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Vioxx
(rofecoxib)
was launched in the United States in 1999. Since its introduction, the drug has been marketed in over 80 countries. Vioxx is a blockbuster drug - more than 20 million people have taken Vioxx and reported sales in 2003 reached $2.5 billion. In some countries the product is marketed as CEOXX.
Vioxx belongs to a class of drugs known as COX-2 inhibitors and non-steroidal anti-inflammatory drugs (NSAIDs). When this class of drugs was introduced a few years ago, they were thought to be safer and more effective than other drugs such as Aspirin and Ibuprofen. However, now studies suggest that all NSAID drugs have risks when taken chronically, including gastrointestinal bleeding and liver and kidney toxicity. Some experts are now stating that Vioxx is no more effective in treating pain than some, safer, over-the-counter medications.
In addition to problems typically associated with NSAIDs, several studies have also questioned the cardiovascular safety of Vioxx. In 2000, the Vioxx Gastrointestinal Outcomes Research (VIGOR) compared Vioxx and traditional NSAID (non-steroidal anti-inflammatory drug) naproxen among 8,000 patients and found the risk of cardiovascular problems, including heart attack, chest pain, stroke, blood clots and sudden death, was more than two times higher in the Vioxx group than in the control group.
After carefully reviewing the results of the VIGOR Study, the U.S. Food and Drug Administration (FDA) agreed with the Arthritis Advisory Committee recommendations of February 8, 2001 that the label for Vioxx should include the gastrointestinal and cardiovascular information. Later analysis of the VIGOR study showed that Vioxx patients had five times the risk of heart when compared to patients taking naproxen.
Despite these early warnings, the manufacturer of Vioxx continued to aggressively market the drug. In response, on September 17, 2001, the Food and Drug Administration (FDA) issued a Warning Letter to the manufacturer of Vioxx, directing the company to cease certain marketing material due to "false, lacking in fair balance, or otherwise misleading" advertising and materials which violated the Federal Food, Drugs and Cosmetic Act and other regulations.
In April 2002, the FDA published a Talk Paper and implemented labeling changes for the Vioxx based on the results of the Vioxx Gastrointestinal Outcomes Research (VIGOR). Other independent controlled studies also revealed an increased incidence of cardiovascular problems, including heart attack.
On September 30, 2004, the manufacturer announced the voluntary withdrawal of Vioxx from the market after a long term study revealed that participants had twice the risk of heart attack than other participants taking placebos after taking the drug for 18 months. In response to the Vioxx recall, the FDA published a Vioxx Public Health Advisory and a Vioxx Recall Questions & Answer page on its website. The withdrawal marks the biggest drug recall in history. FDA commissioner
Lester M. Crawford stated that though the risk of heart attack or stroke related to Vioxx is very small, Merck did the right thing in voluntarily recalling the drug in light of the new study's findings.
Days after the recall, Dr. Eric Topol of the Cleveland Clinic publicly criticized the FDA for not requiring Merck to do studies investigating heart problems with Vioxx when hints of such problems first appeared years ago. He also chastised the FDA for allowing Merck to blitz consumers with Vioxx TV ads. Dr. Topol blamed the FDA and Merck stating that, "neither Merck nor the FDA fulfilled its responsibilities to the public" and that such a "debacle" could have been prevented had the FDA heeded the many warning signs. Dr. Topol also called for a "full Congressional review of this case." Soon after, the Chairman of the Congressional House Government Reform Committee initiated an inquiry about the monitoring of drug safety.
The FDA came under attack again when the chairman of the Senate Finance Committee reported that the FDA
silenced one of its drug experts who raised safety concerns weeks before Merck & Co. recalled Vioxx.
Dr. David J. Graham, associate director for science in the FDA Drug Center's Office of Drug Safety, told the Congressional Committee that he
faced stiff resistance for his findings and that
he was "ostracized," "subjected to veiled threats" and "intimidation."
On November 2, 2004,
the FDA released a study, which analyzed the medical records of 1.4 million adult members of Kaiser Permanente and suggests that Vioxx may have contributed to an additional 27,785 heart attacks or sudden cardiac deaths from 1999 to 2003.
On November 4, 2004, the British medical journal The Lancet published a study which analyzed
18 clinical trials and 11 observational studies from 1997 to 2001 involving more than 20,000 patients. The study concluded that, the risk of side effects from Vioxx was "both substantial and unlikely to be chance finding'' at the end of 2000. The study identified 52 patients who had heart attacks, amounting to twice the risk for patients given Vioxx compared with those given a placebo or other painkiller. The editor of the The Lancet commented that, "The unacceptable cardiovascular risks of Vioxx were evident as early as 2000," and faulted Merck for "astonishing failures" in monitoring the safety of its drugs and the FDA for "lethal weaknesses" in oversight.
On November 14, 2004, the CBS news program 60 Minutes, reviewed allegations that Merck new that Vioxx was unsafe as early as 2000. On the news program, Dr.
Dr. Eric Topol, chief of cardiovascular medicine at the Cleveland Clinic, said that studies show that by 2000 Merck was aware that that Vioxx was unsafe. According to Topol, a 1998 unpublished clinical trial of Vioxx by Merck in 1998 showed patients who took the drug were six times more likely to have serious cardiovascular events, including heart attacks and strokes, than patients who took another arthritis drug or placebo. Additionally, an analysis of the 1999 VIGOR study
found that Vioxx users had nearly a fivefold increase in heart attacks.
