Merck Sharp & Dohme (Australia) Pty Ltd v Peterson

[2011] FCAFC 128

FEDERAL COURT OF AUSTRALIA

Merck Sharp & Dohme (Australia) Pty Ltd v Peterson [2011] FCAFC 128

Citation:

Merck Sharp & Dohme (Australia) Pty Ltd v Peterson [2011] FCAFC 128

Appeal from:

Peterson v Merck Sharpe & Dohme (Aust) Pty Ltd (No 5) [2010] FCA 605

Application for leave to appeal: Peterson v Merck Sharpe & Dohme (Aust) Pty Ltd [2010] FCA 180

Parties:

MERCK SHARP & DOHME (AUSTRALIA) PTY LTD (ACN 000 173 508) v GRAEME ROBERT PETERSON

MERCK SHARP & DOHME (AUSTRALIA) PTY LTD (ACN 000 173 508) v GRAEME ROBERT PETERSON AS REPRESENTATIVE OF PERSONS WHO ALLEGE THEY ARE GROUP MEMBERS BY REASON OF THE CIRCUMSTANCE IN PARAGRAPH 2(c)(i) OF THE FURTHER AMENDED STATEMENT OF CLAIM IN VID 451 OF 2006

File numbers:

VID 570 of 2010
VID 571 of 2010

Judges:

KEANE CJ, BENNETT AND GORDON JJ

Date of judgment:

12 October 2011

Catchwords:

TORTS – negligence – product liability – prescription medicine for relief of inflammation – side-effects – whether medicine caused or contributed to cardiovascular disease – content of duty of care – state of scientific uncertainty as to side-effects of medicine – state of scientific uncertainty as to plausibility of scientific hypothesis

TORTS – negligence – product liability – causation – prescription medicine for relief of inflammation – side-effects – whether medicine materially contributed to respondent’s heart attack – whether respondent’s consumption of medicine was a necessary precondition for occurrence of heart attack – interpretation and application of epidemiological evidence as a strand in the cable of circumstantial proof of causation – whether respondent established a causative link between cardiovascular events and the consumption of medicine

TORTS – negligence – product liability – prescription medicine for relief of inflammation – side-effects – legislation establishing minimum safety standards for the availability and use of regulated medicines – whether legislation intended to abrogate the common law rights of individual consumers

TRADE PRACTICES – misleading or deceptive conduct – prescription medicine for relief of inflammation associated with doubling of risk of heart attack – side-effects – whether manufacturer knew or ought to have known of increased risk – whether manufacturer negligently failed to warn of risk and represented safety of medicine – whether manufacturer took reasonable steps to ensure medical practitioners were sufficiently informed of clinical trials presenting signal of cardiovascular risk – whether doctors, pharmacists, health care professionals and the public were adequately warned of risk – whether amendment to “Product Information” sufficient – whether manufacturer entitled to assume that a medical practitioner would rely on amended “Product Information” – whether respondent would have declined to take medicine if appropriately warned of risk – whether respondent’s doctor relied on conduct of corporation in prescribing medicine to him – whether respondent’s doctor would have chosen not to prescribe medicine – whether respondent’s doctor would have prescribed medicine in any event

TRADE PRACTICES – unsuitable goods – prescription medicine for relief of inflammation associated with doubling of risk of heart attack – whether respondent made purpose of acquiring medicine known to manufacturer – whether medicine not reasonably fit for purpose – substantive and procedural issues – whether purpose made known by respondent was a purpose properly to be identified – whether demonstrating an increase in risk alone proves unfitness for purpose

TRADE PRACTICES – goods of unmerchantable quality – prescription medicine for relief of inflammation associated with doubling of risk of heart attack – whether respondent suffered loss by reason that medicine was not of merchantable quality – whether medicine not fit for purpose for which goods of that kind commonly bought and as was reasonable to expect

TRADE PRACTICES – defective goods – prescription medicine for relief of inflammation associated with doubling of risk of heart attack – whether medicine defective – whether safety of medicine not such as persons generally entitled to expect – whether respondent suffered injury because of defect – state of the art defence – whether state of scientific knowledge not such as to enable defect to be discovered

Legislation:

Federal Court of Australia Act 1976 (Cth)
Therapeutic Goods Act 1989 (Cth)
Trade Practices Act 1974 (Cth)
Trade Practices Amendment Bill 1992 (Cth)
Explanatory Memorandum, Trade Practices Amendment Bill 1992 (Cth)

Cases cited:

Amaca Pty Ltd v Ellis (2010) 240 CLR 111 applied
Australian Knitting Mills Ltd v Grant (1933) 50 CLR 387 cited
Bendix Mintex Pty Ltd v Barnes (1997) 42 NSWLR 307 cited
Butcher v Lachlan Elder Realty Pty Ltd (2004) 218 CLR 592 cited
Carey-Hazellv Getz Bros & Co (Aust) Pty Ltd (2004) ATPR 42-014 cited
Carr v Baker (1936) 36 SR (NSW) 301 cited
Chappel v Hart (1998) 195 CLR 232 applied
Evans v Queanbeyan City Council [2011] NSWCA 230 followed
Grant v Australian Knitting Mills Ltd (1935) 54 CLR 49 cited
Henville v Walker (2001) 206 CLR 459 cited
I & L Securities Pty Ltd v HTW Valuers (Brisbane) Pty Ltd (2002) 210 CLR 109 cited
Medway Oil and Storage Co v Silica Gel Corporation (1928) 33 Com Cas 195 cited
Medtel Pty Ltd v Courtney (2003) 130 FCR 182 cited
Naxakis v Western General Hospital (1999) 197 CLR 269 cited
Rasell v Cavalier Marketing (Australia) Pty Ltd [1991] 2 Qd R 323 cited
Seltsam Pty Ltd v McGuiness (2000) 49 NSWLR 262 applied
State Government Insurance Commission (South Australia) v Laube (1984) 37 SASR 31 cited
Tabet v Gett (2010) 240 CLR 537 applied

Date of hearing:

15, 16, 17, 18 August 2011

Place:

Melbourne

Division:

GENERAL DIVISION

Category:

Catchwords

Number of paragraphs:

212

Counsel for the Appellant:

Mr B Walker SC with Mr C Loveday

Solicitor for the Appellant:

Clayton Utz

Counsel for the Respondent:

Mr JWK Burnside QC with Mr G Dalton

Solicitor for the Respondent:

Slater & Gordon

IN THE FEDERAL COURT OF AUSTRALIA
VICTORIA DISTRICT REGISTRY
GENERAL DIVISION	VID 570 of 2010

ON APPEAL FROM THE FEDERAL COURT OF AUSTRALIA

BETWEEN:	MERCK SHARP & DOHME (AUSTRALIA) PTY LTD (ACN 000 173 508) Appellant/Cross Respondent
AND:	GRAEME ROBERT PETERSON Respondent/Cross Appellant

JUDGES:	KEANE CJ, BENNETT & GORDON JJ
DATE OF ORDER:	12 OCTOBER 2011
WHERE MADE:	MELBOURNE

THE COURT ORDERS THAT:

1.The appellant’s appeal be allowed.

2.The judgment in favour of the respondent be set aside and the respondent’s action be dismissed.

3.Time be extended to allow the respondent to file the notice of cross-appeal but that the cross-appeal be dismissed.

4.The parties confer and thereafter by 4:00pm on 26 October 2011 file minutes of orders (including as to costs), and in the event of disagreement file and serve written submissions as to the contentions of the parties.

Note:Entry of orders is dealt with in Rule 39.32 of the Federal Court Rules 2011.

IN THE FEDERAL COURT OF AUSTRALIA
VICTORIA DISTRICT REGISTRY
GENERAL DIVISION	VID 571 of 2010

APPLICATION FOR LEAVE TO APPEAL FROM THE FEDERAL COURT OF AUSTRALIA

BETWEEN:	MERCK SHARP & DOHME (AUSTRALIA) PTY LTD (ACN 000 173 508) Applicant
AND:	GRAEME ROBERT PETERSON AS REPRESENTATIVE OF PERSONS WHO ALLEGE THEY ARE GROUP MEMBERS BY REASON OF THE CIRCUMSTANCE IN PARAGRAPH 2(c)(i) OF THE FURTHER AMENDED STATEMENT OF CLAIM IN VID 451 OF 2006 Respondent

JUDGES:	KEANE CJ, BENNETT & GORDON JJ
DATE OF ORDER:	12 OCTOBER 2011
WHERE MADE:	MELBOURNE

THE COURT ORDERS THAT:

1.The respondent’s application for leave to appeal be granted.

2.The appeal be allowed to the extent indicated in the reasons for judgment.

Note:Entry of orders is dealt with in Rule 39.32 of the Federal Court Rules 2011.

