The cyclo-oxygenase 2 (COX-2) inhibitor rofecoxib (Vioxx) was withdrawn by Merck on September 30 2004 because of adverse cardiovascular effects identified by the unpublished Adenomatous Polyp Prevention on Vioxx (APPROVe) study. An increased risk of heart attack had been observed in 2000 in the Vioxx Gastrointestinal Outcomes Research study (VIGOR), but was attributed to a protective effect of another non-steroidal anti-inflammatory drug, naproxen, rather than an adverse effect of Vioxx.
Peter Jüni (University of Berne, Switzerland) and colleagues pooled the results of all randomised trials and observational studies involving Vioxx to establish whether the drug's poor safety profile was evident earlier than September 2004. This was done by searching bibliographic databases and relevant files of the US Food and Drug Administration. The investigators identified 18 randomised controlled trials and 11 observational studies. By the end of year 2000, 52 out of around 20,000 patients had a heart attack; this equated to more than a doubling of the risk in patients given Vioxx, compared to patients on placebo or other non-steroidal anti-inflammatory drugs.
Co-author Matthias Egger comments: "If Merck's statement in their recent press release that "given the availability of alternative therapies, and the questions raised by the data, we concluded that a voluntary withdrawal is the responsible course to take" was appropriate in September, 2004, then the same statement could and should have been made several years earlier, when the data summarised here had become available. Instead, Merck continued to market the safety of rofecoxib."
The Lancet is critical of both Merck and the FDA for their role in the Vioxx affair. Editor Richard Horton states in an accompanying commentary: "The licensing of Vioxx and its continued use in the face of unambiguous evidence of harm have been public-health catastrophes. This controversy will not end with the drug's withdrawal. Merck's likely litigation bill is put at between US $10 and $15 billion. The company has seen its revenues and market capitalisation slashed. It has been financially disabled and its reputation lies in ruins. It is not at all clear that Merck will survive this growing scandal."
"But the most important legacy of this episode is the continued erosion of trust that public-health institutions will suffer. Failure to act decisively on signals of risk might minimise short-term political criticism for regulators, or shareholder unrest for company chief executives. But the long-term consequence of prevarication is a tide of public scepticism about just whose interests drug makers and regulators truly represent."
Dr Horton concludes: "It is no good saying, as some academic physicians have said to me, that one must expect pharmaceutical companies to do all they can to protect their products, even in the face of clear evidence of risk. And it is of little help to suggest that regulators have a nearly impossible job of balancing harms and benefits. Defenders of our systems of drug regulation argue that the blame for the Vioxx debacle instead rests on allegedly credulous specialists who should have asked tougher questions about the drug they were prescribing. Why clinical investigators studying Vioxx did not do more to raise concerns is a fair question that needs to be answered. But in doing so, we must not diminish the importance of the covenant of trust that society has established with powerful commercial and governmental institutions. For with Vioxx, Merck and the FDA acted out of ruthless, short-sighted, and irresponsible self-interest."
Contact: (study authors) Mathis Brauchbar, Media Officer NRP 53, Signaustrasse 11, CH-8008 Zürich, Switzerland; T) +41 79 407 9362; firstname.lastname@example.org