to: (a) any description applied to the goods by the corporation; (b) the price received by the corporation for the goods (if relevant); and (c) all the other relevant circumstances. 970 The applicant submitted that the meaning of the term "merchantable quality" was given by subs (3) of s 74D and that, in determining what it was objectively reasonable for the consumer to expect, the court had to take into account all relevant information available at the time of the trial: the court was not limited to a consideration of the information available at the time of supply to the consumer. Nor, according to the applicant, was it relevant whether the manufacturer had any means of knowing, at the time of supply, that the relevant goods were not of merchantable quality. The applicant's submissions continued: · MSDA supplied Vioxx tablets to pharmacies; · pharmacies supplied Vioxx tablets to the applicant and other group members; · it was objectively reasonable to expect that Vioxx would be fit for the purpose of consumption as a drug for the treatment of arthritis which did not materially increase the risk of potentially life‑threatening conditions - after all, the purpose for which Vioxx was developed was to provide an arthritis medication without the potentially serious gastrointestinal side effects of traditional NSAIDs and MSDA's marketing campaign promoted Vioxx as having a gastrointestinal and overall safety profile which was superior to traditional NSAIDS; · the Vioxx tablets were not of merchantable quality in that the consumption of Vioxx materially increased the risk of suffering life‑threatening cardiovascular conditions. 971 Because of the terms of s 74D(3), many of the questions arising under the section correspond with the like questions arising under s 74B with which I have dealt above. The differentiating circumstance as between the two sections lies in paras (c) and (d) of s 74B(1) and para (c) of s 74D(1). Under the former, the goods must have been acquired for a purpose that was made known to the manufacturer. If the goods are not reasonably fit for that purpose, the manufacturer is liable. Under the latter, the purpose for which the goods were acquired is irrelevant: if they are not as fit for the purpose or purposes for which goods of the kind in question are commonly bought as it is reasonable to expect, having regard to the matters set out in s 74D(3), the manufacturer is liable. However, the inherent concept of fitness for purpose is the same in each section. Further, I consider that the objective test of reasonable fitness under s 74B(1)(d) is relevantly indistinguishable from the like test of what degree of fitness is reasonable to expect under s 74D(3). In the present case, no party submitted otherwise. 972 As they said about s 74B, the respondents likewise submitted that the claims of parties in a representative proceeding under s 74D could not be resolved without an individualised consideration of the position of each group member. At least in a case in which none of the defences referred to in subs (2) is raised, at first blush it looks as though the position arising under s 74D would differ from that arising under s 74B, because the condition of merchantable quality of the goods in question is not related to the purpose of the consumer in question. However, in Ryan, Wilcox J thought otherwise. His Honour said ([1999] FCA 177 at [375]): The s 74D claim should be determined in the same way as that arising under s 74B: the applicant is entitled to succeed on his own behalf against Barclay Oysters, although not Barclay Distributors. His representative claim against Barclay Oysters should be reserved. Although his Honour did not state the reasoning behind the second sentence in this extract, I accept that it is theoretically possible that facts which might be brought forward under paras (a) and (c) of s 74D(3) for, or against, other group members would not be the same as those to which the court has been exposed on the case concerning the applicant himself. Thus, like Wilcox J, I shall stand over the s 74D claims of the other group members. 973 The respondents made the same point about there being no "supply" of goods within the meaning of s 74D(1)(b) in the circumstances of prescription medicines as they had under s 74B(1)(b). I would decide the point the same way as I did in paras 936‑937 above. 974 Turning to the "acquisition" point in its application to s 74D, the respondents submitted that s 74D(1)(d), like s 74B(1)(c), required that "the goods [be] acquired by the consumer". (The respondents actually made this submission about an entirely irrelevant provision of the Trade Practices Act, s 75B(1)(d), but I take that to be a typographical error, and shall read it as a reference to s 74D(1)(d)). However, s 74D(1)(d) imposes no such requirement. To the extent that it deals with an acquisition of goods, the paragraph is concerned with a person - not the consumer - who acquires the goods from the consumer. In addition to the reasons given above for rejecting the "acquisition" point in relation to s 74B(1)(c), I would also hold that the point, in relation to s 74D(1)(d), is misconceived. For the sake of completeness, I would add that no submission was made by the respondents that, should I find that the applicant consumed tablets obtained under his wife's prescription in November and early December 2003, he did not "acquire" those tablets from her within the meaning of s 74D(1)(d). 975 I turn next to the central question arising under s 74D, namely whether the Vioxx tablets taken by the applicant were as fit for the purpose (or purposes) for which goods of that kind were commonly bought as it was reasonable to expect. For reasons given above in the context of s 74B, I consider that the Vioxx tablets taken by the applicant were not as fit for the purpose for which goods of that kind were commonly bought as it was reasonable to expect because they increased the risk of heart attack by a factor of about 2. It was, in my view, reasonable to expect that a medication for the relief of arthritic pain would not carry that risk. As with s 74B, I do not think it is any answer to this point to say that the risk was in the nature of a "side-effect". 