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How Did the Vioxx Debacle Happen? USA Today / Lancet

Tue, 12 Oct 2004

Dr. Eric Topol of the Cleveland Clinic: "The senior executives at Merck and the leadership at the FDA share responsibility for not having taken appropriate action and not recognizing that they are accountable for the public health."

In fact, FDA's record as the nation's gatekeeper for marketed has in recent years has been dismal. The FDA has lent its seal of approval to one after another lethal drug, allowing them to be marketed even as the death toll rose: More than 2 million Americans were taking Vioxx when it was pulled--despite evidence of it causing cardiac arrest.

How many preventable deaths are attributable to Rezulin, Propulsid, Fen-phen, Baycol, Vioxx? How many deaths by suicide are attributable to adverse reactions to Paxil, Zoloft, Prozac, Neurontin, Celexa, Lexapro, Luvox?

How many homicides were triggered by drug-induced hostility, mania, aggression?

Has the FDA assumed the role of industry's profit maximizer?

An editorial in The Lancet (below) states: "Finally, drug regulators must now reassess the safety and efficacy thresholds required for the licensing of a new pharmaceutical product. Clearly, this is an immensely complicated equation involving, among other factors, the nature of the condition being treated, the therapeutic strategies already available, and the perceived benefit-to-hazard ratio of the new treatment. The Vioxx story is one of blindly aggressive marketing by Merck mixed with repeated episodes of complacency by drug regulators."

Contact: Vera Hassner Sharav
212-595-8974

http://www.usatoday.com/life/lifestyle/2004-10-11-vioxx-main_x.htm?POE=click-refer

How did Vioxx debacle happen?
By Rita Rubin, USA TODAY

As drugmakers scramble to grab Vioxx's multi-billion-dollar share of the arthritis and pain-relief market, patients might find themselves wondering whether the competing medications are much safer. (Related stories: Similar indications are under scrutiny)is critical of how the FDA handled Merck and Vioxx.

The fact that no one can answer that question conclusively, and the fact that Vioxx remained on the market as long as it did, point to serious deficiencies in how the Food and Drug Administration regulates prescription drugs, critics say.

Merck yanked Vioxx on Sept. 30 because a new study had found a higher rate of heart attacks and strokes in patients taking the drug than in those on a placebo. The move was a stunning denouement for a blockbuster drug that had been marketed in more than 80 countries with worldwide sales totaling $2.5 billion in 2003. Vioxx, hawked by the likes of Olympic gold medalists Dorothy Hamill and Bruce Jenner, had been sold in the USA for more than five years.

But the new Vioxx study was not the first to raise concerns about heart attack and stroke risk. "We have been concerned and aware of the potential for cardiovascular effects for the last few years," Steven Galson, acting director of the FDA's Center for Drug Evaluation and Research, said the day Merck announced the withdrawal. "This is not a total surprise."

In fact, in April 2000 the FDA required Merck to add labeling information about a possible link to such problems. Yet 2 million Americans were taking Vioxx when it was pulled.

Critics describe the rise and fall of Vioxx as a cautionary tale of masterful public relations, aggressive marketing and ineffective regulation. "The FDA didn't do anything," says Eric Topol, chief of cardiovascular medicine at the Cleveland Clinic. "They were passive here."

Sen. Chuck Grassley, R-Iowa, says the FDA was worse than passive.

Investigators for the Senate Finance Committee, which Grassley chairs, met Thursday with FDA researcher David Graham, lead scientist on a study presented in August at a medical meeting in France.

The study, an analysis of a database of 1.4 million Kaiser Permanente members, found that those who took Vioxx were more likely to suffer a heart attack or sudden cardiac death than those who took Celebrex, Vioxx's main rival. Based on their findings, Graham and his collaborators linked Vioxx to more than 27,000 heart attacks or sudden cardiac deaths nationwide from the time it came on the market in 1999 through 2003.

Graham told the finance committee investigators that the FDA was trying to block publication of his findings, Grassley said in a statement. "Dr. Graham described an environment where he was 'ostracized,' 'subjected to veiled threats' and 'intimidation,' " Grassley said. Graham gave Grassley copies of e-mail that appear to support his claims that his superiors suggested watering down his conclusions.

Rep. Tom Davis, R-Va., chair of the House Government Reform Committee, last week wrote acting FDA commissioner Lester Crawford to ask what the agency knew about Vioxx and when. Davis also asked whether the FDA plans to collect more data on related drugs.

"In light of Merck's withdrawal of Vioxx ... and other recent news stories examining FDA's review of the safety and efficacy of antidepressant drug use by children, I am concerned whether FDA has been sufficiently aggressive in monitoring drug safety," Davis wrote.

