APPROVe Study Terminated Early
As discussed in Vioxx Clinical History, the worldwide withdrawal of Vioxx was a direct result of the APPROVe study. The APPROVe study was designed to measure the effectiveness of Vioxx in preventing the recurrence of colorectal polyps in post-surgical patients. Before the study could be completed, an unexpected result took precedence…the patients in the Vioxx group started experiencing a disproportionate number of cardiovascular events. Researchers stopped the trial at the same time Vioxx was being withdrawn from the market worldwide.
Merck concluded, in its official report to the federal Food and Drug Administration (FDA) on APPROVe, that the cardiovascular risks of Vioxx appeared after 18 months of treatment. Thousands of lawsuits followed, a majority of which involved patients who had used Vioxx for extended periods. Merck insisted that its clinical trials of Vioxx showed no risk of heart attack or stroke until after patients had taken the drug for 18 months, and this claim was the basis of Merck’s legal defense.
Merck maintained the “18-month benchmark” theory until 2006, when results of the APPROVe study and several other studies demonstrated that there was an equal risk before and after the benchmark of 18 months. Merck admitted in a statement to the FDA that it had misinterpreted the results of the APPROVe study, and that the risk of cardiovascular events with Vioxx appeared as early as 2-4 weeks into treatment. Additionally, the risks appeared to have steadily increased in the Vioxx group, while remaining constant in the placebo group, demonstrating an increasing risk proportionate to the duration of treatment.
There is no question that Merck understood the impact of this statement for its future legal defense. It could no longer maintain the position that short-term use of Vioxx posed no proven cardiovascular risk.
FDA Statements about Vioxx in 2004
When a drug is withdrawn or recalled for safety reasons, the public turns a suspicious eye not only toward the manufacturer of the drug, but toward the FDA, the federal government organization responsible for telling us which drugs are safe and which are dangerous. When the FDA delivered the news of the Vioxx withdrawal and the results of the clinical trials became public, the FDA faced a barrage of angry consumers who wanted an explanation of why they had approved the drug in the first place.
On September 30, 2004, the FDA released its initial statement regarding the Vioxx withdrawal, informing the public that Merck had voluntarily instituted an immediate withdrawal of Vioxx from the worldwide market. The FDA had been informed of this decision during a meeting with Merck officials two days ealier. According to the FDA report, the withdrawal was a recommendation of the DSMB (Data Safety Monitoring Board) overseeing the APPROVe study. The FDA added that, although the overall risk of heart attack was statistically small, Vioxx patients in clinical trials had consistently shown approximately double the cardiovascular risk. Additionally, it was stated that the cardiovascular risk appeared after 18 months of treatment, which explained why the APPROVe trial had not been stopped sooner.
The FDA reiterated that the motivation behind the COX-2 inhibitors introduction was to offer pain relief without the gastrointestinal side effects of traditional NSAIDs. Vioxx, according to the FDA statement, was the only NSAID to have demonstrated the intended gastrointestinally-protective effect.
Next, the FDA briefly reviewed the results of the VIGOR study, which in 2002 had prompted the FDA to mandate a black box warning of cardiovascular events to be added to Vioxx packaging. The DSMB of the APPROVe study concluded that that warning was not enough, and that the cardiovascular risks of Vioxx warranted a worldwide withdrawal of the drug. The FDA reported that it had been in the process of reviewing Vioxx studies in detail when the withdrawal was announced by Merck.
What Happens When a Drug is Withdrawn
In 2004, the FDA published an online Q&A for consumers explaining the background and ramifications of the Vioxx withdrawal. A withdrawal is different from a recall. In a drug recall, patients are encouraged to return any unused portion of their medication to the pharmacy, and pharmacies are instructed to return the drugs to the manufacturer. In the case of Vioxx, a prescription-only drug, any prescriptions that were not filled before the date of the withdrawal (September 30, 2004) could not be filled by any pharmacy worldwide. This meant that patients could choose whether to continue taking the medication until their current prescriptions ran out.
Patients who were currently taking Vioxx were told to contact their physicians before stopping the drug suddenly. Many Vioxx patients switched to one of Pfizer’s sister drugs: Celebrex, which is still available, or Bextra, which was withdrawn shortly after Vioxx, in 2005. Patients who experienced significant pain relief from Vioxx were devastated by its loss, and there was no assurance that Celebrex or Bextra could offer safer alternatives.
From the moment that Merck announced its withdrawal of Vioxx, the company has been subject to countless investigations attempting to unravel the series of events contributing to the Vioxx disaster. Merck’s marketing strategies have been a topic of heated debate, along with the partial or incomplete reporting of several clinical trials.
Merck’s handling of clinical trial results revealing the cardiovascular risks of Vioxx has been the basis of many successful lawsuits. Plaintiffs sought to prove that Merck was aware of the elevated cardiovascular risks of Vioxx before the APPROVe study, and they gained fuel for the lawsuits by looking back at earlier clinical trials that demonstrated the same risks. Not only was there clinical evidence of a 4- to 5-fold increase of cardiovascular events in Vioxx patients as early as 2000, but suits claimed that several trials were selectively reported, unreported, or the results were improperly calculated by Merck scientists. Lawyers also used evidence of misleading advertising strategies by Merck to discredit the drug company in court.
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