IN THE FEDERAL COURT OF AUSTRALIA
VICTORIA DISTRICT REGISTRY
GENERAL DIVISION	VID 570 of 2010

ON APPEAL FROM THE FEDERAL COURT OF AUSTRALIA

BETWEEN:	MERCK SHARP & DOHME (AUSTRALIA) PTY LTD (ACN 000 173 508) Appellant/Cross Respondent
AND:	GRAEME ROBERT PETERSON Respondent/Cross Appellant

IN THE FEDERAL COURT OF AUSTRALIA
VICTORIA DISTRICT REGISTRY
GENERAL DIVISION	VID 571 of 2010

APPLICATION FOR LEAVE TO APPEAL FROM THE FEDERAL COURT OF AUSTRALIA

BETWEEN:	MERCK SHARP & DOHME (AUSTRALIA) PTY LTD (ACN 000 173 508) Applicant
AND:	GRAEME ROBERT PETERSON AS REPRESENTATIVE OF PERSONS WHO ALLEGE THEY ARE GROUP MEMBERS BY REASON OF THE CIRCUMSTANCE IN PARAGRAPH 2(c)(i) OF THE FURTHER AMENDED STATEMENT OF CLAIM IN VID 451 OF 2006 Respondent

JUDGES:	KEANE CJ, BENNETT & GORDON JJ
DATE:	12 OCTOBER 2011
PLACE:	MELBOURNE

REASONS FOR JUDGMENT

THE COURT:

THE PROCEEDINGS

1. Mr Graeme Peterson had suffered from arthritic back pain for many years when he was first prescribed Vioxx by a medical practitioner, Dr John Dickman, on 10 May 2001.  Vioxx provided Mr Peterson with relief from arthritic pain without the adverse gastrointestinal side-effects which he had suffered when using other drugs for his arthritis.  Accordingly, he took it regularly pursuant to prescriptions provided by Dr Dickman over the next two and a half years. 

2. In early December 2003, Mr Peterson experienced episodes of chest pain associated with atherosclerosis.  Later, on 8 December 2003, he suffered a serious heart attack.  The withdrawal of Vioxx from the market in September 2004 led Mr Peterson to suppose that there was a connection between his consumption of Vioxx and the occurrence of his heart attack.  Mr Peterson brought proceedings in the Supreme Court of Victoria alleging that his consumption of Vioxx contributed to the heart attack.  

3. The first respondent to the proceedings was Merck Sharp & Dohme (Australia) Pty Ltd (MSDA).  The second respondent was MSDA’s parent company, Merck & Co., Inc (Merck), a corporation based in the United States of America engaged in the development, manufacture, distribution and sale of pharmaceutical products which included Vioxx.  The proceeding commenced by Mr Peterson was transferred to the Federal Court of Australia on 10 April 2006.

4. Mr Peterson’s pleaded case was that MSDA knew, or ought to have known, before December 2003, that the consumption of Vioxx increased the risk of heart attack and should have warned him of that increased risk. Mr Peterson alleged that MSDA was negligent in this respect and was also guilty of misleading or deceptive conduct in contravention of s 52 of the then Trade Practices Act 1974 (Cth) (the TPA).

5. Mr Peterson also alleged that Vioxx was not fit for purpose and not of merchantable quality within the meaning of those terms in ss 74B and 74D respectively of the TPA. Finally, Mr Peterson alleged that MSDA was liable to compensate him pursuant to s 75AD of the TPA for injury suffered by him because Vioxx was a defective product.

6. The proceedings in the Federal Court were constituted as representative proceedings under Pt IVA of the Federal Court of Australia Act 1976 (Cth) (Federal Court Act) in respect of group members who had consumed Vioxx on prescription by a medical practitioner in the period after 30 June 1999 and were subsequently diagnosed as having suffered (within 30 weeks after last consuming Vioxx) one or more of a number of conditions including myocardial infarction (MI).  The only condition now relevant is MI.  It was alleged that the MI suffered by each group member was caused by his or her consumption of Vioxx.

   THE PRIMARY JUDGE’S DECISION

7. Whether the consumption of Vioxx caused or contributed to Mr Peterson’s MI was the major issue at trial.  It was important in relation to all of Mr Peterson’s causes of action.  

8. The case against Vioxx was circumstantial:  there was no medical “signature” for Vioxx which might indicate that Mr Peterson’s heart attack was caused by Vioxx.  In finding the circumstantial case against Vioxx proved, the primary judge relied upon a theory as to a physiological mechanism which might explain the operation of Vioxx in the body to produce an occlusion of the vasculature, and upon statistical evidence bearing upon the extent of the risk of harm from Vioxx in the population at large. 

9. The first principal strand in his Honour’s reasoning was based on evidence supporting the theory by which it was proposed that the consumption of Vioxx disturbed the body’s balance of prostacyclin (a vaso-dilator that also inhibits blood clot formation) and thromboxane (a vaso-constrictor and hypertensive factor that facilitates clot formation).  This disturbance might lead to the formation of a thrombus or thrombi (clot or clots) from platelets resulting from the rupture of plaque in the endothelium of atherosclerotic blood vessels.  The thrombus or thrombi so formed were large enough to cause an occlusion of a major vessel supplying blood to the heart.  The second principal strand in his Honour’s reasoning was based upon epidemiological evidence which suggested that the consumption of Vioxx almost doubled the relative risk of heart attack in the population.    

10. On the basis of this circumstantial evidence, the primary judge drew the inference that the consumption of Vioxx made a material contribution to the occurrence of Mr Peterson’s MI.

11. On the other hand, his Honour did not accept a variation of the mechanism hypothesised on Mr Peterson’s behalf whereby it was proposed that the consumption of Vioxx accelerated atherosclerosis by the absorption of thrombi into endothelial plaque.  This alternative mechanism was essential to the case that Vioxx might contribute to a consumer’s heart attack after consumption had ceased.

12. As to Mr Peterson’s claim in negligence, the primary judge rejected Mr Peterson’s pleaded contention that MSDA knew, or ought to have known, that the consumption of Vioxx increased the risk of MI.  His Honour held that it was only in September 2004, when the results of the APPROVe trial became available and Vioxx was promptly withdrawn from the market, that MSDA knew or ought to have known of the increased relative risk resulting from the consumption of Vioxx.

13. Nevertheless, his Honour held that MSDA failed to exercise reasonable care for the safety of consumers because MSDA had failed to warn consumers of “a worrisome and important signal of potential cardiovascular risk associated with Vioxx” (primary judge’s reasons for judgment (Reasons) at [594]).  In this regard, his Honour held that the November 2001 amendment to the Product Information (PI) should have been, but was not, communicated to Dr Dickman by a “Dear Doctor” letter. His Honour held that MSDA thereby failed to exercise reasonable care for Mr Peterson’s safety. His Honour’s resolution of this issue in the negligence claim also informed his Honour’s answer to a question posed for the purpose of the representative proceedings under Pt IVA of the Federal Court Act.

14. Nevertheless, Mr Peterson’s claim in negligence failed.  That was because Dr Dickman gave evidence that the necessary information was available to him and that he would have continued to prescribe Vioxx for Mr Peterson, who would have continued to take it, even with knowledge of the potential cardiovascular risk. 

15. Mr Peterson’s claim under s 52 of the TPA also failed. The primary judge found that MSDA’s marketing of Vioxx was not misleading or deceptive. The primary judge concluded that the publication by MSDA of an amended PI after November 2001 when the Vioxx Gastrointestinal Outcomes Research (VIGOR) results had been obtained meant that MSDA’s conduct in marketing Vioxx was not misleading or deceptive.  This conclusion had adverse consequences both for Mr Peterson and for the representative proceedings.  Further, his Honour found that Dr Dickman had not been influenced by MSDA’s marketing, in that he would have prescribed Vioxx for Mr Peterson in any event.  That finding also has adverse consequences for Mr Peterson’s claim but not for the representative proceedings.

16. Mr Peterson’s claim under s 75AD of the TPA against MSDA also failed. The primary judge held that Vioxx was defective within the meaning of this provision, but that MSDA was entitled to the “state of the art” defence afforded by s 75AK(1)(c) of the TPA. The primary judge held that the state of scientific or technical knowledge at the time the drug was supplied was not such as to enable the defect, namely the prothrombotic tendency of Vioxx, to be discovered.

17. The primary judge held that Mr Peterson was entitled to recover damages pursuant to ss 74B and 74D of the TPA. As to s 74B, Vioxx was not reasonably fit for the purpose implicitly made known to MSDA, viz, the safe relief of arthritic pain, in that an arthritic pain medicine which involved a relative risk of MI of 2 was not reasonably fit for that purpose. As to s 74D, Vioxx was not of merchantable quality because it was reasonable for a consumer to expect that a medication for the relief of arthritic pain would not involve a relative risk of MI of 2.

18. On the basis of the success of Mr Peterson’s claims under ss 74B and 74D, an award of damages was made in his favour in the amount of $330,465.35.

19. On 18 June 2010 the primary judge determined questions relating to the claims of other class members.  Some of these questions raised issues common to those raised in Mr Peterson’s claim.  The Schedule of the questions and his Honour’s answers is attached as Annexure A to these reasons.

20. No decision has yet been made concerning the entitlements of other class members.

21. The claims against Merck were dismissed.  It is not a party to the appeal to this Court by MSDA or the cross-appeal by Mr Peterson.

    THE APPEAL AND CROSS-APPEAL

22. MSDA appeals against the decision of the primary judge challenging his Honour’s conclusions on the issues of causation, negligence and contravention of ss 74B and 74D of the TPA. MSDA also contends that his Honour erred in holding that Vioxx was defective within the meaning of s 75AD of the TPA.

23. MSDA also seeks leave to appeal from the Order by the primary judge on 18 June 2010, seeking to argue that the primary judge erred in his determinations of the questions relating to group members.  Leave to appeal is required because each determination is an interlocutory judgment.

24. Mr Peterson cross-appeals against the decision of the primary judge challenging his Honour’s conclusions in relation to:

    ·The availability of the “state of the art” defence in s 75AK(1)(c) of the TPA; and

    ·The rejection of the alternative mechanism by which Vioxx might have contributed to Mr Peterson’s MI.  The relevance of this variant mechanism is for the representative proceedings involving persons who had ceased to take Vioxx some time before suffering injury.

