Major Vioxx Studies
VIGOR Study (Vioxx GI Outcomes Research)
The VIGOR study began in January 1999 and concluded in March 2000. The study was designed to measure the safety of Vioxx vs. naproxen in arthritis patients, but it did not test the efficacy of Vioxx in treating arthritis.
As early as 4-6 weeks into the trial, the Vioxx group began showing a higher rate of fatal cardiovascular events including heart attack and stroke. By December of 1999, there were twice as many deaths in the Vioxx group. The Data Safety Monitoring Board (DSMB) overseeing the VIGOR study was notified about the deaths, but the data was not immediately interpreted as evidence of the risks of Vioxx. It was hypothesized that the difference in fatalities might have been attributable to the protective anti-platelet effects of naproxen, instead of indicating a complication of Vioxx.
However, in 2006, an investigative report by National Public Radio revealed that the percentage of deaths was steadily rising in the Vioxx group, while remaining almost constant in the naproxen group, which indicated an increased danger with extended use of Vioxx. Additionally, there is no evidence that naproxen’s anti-platelet effects were significant enough to have caused the discrepancy in the VIGOR study.
Perhaps the most ironic finding of the VIGOR study was that the incidence of peptic ulcers was the same in both the Vioxx and naproxen groups. Thus, VIGOR proved that Vioxx had no benefit over traditional pain killers in preventing ulcers.
The results of VIGOR were submitted to the FDA in 2001, and consequently in 2002 a black box warning was ordered for Vioxx packaging, informing consumers of the possible risk of heart attack, stroke, and fatal blood clots.
APPROVe Study (Adenomatous Polyp PRevention On Vioxx)
The APPROVe trial began in 2001 as a 3-year study of the effectiveness of Vioxx vs. placebo in preventing the regrowth of colon and rectal polyps in 2,586 patients with a history of colorectal adenomatous polyps (pre-cancerous masses in the colon and rectum). The study was terminated in September 2004 because of a drastic increase in heart attacks in the Vioxx group. It was due to this study that Merck made the long-standing claim that the risks of Vioxx did not appear until after 18 months of treatment. Merck maintained the 18-month theory until 2008, when the results of several Vioxx studies were scrutinized and it was discovered that as many as 25% of the heart attacks in Vioxx trials occurred within the first month of treatment.
As a direct result of the APPROVe study, Vioxx was withdrawn from the market. The APPROVe study publicized the cardiovascular risks of Vioxx, and it marked the beginning of a string of lawsuits that have cost Merck billions. Because of the drug’s withdrawal, Merck’s handling of Vioxx was placed under intense scrutiny. It was later discovered that the APPROVe study results revealed that taking Vioxx carried even more risk than previously thought.
In 2006, a New England Journal of Medicine article revealed that the APPROVe study results, specifically the number of Vioxx-related deaths during and after the study period, were improperly calculated in order to make the drug appear safer. Some numbers appeared not to have been reported at all.
Merck claimed that numbers were “transposed.” However, later inquiries showed that the numerical discrepancy in the results of the APPROVe trial resulted from the fact that, in the “off-drug period” immediately following the discontinuation of the study, deaths in the placebo group were counted for a year, but deaths in the Vioxx group were counted for only 14 days. During that unreported period, the proportion of deaths in the Vioxx group was much greater than in the control group.
In addition to several audits of Merck’s study results for APPROVe, Merck was investigated for their handling of Vioxx from a “sponsorship” perspective. Merck was accused of utilizing professional ghostwriters to author clinical studies, with the idea of making the results sound more favorable.
At every turn, Merck made decisions and oversights that came back to haunt the drug giant later. The entire medical community scrambled to analyze the Vioxx disaster and answer the big questions: how did it happen, and could it happen again?
Several editorials were published accusing Merck, and the drug industry at large, of corruption and profiteering at the cost of public health. In 2006, Merck made an official statement admitting that it had misinterpreted the results of the APPROVe study, and admitting that the cardiovascular risks of Vioxx appeared to be the same before and after the 18-month benchmark. This statement was expected to have disastrous effects for Merck in its legal battles over Vioxx because now patients who had taken Vioxx for a short time were more likely to file successful lawsuits.
ADVANTAGE Trial (Assessment of Differences between Vioxx and Naproxen To Ascertain Gastrointestinal Tolerability and Effectiveness)
ADVANTAGE was a 12-week trial in 2000 designed to measure Vioxx safety. The results of the 6,000-patient ADVANTAGE study were not publicized until 2005, when all Merck-sponsored clinical trials were under intense scrutiny. In its 2001 report to the FDA on the ADVANTAGE trial, Merck reported a total of eight cardiovascular events. But in 2005, it was discovered that one death had been omitted from the results, bringing the total number of events to 9 — 8 of which were in the Vioxx group. It was later speculated that these results were not made public earlier because they did not support Merck’s claim that Vioxx risks only appeared after 18 months of continuous treatment.
VICTOR Trial (Vioxx in Colorectal Cancer Therapy: Definition of Optimal Regime)
Beginning in 2002, the VICTOR trial was designed to measure the effectiveness of Vioxx vs. placebo in preventing the regrowth of colorectal tumors, in patients who had previously undergone surgery to remove colorectal tumors. The study was terminated prematurely in 2004 because of the worldwide Vioxx withdrawal, and the partial results were never published.
In 2007, an article in The Wall Street Journal included a description of the unpublished VICTOR study. According to Merck’s own records, there were 23 cardiovascular events during the study, 16 of which were in the Vioxx group. Of those 16, 12 occurred during the first 12 months of treatment. These findings came as another blow to Merck’s claim that Vioxx posed no cardiovascular risk until after 18 months of treatment. In response to the publication of these results, Merck announced that they would not make an official statement until the data was re-examined more closely.
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