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Vioxx: an unequal partnership between safety and efficacy
Rofecoxib (Vioxx) is, or was, Merck and Co’s leading shared by the FDA, who implemented labelling drug for control of acute pain, and pain associated with changes in 2002 to reflect the findings from the VIGOR osteoarthritis, rheumatoid arthritis, and menstruation.
trial. However, even following these warnings, and in Last year worldwide sales of rofecoxib reached US$2·5 the face of mounting evidence for the cardiovascular billion following the most impressive global sales side-effects of rofecoxib, aggressive direct-to-con- growth for any drug in 2001. Last week, after urgent sumer marketing of this questionable drug continued discussions with the US Food and Drug Administration (FDA), Merck felt compelled to withdraw rofecoxib What then finally tipped the balance in the risk- after its most recent trial, APPROVe (Adenomatous benefit equation leading to last week’s dramatic Polyp Prevention On Vioxx), showed an adverse global withdrawal of rofecoxib? APPROVe was cardiovascular side-effect profile. For Merck to act so multi-centre, randomised, placebo-controlled, promptly in the face of these most recent safety double-blind study investigating the effects of concerns is commendable and should serve as an rofecoxib on the recurrence of neoplastic large bowel example of responsible pharmaceutical industry polyps in 2600 patients with a previous history of practice. However, the short history of cyclooxygenase colorectal adenoma. It was stopped prematurely on (COX)-2 inhibitors has been plagued by persistent the instruction of the data and safety monitoring safety concerns. The question that must now be board after the investigators found that after answered is why has it taken so long for Merck and 18 months treatment, patients taking rofecoxib had government drug regulators to address these signals twice the risk of a myocardial infarction compared with those receiving placebo. Advice is now being The story of COX-2 inhibitors began for clinicians and issued to pharmacists and doctors in each of the their patients in 1999 with the licensing of two first 80 countries where rofecoxib is marketed to stop generation drugs, rofecoxib and celecoxib, by the FDA.
prescribing the drug with immediate effect. 2 million Their primary indications were for the control of pain patients already taking rofecoxib will be contacting associated with several different conditions and their their physicians to discuss discontinuing treatment—a debut was announced in 2000 in the medical literature busy and anxious time for doctors around the world. See N Engl J Med 2000; 343:
with two landmark trials: VIGOR for rofecoxib, and A key question remains as to why it took this risk to 1520–28; and JAMA 2000; 284:
CLASS for celecoxib. Subsequently, a number of second be identified from a relatively small trial investigating a generation COX-2 inhibitors have been developed.
novel use for rofecoxib, after it had been licensed for These include valdecoxib, parecoxib, etoricoxib, and several years and prescribed to so many patients? lumiracoxib. The indications for their use have Although Peter Kim, president of Merck Research remained largely unchanged and more “me-too” Laboratories, recently said “Merck has always believed that prospective, randomized, controlled clinical trials From the outset, questions have been raised about are the best way to evaluate the safety of medicines.