976 I next mention three aspects of the present question upon which I was not addressed by the parties, but which I have not overlooked. The first relates to the presently material connotation of the expression "goods of that kind" in subs (3). It does seem as though the provision requires one to identify a class to which the goods in question belong, and to consider the purpose for which goods of that class are commonly bought. There may be a question, for example, whether the "kind" of goods that is relevant in the present case is prescription medicines, or prescription medicines for the relief of pain, or prescription medicines for the relief of arthritic pain. There may also be a question whether the "kind" of goods which should be regarded as relevant in the case of Vioxx was NSAIDs generally or coxibs in particular. If the latter, would Vioxx have been less fitted for purpose than was reasonable to expect if, in a particular case, consumption of it gave rise to gastrointestinal complications? These questions, interesting though they are, do not arise in the present case as, whether the connotation of "kind of goods" be narrow or broad, the complaint made by the applicant is that Vioxx was less fitted for purpose than it was reasonable to expect by reason of a circumstance that would likewise disqualify any medicine for the symptomatic relief of arthritic pain. It is sufficient, in other words, to say that Vioxx was a member of a class of medicines which were commonly bought for that purpose. 977 The second point is whether any description "applied to the goods" by MSDA bears upon the resolution of the question whether Vioxx was as fit for purpose as it was reasonable to expect. As I have observed elsewhere, no party tendered the packet in which Vioxx was sold. Nor was a copy of the Consumer Medicine Information put in evidence, although different drafts of the text for that document for which the approval of the TGA was sought were. There is nothing in those drafts, or in the evidence otherwise, that would tend to indicate a conclusion under s 74D(3) different from that which would otherwise be drawn. To the extent that it might be considered that the Product Information was "applied to the goods" within the meaning of para (a) of that subsection, I refer to my reasons in paras 951‑952 above. In the result, if the court would otherwise reach the conclusion that Vioxx was not as fit for the purpose for which drugs for the symptomatic relief of arthritic pain were commonly bought as was reasonable to expect, I do not consider that such a conclusion is to be qualified by reference to any description applied to the goods. 978 The third matter which I mention for completeness merely involves noting that the respondents did not ask me to find that Vioxx tablets were as fit for the purpose for which goods of their kind were commonly bought because NSAIDs generally carried a risk of myocardial infarction; nor because all coxibs carried such a risk to the same or a similar extent as did Vioxx; nor because the risk was not reasonably discernable by MSDA by reference to the state of scientific understanding at the relevant times. 979 The respondents made five further (very brief) submissions about the applicability of s 74D to the circumstances of the applicant. First, they submitted that, under s 74D(3), goods do not have to be absolutely fit for their general purpose: it is sufficient if they are, objectively, as fit for that purpose as it is reasonable to expect. I accept that submission. So, as I understand it, would the applicant. In my disposition of the applicant's case under s 74D, I have approached the matter as here proposed by the respondents. 980 Secondly, the respondents submitted that, as a matter of law, prescription medicines made available in accordance with the terms of an approval from the TGA are of merchantable quality for the purposes of s 74D. This point was not developed, elaborated upon, or explained either in writing or orally. The court, in my view, is under no obligation to attempt to divine what might be the content of, or the jurisprudential justification for, a point so inadequately presented as this one. I reject it. 981 Thirdly, the respondents submitted that the feature of Vioxx alleged to render it unmerchantable was not an error in formulation or manufacture, but was inherent in the proper formulation of the drug for its intended purposes. I have effectively dealt with this point in my consideration of the judgment of Branson J in Medtel, in para 963 above. To elaborate upon what I said there, I do not accept that the only basis upon which goods may be less than as fit for purpose as it is reasonable to expect is because of a manufacturing or like fault, or some departure from specification. Prescription drugs, where the object is to modify the body's biochemistry, provide a conspicuous example of goods which may be faultless so far as specification and production quality are concerned, but which may be unfit for purpose because of some unintended, but inherent, effect which they have. In my view, there is nothing in this point which would stand in the way of the applicant succeeding under s 74D. 982 Fourthly, the respondents submitted that the fact that a product had been included in a hazard alert or product recall notice was not alone sufficient to render the product unmerchantable. I accept this point. Nothing in these reasons relies upon the withdrawal of Vioxx from the market in September 2004 as a basis for upholding the applicant's case under s 74D. 983 Fifthly, there was one further point which the respondents sought to raise in opposition to the applicant's case under s 74D. It involved reliance on paras (b) and (c) of subs (2). If good, the point arises by way of a defence, and was not pleaded. I do not consider that it is open to the respondents to rely on those paragraphs. As it happens, neither in the brief submissions relevantly made by the respondents nor in any of the evidence is there support for either of the circumstances postulated by paras (b) and (c). I would find as a fact that the tendency of Vioxx to give rise to an increased risk of heart attack was not specifically drawn to the applicant's attention before he purchased (or his wife purchased) any of the Vioxx tablets the consumption of which gave rise to that increase in risk; and that no examination of the tablets by the applicant would have, or could have, revealed that tendency. 984 Save to the extent expressly mentioned above, I would decide the case under s 74D consistently with my decision under s 74B. I uphold the applicant's case, and shall consider his entitlement to compensation under s 74D(1).