25. His Honour’s findings of primary fact are not challenged in either the appeal or the cross-appeal save in relation to his Honour’s rejection of the alternative mechanism by which the consumption of Vioxx might have contributed to Mr Peterson’s MI by the absorption of thrombi into endothelial plaque.  In the interests of accuracy, we propose to address the parties’ arguments on the issues raised in the appeal and cross-appeal with close attention to the specific findings of primary fact made by his Honour.  Before we turn to this discussion, it is necessary in the interests of coherence of exposition to summarise more broadly the primary judge’s reasons relating to the evidence of the development and investigation of Vioxx, and the suggested bases for concluding that the consumption of Vioxx caused Mr Peterson’s heart attack.  We acknowledge that this approach will result in a degree of repetition of his Honour’s findings and of the evidence on which they were based, but that cannot be avoided having regard to the complexity of the terms and hypotheses with which his Honour was obliged to grapple.

    THE PRIMARY JUDGE’S REASONS

1. The primary judge set out some background material concerning cyclooxygenase (COX) in the Reasons at [6]-[7].  COX is an enzyme that is ubiquitous in the body and, depending on its location in the body, the action of COX may be constitutive (that is, operating all the time) or inducible (that is, operating only in response to particular stimuli).  In the vicinity of arthritic joints, COX is induced by the pathological state of the joint but, in a situation in which the condition is chronic, the action of the enzyme is effectively continuous.  In the stomach and duodenum, COX operates constitutively as a defence factor that helps the stomach and duodenum resist being digested by their own corrosive acid juice.  In the vasculature, COX is involved in the production of thromboxane A₂ (thromboxane), a clotting and vaso-constricting agent.  In the endothelium of blood vessels it is involved in the production of prostacyclin, an anti-coagulant and vaso-dilating agent.  In 1990 it was discovered that there are in fact two isoforms of COX; one of which is constitutive (COX-1) and the other inducible (COX-2).  Vioxx (containing the active ingredient rofecoxib) inhibits only COX-2.  As such it is referred to as a COX-2 inhibitor or a coxib.

2. At [477]-[478], his Honour set out the basic steps in the development of cardio-vascular thrombotic (CVT) disease as follows:

   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.

   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 [MI].

3. It is uncontroversial that the production of thromboxane is the work of COX-1.  A question before the primary judge was the work of COX-2.  Mr Peterson contended that the production in the endothelium of prostacyclin is the work of COX-2.  Accordingly, he contended that Vioxx blocks the production of endothelial prostacyclin in blood vessels.  The theory which became known as the “FitzGerald hypothesis” was that Vioxx inhibited the synthesis of prostacyclin. 

   The FitzGerald Hypothesis

4. The FitzGerald hypothesis was named after Dr Garret FitzGerald, an author of a publication in which the results of what was known as Protocol 023 were published.  The authors concluded that the extrarenal (outside the kidney) biosynthesis of prostacyclin was mediated by COX-2 (Reasons at [46]).  The authors suggested several explanations as to how it might be that COX-2 mediated the production of vascular prostacyclin.  His Honour noted at [46]:

   However, it was the realisation that COX-2 may be responsible for the production of endothelial prostacyclin that effectively initiated the scientific debate that lies at the heart of this proceeding.  The authors of this article raised the question whether the selective inhibition of COX-2, by turning off the production of prostacyclin in circumstances where it might otherwise be induced while leaving the production of thromboxane unaffected, might have a prothrombotic tendency.

5. A description of a possible mechanism appeared in the considerations of the Merck Board of Scientific Advisers, as reported by the primary judge at [53]. The possibility was described as follows:

   After the rupture of a coronary plaque, factors which regulate thrombus formation and which regulate the occurrence of ischemic ventricular fibrillation are critical to the clinical outcome.  The initial thrombus at the site of plaque-rupture is platelet-rich and is labile.  Accordingly, it is susceptible to any anti-aggregatory influences… Prostacyclin is the most potent endogenous inhibitor of platelet-aggregation, and studies in animal models indicate that its participation in inhibiting platelet activation is substantial. … Not only does prostacyclin inhibit platelet activation, but it also potently inhibits the development of ischemic ventricular fibrillation in the canine model of [MI].

6. The Board noted that it had been found that Vioxx reduces the urinary excretion of a prostacyclin metabolite and concluded that while the data were not obligatory to any conclusion, they should be taken as a basis for a hypothesis that should be “actively pursued” in order to understand any possible influences of a COX-2 inhibitor on coronary morbidity and mortality.

7. Put simply, the FitzGerald hypothesis, as it was advanced on behalf of Mr Peterson, was as follows:

   ·Vioxx did not cause atherosclerosis or plaque rupture (Reasons at [771]).

   ·Vioxx causes the build-up of lipid material within the arteries.

   ·Many people suffer from atherosclerosis that does not result in any negative medical event.  This can be referred to as “silent atherosclerosis”.

   ·Vioxx did not participate in or cause the rupture of an atherosclerotic plaque and caused it to separate from the blood vessels.

   ·Vioxx did not cause the material to aggregate.  Mr Peterson’s contention was that the explanation for a MI was that Vioxx prevented the synthesis of endothelial prostacyclin in blood vessels, leaving the production of platelet thromboxane unaffected.  Prostacyclin acts to prevent the aggregation of the platelets and also acts as a vaso-dilator, to expand the lumen of the blood vessels.  If this action is successful, there is not sufficient aggregation to cause a thrombotic event, or the blood vessel expands so that the aggregated plaque does not occlude the blood vessel.

   While it can be accepted that a free and uninhibited production of prostacyclin does not necessarily prevent occlusion and MI, the theory is that there is a range of cases where the prostacyclin could succeed in breaking down the aggregation and/or dilating a blood vessel, so that MI did not occur.  Mr Peterson contended that he was one of those cases.  The absence of prostacyclin meant that where there was an aggregation of platelets and the consequent clotting of blood, the mitigating effects of prostacyclin being absent rendered it more likely that the aggregation had thrombotic consequences.  The consequences were cardiovascular events.

8. The FitzGerald hypothesis is, in essence, that if the production of endothelial prostacyclin is blocked but that of platelet thromboxane is unaffected, an imbalance will result with possible thrombotic outcomes.  The thesis was predicated upon the blockage of the production of endothelial prostacyclin.  That is, the presence of COX-2 in the endothelium was a necessary precondition to the validity of the FitzGerald hypothesis (Reasons at [487]).  On the balance of probabilities, the primary judge was not satisfied (Reasons at [495] and [523]) that the presence of COX-2 in the endothelium was not shown.

   The VIGOR study

9. In 1998, Merck commenced the design of a major study into Vioxx, the VIGOR trial.  It was a prospective, double-blind study of patients with rheumatoid arthritis (Reasons at [72]).  The VIGOR trial compared Vioxx with naproxen, a traditional non‑steroidal anti‑inflammatory drug (NSAID) that had been on the market for 30 years.  The trial tested the gastrointestinal effects.  Four percent of the patients in the overall cohort were indicated for the regular taking of low-dose aspirin for cardioprotection.  This meant, as the primary judge found at [123], that these patients had medical histories involving, inter alia, MI.  A disproportionate number of the adverse effects were experienced by these patients.  For example, some 38% of MIs were suffered within this 4% of the group.  Patients in the Vioxx arm of the VIGOR trial had five times as many MIs as patients in the naproxen arm, with a disproportionate number of MIs occurring in patients in the Vioxx sample already at risk of elevated heart attack, as evidenced by their taking of aspirin.  Four percent of the Vioxx cohort was assessed as being at elevated risk of heart attack.

10. On 12 January 2001 Merck applied to amend the PI for Vioxx with respect to the VIGOR data.  The PI amendment was approved by the Therapeutic Goods Administration (TGA) and was amended to incorporate the results of the VIGOR study on 16 November 2001.  An amendment to the Vioxx PI was made on 17 January 2002 to add information about the VIGOR study for patients with rheumatoid arthritis and the TGA approved a new indication for Vioxx for rheumatoid arthritis.

11. In the Precautions section of the PI as approved on 16 November 2001, a new subheading 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.  There was also a reference to cardiovascular effects of Vioxx in the terms of the VIGOR study which included the statement (Reasons at [258]):

    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.

12. Mr Peterson argued that, at least after the VIGOR results were submitted by MSDA to the TGA on 11 April 2000 or, at the very latest, when the VIGOR study results were published in the New England Journal of Medicine on 23 November 2000, MSDA knew that the use of Vioxx resulted in an increased risk of MI.  At trial, Mr Peterson relied on the fact that MSDA knew the VIGOR results by the end of March 2000, before the time when it began marketing Vioxx in Australia in February 2001 (Reasons at [229]).  He made no complaint about the fact that MSDA began marketing Vioxx. 

13. Merck explained the results of the VIGOR trial as demonstrating not an increased risk caused by Vioxx, which it said was not prothrombotic, but rather as the effect of the removal of the cardioprotective action of naproxen, which was said to have an “aspirin-like ability” to inhibit platelet aggregation.  Merck summarised the results of the VIGOR group trial, in part, as follows (Reasons at [124]):

    In the VIGOR study population, therapy with naproxen was associated with a reduction in the incidence of thrombotic cardiovascular serious adverse experiences.  The difference between the treatment groups in the rates of thrombotic cardiovascular events was due primarily to a reduction in the incidence of [MI] in patients treated  with naproxen.

14. Merck’s analysis was not that Vioxx caused an increase in MI but that Vioxx did not provide the cardioprotective effect of some NSAIDs by reason of the effect of those NSAIDs on COX-1 and, through that enzyme, on platelet aggregation by its effect on the production of thromboxane.