Topol, in a column posted last week on The New England Journal of Medicine's Web site, called for a congressional review of the Vioxx "catastrophe." "The senior executives at Merck and the leadership at the FDA share responsibility for not having taken appropriate action and not recognizing that they are accountable for the public health."

So far, Vioxx is the only drug in its class linked to a significant increase in heart attacks and strokes. But the European Agency for the Evaluation of Medicinal Products last week announced it will review all long-term cardiovascular safety data for Vioxx and the four other related drugs licensed in Europe.

"It is important to note that the results of clinical studies with one drug in a given class are not necessarily applicable to others in a class," Peter Kim, president of Merck Research Laboratories, was quick to say at a news conference announcing Vioxx's withdrawal.

Merck happens to have a Vioxx classmate called Arcoxia in the wings. It is sold in 47 countries but not yet in the USA. The company expects to hear about its application to the FDA by month's end, spokesman Christopher Loder says.

Digesting NSAIDs

Like ibuprofen and naproxen, Vioxx is a non-steroidal anti-inflammatory drug, or NSAID. But Vioxx belongs to a fairly new class of NSAIDs called COX-2 inhibitors. With Vioxx's demise, Pfizer's Celebrex and Bextra are the only COX-2 inhibitors sold in U.S. markets.

No one has ever said that COX-2 inhibitors are more effective than classic NSAIDs. Their selling point always has been that they're less likely to cause bleeding and other digestive tract complications.

Although FDA approved the COX-2 inhibitors, it wasn't convinced they were safer. The drugs had to carry the same digestive warning as classic NSAIDs. So Merck and Pharmacia, which later merged with Pfizer, launched studies to prove their drugs shouldn't be lumped with other NSAIDs.

The Celebrex trial failed to convince the FDA that the drug was safer, but it didn't appear to be riskier, either. Merck's trial backfired. Though the study did demonstrate that Vioxx was safer on the digestive tract than naproxen, it also unexpectedly found that the COX-2 inhibitor doubled the risk of cardiovascular problems.

In a written response to Topol's New England Journal of Medicine column, Merck said it "promptly disclosed these results to the FDA, the scientific community and the media beginning in March 2000."

But from the start, Merck put a positive spin on the data. A press release on March 27, 2000, led off with the finding that Vioxx caused fewer digestive tract problems than naproxen. It did go on to say that "significantly fewer thromboembolic events (in other words, heart attacks and strokes) were observed in patients taking naproxen."

However, it wasn't that Vioxx caused cardiovascular problems, but that naproxen protected against them, Merck argued for the next 4 years. Yet, Merck acknowledged in the March 2000 press release, "this effect ... had not been observed previously in any clinical studies for naproxen." Worrisome findings

In February 2001, Merck tried to convince an FDA advisory committee that Vioxx be allowed to drop the digestive tract warning. But the committee couldn't ignore the cardiovascular findings.

Still, Merck's marketing machine churned on. In September 2001, the FDA ordered the company to send doctors a letter "to correct false or misleading impressions and information" about Vioxx's effect on the cardiovascular system.

In April 2002, the FDA followed its advisory panel's recommendation and required that Merck note a possible link to heart attacks and strokes on Vioxx's label.

"Meanwhile," Topol writes in The New England Journal of Medicine, "Merck was spending more than $100 million a year in direct-to-consumer advertising another activity regulated by the FDA and a critical mechanism in building the 'blockbuster' status of a drug."

Direct-to-consumer advertising was meant to heighten awareness of drugs, not to hype them, says pharmacologist Raymond Woosley, vice president for health sciences at the University of Arizona. "Do we need to be told how much greater one drug is than the other?" Woosley asks. "The public can't understand the subtle differences."

Merck continued to minimize unfavorable findings up to a month before withdrawing Vioxx. On Aug. 26, the company fired off a press release refuting Graham's study. "Merck stands behind the efficacy, overall safety and cardiovascular safety of Vioxx," it said.

Only randomized, controlled trials, in which patients are randomly assigned to treatment groups (the type of study that first raised heart concerns back in 2000) can provide unimpeachable data about a drug's safety and effectiveness, the release pointed out.

Finally, late last month, Merck confronted unfavorable findings that it could not explain away. Merck had sponsored a three-year, 2,600-patient randomized trial to see whether Vioxx, like Celebrex, could claim that it protects against the recurrence of colon polyps, which can become cancerous.

Again, the study backfired. After 18 months of treatment, researchers observed a higher heart attack and stroke risk in patients on Vioxx, Merck says. The drug was compared with a placebo and not another NSAID, so Merck could not divert blame away from Vioxx. Merck has not yet reported the study results, but the FDA says 3.5% of the subjects on Vioxx had suffered a heart attack or stroke, compared with 1.9% on placebo.