Compensation 985 Under s 74B(1)(e) and s 74D(1)(d) of the Trade Practices Act, the applicant's entitlement to compensation depends upon the following circumstances: (1) that he was the consumer referred to in the subsection or a person who acquired the goods from the consumer; and (2) that he suffered loss or damage by reason that the goods were not reasonably fit for purpose, or were not of merchantable quality. The "goods" referred to in each of these circumstances are the same goods. That is to say, the loss or damage must have the necessary connection with the goods which were supplied to the applicant as consumer or which he acquired from the consumer. 986 These points, which may appear obvious, are important in the context of the present case because I have held that the Vioxx tablets taken by the applicant did contribute to his heart attack, but that the tablets he took between 3 November and 2 December 2003 were most probably obtained under his wife's prescription. That means, of course, that, in relation to those tablets, Mrs Peterson was the consumer under ss 74B and 74D, and the applicant was the person who acquired the goods from her. That would still give the applicant a cause of action, and probably nothing turns on the distinction. I mention the point here for the sake of completeness, and note that the respondents made nothing of it in their submissions. Although they submitted that I should find that the applicant took no Vioxx at all between 8 October and 2 December 2003, they made no submission in the alternative to the effect that, if I should find that he took his wife's tablets after 3 November, those tablets were not properly to be regarded as the "goods" apropos the applicant's own claim under ss 74B and 74D. 987 Neither did the respondents submit that, if I should find that the Vioxx tablets which the applicant took were not reasonably fit for purpose and/or not of merchantable quality, and that those tablets did contribute to the applicant's heart attack, the loss or damage presumptively associated with and arising from the heart attack should not be regarded as having occurred by reason of that unfitness for purpose or lack of merchantable quality. They conducted their case on the footing that, if these elements were established by the applicant, the debate could then move to questions of the quantification of the compensation to which the applicant was entitled under ss 74B and 74D. The applicant is, of course, to be compensated once only, notwithstanding that I have held that there is an entitlement arising under each section. That entitlement is the same in each case, and is the matter to which I now turn. 988 In assessing damages for pain, suffering, inconvenience and loss of amenity of life, the following are, in my view, the significant factors. First, the applicant's heart attack was directly associated with quite severe pain. This occurred over a period of about two hours in the early hours of 8 December 2003. I also infer that this was a frightening experience for him. Secondly, the applicant's condition required him to be hospitalised, to undergo surgery, to endure a period of recovery and to participate in rehabilitation. Thirdly, the permanent damage to the applicant's heart muscle was substantial, and has limited him in the range of occupational and recreational activities which he can undertake. He more readily tires from levels of physical activity that would previously have been of little concern to him. His "whole of person impairment" is of the order of 25-30%. Fourthly, he is obliged to adhere to a regime of medication and to implement what Prof Harper described as "lifestyle modification" to ward off the prospect of further heart disease. And fifthly, the damage to his heart has left him in a less robust condition to resist the impact of a future heart attack, should he have one. 989 As against these factors, the surgery which the applicant underwent was, it seems, as routine as could be expected given the serious condition from which he suffered, the outcome was successful and his recovery was uncomplicated. The relief of his stenosis was complete. There is no evidence that the heart attack (as distinct, possibly, from factors such as anxiety) has left the applicant with any periods of pain or discomfort. Subject to the lifestyle modification to which I have referred, and to compliance with the regime of medicines which has been laid out for him, the applicant seems able to lead a normal and comfortable life. To the extent that his ability to work is compromised, I shall consider his past and future loss of earnings capacity below. At what might be regarded as the emotional level, however, the applicant did not complain that an inability to work harder and longer was a source of distress or frustration for him. I note that he continues to operate (with no assistance other than that of his wife) his "Lockout" business, and did not suggest that his capacity to do so had been impaired by his heart attack. 990 The applicant now seems to be at less risk of a further heart attack than he was at risk of the heart attack which he had. Looking at the applicant's risk factors as at 2001, Prof Harper expressed the view that there was about a 25% risk that the applicant would have a heart attack over the ensuing five years. By December 2003, because of the improvements which the applicant had achieved in his lipid profile (but not taking into account the effect of the consumption of Vioxx), the risk had reduced slightly, to be somewhere in the region 20­25%. At present (ie, I assume, as at his consultation with the applicant in October 2008) Prof Harper would estimate the risk of heart attack over the next five years as in the region of 5-10%. No doubt because of this evidence, it was not submitted on behalf of the applicant that the events of 8 December 2003 had made it likely that he would have a further heart attack sooner than would otherwise have been the case. 991 On the other hand, counsel for the applicant did submit that, if the applicant were to have a further heart attack, the one which he had in December 2003 would increase the likelihood of the next one being fatal. That submission is based on the unchallenged evidence of Prof Harper, and I accept it. It does not follow, however, that, overall, the applicant's expectation of life is less now than it would have been in the absence of the heart attack which he had. For the reasons given in the previous paragraph, and doubtless because of the changes which that heart attack has obliged the applicant to make, I could not find on the probabilities that his expectation of life is less than it presently would have been had he never taken Vioxx. 992 It was submitted on behalf of the applicant that an appropriate award for the kind of general damages which I am now discussing would be in the range $175,000−$250,000. In my view, an award of such an order would go beyond anything that could be regarded as reasonable compensation for the general non-economic loss and damage which the applicant has endured and will endure. The respondents submitted that the figure should be in the range $50,000−$75,000, including interest. This range is, in my view, somewhat more realistic than that proposed on behalf of the applicant, but I should make it clear that I do not propose to enter upon the question of interest in these reasons. I shall receive submissions from the parties in that regard in due course. 