More studies prior to Vioxx recall were needed
Should Merck have conducted more studies of cardiovascular risk of Vioxx? This is a central question regarding drug safety worldwide. And this issue was raised during recent hearings at the Capitol Hill. John E. Calfee, Ph.D. of the conservative think tank American Enterprise Institute tried to answer this question. Below are excerpts from his testimony.
The clinical trials that provided the foundation for FDA approval of Vioxx had revealed no excess cardiovascular problems in comparison to traditional NSAID. There were some signs of risk relative to placebos) i.e., relative to the use of no pain reliever at all) but as FDA staff noted at the time, this was true of all NSAIDs. The large-scale VIGOR trial, published in November 2000 (more than a year after Vioxx was approved for marketing), revealed dramatically lower G.I. problems but unexpectedly showed a significantly higher level of heart attacks and strokes. The implications of this result were far from clear. (Related article: Vioxx should have never been approved, Dr. David Graham says)
A substantial fraction (38 percent) of heart attacks was in patients for whom low-dose aspirin was indicated (due to history of heart attacks or other cardiovascular complications) but who failed to take it (the trial avoided accepting patients on aspirin). For other patients, heart attack rates did not differ significantly. Because heart attacks were not a pre-defined endpoint in the VIGOR trial, because Vioxx had been compared to naproxen, a traditional NSAID, rather than to a placebo, and because other trials involving both Vioxx and Celebrex had not revealed significant cardiovascular problems, it was by no means obvious that Vioxx would in fact cause excess heart attacks compared to placebos. Obvious alternatives were that the result was partly a statistical fluke (always possible when selecting a non-predefined endpoint for analysis) or that the comparator, naproxen, was instead cardio-protective. Subsequent research strongly suggested that naproxen is at least moderately cardioprotective. (Related article: Merck sold Vioxx ruthlessly prior to recall)
A natural question, raised in the medical literature and elsewhere was whether Merck should immediately mount another clinical trial, presumably against a placebo instead of another NSAID, in order learn with more certainty whether Vioxx causes heart attacks. But what trial to run? Considerable debate centered on what population to study: patients with high risk for heart attacks and strokes (whose comorbidities and multiple drug use would greatly complicate the trial), or some other population? (Related article: Merck reportedly hid Vioxx risks prior to recall)
Yet running even a single trial with sufficient power to detect a doubling of a small long-term risk would involve thousands of patients spread across scores or hundreds of medical practices, at a cost of tens of millions of dollars or more, and require one to three years for design, execution and analysis. An equally important question was which drug to test. Vioxx was probably not the best target. As the FDA has repeatedly pointed out, traditional NSAIDs had never been subjected to large, long-term trials like VIGOR. The fact that NSAIDs reduce inflammation, which is implicated in heart attacks, suggests that they could prevent heart attacks. But analysis of the biological mechanisms involved in NSAIDs generates ambiguous results, suggesting that Cox-2s and other NSAIDs could facilitate rather than impede the processes that lead to heart attacks. (Related article: Merck hid risks of death from Vioxx)
Given the fact that none of the traditional NSAIDs are under patent, such trials would have to be sponsored by NIH or another public source. It so happened that in 2001, Merck was already planning a large, placebo-controlled trial (called APPROVe) to test whether Vioxx could prevent colorectal cancer. By adding cardiovascular endpoints, the APPROVe trial could detect significant cardiovascular risk. Given these circumstances, it is hard to see why Merck had an obligation to do more than run the very expensive APPROVe trial with its cardiovascular endpoints. Events have vindicated this view. The tight focus of academic and other critics on Vioxx and Merck proved misplaced. When the FDA issued its most definitive report on NSAIDs and undertook a major initiative in the NSAID market on April 7, 2005, it made perfectly clear that what began as a Vioxx incident was in fact an NSAID issue. It stated that there is no convincing evidence that Vioxx is more dangerous than other Cox-2s in terms of cardiovascular risk or that Cox-2s as a class are more dangerous than traditional NSAIDs. The agency therefore required cardiovascular warnings for all NSAIDs and urged NIH and other agencies to undertake large-scale clinical trials of traditional NSAIDs.
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