the safety profile of these drugs. Although the CLASS APPROVe is precisely this type of study . . . “, it is trial did not find a difference in the incidence of unlikely that APPROVe was designed and executed cardiovascular side-effects between celecoxib and with a general safety assessment as its primary goal. A ibuprofen or diclofenac, the VIGOR trial revealed a further question relates to the safety of the other COX- significant increase in the number of myocardial 2 inhibitors being actively marketed today. Although infarctions in patients taking rofecoxib compared with the TARGET trial published in The Lancet in August this See Articles
those receiving naproxen. These concerns were year, and the largest COX-2 trial to date, failed to Lancet 2004; 364: 665–674,
675–84; and Comment
crystallised the following year by Debabrata Mukherjee, demonstrate a statistically significant difference in Lancet 2004; 364: 639–40
Steven Nissen, and Eric Topol in JAMA in their review cardiovascular side-effects between lumiracoxib and See JAMA 2001; 286: 954–59
paper specifically highlighting the cardiovascular side- naproxen or ibuprofen, more people taking effect profile of COX-2 inhibitors. Concerns were lumiracoxib had a myocardial infarction. Vol 364 October 9, 2004
For personal use. Only reproduce with permission from Elsevier Ltd
Doctors need to be more aware of the very small trial in a novel application to reveal them. In preliminary nature of data, both for safety and the end it is patients, now understandably confused efficacy, provided with newly licensed drugs. For by the implications of rofecoxib’s withdrawal, who rofecoxib the original safety data were based on will lose the most. Which drugs, they will ask, should results from approximately 5000 patients. In comparison with the 2 million people receiving the Finally, drug regulators must now reassess the drug until last week, this is a very small number and safety and efficacy thresholds required for the helps to explain how an important side-effect could licensing of a new pharmaceutical product. Clearly, have been missed, and subsequent confidence in the this is an immensely complicated equation drug misplaced. For all newly licensed drugs, confi- involving, among other factors, the nature of the dence about safety can only be provisional. condition being treated, the therapeutic strategies Pharmaceutical companies also have lessons to already available, and the perceived benefit-to- learn. Merck responded well to this latest piece of hazard ratio of the new treatment. The Vioxx story is the rofecoxib jigsaw puzzle. However, the real one of blindly aggressive marketing by Merck mixed picture of cardiovascular risk has been apparent for with repeated episodes of complacency by drug some time and Merck’s vigorous defence of this regulators. We need clear statements from all parties drug in the past was clearly an error. If the dangers in this sorry tale about the lessons to be learned.
associated with rofecoxib were not proven, they Without more vigilant drug regulation in the future, were certainly possible, even probable, given the doctors will continue to be misled and patients’ lives available data, and it should not have been left to a will continue to be endangered. ■ The Lancet A steppe towards a cooler world
On Sept 30, Russia’s President Vladimir Putin gave the One US Governor has outed himself as an opponent kiss of life to the embattled 1997 Kyoto Protocol on to Bush on climate matters. The Republican Arnold greenhouse-gas emissions by having his cabinet Schwarzenegger, a Bush fan in most respects, seems an approve ratification of the treaty. The Russian unlikely bedfellow for Putin, but he has pitched parliament will in all likelihood concede Putin’s wishes.
California in with other US states in a legal battle to With the USA, the world’s largest greenhouse-gas make Bush say that carbon dioxide is a pollutant, which emitter (over a third of the 1990 total) withdrawing would force the Government to act. Schwarzenegger is from the treaty in 2001, Putin’s resuscitation is also playing one of the good guys, in a state where the car rules. He is backing plans to reduce carbon dioxide With Russia signing up to the Protocol—ratification is expected early next year—enough signatories will exist Russia’s signing of the protocol, itself criticised for for the treaty to come into force. With that comes the being insufficient and not tackling pollution from the binding agreement for 36 industrialised countries to developing world, is only a start. And Putin is not reduce their collective emissions of six greenhouse being completely altruistic—his new green creden- gases (mostly carbon dioxide, and from motor tials are designed to impress the European Union vehicles, power stations, and factories) by at least 5% enough for them to support Russia’s entry to the of their 1990 levels, by 2008–12. The targets are World Trade Organisation. But other Kyoto signa- achievable and beyond: the UK’s target of a 12·5% tories will now start falling into line. Japan, the reduction has already been surpassed (it is now world’s fourth worst polluter, with a new tax this year 14·5%). Without reductions in greenhouse gases, the on the use of fossil fuels, will now be on notice to do world will see more and more respiratory and more. Putin sends a strong message to that other cardiovascular diseases, cancer, and, as a result of renegade country: the USA, and a new president climate change, global shifts and increases in infectious perhaps, must face up to its responsibilities as the diseases previously confined to the tropics.
world’s worst polluter. ■ The Lancet Vol 364 October 9, 2004
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