993 The applicant sought to rely on s 28HA of the Wrongs Act 1958 (Vic), which provides: (1) In determining damages for non-economic loss, a court may refer to earlier decisions of that or other courts for the purpose of establishing the appropriate award in the proceedings. (2) For that purpose, the parties to the proceedings or their counsel may bring the court's attention to awards for damages for non-economic loss in those earlier proceedings. (3) This section does not alter the rules for the determination of other damages. Despite what I presume is a wealth of precedent in Australia (whether or not relating to cardiovascular disease as such), however, the only "decision" to which the applicant referred me in this regard was Bowling v Pfizer, Inc 143 FRD 141 (1992), a judgment by the United States District court, SD Ohio, Western Division, approving a scheme for the settlement of a class action involving faulty artificial heart valves. The court itself made no decision as to the appropriate level of damages for the injury suffered by any member of the class. The actual entitlement of individual members was, apparently, to be left to an "expert panel", and the applicant here sought to refer to details of the panel's determination. But there was no evidence of it. I also note that the damages claimed by the plaintiffs included what the court described as "punitive damages". Whatever role s 28HA might have played in the present proceeding, the applicant's reference to Bowling was of no assistance to me. 994 In my view, an appropriate sum by way of compensation for the pain, suffering, inconvenience and loss of amenity of life endured, and to be endured, by the applicant is $85,000. 995 Turning to economic loss, in order to provide an estimate of the loss which the applicant suffered between the date of his heart attack and the trial of the proceeding, he called Mark Thompson, a chartered accountant and a director of Vincent's Chartered Accountants of Brisbane. Mr Thompson estimated that the applicant's loss to 30 June 2008 was $134,765. He made that estimate by reference to the following table: Jan to June 2005 2006 2007 2008 2004 Notional Gross Consulting Fee Income 50,000 125,000 150,000 175,000 195,000 Less: Actual Gross Consulting Fee Income 28,793 48,350 88,005 100,892 156,061

Loss of Gross Consulting Fee Income 21,207 76,650 61,995 74,108 38,939

Less:Allowance for Direct expenses (3,711) (13,414) (10,849) (12,969) (6,814) Saved (at 17.5%)

NET LOSS (before tax) 17,496 63,236 51,146 61,139 32,125 Less: Income Tax applicable (8,485) (25,674) (15,906) (25,373) (14,938)

NET LOSS (after tax) 9,010 37,562 35,240 35,766 17,187

TOTAL LOSS TO 30 JUNE 2008 134,765

996 The respondents took issue with the first line of Mr Thompson's table, that relating to "Notional Gross Consulting Fee Income". That was the level of income which Mr Thompson estimated would have been derived by Mr Peterson from his consulting activities if he had not had a heart attack. Mr Thompson derived these figures as follows. He accepted an estimate given to him by Mr Peterson of the extent to which his consulting activities were curtailed by his having had a heart attack. That estimate was 20%. Mr Thompson then took the applicant's actual gross consulting fee income for the year ended 30 June 2008 ($156, 061), and treated that as 80% of the income which he would have earned in the absence of his heart attack. That income, therefore, was $195,000. Mr Thompson then assumed that the full-year equivalent for the applicant's consulting fee income in the year ended 30 June 2004 would have been $100,000. He then, in effect, drew a straight line between that figure and $195,000 to derive the figures set out in the first line of his table above. 997 Under cross-examination, Mr Thompson accepted that he had no documents which would support his assumption that $100,000 was the appropriate starting point for the year ended 30 June 2004. Further, it seems that there was no particular basis for his assumption that the applicant's consulting fee income would increase at a constant rate between that year and the year ended 30 June 2008. As it happened, by correspondence dated 18 February 2008, Mr Thompson addressed a series of questions to Mr Gibb, one of which was: How has your business activity increased over the period after you ceased with BHP? This response if possible will provide either dollar value turnover's [sic] for 2004, 2005, 2006, 2007 and year to date or alternatively % changes over those years. On 19 February 2008, Mr Gibb replied that his company's growth had been 36%, 8% and 40% in the financial years to 30 June 2005, 2006 and 2007 respectively. In his oral evidence, Mr Gibb said that the growth had been between 25% and 30% in the year to 30 June 2008 (his best estimate was 27.5%). 998 The respondents submitted that Mr Thompson could have done better than to make what they said was an artificial assumption as to the growth of the consulting fee income which the applicant notionally would have derived between 2004 and 2008. They submitted that the growth figures provided for SWS by Mr Gibb represented the actual experience of a consulting business in the real world, and would have been a more realistic basis for the task of estimation on which Mr Thompson was engaged. What the respondents proposed was that one should commence with the known figure of $195,000 in the year to 30 June 2008, and work back to the year ended 30 June 2004 by the application of Mr Gibb's percentages. If this were done, instead of the sums appearing in the first line of Mr Thompson's table as set out above, the income figures would be $37,286, $101,419, $109,533, and $153,346 for the years 2004, 2005, 2006 and 2007 respectively. The total figure to 30 June 2008 would become $84,354. 999 Neither in his counsel's re-examination of Mr Thompson, nor in his submissions in reply, did the applicant join issue with the respondents with respect to their recalculation of the first line of Mr Thompson's table. Indeed, in their final submissions, counsel for the applicant referred to Mr Thompson's original calculations as though there had been no challenge to the basis upon which they were made. I am persuaded that the recalculation proposed by the respondents provides a better estimate of the way in which the applicant's consulting fee income would have grown in the absence of his heart attack than that originally provided by Mr Thompson. I accept that the percentage figures provided by Mr Gibb represent a steeper growth profile for this kind of work, and require a conclusion that the applicant's notional annualised consulting fee income for the year ended 30 June 2004 was of the order $75,000, not $100,000. In the circumstances, I accept the respondents' figure of $84,354 as an estimate of the consulting fee income lost by the applicant down to 30 June 2008. 1000 The respondents made a series of further points by reference to which they proposed that Mr Thompson's figure for past economic loss (and even the figure of $84,354, as I understand it) should be qualified. The first related to Mr Thompson's analysis (from the invoices provided by the applicant) of the days of consulting, and the total days of work, undertaken by the applicant in the period to 30 June 2008. In this respect, Mr Thompson provided the following table: Year ended /period No. of days consulting No. of days travelling Total Days November 2003 to June 2004 30.5 0.5 31.0 30 June 2005 60.75 1.0 61.75 30 June 2006 55.13 9.00 64.13 30 June 2007 62.0 6.0 68.00 30 June 2008 75.0 18.0 93.00