15. It was also relevant, as noted at [127] of the Reasons, that no similar incidence of increased MI was demonstrated in studies of other populations, including patients suffering from osteoarthritis and early Alzheimer’s disease.  In those studies the incidences of serious thrombotic cardiovascular serious adverse experiences were comparable between patients who received Vioxx, placebo or comparator non-selective NSAIDs.

16. Mr Peterson attacks Merck’s conclusion as indicating some lack of bona fides on the part of Merck and MSDA.  However, it is clear from his Honour’s analysis of the results of the VIGOR trial and of Merck’s analysis that he found that Merck analysed the results and came to a reasoned conclusion that explained the results in terms of naproxen protection rather than Vioxx causation.  There is no challenge to that finding of the primary judge by Mr Peterson.  The primary judge set out in some detail the various stages of the analysis of the VIGOR results.  This included not only the variables involved, but also the theory as to the cardioprotective effect of NSAIDs that were potent in antiplatelet effects but which tended to be associated with clinical outcomes involving bleeding, compared to Vioxx, which did not have an antiplatelet effect but had an improved gastrointestinal effect.

17. One explanation for the different mechanisms of action that gave rise to the VIGOR results concerned the effect on platelet aggregation, as in the FitzGerald hypothesis.  As his Honour noted at [128], Merck’s analysis was that COX-2 selective compounds such as Vioxx would not be expected to provide vascular protective effect similar to those observed following chronic aspirin therapy.  Merck considered whether:

    The moderate reductions in the synthesis of prostacyclin without COX-1 mediated inhibition of platelet aggregation … observed with COX-2 selective inhibitors theoretically could have mildly proaggregatory platelet effects.

    However, it was considered that partial inhibition of prostacyclin synthesis was a less likely explanation for the results of VIGOR than the potent anti-aggregatory effect of naproxen, a conclusion contrary to the FitzGerald hypothesis. 

18. As the primary judge noted at [127], Mr Peterson was critical of Merck for having expressed the VIGOR results as though the question was whether naproxen was cardioprotective.  That criticism is also made in the appeal.

19. The primary judge considered the evidence of the concerns expressed at the time of the publication of the results of the VIGOR trial and concluded, for example at [156], that while the potential for Vioxx to be prothrombotic was recognised as real, the consensus seemed to be that the antiplatelet activity of naproxen was, to an extent, responsible for the results of the VIGOR trial.

20. The primary judge analysed in detail the various assertions, articles and explanations offered for the results of the VIGOR study, both within Merck and in the literature.  His Honour discussed various studies, including a pooled analysis that was provided to the Food and Drug Administration (FDA) on 22 May 2002, the results of which MSDA noted (Reasons at [183]) were “most consistent with naproxen having provided a relative cardioprotective benefit in these studies and argue against a prothrombotic effect of [Vioxx]”.  Some of the published material contained a reference to the FitzGerald hypothesis.  However, even as at 22 March 2004, Dr Reicin of Merck interpreted the results of all relevant studies including VIGOR as “most consistent with the conclusion that Vioxx was cardioneutral, whereas naproxen was cardioprotective” (Reasons at [188]).

21. His Honour also dealt with a list of criteria proposed in 1965 by Sir Austin Bradford Hill (the Bradford Hill criteria) by reference to which questions of causation in epidemiology might conveniently be addressed (Reasons at [321]).  The purpose of these criteria was to bridge the gap between association and causation (Reasons at [322]).

22. The results of the VIGOR trial yielded a relative risk of taking the Vioxx rather than naproxen of 5.00 (1.72, 14.29) in the case of MI (Reasons at [348]).  His Honour noted (Reasons at [348]) that Professor Celermajer said that the strength of an association was often expressed as a relative risk, such that the higher the relative risk, the more likely the exposure is to be causally linked to the effect.  His Honour noted at [350] that the controversy surrounding the VIGOR data related not to the apparent strength of the association indicated by them, but to one of the Bradford Hill criteria, the seventh criterion, namely whether the circumstance that naproxen was the comparator provided a convincing alternative explanation.  His Honour accepted, apparently, that Merck in fact took the view that the results could and should be explained by the cardioprotective effect of naproxen rather than by a cardiotoxic effect of Vioxx.

23. The difficulty in drawing definite conclusions from the VIGOR trial is apparent from the primary judge’s reasons.  After examining the evidence in detail, including evidence from Merck and from independent cardiologists and statisticians, his Honour said (Reasons at [381]) that he was not prepared to find that it was not only possible but also likely that part of the observed discrepancy in the MI results in the VIGOR trial was due to the especially pronounced beneficial work of naproxen in the context of patients with a systemically inflammatory condition.  His Honour also referred to evidence in which it was concluded that the cardioprotective effect of naproxen was about 2% and concluded (Reasons at [383]) that he was not satisfied that the cardioprotective effect of naproxen was sufficient to explain the MI data yielded by the VIGOR trial.  The primary judge also referred (Reasons at [385]) to another dimension of the problem, which was what was described as “the fragility of the best estimate”, such that when a trial is dealing with very low numbers, very subtle shifts have major effects on the best point estimate.  Indeed, in a publication in September 2004, the authors, who included Dr FitzGerald, concluded that the combination of some cardioprotective effect of naproxen and “the play of chance” seemed to offer a plausible explanation for the apparent excess risk of MI in the VIGOR trial.  They also said that “[w]hile other mechanisms cannot be discounted, there is currently little evidence in humans to support a prothrombotic effect of coxibs” (Reasons at [385]).  It is pointed out by MSDA that this is not supportive of the FitzGerald hypothesis.

    The APPROVe study

1. In a study called APPROVe, which commenced in February 2000, a total of 2586 patients with a history of colorectal adenomas were randomised to either Vioxx or a placebo.  The patients in the study were men with a mean age of 63.6 years.  This study was ongoing in September 2004.  On 23 September 2004 Merck became aware that the APPROVe External Safety Monitoring Board had observed the statistically significant increased risk of CVT events in those taking Vioxx compared to the placebo.  Data from the study led the External Safety Monitoring Board for that trial to recommend that the trial be unblinded and that the trial be discontinued.  That recommendation was accepted.  On 30 September 2004 Vioxx was voluntarily withdrawn from the market.

2. The results of that trial were published in 2005.  The relative risk of encountering a CVT event from taking Vioxx rather than a placebo was 1.92 (1.19, 3.11) (Reasons at [327]).  For MI, the relative risk was 2.53 (1.11, 6.28).  At [342] the primary judge concluded, after analysing the detailed evidence on the conclusions that could be drawn from the APPROVe trial, that at the 95% probability level the trial established, at least for a population of persons having the characteristics there studied, that the true relative risk of a MI from taking Vioxx in comparison with taking nothing at all, was 1.11 to 6.28.  His Honour also noted the difficulties of extrapolating from the population of the APPROVe study to the population at large.  At [347] his Honour said that he was prepared to accept that the APPROVe results reflect, at the 95% probability level, the true relative risk of taking Vioxx rather than placebo amongst persons in the broader population who have the characteristics of the patients in the trial.  However, his Honour also accepted evidence that there was some uncertainty as to the generalisability of those results to the population at large.

3. In the APPROVe study the absolute event rates for MI were 21 events or 0.69 events per 100 patient years for patients consuming Vioxx, and nine events or 0.27 events per 100 patient years for patients consuming a placebo.

   Other meta analyses

4. In a publication in 2006 (Kearney), there was a summary by way of meta analysis of published and unpublished tabular data from any randomised trial comparing COX-2 inhibitor use to placebo or traditional NSAIDs.  In the placebo comparison, the authors found a relative risk of 1.42 at the 95% confidence level (1.13 to 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 MI at 1.86 (1.33 to 2.59).  As his Honour noted (Reasons at [424]), Mr Peterson relied on the relative risk figures of 1.42 for serious vascular events and 1.86 for MI as providing support for his case on risk.  The authors stated the relative risk when giving the composite results for the five coxibs being studied.  Using the data in Kearney, Professor Woodward, a witness called by Mr Peterson, calculated the relative risk of MI from taking Vioxx.  It was 1.74 (1.11, 2.72).  At [428], his Honour stated that:

   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 [Vioxx].

   Conclusion on relative risk based on the studies

5. To assess consistency across a broad range of studies, the primary judge set out a summary of the relative risk figures referred to in a table (Reasons at [464]):

MI
Lower	Point	Upper
VIGOR	1.72	5.00	14.29
APPROVe	1.11	2.53	6.28
APPROVe extend (Baron)	1.09	1.94	3.34
Kearney (all coxibs)	1.33	1.86	2.59
Kearney (Vioxx) per Woodward	1.11	1.74	2.72

1. His Honour noted at [465] that save for VIGOR (where the comparator was naproxen) the comparator in each of the other groups of data was placebo.  The point estimate is between the lower and upper 95% confidence limits.  This, as his Honour said, emphasised 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.  As his Honour observed at [466], the higher figure for the VIGOR results does support the Merck-asserted effect of naproxen.

2. At [471] his Honour noted the difference in conclusions to be drawn from the APPROVe results as between the experts.  Professors Zipes and Harper (for Mr Peterson) were of the view that the risk of MI would be increased by a factor of about 2.5.  Professors Celermajer and Vaughan (for Merck) did not agree, with Professor Celermajer’s reading of the results taken as a whole as yielding a more typical relative risk figure of about 1.4 (for CVT events).