Monitoring the drugs

FDA spokeswoman Crystal Rice says the agency will continue to monitor drugs in the same class as Vioxx. Besides Merck's Arcoxia, the FDA is considering whether to approve Novartis' Prexige. Pfizer is expected to resubmit an application for parecoxib by year's end. The FDA turned down its original application in 2001 for lack of data.

Since becoming aware of the Vioxx study's finding, Rice says, the FDA is "much more sensitized to the possibility of seeing this adverse event" in related drugs.

Simply looking for heart attacks and strokes in individuals taking the drugs isn't enough, says Alastair Wood, chair of pharmacology at Vanderbilt University.

Sometimes, a drug triggers such an unusual problem that it's fairly easy to connect the dots, Wood says. "But there was no possibility that you could discern a heart attack due to Vioxx from a heart attack not due to Vioxx," he says.

Wood, Topol and others speculate that drugs in the same class as Vioxx may appear to be safe because the FDA has not yet asked for the randomized, controlled trials necessary for definitive answers.

"The spotlight is now on Pfizer and the FDA," says Garret FitzGerald, chair of pharmacology at the University of Pennsylvania. "The agency needs to scrutinize all ongoing trials in the light of these data and to decide swiftly" if all COX-2 inhibitors should carry a warning about heart attacks and strokes.

Topol says the drugs should be specifically tested in patients known to have cardiovascular disease, which is common in patients who need medication for osteoarthritis. So far, such patients have virtually been excluded from trials of the COX-2 inhibitors, Topol says.

In a yearlong study of more than 18,000 osteoarthritis patients published in August, Prexige did not increase heart attack or stroke risk when compared with ibuprofen or naproxen. However, Topol wrote in an accompanying editorial, fewer than 2% of study participants had had a heart attack or undergone bypass surgery or angioplasty before enrolling.

Back in 2000, when Merck first notified the FDA that Vioxx appeared to carry a higher risk of heart attacks and strokes than naproxen, the agency should have quickly ordered a trial comparing Vioxx with a placebo, Wood says. In the end, he notes, "a relatively small study was all that it took to show this problem."

Meanwhile, patients try not to worry.

Marjorie Chepp of Milwaukee had been taking Vioxx for nearly two years. Her doctor first prescribed it for a knee injury, but Chepp found that it also relieved her osteoarthritis and fibromyalgia. She asked to remain on it.

"For years I had refused to take meds other than over-the-counter because I was always afraid of the long-term effects," says Chepp, 47, an exercise instructor who had an ulcer at 16. "Of course, what happens with the first one I take? It gets recalled." Vioxx timeline May 1999 : FDA approves Vioxx.

March 2000: Merck reveals that a new study found Vioxx patients had double the rate of serious cardiovascular problems than those on naproxen, an older nonsteroidal anti-inflammatory drug, or NSAID.

November 2000: The New England Journal of Medicine publishes the study, called VIGOR.

February 2001: An advisory panel recommends the FDA require a label warning of the possible link to cardiovascular problems.

September 2001:The FDA warns Merck to stop misleading doctors about Vioxx's effect on the cardiovascular system.

April 2002:The FDA tells Merck to add information about cardiovascular risk to Vioxx's label.

Aug. 25, 2004:An FDA researcher presents results of a database analysis of 1.4 million patients; it concludes that Vioxx users are more likely to suffer a heart attack or sudden cardiac death than those taking Celebrex or an older NSAID.

Sept. 23, 2004:Merck says it learned this day that patients taking Vioxx in a study were twice as likely to suffer a heart attack or stroke as those on placebo.