Under cross examination, Mr Thompson accepted that the figures in the column headed "No. of days travelling" related only to the travelling days for which the applicant had rendered an invoice. An examination of the destinations at which the applicant had provided consulting services, however, showed that there were, at least in some cases, days occupied travelling for which the applicant had not charged. These had not been taken into account by Mr Thompson, and, if they were, the figures in the column headed "Total Days" would be higher than those presently appearing. Mr Thompson accepted this criticism of his methodology, but, in their final submissions, the respondents did not make it clear how, if at all, Mr Thompson's estimate of past economic loss should be adjusted as a result of this circumstance. They submitted that what they described as "unaccounted travel" was "relevant to the levels of consultancy work which the applicant claims he would have been able to undertake" in the absence of his heart attack. However, notwithstanding having cross-examined Mr Thompson by reference to records from which (they submitted) quite reliable inferences could be made as to the additional days of travelling undertaken by the applicant, in their final submissions the respondents provided no overall analysis as to the extent of this problem over the period with which Mr Thompson's calculations were concerned. All the court knows is that there was, in effect, a day here and a day there in which the applicant had been travelling, but for which he had not rendered an invoice. The respondents contented themselves with submitting that "an appropriate adjustment needs to be made to effect this understatement of the number of days for which Mr Peterson actually was engaged as a consultant". That was, in my view, an unsatisfactory place to leave the matter, at least if the respondents expected the court to reject some aspect of Mr Thompson's calculations on account of it. I do not propose to do so. 1001 The respondents' next point was that the steadily increasing success of the applicant's "Lockout" business would necessarily have required his personal attention, and thereby have reduced the number of days for which he would have been available to consult. It was the applicant's case that the "Lockout" business, even as it became more successful, could be managed (with his wife's assistance) without compromising his availability to consult. It was implicit in that case that, in the absence of his heart attack, the applicant would have undertaken consulting work 20% more than he did, while still deriving the same level of income from his other business. This point requires a broad understanding of the applicant's "Lockout" business and of what direct attention it required from him. 1002 I described the "Lockout" system at para 694 above. The product actually sold by the applicant (or, more accurately, by GPA) is a kit consisting of locks and associated parts, appropriately coloured, coded and accompanied by instructions for a particular ship, or class of ships. Each kit, when complete and ready for despatch, measures about 1.1 x 0.5 x 0.5 m. The individual parts of the kit are made by manufacturers, but the applicant himself undertakes the final assembly, at times with the assistance of his wife. He does not employ any other person. Compendiously, the work involved in the "Lockout" business is the receipt of orders from customers, the ordering and receipt of component parts of the kits, the assembly of the kits, the despatch of the kits and the invoicing. The applicant accepted that, while he was occupied in these tasks, he could not be carrying out his consulting work. However, it seems that the time intervals involved in the "Lockout" business were such as to permit the applicant a degree of discretion with respect to when he would physically carry out the work involved in that business. He was asked about these matters, and he maintained the position that the operation of the business would not have compromised his ability to undertake consulting work about 25% more than he did (ie for about 100%, instead of about 80%, of the time) had he been in completely good health. There was nothing obviously implausible about the applicant's position in this regard, and he was cross-examined only (as indicated in this paragraph) by drawing his attention to some of the practical aspects of the "Lockout" business which would require his attention. Valid though the respondents' points were conceptually, I am unable to second-guess the applicant's own estimation of what he would have been able to do absent his heart attack, and I am not persuaded that it has been undermined. 1003 The respondents next took issue with the applicant's claim that his heart attack reduced his ability to take on consulting jobs which required extensive travel. They referred to invoices which showed that the applicant had travelled to quite distant places overseas, including Japan and Dubai, and that he undertook regular interstate travel, including travel to remote mine sites on occasion. They referred to the evidence of Mr Gibb that he unilaterally assessed the appropriateness of a particular job for the applicant, only then conferring with the applicant as to his readiness to undertake the job in question. The respondents submitted that the evidence demonstrates that the applicant is well able to undertake most of the assignments which Mr Gibb would be disposed to give him, and that, in the result, any diminution in the amount of work which he carries out − in comparison to a notional full time program − is unrelated to his heart attack. However, Mr Gibb made it clear that there was an element of discretion exercised by him (on account of the applicant's heart condition) in the assignment of work to the applicant. Mr Gibb would not assign the applicant to locations which lacked the appropriate medical facilities, nor for jobs which would have required the applicant to undertake arduous travel. 1004 There does not seem to be any real doubt but that the applicant's heart attack has limited the range of work assignments that he would otherwise be able to undertake. For that reason, the applicant has limited himself to about 8-10 days per month. He was not cross-examined about the appropriateness of this limitation. It was not directly suggested to him that, if the work were available, he could exceed this limitation. It was not put to him that the limitation was an unreasonably conservative response on his part to the fact that he had had a heart attack. In my view, although a reluctance to travel to inappropriate destinations may be part of the story, the effective limitation upon the applicant's work is the 8-10 day one to which I have referred. I do not, therefore, think that much turns on the question whether the applicant might be able to undertake more distant assignments than he presently concedes. 1005 The respondents' final point is that Mr Thompson had made no allowance for the global financial crisis. They went, however, no further than to make a submission in those terms. I am not prepared to qualify what would otherwise be my conclusion in relevant respects by reference to this consideration. 1006 For the above reasons, I accept so much of the respondents' case as proposed that the growth figures for SWS provided by Mr Gibb should stand as a proxy for the extent to which the applicant's consulting income would have grown between January 2004 and June 2008. I do not accept their attack on the applicant's estimate that his heart attack compromised his ability to earn that income by about 20%. It follows that the figure which I would accept as representing the applicant's economic loss over that period is $84,354. 1007 Mr Thompson also calculated a figure representing the future economic loss which he estimated would be suffered by the applicant. He did this using the present value (as of 28 February 2009) of the same weekly loss of income as he had estimated for the period 1 July 2008 − 28 February 2009. He assumed that the applicant would have worked until his 65th birthday and he reduced the figure by 15% for "contingencies". His estimate was $84,788. Subject to the matters with which I have already dealt, the respondents accepted that estimate. I shall do likewise. 1008 It was submitted on behalf of the applicant that the assumption that he would, in the absence of his heart attack, have worked only to the age of 65 was a conservative one. This submission was based on evidence by the applicant in his witness statement that he never had a retirement date in mind, that he wanted to work as long as possible, and that retirement was "a very unappealing idea" to him. Counsel submitted that the applicant "might reasonably be allowed another two years' loss of capacity to earn". There was, however, no basis in the evidence for an allowance of that particular order (ie rather than of some other order). Indeed, ultimately counsel did not invite me to depart from Mr Thompson's calculation as to future economic loss, contenting themselves with proposing that, if the court were to consider that there were factors raised by the respondents that might otherwise have an impact on the "economic loss outcome", those factors might be "balanced against such considerations as the conservative assumption of only 20% loss … and the conservative assumption of age 65 retirement instead of 67 or older". However, the only respect in which I have not accepted the applicant's case on economic loss is one which is unrelated to the future. It would, therefore, be inappropriate to qualify the conclusion which I reached above in that respect by reference to a view (which, as it happens, I do not entertain) about the likelihood of the applicant working beyond the age of 65. 