[e-drug] Vioxx, the implosion of Merck, and aftershocks at the FDA

["E-Drug" <e-drug@healthnet.org>]

E-DRUG: Vioxx, the implosion of Merck, and aftershocks at the FDA
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[A hard-hitting Lancet editorial and article on the rofecoxib debacle; copied as fair use. WB]

http://www.thelancet.com/journal/vol364/iss9449/full/llan.364.9449.early_online_publication.31376.1

Vioxx, the implosion of Merck, and aftershocks at the FDA
by Richard Horton 

Summary 

Today we publish results from a cumulative meta-analysis which show that the unacceptable cardiovascular risks of Vioxx (rofecoxib) were evident as early as 2000-a full 4 years before the drug was finally withdrawn from the market by its manufacturer, Merck. This discovery points to astonishing failures in Merck's internal systems of post-marketing surveillance, as well as to lethal weaknesses in the US Food and Drug Administration's regulatory oversight. In a recent Editorial, we commended Merck for acting promptly in the face of new findings about the safety of Vioxx. Our praise was premature. The evidence showing that Vioxx caused significant adverse events was apparent well before data from the APPROVe trial triggered Merck's overdue intervention. This week's report by Peter J|ni and colleagues will add significant weight to ongoing litigation against Merck by patients who believe they were harmed by this drug. 

These findings also come in the wake of new disclosures that suggest Merck was indeed fully aware of Vioxx's potential risks by 2000. Investigations by the Wall Street Journal have revealed e-mails that confirm Merck executives' knowledge of their drug's adverse cardiovascular profile-the risk was "clearly there", according to one senior researcher. Merck's marketing literature included a document intended for its sales representatives which discussed how to respond to questions about Vioxx-it was labelled "Dodge Ball Vioxx". Given this disturbing contradiction- Merck's own understanding of Vioxx's true risk profile and its attempt to gloss over these risks in their public statements at the time-it is hard to see how Merck's chief executive officer, Raymond Gilmartin, can retain the confidence of the public, his company's most important constituency. 

The FDA's position is no less comfortable. The public expects national drug regulators to complete research, such as that published by J|ni and colleagues, in their ongoing efforts to protect patients from undue harm. But, too often, the FDA saw and continues to see the pharmaceutical industry as its customer-a vital source of funding for its activities-and not as a sector of society in need of strong regulation. 

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http://www.thelancet.com/journal/vol364/iss9449/full/llan.364.9449.early_online_publication.31375.1

Risk of cardiovascular events and rofecoxib: cumulative meta-analysis  

Peter J|ni, Linda Nartey, Stephan Reichenbach, Rebekka Sterchi, Paul A Dieppe, Matthias Egger 

Summary 

Background The cyclo-oxygenase 2 inhibitor rofecoxib was recently withdrawn because of cardiovascular adverse effects. An increased risk of myocardial infarction had been observed in 2000 in the Vioxx Gastrointestinal Outcomes Research study (VIGOR), but was attributed to cardioprotection of naproxen rather than a cardiotoxic effect of rofecoxib. We used standard and cumulative random-effects meta-analyses of randomised controlled trials and observational studies to establish whether robust evidence on the adverse effects of rofecoxib was available before September, 2004. 

Methods We searched bibliographic databases and relevant files of the US Food and Drug Administration. We included all randomised controlled trials in patients with chronic musculoskeletal disorders that compared rofecoxib with other non-steroidal anti-inflammatory drugs (NSAIDs) or placebo, and cohort and case-control studies of cardiovascular risk and naproxen. Myocardial infarction was the primary endpoint. 

Findings: We identified 18 randomised controlled trials and 11 observational studies. By the end of 2000 (52 myocardial infarctions, 20742 patients) the relative risk from randomised controlled trials was 2730 (95% CI 1722-4733, p=07010), and 1 year later (64 events, 21432 patients) it was 2724 (1724-4702, p=07007). There was little evidence that the relative risk differed depending on the control group (placebo, non-naproxen NSAID, or naproxen; p=0741) or trial duration (p=0782). In observational studies, the cardioprotective effect of naproxen was small (combined estimate 0786 [95% CI 0775-0799]) and could not have explained the findings of the VIGOR trial. 

Interpretation: Our findings indicate that rofecoxib should have been withdrawn several years earlier. The reasons why manufacturer and drug licensing authorities did not continuously monitor and summarise the accumulating evidence need to be clarified.