Sept. 30, 2004:Merck withdraws Vioxx from the U.S. and the more than 80 other countries in which it was marketed.

~~~~~~~~~~~~~~~~~~

http://www.thelancet.com/journal/vol364/iss9442/full/llan.364.9442.analysis_and_interpretation.30941.1

THE LANCET
Volume 364, Number 9442
09 October 2004
Editorial:
Vioxx: an unequal partnership between safety and efficacy

Rofecoxib (Vioxx) is, or was, Merck and Co's leading drug for control of acute pain, and pain associated with osteoarthritis, rheumatoid arthritis, and menstruation. Last year worldwide sales of rofecoxib reached US$25 billion following the most impressive global sales growth for any drug in 2001. Last week, after urgent discussions with the US Food and Drug Administration (FDA), Merck felt compelled to withdraw rofecoxib after its most recent trial, APPROVe (Adenomatous Polyp Prevention On Vioxx), showed an adverse cardiovascular side-effect profile. For Merck to act so promptly in the face of these most recent safety concerns is commendable and should serve as an example of responsible pharmaceutical industry practice. However, the short history of cyclooxygenase (COX)-2 inhibitors has been plagued by persistent safety concerns. The question that must now be answered is why has it taken so long for Merck and government drug regulators to address these signals properly?

The story of COX-2 inhibitors began for clinicians and their patients in 1999 with the licensing of two first generation drugs, rofecoxib and celecoxib, by the FDA. Their primary indications were for the control of pain associated with several different conditions and their debut was announced in 2000 in the medical literature with two landmark trials: VIGOR for rofecoxib, and CLASS for celecoxib. Subsequently, a number of second generation COX-2 inhibitors have been developed. These include valdecoxib, parecoxib, etoricoxib, and lumiracoxib. The indications for their use have remained largely unchanged and more "me-too" COX-2 inhibitors are on the horizon.

>From the outset, questions have been raised about the safety profile of these drugs. Although the CLASS trial did not find a difference in the incid ence of cardiovascular side-effects between celecoxib and ibuprofen or diclofenac, the VIGOR trial revealed a significant increase in the number of myocardial infarctions in patients taking rofecoxib compared with those receiving naproxen. These concerns were crystallised the following year by Debabrata Mukherjee, Steven Nissen, and Eric Topol in JAMA in their review paper specifically highlighting the cardiovascular side-effect profile of COX-2 inhibitors. Concerns were shared by the FDA, who implemented labelling changes in 2002 to reflect the findings from the VIGOR trial. However, even following these warnings, and in the face of mounting evidence for the cardiovascular side-effects of rofecoxib, aggressive direct-to-consumer marketing of this questionable drug continued unabated.

What then finally tipped the balance in the risk-benefit equation leading to last week's dramatic global withdrawal of rofecoxib? APPROVe was a multi-centre, randomised, placebo-controlled, double-blind study investigating the effects of rofecoxib on the recurrence of neoplastic large bowel polyps in 2600 patients with a previous history of colorectal adenoma.

It was stopped prematurely on the instruction of the data and safety monitoring board after the investigators found that after 18 months treatment, patients taking rofecoxib had twice the risk of a myocardial infarction compared with those receiving placebo. Advice is now being issued to pharmacists and doctors in each of the 80 countries where rofecoxib is marketed to stop prescribing the drug with immediate effect. 2 million patients already taking rofecoxib will be contacting their physicians to discuss discontinuing treatment--a busy and anxious time for doctors around the world.

A key question remains as to why it took this risk to be identified from a relatively small trial investigating a novel use for rofecoxib, after it had been licensed for several years and prescribed to so many patients? Although Peter Kim, president of Merck Research Laboratories, recently said "Merck has always believed that prospective, randomized, controlled clinical trials are the best way to evaluate the safety of medicines. APPROVe is precisely this type of study . . . ", it is unlikely that APPROVe was designed and executed with a general safety assessment as its primary goal. A further question relates to the safety of the other COX-2 inhibitors being actively marketed today. Although the TARGET trial published in The Lancet in August this year, and the largest COX-2 trial to date, failed to demonstrate a statistically significant difference in cardiovascular side-effects between lumiracoxib and naproxen or ibuprofen, more people taking lumiracoxib had a myocardial infarction.

Doctors need to be more aware of the very preliminary nature of data, both for safety and efficacy, provided with newly licensed drugs. For rofecoxib the original safety data were based on results from approximately 5000 patients. In comparison with the 2 million people receiving the drug until last week, this is a very small number and helps to explain how an important side-effect could have been missed, and subsequent confidence in the drug misplaced. For all newly licensed drugs, confidence about safety can only be provisional.

Pharmaceutical companies also have lessons to learn. Merck responded well to this latest piece of the rofecoxib jigsaw puzzle. However, the real picture of cardiovascular risk has been apparent for some time and Merck's vigorous defence of this drug in the past was clearly an error. If the dangers associated with rofecoxib were not proven, they were certainly possible, even probable, given the available data, and it should not have been left to a small trial in a novel application to reveal them. In the end it is patients, now understandably confused by the implications of rofecoxib's withdrawal, who will lose the most. Which drugs, they will ask, should they trust?

Finally, drug regulators must now reassess the safety and efficacy thresholds required for the licensing of a new pharmaceutical product. Clearly, this is an immensely complicated equation involving, among other factors, the nature of the condition being treated, the therapeutic strategies already available, and the perceived benefit-to-hazard ratio of the new treatment. The Vioxx story is one of blindly aggressive marketing by Merck mixed with repeated episodes of complacency by drug regulators. We need clear statements from all parties in this sorry tale about the lessons to be learned. Without more vigilant drug regulation in the future, doctors will continue to be misled and patients' lives will continue to be endangered.


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