1009 The applicant's heart attack will make it necessary for him to take medications into the future, and to undergo a range of regular medical tests and examinations. Prof Harper gave evidence of these requirements, and of the approximate anticipated cost of them. In final submissions made on his behalf, the applicant calculated that the present value of the costs associated with these requirements over the applicant's expected life, discounted by 15% for contingencies, was $33,770. The only respect in which the respondents challenged this figure was to resist the inclusion of three drugs required to be taken by the applicant which, as Prof Harper agreed in his oral evidence, ought to have been taken by him in any event: aspirin, Coversyl and Lipitor. In final submissions, the applicant did not deal with this submission of the respondents. I accept the submission. The figure of $33,770 should be re-calculated to exclude the cost of the three drugs referred to. 1010 The applicant seeks the inclusion in damages of the sum of $4,175.35 said to be payable by him pursuant to a Notice of Charge, dated 20 April 2009, under s 8 of the Health and Other Services (Compensation) Act 1995 (Cth). The respondents accepted that the applicant had produced the notice to them, but added: "[h]owever it is not in evidence". There appears to be substance in that unworthy submission. As things stand, I could not allow the applicant this modest amount, but I do not exclude the possibility that the applicant might seek leave to tender the notice when the proceeding is listed to settle the orders to be made. 1011 The applicant sought damages for "the costs associated with any future cardiovascular event causally related to this myocardial infarction in accordance with the risk of future occurrence of such an event", relying in this regard upon Malec v JC Hutton Pty Ltd (1990) 169 CLR 638. However, the evidence would not sustain the conclusion that the heart attack which the applicant had in December 2003 has made it more likely that he will have another one: see para 990 above. For that reason, I reject this lead of damages. 1012 The applicant sought damages in respect of a contingent need for attendant care should he suffer "heart failure" in the future, even in the absence of a heart attack. This claim was based on the following paragraphs in Prof Harper's report: Mr Peterson currently has about a 5% to 10% chance of a further heart attack over the next five years. A subsequent heart attack would be likely to cause further damage to his heart muscle and because of the damage his heart muscle has already sustained as a result of his heart attack in 2003, there is arisk that a further heart attack would cause heart failure sooner rather than later. Heart failure is a condition where the heart does not supply sufficient oxygenated blood to meet the needs of the body. This means that daily activities become extremely difficult to perform, as the smallest exertion can place an unacceptable burden on the heart. If Mr Peterson went into heart failure his future medical needs would be likely to involve more intensive drug therapy, more frequent visits to both his cardiologist and his general practitioner. He may require rehabilitation. He may require attendant care. The degree of attendant care would depend on the severity of the heart failure. The 5 year survival prognosis for patients with heart failure is 50%. With the passage of time, Mr Peterson may develop heart failure even in the absence of further heart attacks. Such a scenario would be unlikely to occur within the next 15 years. If Mr Peterson developed heart failure without further heart attack, his needs would be as described in paragraph 61 above. From this the applicant submitted that, although his risk of a further heart attack in the next five years was only 5% − 10%, if that did occur it would likely have consequences that required the engagement of attendant care. So much may be accepted, but it seems very problematic, and has not been satisfactorily established, that the events of December 2003 have on balance made it more likely that the applicant would at some time in the future require attendant care than would otherwise have been the case. 1013 Neither was the applicant's quantification of this head of damage satisfactory. There was no evidence about the cost of attendant care. The applicant proposed that I should "assess a sum of $100,000", and then discount that sum by 50% to take account of various uncertainties and contingencies to which he referred in his submissions. Those submissions were, however, almost entirely intuitive. There was neither evidence nor submission to explain why $100,000, rather than some other sum, should be assessed. Neither did the applicant explain why some evidence on this subject had not been called. For my own part, it does not seem at all obvious that some short evidence about the nature and cost of the kind of attendant care typically required by people who had suffered heart failure might not have been called. The respondents resisted the applicant's claim under this head upon the ground (amongst others) that there was no "detailed basis" for the figure claimed. For reasons set out above, I am bound to uphold their position. I reject this head of damages. 1014 I shall require the applicant to bring in minutes of orders appropriate to give effect to my determination his claim for compensation under ss 74B and 74D of the Trade Practices Act, conformably with my reasons set out above. I certify that the preceding One thousand and fourteen (1014) numbered paragraphs are a true copy of the Reasons for Judgment herein of the Honourable Justice Jessup.

IN THE FEDERAL COURT OF AUSTRALIA VICTORIA DISTRICT REGISTRY No: (P)VID451/2006 GRAEME ROBERT PETERSON Plaintiff MERCK SHARPE & DOHME (AUST) PTY LTD First Defendant MERCK & CO INC Second Defendant ORDER JUDGE: Justice Jessup DATE OF ORDER: 30 March 2009 WHERE MADE: Melbourne

THE COURT ORDERS THAT:

1. Pursuant to section 33ZF of the Federal Court of Australia Act 1976, that at the hearing to commence on 30 March 2009, in advance of all other issues in the proceeding, the following issues are to be determined: a. the issues of fact and law in the claim brought by Mr Peterson in his personal capacity; and b. those issues of fact and law set out in the Schedule attached to this Order that the Court finds to be common to the claims of the group members. Date that entry is stamped: 15 June 2009 Deputy District Registrar IN THE Federal Court OF AUSTRALIA No. VID 451 of 2009 Victoria District Registry

GRAEME ROBERT PETERSON Applicant -and- Merck Sharp & Dohme (Australia) Pty Ltd ACN 000 173 508 First Respondent MERCK & CO., INC. Second Respondent SCHEDULE Definitions In this Schedule: Health care professionals includes medical practitioners, pharmacists and other health care professionals. Vioxx cardiovascular conditions means each of myocardial infarction; thrombotic stroke; unstable angina; transient ischaemic attack; and peripheral vascular disease. Vioxx includes a reference to Vioxx tablets and rofecoxib. Commonality

1. Are any and which of the questions set out below common to the claims of the group members? Materially increased risk
2. Is there a physiological mechanism by which the consumption of Vioxx is capable of causing any and which of the Vioxx cardiovascular conditions?