Merck disputed Topol's findings, stating that
1998 study was too small and not statistically significant enough to be able to draw any conclusions.
On November 18, 2004, Congressional hearings began probing whether the US Food & Drug Administration neglected its its duty by ignoring safety concerns about Vioxx raised by its own reviewers and outside scientists. One FDA reviewer, Dr. David Graham, who concluded that risks posed by Vioxx were so high that patients should not use the drug, told congressional investigators that superiors at the FDA pressured him to soften his views.
A report authored by Dr. Graham on Vioxx risks was originally scheduled to be published in the medical journalThe Lancet in November 2004, but the article was withdrawn after the FDA warned Graham not to publish it.
According to a January 25, 2005 Los Angeles Times article, Graham stated
"I was ordered to withdraw the paper or 'face severe consequences' — which I interpreted to mean that I would be fired." The FDA withdrew its opposition in January 2005 and the report was finally published.
The study found that as many as 140,000 cases of heart disease in the United States and as many as 56,000 deaths were caused by the painkiller during the five years that it was on the market. Similar to other research released last year, the study of 1.4 million patients found that low doses of Vioxx increased the risk of heart disease by about 50%, and higher doses increased it by 358%. Graham's study found 8,143 cases of serious coronary heart disease and 1,508 deaths among all the painkiller users. The risk of heart disease and death was substantially higher for those taking Vioxx. Extrapolating the results on a nationwide scale, Graham and his colleagues estimated that Vioxx was responsible for 88,000 to 140,000 cases of heart disease.
In February 2005, the Annals of Internal Medicine published a major Canadian study further supporting evidence that Vioxx increasing the risk of heart attack and stroke especially at higher doses. The study included 113,927 older residents of Quebec who took painkillers between January 1999 and June 2002. The incidence of heart attacks increased 21 percent among those who took low doses of Vioxx and by 73 percent in those who took high doses -- more than 25 milligrams a day, the study found. The recall has left a large number of Vioxx confused about treatment options. According to a Los Angeles Times article, physicians across the country have been flooded with phone calls from Vioxx users worried about the dangers of Vioxx and seeking alternative treatments they can use in place of Vioxx. Decisions regarding treatment options are further complicated by worries that other COX-2 inhibitors (such as Celebrex) might cause similar problems as Vioxx. Some doctors are acting cautiously, recommending over the counter medications for pain relief, especially for patients with heart disease. If you have taken Vioxx you should discuss treatment options with your doctor.
Internal Company Documents Suggest Merck Knew of Vioxx Dangers
On November 1, 2004 the Wall Street Journal reported that internal e-mails and other documents from Merck & Co. show the company fought for years to keep safety concerns from negatively impacting Vioxx sales.
A memorandum by a Merck representative, dated November 21, 1996, reveals that even before the drug was introduced into the market, the company wrestled with Vioxx's potential to induce a cardiac event.
Several company officials discussed in emails how to design a study that would minimize data showing Vioxx increased the risk of heart attacks when compared to cheaper painkillers. An email by a Merck official, dated February 27, 1997, argued that unless Vioxx study patients also got aspirin, they would experience more blood clots, which would "kill" the drug. Additionally, Merck's current vice president for clinical research, proposed that people with a high risk of cardiovascular disease be kept out of the study so that the rate of cardiovascular problems among Vioxx patients "would not be evident." Despite the exclusion of patients who had a high risk of heart problems, the company's 1999 VIGOR study revealed four times the risk of heart attack among Vioxx patients, as well as other serious cardiovascular problems, when compared to patients taking naproxen. An e-mail by Merck's research chief, dated March 9, 2000, acknowledged that the VIGOR results showed that the cardiovascular events were "clearly there" and that some "mechanism" in Vioxx was linked to increased heart risk. The company, in its subsequent press release and other documents, avoided mention of any problem with Vioxx and suggested the VIGOR data simply highlighted the cardiovascular benefits of naproxen. One company training document instructed company representatives to "DODGE!" tough questions about Vioxx.
Other documents cited by the Wall Street Journal show that Merck acted aggressively to suppress negative information by academic researchers. The company sued one Spanish pharmacologist who had published repeated criticisms of Merck's handling of Vioxx and warned a Stanford University medical researcher, who criticized Merck's missing cardiovascular data, to stop giving "anti-Merck" lectures. Another Stanford Medical School professor, reported to Merck that several top medical schools complained about "a consistent pattern of intimidation of investigators by Merck."
On May 5, 2005, documents produced at a Congressional hearing revealed further evidence that Merck
sales personnel took extensive measures to deflect doctors' questions about the safety of the Vioxx before it was taken off the market. One memo, told sales representatives, "Do not initiate discussions" on a study that raised heart concerns. Other documents showed that when doctors did ask about heart risks, Merck sales reps were to provide a "cardiovascular card" with data suggesting that Vioxx could be eight to 11 times safer than other anti-inflammatory drugs. The documents prompted California representative Henry Waxman
to say, "Merck's answer seems to be disinformation and censorship...the goal was sales, not education."
The internal documents are expected to be used in the ongoing litigation against the company. Merck has argued that such statements and documents are being used "out of context." (return to top) |
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