3. At [473]-[476] the primary judge considered the appropriate figure to adopt for the relevant risk for MI.  His Honour was not persuaded that the VIGOR results were useful in the quantification of the risk.  Taken as a whole, his Honour concluded that the data referred to in the evidence warranted the generalisation that, over a population, the consumption of Vioxx increased the risk of MI “by a factor of about 2”.  His Honour also observed that the data took no account of issues of mechanism and related to people generally.  As his Honour said (Reasons at [476]):

   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 validity of the FitzGerald hypothesis

4. As the primary judge noted at [302], Mr Peterson’s case was opened substantially by reference to the FitzGerald hypothesis, although 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, which included MI.  Even as at the date of hearing, the primary judge noted (Reasons at [304]) that there was no scientific consensus with respect to the relevant mechanism of action of Vioxx or as to whether the consumption of Vioxx caused, or involved an increase in risk of, Mr Peterson’s MI.

5. The FitzGerald hypothesis was important for Mr Peterson’s case on causation because under the Bradford Hill criteria the third criterion is the existence of a plausible biological explanation.  MSDA says that the validity of the FitzGerald hypothesis was “the essential plank to build Mr Peterson’s case”, and that Vioxx made the difference between his suffering MI or not.  Mr Peterson’s case was that the FitzGerald hypothesis was biologically plausible and provided a reasonable explanation for the observed statistical association between the consumption of Vioxx and adverse cardiovascular events incurred by the taking of the COX-2 inhibitor Vioxx (Reasons at [480]).  Mr Peterson says that it was not necessary for him to establish the FitzGerald hypothesis as an accepted fact in order to succeed.

6. As the primary judge stated at [479], it was the seventh step of Professor Vaughan’s sequence or the fourth stage referred to by Professor Zipes, as set out at [478], where the imbalance induced by the selective inhibition of COX-2 hypothesised by Dr FitzGerald and his colleagues was said to have a biological impact, favouring the development of thrombotic material in the vasculature.

7. Professors Celermajer and Vaughan said that they were “not convinced that the FitzGerald hypothesis [was] biologically relevant to an understanding of the pathophysiology of plaque rupture and thrombosis” (Reasons at [480]).  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 (Reasons at [481]).

8. Basically, as stated earlier, the FitzGerald hypothesis is that Vioxx, as a selective inhibitor of COX-2 enzyme, affected the balance between the production of thromboxane and the protective production of prostacyclin.  Thromboxane is a potent vaso-constricting compound that is highly active in aggregating platelets and acts to promote clot formation.  Prostacyclin is a vaso-dilator which causes dilation of the blood vessels and directly antagonises the constricting and procoagulant effect of thromboxane.  The FitzGerald hypothesis is that Vioxx increases the risk of clot formation on an atherosclerotic plaque.

9. At [482] and following, the primary judge noted the reservations on the acceptance of the hypothesis as advanced by Professors Celermajer and Vaughan.  One of the key assumptions necessary for the FitzGerald hypothesis to be operative is that COX-2 would need to be present in the endothelium.  As the primary judge noted at [487], all of the cardiologists agreed that that circumstance was a necessary precondition to the validity of the hypothesis.  His Honour considered the various opinions and the inferences that the cardiologists drew from the available data and said (Reasons at [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.

10. His Honour said that it did not appear to have been scientifically established that the prostacyclin has an endothelial source.  However, his Honour concluded (Reasons at [495]) that:

    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. 

    This does not make it quite clear as to whether his Honour made a positive finding as to whether the presence of the enzyme was or was not established.

11. His Honour then observed at [503] that no increase in the generation of platelet thromboxane consequent upon the administration of a COX-2 inhibitor had been seen.  His Honour said that such consideration does compromise to an extent the utility of the FitzGerald hypothesis, although he could not say that it must be taken to have been disproven.  His Honour concluded by saying (Reasons at [503]):

    To the extent that the applicant relies on the [FitzGerald] 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 [FitzGerald] 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.

    [Emphasis added].

12. MSDA submits that, as this conclusion is expressed, the primary judge wrongly shifted the onus to MSDA and, in any event, his Honour found that the validity of the hypothesis could not be accepted.  Nevertheless, accepting the opinion of  Professor Harper (Reasons at [516]), the primary judge then said in summary at [519]:

    ·if an outcome occurs such as a thrombus then clearly the compensatory system has not been sufficient;

    ·a plaque rupture is a very strong stimulus to clot formation and therefore the compensatory system has to be strong to overcome it;

    ·in some plaque ruptures the stimulus is so strong that nothing can overcome it and, irrespective of whether a patient is or is not on Vioxx some plaque ruptures will clearly lead to a heart attack;

    ·it is “possible” that some plaques are ruptures that would otherwise not lead to an event;

    ·Quoting Professor Harper: “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”.

13. The primary judge repeated at [521] that the FitzGerald hypothesis had not been scientifically validated.  Professors Zipes and Harper had contended that it was a biologically plausible explanation for what was observed in APPROVe and elsewhere.  Professors Celermajer and Vaughan had concluded that the burden of the evidence was that the FitzGerald hypothesis, as an explanation of the consequences of the inhibition of COX-2 in the vasculature, was still no more than a hypothesis.

14. In assessing the plausibility of the FitzGerald hypothesis as an explanation for what was observed, his Honour emphasised that it sought to provide an explanation for adverse events which occurred only in a small minority of patients who took Vioxx.  From the study, it could not be said that taking Vioxx “caused” the endpoints of a CVT event in the sense of giving rise to them as “a direct and inevitable consequence” (Reasons at [522]).  His Honour repeated the fact that there was no scientific consensus as to the presence of COX-2 in the endothelium or as to its activity in a situation of atherosclerosis.  As prostacyclin acts only in the immediate vicinity of its synthesis, 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.  His Honour repeated that scientifically whether this is so remains a matter of hypothesis (Reasons at [523]).  Further, while it was not conclusive, there was no report of an increase in the production of platelet thromboxane in response to the inhibition of COX-2 in the context of an inflamed vasculature which, his Honour concluded (Reasons at [524]), would have added to, rather than reduced, the uncertainty associated with the consequences in the vasculature of inhibiting COX-2 while sparing COX-1.

15. At [527] the primary judge emphasised that, whether or not the FitzGerald hypothesis is valid, “we are not here talking about absolutes”.  This is highlighted by his Honour’s observation that (Reasons at [527]):

    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.

    [Emphasis added].

    It should be noted that this observation concerned the increased risk in the group of Vioxx takers as a whole and does not deal with an individual case.  The effect of the FitzGerald hypothesis if valid was as the primary judge pointed out at [528], to leave the vasculature with “one less defensive mechanism than it has in the unmedicated state”.  However, there is a continued existence and importance of the other defensive mechanisms, so that the inhibition of COX-2 by Vioxx will not necessarily render thrombotic all events or circumstances which otherwise would not have been so.  As the primary judge observed (Reasons at [528]):

    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.

16. The middle ground between the experts seemed to be that, if the FitzGerald hypothesis is valid, there are some stimuli that would be effectively counteracted by the compensatory systems as they exist in the unmedicated vasculature, but where the removal of prostacyclin by the inhibition of its synthesis would make a clinical difference.  The primary judge noted that, taking into account the various combinations and permutations involved in the FitzGerald hypothesis, “it is not surprising that the studies that have looked at the cardiovascular consequences of COX-2 inhibition have produced varying results” (Reasons at [529]).

17. Vioxx was identified as possibly having harmful effects in the:

    ·elevation of blood pressure;

    ·acceleration of atherogenesis; and

    ·exaggeration of the thrombotic response to plaque rupture (the FitzGerald hypothesis).

18. The primary judge concluded that Vioxx did contribute to hypertension in some people but not to an extent that it would be outside the range of contribution by NSAIDs generally.  Cardiologists agreed that the available data as to the effect of COX-2 inhibition on the progression of atherosclerosis are conflicting.

19. There was some evidence that Vioxx either had no effect, or had an effect by way of reduction, on the development of plaque (Reasons at [536]).  Professor Zipes was of the opinion that Vioxx contributed to the progression of atherosclerosis.  Having considered the whole of the evidence, his Honour concluded (Reasons at [541]) that he was not persuaded that the evidence was sufficient to justify a conclusion that Vioxx contributed to the acceleration of atherosclerosis in any or all of the respects identified by Professor Zipes.  However, his Honour (Reasons at [542]) seemed to accept the evidence of Professor Harper that, while there was no evidence that Vioxx caused atherosclerosis:

    …the pro-thrombotic work of Vioxx most probably contributed to the thickening of plaque by a series of minor, clinically silent, events which, over time, accelerated the process of atherosclerosis.

    Professor Harper did not suggest that Vioxx had anything to do with the process of incorporation into plaques and thus the acceleration of the development of atherosclerosis.  If the FitzGerald hypothesis was correct, Vioxx could promote the formation of thrombotic material over time and thus have an indirect effect on the acceleration of atherosclerosis.

20. The primary judge concluded that these propositions seemed to be conceptual or logical rather than empirical and were unsupported by data.  In the result, his Honour said at [544] that in the circumstances:

    …it would be to overreach the science to conclude that Vioxx accelerated atherosclerosis, or to infer that the results of the studies and trials of Vioxx to which I have referred were given a plausible biological explanation not merely by the FitzGerald hypothesis itself but also by a state of affairs in the vasculature which was assumed, conceptually as it were, the more readily to arise if that hypothesis were valid.

21. After a detailed assessment of the evidence, including the results of the APPROVe study, the primary judge said he was “persuaded” that the FitzGerald hypothesis does provide (Reasons at [561]):

    …a plausible biological explanation for the excess of CVT events, and of [MIs] particularly, observed in APPROVe.