3. If the answer to question 2 is in the affirmative, then for each such condition, what is the physiological mechanism?
4. Did the consumption of Vioxx increase the risk of suffering any and which of the Vioxx cardiovascular conditions?
5. If the answer to question 4 is in the affirmative, was the increase in risk material? Negligence
6. If the answer to question 5 is in the affirmative: (a) when, if ever, did the First Respondent ("Merck Australia") first know that the consumption of Vioxx materially increased the risk of suffering the condition? (b) when, if ever, ought Merck Australia have first known that that consumption of Vioxx materially increased the risk of suffering the condition? (c) did Merck Australia owe the group members a duty to take reasonable care to avoid acts and omissions that may expose them to a material increase in the risk of suffering the condition as a consequence of consuming Vioxx tablets?
7. Did Merck Australia: (a) not owe group members the duty of care alleged; or (b) satisfy the applicable standard of care by virtue of compliance with the relevant legislative requirements referred to in paragraph 61 (a)-(t) of the Defence to Further Amended Statement of Claim and requirements imposed upon it in respect of Vioxx tablets by the Therapeutic Goods Administration ("TGA") pursuant to the powers granted by the Therapeutic Goods Act 1989 (Cth)?
8. Did Merck Australia: (a) not owe group members the duty of care alleged; or (b) satisfy the applicable standard of care by reason of the learned intermediary defence pleaded in paragraph 63 of the Defence to Further Amended Statement of Claim?
9. If the answer to question 5 is in the affirmative: (a) did Merck Australia fail to make adequate inquiries of the Second Respondent ("Merck Inc") regarding the adverse side effects and health risks that may be associated with the consumption of Vioxx including a material increase in the risk of suffering the condition? If so, was that failure less than reasonable in all of the circumstances? (b) Did Merck Australia fail to undertake or cause to be undertaken any or any adequate research, investigations, clinical trials or observational studies in order to ascertain the adverse side effects and health risks that may be associated with the consumption of Vioxx including a material increase in the risk of suffering the condition? If so, was that failure less than reasonable in all of the circumstances? (c) Did Merck Australia fail to have adequate regard to the results of any research, investigations, clinical trials or observational studies undertaken or caused to be undertaken by Merck Australia, Merck Inc or others suggesting that the consumption of Vioxx materially increased the risk of suffering the condition? If so, was that failure less than reasonable in all of the circumstances? (d) Did Merck Australia fail to provide adequate information, advice or warning to the general public or to health care professionals to the effect that the consumption of Vioxx materially increased the risk of suffering the condition? If so, was that failure less than reasonable in all of the circumstances? (e) Did Merck Australia develop and implement a marketing strategy or campaign by which it formulated and disseminated to health care professionals in Australia any and which of the following representations about Vioxx: (i) Vioxx has an excellent gastrointestinal safety profile compared with other non-steroidal anti-inflammatory drugs ("NSAIDs"); (ii) Vioxx has an excellent overall safety profile compared with other NSAIDs; (iii) Vioxx does not increase the incidence of adverse cardiovascular events; (iv) higher rates of myocardial infarction and other cardiovascular events among persons taking Vioxx relative to persons taking other traditional NSAIDs (in particular naproxen) did not indicate that Vioxx increased the risk of suffering adverse cardiovascular events but were attributable to the fact that the consumption of naproxen produced a lower incidence of cardiovascular events because naproxen inhibits platelet aggregation in a manner similar to aspirin while Vioxx does not; (v) the higher rates of myocardial infarction among persons taking Vioxx relative to persons taking naproxen observed in the Vioxx Gastrointestinal Outcomes Research Trial ("Vigor") did not indicate that Vioxx increased the risk of suffering adverse cardiovascular events; (vi) any information to the effect that Vioxx was not as safe as other NSAIDs because the consumption of Vioxx materially increased the risk of suffering the condition was incorrect, misleading, exaggerated and/or unreliable. If so, was that conduct less than reasonable in all of the circumstances?
10. Was it less than reasonable in all of the circumstances, at any time before 30 September 2004, for Merck Australia to distribute Vioxx in Australia? If so, when?
11. Is the fact that the Product Information for Vioxx was approved by the TGApursuant to the Therapeutic Goods Act , if proved, a complete answer to an allegation that Merck Australia was in breach of any common law duty by unreasonably failing to adequately disclose information in the Product Information? Section 52 of the Trade Practices Act 1974 (Cth)
12. If the answer to question 5 is in the affirmative, did Merck Australia: (a) label Vioxx without providing adequate information, advice or warning to the general public or to health care professionals to the effect that the consumption of Vioxx materially increased the risk of suffering the condition? (b) market and distribute and/or supply Vioxx for sale in Australia without providing adequate information, advice or warning to the general public or to health care professionals to the effect that the consumption of Vioxx materially increased the risk of suffering the condition? (c) develop and implement a marketing strategy or campaign by which it formulated and disseminated to health care professionals in Australia, any and which of the following representations about Vioxx: (i) Vioxx has an excellent gastrointestinal safety profile compared with other NSAIDs; (ii) Vioxx has an excellent overall safety profile compared with other NSAIDs; (iii) Vioxx does not increase the incidence of adverse cardiovascular events; (iv) higher rates of myocardial infarction and other cardiovascular events among persons taking Vioxx relative to persons taking other traditional NSAIDs (in particular naproxen) did not indicate that Vioxx increased the risk of suffering adverse cardiovascular events but were attributable to the fact that the consumption of naproxen produced a lower incidence of cardiovascular events because naproxen inhibits platelet aggregation in a manner similar to aspirin while Vioxx does not; (v) the higher rates of myocardial infarction among persons taking Vioxx relative to persons taking naproxen observed in Vigor did not indicate that Vioxx increased the risk of suffering adverse cardiovascular events; (vi) information to the effect that Vioxx was not as safe as other NSAIDs because the consumption of Vioxx materially increased the risk of suffering the condition was incorrect, misleading, exaggerated and/or unreliable?
