2005 Statements by the FDA Regarding Vioxx and NSAIDs
In April 2005, the Center for Drug Evaluation and Research (CDER), a branch of the FDA, sent out letters to the manufacturers of all NSAIDs, even over-the-counter (OTC) NSAIDs, urging them to include with their products more detailed information about the cardiovascular and gastrointestinal risks of the entire class of NSAIDs. The statement was directly aimed at the manufacturers of Celebrex, Bextra, and OTC NSAIDs.
This statement was not intended as a call for consumers to stop taking COX-2 inhibitors, but rather for drug manufacturers to assure consumers that their products were well labeled and that patients were provided with accurate information about their risks. It also recognized the need for further research on the safety of selective COX-2 inhibitors.
Statements regarding Bextra and Celebrex
At the same time as it announced these new packaging requirements, the FDA recommended the withdrawal of Vioxx’s sister drug Bextra, produced by Pfizer. As reasons for its decision, the FDA cited safety concerns about Bextra, including unpredictable and potentially fatal skin reactions, and known cardiovascular complications in bypass patients. In addition to bearing these serious risk factors, the FDA noted, Bextra had not demonstrated any advantages over other COX-2 inhibitors. At that time, Pfizer agreed to suspend advertising of Bextra in the US pending a follow-up with the FDA. The drug was withdrawn soon after.
Pfizer’s Celebrex was allowed to retain its FDA approval, leaving it the only available COX-2 inhibitor. Pfizer was instructed to include additional labeling warnings in the Celebrex packaging regarding cardiovascular risks. It was also recommended that Celebrex be used in the lowest effective dosages, and that a clinical trial measuring its long-term risks be conducted immediately.
Searching for the Culprit in the Vioxx Snafu
When Vioxx was withdrawn, Merck was the immediate target of public outrage. All Merck-sponsored clinical studies of Vioxx were examined and re-examined; in several cases, it was discovered that Merck had improperly reported or calculated the cardiovascular events in clinical studies.
Merck was questioned not only for its handling of Vioxx clinical trials, but also for its mass marketing of Vioxx as a safe alternative to aspirin. Merck spent more than $146 million to advertise Vioxx in 2000 alone. The company was criticized for neglecting to mention the cardiovascular risks of Vioxx in its marketing. Many critics claimed that, as a result of massive advertising directed both at consumers and at doctors, Vioxx was grossly over-prescribed. This led some of the blame to be placed on doctors, as well. According to the New England Journal of Medicine, 100 million patients were prescribed Vioxx between its release in 1999 and its withdrawal in 2004.
Whether the fault lay with Merck’s scientists, Merck’s marketing, the FDA, or the prescribing doctors, is hard to determine. It was really a combination of all of these factors that helped Vioxx reach so many uninformed or ill-informed patients.
New England Journal of Medicine Report on Vioxx
In June, 2005, the New England Journal of Medicine (NEJM) published an editorial examining Merck’s marketing of Vioxx. The article criticized Merck for having published incomplete results of the VIGOR study in the publication.
The editorial recounts a meeting between the Arthritis Drugs Advisory Committee of the FDA and Merck in 2001 to discuss the results of the VIGOR study, which had shown an increased risk of myocardial Infarction (heart attack) in patients taking Vioxx compared to those taking naproxen. At this meeting, the FDA argued that this imbalance in the VIGOR results was evidence of the protective anti-platelet effects of naproxen. The FDA concluded that this explanation was insufficient and ordered Merck to notify physicians about the results of the study. In reaction to this meeting, the NEJM article reports, Merck instructed its sales force not to discuss the results of the VIGOR study except to say that VIGOR showed a reduction in gastrointestinal complications.
To comply with the FDA’s orders, Merck created the “Cardiovascular Card,” a short pamphlet that included a non-specific summary of some Vioxx pre-approval trials. The Cardiovascular Card did not mention the VIGOR study and did not include data about cardiovascular events during the trials. The NEJM article claims that the information on the Cardiovascular Card, which was written by Merck’s marketing team, was misleading and only sought to further minimize the apparent cardiovascular risks of Vioxx that had been evidenced by multiple clinical trials.
Further, the article reports that Merck offered special training to its sales team, including using subliminal techniques and other misleading sales tactics, to influence doctors’ overall impressions of Merck. All of this was designed to sell more drugs and to downplay their possible risks. Merck, which had had a solid reputation with the FDA prior to the Vioxx dispute, was now accused of transparent salesmanship at the expense of objective drug information.
The article closes by observing that the questionable marketing practices employed by Merck were most likely representative of drug companies as a whole, and advising that the FDA take a larger role in overseeing the approval process for new drugs.
Off-Drug Follow-ups of Vioxx Trials
In 2006, Merck released results of its off-drug follow-up of the APPROVe study. The research showed that, in the year following treatment, Vioxx patients were 74% more likely to experience a cardiovascular event. Merck claimed that these results were statistically insignificant, but many experts in the medical field disagreed. Merck lawyers still insisted that the risks of Vioxx had only been conclusively demonstrated after the drug had been taken for 18 months.
Cardiologist Steve Nissen of the Cleveland Clinic was among medical professionals who believed these off-drug results were significant, in that they may have indicated that Vioxx caused some kind of arterial damage that might be permanent.
In April of 2008, the Journal of the American Medical Association, or JAMA, reported on the off-drug follow-up results of a Merck-sponsored study called Protocol 078. This study, published in 2004, measured the effectiveness of Vioxx in preventing the symptoms of Alzheimer’s Disease. During Protocol 078, 39 deaths occurred, 24 of which were in the Vioxx group. In the off-drug period, 22 additional deaths occurred, 17 of which were in the Vioxx group. In another study, called Protocol 091, 11 deaths were recorded as non-drug-related, 9 of which were in the Vioxx group. In the opinion of the AMA, these results showed a disproportionate number of deaths among Vioxx users, both during the trials and after they stopped taking the medication.
Merck’s official conclusion on these trials upon publication was that Vioxx was “well tolerated” by patients. Nissen and others in the medical community, as well as representatives of the AMA, disagreed.
Read more about how Merck reacted to the Vioxx withdrawal.
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