    His Honour said that he should make it clear that this conclusion did not involve a finding that the FitzGerald hypothesis was valid; much less did it involve a finding that, in every person who took Vioxx, the mechanism proposed by the FitzGerald hypothesis was active such that any CVT events suffered by that person must necessarily have been contributed to by Vioxx (Reasons at [562]).  His Honour repeated that Mr Peterson only sought to establish that the FitzGerald hypothesis provided a plausible biological explanation for the results of APPROVe and the other clinical studies.

22. The primary judge then turned to the questions of whether an association between the consumption of Vioxx and MIs exists, and whether the consumption of Vioxx in fact contributed to Mr Peterson’s condition. 

    Vioxx and the risk of MI across a population

1. The primary judge repeated that, at the population level, the consumption of Vioxx increased the risk of MI (Reasons at [568]), and that the mechanism proposed by the FitzGerald hypothesis provides a plausible explanation for the MI results of APPROVe.  His Honour also stated (Reasons at [568]):

   At the same time, [the FitzGerald hypothesis] provides a rational justification for exercising caution in the application of population risk increase data to every individual.

   It may also provide a “more obviously persuasive explanation” for the increase in risk in the case of patients with symptomatic atherosclerotic cardiovascular disease (Reasons at [568]).

2. His Honour found that the consumption of Vioxx increased the risk of suffering MI by a factor of about 2 (Reasons at [570]).  The primary judge expressed the view that as a doubling of risk would be regarded as significant by the reasonable person, it should therefore be regarded as a material risk.  However, his Honour also observed at [528] that if the FitzGerald hypothesis were valid over a population of patients, inhibition of COX-2 will make a difference for some but there may be no way of knowing before or after the event who those patients are or will be.

   Vioxx and Mr Peterson’s MI

3. The primary judge outlined Mr Peterson’s own circumstances at [764]-[765]. Mr Peterson was characterised by a number of risk factors for MI as at 2001, namely hypertension, hyperlipidemia, obesity and the presence of left ventricular hypertrophy. He was highly likely to have had coronary atherosclerosis that was clinically silent at the time. He was a former smoker, male and aged 51 years. In December 2003 Mr Peterson suffered chest pain caused by a plaque rupture in his proximal left anterior descending coronary artery (Reasons at [759]). He had an MI approximately a week later when a thrombus or blood clot formed in the ruptured plaque, ultimately completely obstructing the artery (Reasons at [766]). By that time the risk factors were “slightly improved”. There were insufficient data to enable the cardiologists to say whether the consumption of Vioxx by Mr Peterson had affected his blood pressure. Mr Peterson did not submit that his MI occurred because of Vioxx induced blood pressure elevation (Reasons at [765]).

4. The primary judge noted at [767] that the cardiologists agreed that, in a patient with multiple risk factors such as Mr Peterson, there was no way definitively to determine which risk factor caused the heart attack and, in the words of Professor Celermajer, there was:

   …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.

   His Honour noted that this was the same as saying that Mr Peterson may have had the very heart attack which he did have at the same time and at the same level of seriousness had he not been taking Vioxx.

5. The primary judge referred to the evidence of Professor Zipes who said that the likelihood of Mr Peterson having an infarction was increased by taking Vioxx and that, in his view, “to a reasonable degree of medical probability Vioxx played a substantial contributing role” (Reasons at [768]).  Professor Harper expressed the view that Vioxx doubled Mr Peterson’s risk of having a heart attack and that “if it is more than two times then it‘s more likely than not that Vioxx contributed to the heart attack”, and that the data from APPROVe indicated a ratio of slightly more than 2:1 (Reasons at [768]).  This meant, as the primary judge observed at [769], that the inference from such a study where the events of interest were twice as numerous in the group taking a particular drug as in the placebo group, half of those in the group taking a particular drug would have experienced the event anyway.  In this context, the primary judge referred to a passage from the reasons of Spigelman CJ in Seltsam Pty Ltd v McGuiness (2000) 49 NSWLR 262 at [137], where Spigelman CJ said that actual persuasion does not require a relative risk in epidemiological studies of 2.0, but that 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; that the “strands in the cable” must be capable of bearing the weight of the ultimate inference.

6. In a key passage (Reasons at [770]), the primary judge looked to the assessment of the attribution of a contributory role to Vioxx in Mr Peterson’s heart attack.  His Honour observed that it came down to interpretation of the data yielded by the various trials and studies.  His Honour placed some weight on what he considered to be an implicit endorsement of the validity of the FitzGerald hypothesis by Professor Harper and the conclusion reached by Professors Harper and Zipes that the consumption of Vioxx increased the risk of Mr Peterson having a heart attack by approximately a factor of 2 (which they derived from APPROVe).  While Professors Celermajer and Vaughan did not agree, his Honour seemed to conclude that this was because they could not come to such a conclusion of a contribution by Vioxx with “a reasonable degree of scientific certainty” (Reasons at [770]).  The primary judge accepted that Vioxx did not cause atherosclerosis and did not cause plaque rupture (Reasons at [771]).  After the events early in December 2003 when Mr Peterson experienced plaque rupture, he was, the primary judge said, in the high risk group referred to in the APPROVe result in that he had symptomatic atherosclerotic cardiovascular disease, that is, he was in that category immediately prior to the MI.  The primary judge again turned to the FitzGerald hypothesis and said that, if valid, it required a potentially thrombotic environment in the vasculature, which existed for Mr Peterson.  The primary judge then said (Reasons at [772]):

   I think it likely that [Mr Peterson’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.

7. At [772] the primary judge again referred to his finding that Vioxx made a material contribution to Mr Peterson’s heart attack.  The primary judge also observed that, had he not found that Mr Peterson had been taking Vioxx continuously, he could not have been satisfied that it contributed to his MI.

8. The parties in the appeal have focused on [772]. On its face there are some inconsistencies. The primary judge seems to be applying the FitzGerald hypothesis to link the MI with the absence of prostacyclin and the taking of Vioxx. In other parts of his Honour’s reasons, he was at pains to say that the FitzGerald hypothesis needed to provide a plausible explanation but declined to find it valid. Without that hypothesis, there was no link between the absence of prostacyclin and the taking of Vioxx. His Honour’s conclusion was that it was the absence of prostacyclin that made “some contribution” to the occlusion.

9. Mr Peterson emphasised that Vioxx would not only have affected prostacyclin synthesis but also the dilation of the blood vessels, which in turn affects whether a thrombus occludes the artery.  The primary judge did not base his conclusion on that aspect of the proposed mechanism and action.  What is clear, however, from his Honour’s reasons is that the primary judge was not able to find that the heart attack would not have occurred other than for the taking of Vioxx.  The data did not support that conclusion.  The expert evidence did not support that conclusion and, as described by the primary judge, the FitzGerald hypothesis, even if accepted as valid, did not support that conclusion.

10. Having concluded our summary of the primary judge’s findings, we turn to address the arguments agitated on appeal.  The first of these concerns his Honour’s conclusions on the issues whether the consumption of Vioxx caused Mr Peterson’s MI.

    CAUSATION

11. Mr Peterson was at risk of suffering a heart attack quite independently of his consumption of Vioxx.  The primary judge said at [764]-[765]:

    The cardiologists said that the applicant’s risk factors for [MI] 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.

    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.

12. The primary judge’s ultimate conclusions on the issue of causation are at [772]-[773]:

    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. 

    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.

13. On the hearing of the appeal, Mr Peterson’s Counsel suggested, initially at least, that the second last sentence of [772], which seemed to contradict the last sentence in that paragraph, was either a reference to the angina attack which Mr Peterson suffered in early December, or to an inability on his Honour’s part to be satisfied, as a matter of scientific fact, that Vioxx consumption was a necessary condition for the occurrence of a MI.  These suggestions are less than compelling. 

14. In the passage in question, the primary judge was expressly making findings in relation to a crucial question of fact of importance to all Mr Peterson’s causes of action; it is impossible to accept that his Honour was speaking of a scientific, as opposed to a legal, conclusion.  That this is so is made clear in the immediately preceding paragraph.  At [771], his Honour said relevantly:

    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.  … 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.

15. One may pause here to observe that the primary judge was correct to recognise that it was not open to him to decline to make a finding one way or the other on the issue of causation.  As the High Court said in Amaca Pty Ltd v Ellis (2010) 240 CLR 111 at [5]-[6]:

    When, as here, medical and scientific examination cannot say whether exposure to respirable asbestos fibres was a cause of [the deceased’s] cancer, the medical practitioner and the scientist have little choice but, as one witness said at trial, to “take it into consideration in looking at what might have caused his lung cancer”.  In their inquiries, the uncertainty about cause means that they cannot “exclude it from the end result”. 

    The courts’ response to uncertainty arising from the absence of knowledge must be different from that of the medical practitioner or scientist.  The courts cannot respond to a claim that is made by saying that, because science and medicine are not now able to say what caused [the deceased’s] cancer, the claim is neither allowed nor rejected.  The courts must decide the claim and either dismiss it or hold the defendant responsible in damages.

16. It is not possible to accept the suggestion put on Mr Peterson’s behalf that his Honour was referring in [772] to the chest pains suffered by Mr Peterson in early December 2003.  His Honour’s findings were directed expressly to the heart attack which was the damage in respect of which Mr Peterson sues.  To accept this argument would mean that his Honour did not make a finding on the crucial issue of causation.