13. If Merck engaged in any of the conduct referred to in question 12 was any of that conduct in trade or commerce within the meaning of the Trade Practices Act ? If so, which conduct?
14. Was any of the conduct identified in question 12, in all of the circumstances and context in which it occurred, misleading or deceptive or likely to mislead or deceive in contravention of section 52 of the Trade Practices Act ?
15. Upon the proper construction of the Therapeutic Goods Act , does the fact that the Product Information for Vioxx was approved by the TGA pursuant to the Therapeutic Goods Act , if proved, exclude the operation of the Trade Practices Act in so far as an allegation is made that a failure to adequately disclose information in the Product Information contravenes: (a) section 52 of the Trade Practices Act? (b) section 75AD of the Trade Practices Act?
16. Is the fact that Vioxx was registered on the Australian Register of Therapeutic Goods pursuant to the Therapeutic Goods Act and available only by prescription of permitted prescribers, and that the Product Information for Vioxx was approved by the TGApursuant to the Therapeutic Goods Act, if proved, a complete answer to an allegation that the respondent contravened: (a) section 52 of the Trade Practices Act; (b) section 75AD of the Trade Practices Act; by failing to adequately disclose information in the Product Information? Sections 75AD, 74B and 74D of the Trade Practices Act 1974 (Cth)
17. Were Vioxx tablets manufactured by Merck Australia "goods" that were "ordinarily acquired" as defined in section 74A(2) of the Trade Practices Act?
18. Is the fact that Vioxx was registered on the Australian Register of Therapeutic Goods pursuant to the Therapeutic Goods Act andavailable in its approved form and packaging only by prescription of permitted prescribers, if proved, sufficient to establish as a matter of law that Vioxx was reasonably fit for purpose within the meaning of s74B of the Trade Practices Act ?
19. Is the fact that Vioxx was registered on the Australian Register of Therapeutic Goods pursuant to the Therapeutic Goods Act and available in its approved form and packaging only by prescription of permitted prescribers, if proved, sufficient to establish as a matter of law that Vioxx was of merchantable quality within the meaning of s74D of the Trade Practices Act ?
20. If the answer to question 5 is in the affirmative, were Vioxx tablets defective within the meaning of section 75AD of the Trade Practices Act in that the safety of Vioxx tablets was not such as persons are generally entitled to expect by reason of the fact that the consumption of Vioxx materially increased the risk of suffering the condition?
21. If the answer to question 5 is in the affirmative, were Vioxx tablets defective within the meaning of section 75AD of the Trade Practices Act in that the safety of Vioxx was not such as persons are generally entitled to expect by reason of the fact that the packaging and labelling of Vioxx and the Vioxx product information did not contain adequate information, advice or warning to the effect that the consumption of Vioxx materially increased the risk of suffering the condition?
22. If the answer to question 5 is in the affirmative, were Vioxx tablets not reasonably fit for the purpose of acquisition within the meaning of section 74B of the Trade Practices Act by reason of the fact that the consumption of Vioxx materially increased the risk of suffering the condition?
23. If the answer to question 5 is in the affirmative, were Vioxx tablets not of merchantable quality within the meaning of section 74D of the Trade Practices Act by reason of the fact that the consumption of Vioxx materially increased the risk of suffering the condition?
24. If the answer to question 5 is in the affirmative, at all times before 30 September 2004 was the state of scientific or technical knowledge such as to enable Merck Australia to discover that the consumption of Vioxx materially increased the risk of suffering the condition?
25. Were the defects pleaded in paragraphs 33, 34 and 37 of the Further Amended Statement of Claim (if found to exist) caused by Merck Australia's compliance with a mandatory standard or standards? Claim against Merck Inc
26. If the answer to question 5 is in the affirmative: (a) when did Merck Inc first know that the consumption of Vioxx materially increased the risk of suffering the condition? (b) when ought Merck Inc to have first known that the consumption of Vioxx materially increased the risk of suffering the condition? (c) did Merck Inc owe the group members a duty to take reasonable care to avoid acts and omissions that may expose them to a material increase in the risk of suffering the condition as a consequence of consuming Vioxx?
27. Did Merck Inc: (a) not owe group members the duty of care alleged; or (b) satisfy the applicable standard of care by virtue of Merck Australia's compliance with the relevant legislative requirements referred to in paragraphs 23(a)-(1) of the Defence to Amended Statement of Claim and the requirements imposed upon Merck Australia by the TGA pursuant to the powers granted by the Therapeutic Goods Act?
28. Did Merck Inc: (a) not owe group members the duty of care alleged; or (b) satisfy the applicable standard of care by reason of the learned intermediary defence pleaded in paragraph 24 of the Defence to the Further Amended Statement of Claim?
29. If the answer to question 5 is in the affirmative: (a) did Merck Inc fail to undertake or cause to be undertaken any or any adequate research, investigations, clinical trials or observational studies in order to ascertain the adverse side effects and health risks that may be associated with the consumption of Vioxx including a material increase in the risk of suffering the condition? If so, was that failure less than reasonable in all of the circumstances? (b) did Merck Inc fail to have adequate regard to the results of any research, investigations, clinical trials or observational studies undertaken or caused to be undertaken by Merck Inc or others suggesting that the consumption of Vioxx materially increased the risk of suffering the condition? If so, was that failure less than reasonable in all of the circumstances? (c) Did Merck Inc withhold from and fail to publish in medical publications or otherwise reveal data and information of which it was aware concerning adverse cardiovascular risks associated with the consumption of Vioxx? If so, was that failure less than reasonable in all of the circumstances? (d) Did Merck Inc fail to provide to Merck Australia, and health care professionals in Australia or the Australian public any or any adequate information, advice or warning to the effect that the consumption of Vioxx materially increased the risk of suffering the condition? If so, was that failure less than reasonable in all of the circumstances?
30. Was it less than reasonable in all of the circumstances at any time before 30 September 2004 for Merck Inc to supply Vioxx to Merck Australia in Australia? If so, when?

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