17. Counsel for Mr Peterson ultimately submitted, possibly in the alternative to their earlier submissions, that the last two sentences of [772] were not self-contradictory and that his Honour in [772] was making a finding that Vioxx made a material contribution to the occurrence of the heart attack even though he could not find that, but for the Vioxx, the heart attack would not have occurred. On this view, his Honour was satisfied on the balance of probabilities that Vioxx made a contribution to the formation of a thrombus sufficiently large to occlude the blood vessel to the heart, but was not satisfied that a thrombus of the necessary size would not have developed without the prothrombotic agency of Vioxx. We consider that this understanding of his Honour’s conclusions is correct. It is consistent with his Honour’s observation at [527] of the Reasons (set out at [68] above), and with his Honour’s references to evidence which he regarded as important. The primary judge said at [519]:

    Prof Harper’s response … 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 primary judge added at [519] the comment that:

    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.”

18. Counsel for Mr Peterson submitted that his Honour’s findings of ultimate fact were sufficient to sustain the judgment.  Counsel for MSDA submitted that the primary judge’s express refusal to find that Mr Peterson’s heart attack would not have happened but for the taking of Vioxx meant that Mr Peterson’s case should have been dismissed for want of an essential factual finding, namely, that it was more probable than not that the consumption of Vioxx caused or materially contributed to the occurrence of his heart attack.

19. We consider that the submission for MSDA must be accepted.  Moreover, in our opinion, the primary judge’s findings of primary fact do not afford a sufficient basis on which we should go further than his Honour and conclude that the consumption of Vioxx was a necessary condition of Mr Peterson’s MI.

20. We proceed now to explain our reasons for these conclusions.  First, we will discuss the legal principles relating to causation; we will then discuss the use of epidemiological studies and then we will discuss his Honour’s findings of primary fact.

    Causation:  The Test

21. In Chappel v Hart (1998) 195 CLR 232 at [27] McHugh J said:

    …If a wrongful act or omission results in an increased risk of injury to the plaintiff and that risk eventuates, the defendant’s conduct has materially contributed to the injury that the plaintiff suffers whether or not other factors also contributed to that injury occurring. …

    This statement was approved in Naxakis v Western General Hospital (1999) 197 CLR 269 at [31] and [127].

22. In Seltsam v McGuiness at [107]-[108] and [119]-[120], Spigelman CJ emphasised that proof that “the risk eventuated” in the specific injury suffered by the plaintiff is part of the plaintiff’s burden, and that this burden is not discharged merely by showing an increased risk of injury by reason of the defendant’s conduct: “Whether or not the increased risk ‘eventuated’, is the issue which must be determined”. It must be shown that “Y had happened because of X” (emphasis in original).

1. For the reasons that follow in relation to the s 75AD claim, we would dismiss MSDA’s appeal and dismiss the cross-appeal. However, independently of the question of “defect” and the state of scientific knowledge, Mr Peterson’s claim under s 75AD must fail on causation. That is, if there was a defect, Mr Peterson did not establish that he suffered injuries “because of the defect” within s 75AD: see [165] above.

   Defect within the meaning of s 75AC

2. A number of matters should be noted about s 75AC. It is an objective standard based upon what the public at large, not any particular individual, is entitled to expect: s 75AC(1) and Carey-Hazellv Getz Bros & Co (Aust) Pty Ltd (2004) ATPR 42-014 at [186]. Next, it does not require goods to be absolutely free from risk. The level of safety required is that which the community is entitled to expect. Third, “defects” in prescription pharmaceuticals raise their own issues. As was explained in the EM at [21] and [24]:

   … [T]he court must take all relevant circumstances into account in determining the safety of goods.  Safety expectations may also depend on matters such as the nature of the product and community knowledge of that product.  For example, there are a number of known negative side effects associated with certain pharmaceuticals and vaccines.  It is also generally accepted and known that these side effects cannot be avoided.  Such products are known to confer substantial benefits which flow to the wider community at large.  The small statistical chance of injury associated with them does not of itself mean that they are “defective”.

   …

   The role which intermediaries may play in the supply of goods may also need to be taken into account.  For example, prescription pharmaceuticals are supplied to the consumer by a qualified pharmacist and only on the prescription of a qualified medical practitioner.  Due to the complex nature and effects of these products, complete instructions and warnings may not be provided to the consumer by the manufacturer.  However, detailed product information is provided to doctors and pharmacists by the manufacturer so these learned intermediaries are sufficiently informed to be able to decide whether or not it is appropriate to dispense pharmaceuticals to particular consumers.  This factor will be relevant in determining whether a pharmaceutical is defective, particularly where a claim of a defect in information provided is made.

3. As the statute expressly provides (reinforced by the EM), goods are “defective” if they do not have the degree of safety which persons are generally entitled to expect in all the circumstances and, in the context of a prescription drug, those circumstances may include the PI and information provided to doctors and pharmacists by the manufacturer. 

4. Mr Peterson’s case at trial was that there was a defect within the meaning of s 75AC because (1) as a matter of its chemistry and human physiology as reflected in epidemiology Vioxx increased the risk of MI, and (2) MSDA failed to provide adequate warning of that increased risk.

5. The primary judge addressed this issue at [914] as follows:

   The circumstances to which [Mr Peterson] 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 [PI] 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 ....

6. The primary judge accepted that items (a) – (d) existed in the present case (Reasons at [915]).  His Honour concluded that there was support in the evidence for item (e).  For items (f) – (h), in the context of MI, the primary judge 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.  So, for example, for a patient in a reasonably advanced state of atherosclerosis, the risk was more pronounced (Reasons at [916]).  As a result, the primary judge concluded that “[a]bsent the provision of any information, advice or warning, … the risk … made the safety of Vioxx less than what persons generally were entitled to expect” (Reasons at [917]).  The primary judge stated that “the withdrawal of Vioxx from the market on 30 September 2004 implied as much” (Reasons at [917]).  

7. It is important to record that the primary judge did not find that persons generally are entitled to expect that all drugs will be free of side-effects.  Instead, his Honour held that “persons generally are 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” (Reasons at [917]).

8. In the context of the present case, the primary judge held that there was “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” (Reasons at [918]).  The primary judge found that until then, the safety of Vioxx (as purchased and consumed by Mr Peterson) was not such as persons generally were entitled to expect (Reasons at [918]).  In particular, the primary judge found that the mere amendment of the Vioxx PI 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 (Reasons at [921]).  His Honour held that the November 2001 amendment to the PI should have been, but was not, communicated to Dr Dickman by a “Dear Doctor” letter.  His Honour made that finding on the bases that:

   1.The PI in its amended form in November 2001 was an instruction or warning within the meaning of s 75AC(2)(d);

   2.In October 2000, MSDA had corresponded with doctors generally including advice about various side-effects which might be associated with the consumption of Vioxx, and various precautions which ought to be observed.  An aspect of that advice was that, in certain osteoarthritis studies, the MI rate amongst those taking Vioxx had been less than 0.1 %;

   3.At all times that Vioxx was on the market in Australia (see [37] above), MSDA had available information to the effect that, in the VIGOR trial, the MI 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, 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;

   4.The November 2001 amendment to the PI should have been, but was not, communicated to Dr Dickman by a “Dear Doctor” letter;

   5.Accordingly, the mere amendment of the Vioxx PI 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.

9. On those bases, the primary judge held that when (after November 2001) MSDA supplied the Vioxx tablets that were ultimately consumed by Mr Peterson, those tablets had a defect within the meaning of s 75AD of the TPA. Although the primary judge did not identify the defect in express terms, it is apparent that he characterised the defect as the risk of Vioxx absent the provision of any information, advice or warning as to this risk (Reasons at [917]). MSDA submitted that the primary judge was wrong to hold that Vioxx had a defect within the meaning of s 75AD(b) as provided by ss 75AC(1) and (2). We reject this submission.

10. By way of cross-appeal, Mr Peterson submitted that his Honour should have found that the defect in Vioxx had been discovered by no later than March 2000 when the results of the VIGOR study were released and provided the signal risk that the consumption of Vioxx materially increased the risk of MI.  We do not accept this aspect of Mr Peterson’s cross-appeal.  It is appropriate to deal with the cross-appeal first.

11. As we have explained earlier in these reasons, we agree with the primary judge that there were difficulties in drawing definite conclusions from the VIGOR study about the risk of MI from the consumption of Vioxx:  see [48] above.  The difficulties identified included that the views of the experts were not consistent, the VIGOR trial was dealing with very low numbers and experts were offering other plausible causes about the relationship between the increased risk of MI and the consumption of Vioxx.  Indeed, in a publication in late 2004, experts expressed that a plausible cause of the apparent excess risk of MI in the VIGOR trial was the combination of some cardioprotective effect of naproxen and “the play of chance”.  They also said that “[w]hile other mechanisms cannot be discounted, there is currently little evidence in humans to support a prothrombotic effect for coxibs” (Reasons at [385]).  Moreover, these conclusions were not supportive of the FitzGerald hypothesis.

12. Notwithstanding these difficulties, the better view is that Vioxx had a defect within the meaning of s 75AC. The defect was one which affected some people, not all. The defect was that in some people, by a mechanism not known and the subject of no hypothesis, it increased the risk of MI and provided no information, advice or warning as to this effect: see [137]-[138] and [198] above. But the conclusion that Vioxx had this “defect” presents two further statutory questions. First, the statute requires that an individual claimant suffer injuries because of the defect: s 75AD(c). As has already been demonstrated, Mr Peterson did not demonstrate that the increased risk affected him, in the sense that the MI he suffered was caused by (because of) his consumption of Vioxx: see [165] above. In other words, Mr Peterson’s claim fails at the first hurdle.

13. Moreover, even if Mr Peterson had demonstrated that the MI he suffered was caused by (because of) his consumption of Vioxx (which he did not), the next relevant statutory enquiry would be whether the defect (as it has been identified) was one which, given the state of scientific or technical knowledge at the time when the goods were supplied by MSDA, was not such as to enable that defect to be discovered.  It is to that issue we now turn.

    Section 75AK(1)(c) – State of Art Defence

14. Section 75AK(1)(c) of the TPA contained the “development of risks” or “state of art defence” and relevantly provided:

    (1)       In a liability action, it is a defence if it is established that:

    …

    (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 ...

    The section was based on Art 7(e) of the Directive. 

15. The defence in s 75AK(1)(c) was described in the EM at [55]-[56] as follows:

    It is the objective state of scientific and technical knowledge, not the subjective knowledge of the individual manufacturer, which is to be taken into account.  It is only if the defect could not have been discovered by anybody that the manufacturer will be able to succeed.  A manufacturer must expect that there may be further scientific or technical advances during the period of testing and production.  The manufacturer should therefore satisfy itself that there have been no further technical advances which affect the safety of the goods before putting them into circulation.

    Similarly, a manufacturer must keep up to date with advances in knowledge after it first puts a product into circulation to ensure that new information is taken into account in the manufacture of subsequent goods, as new information may expose defects in goods.  The crucial time is therefore when the alleged defective good which caused the injury was supplied by the manufacturer, not the time at which the manufacturer first supplied goods of that type.

16. The primary judge dismissed Mr Peterson’s claim under s 75AD because he found that the state of scientific knowledge at the time of supply was not such as to have enabled the defect to have been discovered: s 75AK(1)(c) of the TPA. As will be detailed below, we agree with the primary judge’s findings and conclusions in this respect.

17. The primary judge relied on the factual finding 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 MI (Reasons at [927]).  The primary judge’s reasoning which led to the factual finding was as follows (Reasons at [927]):

    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.”  …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.

    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 [MI].  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(l)(c) refers. 

18. Mr Peterson cross-appealed against the primary judge’s orders dismissing the s 75AD claim. Mr Peterson submitted that the defence in s 75AK(1)(c) cannot apply if, at the time of supply, the defect had already been discovered and that the primary judge should have found that the defect in Vioxx had been discovered by no later than March 2000 (see [199] above), when the results of the VIGOR study were released. Mr Peterson submitted that the primary judge’s failure to make that finding was because he construed s 75AK(1)(c) of the TPA as requiring that for a defect to be discovered, it had to be established at a scientific level rather than when it is known that there is a real and serious risk that it exists, notwithstanding that it may only be later that the defect can be positively proved to exist at the scientific level. However, the state of scientific knowledge at the time of Mr Peterson’s MI was not just the results of the VIGOR study but the conclusions to be drawn from it. This is clear from his Honour’s reasons. Mr Peterson’s cross-appeal raised questions of statutory construction and disputes as to the factual findings made by the primary judge. His complaints should be dismissed.

19. As recorded at [205]-[206] above, the state of scientific knowledge at the time Mr Peterson took Vioxx was such that it was not demonstrated that Vioxx caused an increased risk of MI. As the primary judge said at [929]:

    Section 75AK(l)(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). … 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).

    That is, the state of scientific or technical knowledge at the time when Vioxx was supplied by MSDA to Mr Peterson was not such as to enable the defect to be discovered.  We refer to [35] to [46] above.  We agree with these conclusions.

    CONCLUSION

20. We would allow MSDA’s appeal and set aside the judgment in favour of Mr Peterson and dismiss his action.

21. As to MSDA’s application for leave to appeal in respect of the determination of questions which affect the other applicants, we would grant leave to appeal, and allow the appeal to the extent indicated in our reasons.

22. We extend time to allow Mr Peterson to file a notice of cross-appeal but dismiss the cross-appeal.

23. We direct that the parties confer and thereafter by 4:00pm on 26 October 2011 file minutes of orders (including as to costs), and in the event of disagreement file and serve written submissions as to the contentions of the parties.

I certify that the preceding two hundred and twelve (212) numbered paragraphs are a true copy of the Reasons for Judgment herein of the Honourable Chief Justice Keane and Justices Bennett and Gordon.

Associate:

Dated:       12 October 2011

ANNEXURE A

Commonality

Question 1.Are any and which of the questions set out below common to the claims of the group members?

Answer:Save to the extent indicated in the answers set out below, all the questions are common to the claims of the group members.

Materially increased risk

Question 2.Is there a physiological mechanism by which the consumption of Vioxx is capable of causing any and which of the Vioxx cardiovascular conditions?

Answer:As amended by replacing “causing” with “contributing to the onset of”:  In the case of myocardial infarction, yes;  otherwise, no.

Question 3.If the answer to question 2 is in the affirmative, then for each such condition, what is the physiological mechanism?

Answer:The aggregation of thrombotic material in the vasculature as the result of the blocking of the production of prostacyclin by the inhibition of COX-2 in the absence of any blocking of the production of platelet thromboxane.

Question 4.Did the consumption of Vioxx increase the risk of suffering any and which of the Vioxx cardiovascular conditions?

Answer:          In the case of myocardial infarction, yes;  otherwise, no.

Question 5.If the answer to question 4 is in the affirmative, was the increase in risk material?

Answer:          To the extent that question 4 was answered in the affirmative, yes.

Negligence

Question 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?

Answer:(a) & (b):  Late September 2004.  However, Merck Australia was first presented with a worrisome and important signal of potential cardiovascular risk associated with the consumption of Vioxx in March 2000.

(c):  Yes.

Question 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)?

Answer:          (a) & (b):  No.

Question 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?

Answer:          (a) & (b):  No.

Question 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?

Answer:          (a), (b) & (c):  No

(d):

(i)Merck Australia failed to provide adequate information, advice or warning to healthcare professionals generally about the signal of risk referred to in the answer to question 6.  Whether that failure was less than reasonable in all of the circumstances is not a common question.

(ii)Whether Merck Australia failed to provide adequate information, advice or warning to individual healthcare professionals about the signal of risk referred to in the answer to question 6 is not a common question.

(iii)Merck Australia did not fail to provide adequate information, advice or warning to the general public about the signal of risk referred to in the answer to question 6.

(e):As to the dissemination of representations to health care professionals who treated or advised individual group members, not a common question.  Otherwise, not appropriate to answer.

Question 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?

Answer:          No.

Question 11.   Is the fact that the Product Information for Vioxx was approved by the TGA pursuant 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?

Answer:          No.

Section 52 of the Trade Practices Act 1974 (Cth)

Question 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?

Answer:          (a):  Not a common question.

(b):

(i)Merck Australia marketed, distributed and supplied Vioxx for sale in Australia without providing adequate information, advice or warning to health care professionals generally about the signal of risk referred to in the answer to question 6.

(ii)Whether Merck Australia marketed, distributed and supplied Vioxx for sale in Australia without providing adequate information, advice or warning to individual healthcare professionals about the signal of risk referred to in the answer to question 6 is not a common question.

(iii)Merck Australia did not market, distribute or supply Vioxx for sale in Australia without providing adequate information, advice or warning to the general public about the signal of risk referred to in the answer to question 6.

(c):As to the dissemination of representations to health care professionals who treated or advised individual group members, not a common question.  Otherwise, not appropriate to answer.

Question 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?

Answer:Merck Australia’s promotional interactions with prescribers were in trade and commerce within the meaning of the Trade Practices Act.

Question 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 s 52 of the Trade Practices Act?

Answer:As to the conduct identified in answer 12(b)(i):  Until 16 November 2001, yes;  otherwise, no.

Question 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?

Answer:          (a) & (b):  No.

Question 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 TGA pursuant 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?

Answer:          (a) & (b):  No.

Sections 75AD, 74B and 74D of the Trade Practices Act 1974 (Cth)

Question 17. Were Vioxx tablets manufactured by Merck Australia “goods” that were “ordinarily acquired” as defined in s 74A(2) of the Trade Practices Act?

Answer:          Yes.

Question 18.   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 reasonably fit for purpose within the meaning of s 74B of the Trade Practices Act?

Answer:          No.

Question 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 s 74D of the Trade Practices Act?

Answer:          No.

Question 20. If the answer to question 5 is in the affirmative, were Vioxx tablets defective within the meaning of s 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?

Answer:In the absence of any information, advice or warning, addressed to a particular group member or to his or her medical practitioner, to the effect that the consumption of Vioxx materially increased the risk of myocardial infarction, yes.

Question 21. If the answer to question 5 is in the affirmative, were Vioxx tablets defective within the meaning of s 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?

Answer:With respect to packaging and labelling, not a common question. With respect to the Product Information, the absence of any adequate information, advice or warning therefrom was a circumstance which, together with others, made the safety of Vioxx not such as persons generally were entitled to expect within the meaning of s 75AD.

Question 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 s 74B of the Trade Practices Act by reason of the fact that the consumption of Vioxx materially increased the risk of suffering the condition?

Answer:          Not a common question.

Question 23. If the answer to question 5 is in the affirmative, were Vioxx tablets not of merchantable quality within the meaning of s 74D of the Trade Practices Act by reason of the fact that the consumption of Vioxx materially increased the risk of suffering the condition?

Answer:          Not a common question.

Question 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?

Answer:          No.

Question 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?

Answer:          No.

Claim against Merck Inc

Question 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?

Answer:(a) & (b):  Late September 2004.  However, Merck Inc was first presented with a worrisome and important signal of potential cardiovascular risk associated with the consumption of Vioxx in March 2000.

(c):  Yes.

Question 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?

Answer:          (a) & (b):  No.

Question 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?

Answer:          (a) & (b): No.

Question 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?

Answer:          (a), (b), (c) & (d): No.

Question 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?

Answer:          No.