Merck and Co celebrated victory earlier this month after a New Jersey jury ruled that the company's anti-inflammatory drug rofecoxib (Vioxx) did not cause the heart attack of a 60-year-old postal worker. The verdict evened the score for the pharmaceutical giant, which in August lost a similar trial in Texas and was asked to pay US$253 million compensation.
The August case is under appeal, and Texas law will cut the award by 90%. But the company is just at the beginning of a series of Vioxx-based legal battles, which are expected to continue for years to come.
Plaintiffs have filed around 6400 lawsuits claiming that the cyclo-oxygenase 2 (COX2) inhibitor—which was pulled from the market in Sept, 2004—caused their heart attacks or strokes. Merck's overall liability in the lawsuits could reach $20–35 billion, according to analysts.
The company has vowed not to make any settlements, and instead promises to fight every case in court. It has already set aside $675 million for the effort.
But Vioxx's fallout goes well beyond Merck and its ledgers. Manufacturers facing mounting political pressure have now agreed to scale back advertising—an activity once staunchly defended by the industry. Meanwhile, the US Food and Drug Administration (FDA) has taken what some see as a defensive posture designed to avoid another safety debacle.
Merck is set to begin defending its third case at the end of November. Lawyers for the widow of Richard Irvin will try to show that the drug was responsible for the man's sudden cardiac death and that Merck officials knew of the risk while marketing the drug.
The case will be the first to reach federal court and will also test uncharted scientific ground. Irvin's widow claims that the drug caused his death after only a month of use. That is far shorter than the 18 months of average use it took for increases in cardiovascular risks to show up in Merck's trials.
“The autopsy shows the location of the clot and shows he had no prior significant heart disease problems. That makes our job easier”, Jere Beasley, the attorney representing the widow, Evelyn Irvin Plunkett, said in an interview.
Beasley points to anecdotal warnings Merck received as early as 1997 associating early use of the drug with cardiac death.
The company maintains that rofecoxib could not have caused Irvin's death. Increased risk of cardiac death in the Merck-directed APPROVe placebo-controlled trial did not reach statistical significance until 30 months of use, Bruce Kuhlik, Merck's vice president and associate general counsel, told The Lancet.
Merck stands by its pledge to avoid settling any cases. “We're committed to defending the cases on an individual basis, based on the science behind Vioxx and the individual risk factors that each individual patient has”, Kuhlik says.
Even if the plaintiff's strategy proves successful, it remains unclear what will be the impact on the overall dispensation of suits against Merck. 2 weeks before the federal trial opened, the New Jersey judge overseeing about half the total Vioxx caseload told attorneys that the next string of trials will focus only on plaintiffs who used the drug for 18 months or more.
The New Jersey victory proved to would-be plaintiffs that their suits against Merck will not be easy to win, says Robert Rabin, an expert in mass torts at Stanford Law School in California. The company is unlikely to ultimately stick to its pledge to fight each case, he says. At the same time, it pays in the short term for Merck to be as combative as possible.
“Sixty-four hundred cases are not going to be decided at trial individually. But it's not just 6400 cases if they started settling. Who knows how many other cases that would generate”, Rabin told The Lancet.
But the lawsuits reflect concerns over prescription-drug safety that go well beyond the courtroom. Other manufacturers are also reacting to allegations that they were too cavalier with safety in the rush to get promising new drugs to market.
As the Texas jury was nearing judgment against Merck in August, the Pharmaceutical Research and Manufacturers of America, the industry's main trade group, committed companies to withhold consumer advertisements of new drugs until physicians have been sufficiently educated about risks and benefits.
Pfizer Inc, the maker of COX2 drug celecoxib, marketed as Celebrex, and valdecoxib, marketed as Bextra, volunteered to ban consumer commercials for the first 6 months of drug sales. Bristol-Myers Squibb has said it will impose its bans for a year. Both were shorter than a 2-year moratorium on direct-to-consumer advertisements for new drugs called for by Senate Majority Leader and physician Bill Frist.
The major advantage of the COX2 inhibitors is their reduced risk of causing gastro-intestinal irritation and bleeding compared with non-selective COX inhibitors. But company advertisements were widely criticised for promoting the COX2 drugs to millions of patients who were not at risk for these side-effects. COX2 inhibitors do not offer an analgesia advantage over other anti-inflammatory pain killers.
“They've clearly gotten the message and tried to back away from (consumer advertising) discreetly”, says Alistair Wood, a professor of medicine and pharmacology at Vanderbilt Medical School in Nashville, TN, who chaired a 3-day series of hearings on COX2 safety in February.
Companies are also sensing that the FDA has reacted by making stricter demands on manufacturers, analysts say. Reports of increased suicidal ideation in patients taking antidepressants, defects in cardiac pacemakers, and political fury over the agency's unusual handling of a request to make an emergency contraceptive available without a prescription have all spurred the agency to avoid more mistakes, argues Michael Krensavage, a drug industry analyst. “It's a lot riskier for these companies to play games now than it used to be”, he says.
Krensavage says the new approach was in evidence in October when the agency demanded more safety data from Bristol-Myers Squibb and Merck before agreeing to approve muraglitazar, a jointly-developed type 2 diabetes drug to be marketed as Pargluva. The agency was concerned about data suggesting the drug could double cardiovascular risk, despite an 8-to-1 advisory committee vote backing the drug's approval only a month before.
Others expect any increased scrutiny to be temporary. That was the case in 1997 after fentermine-phenfluramine, the weight-loss combination known as fen-phen, was pulled from the market shortly before a wave of lawsuits connecting it to cardiac death, says Les Funtleyder, a health care analyst with the financial firm Miller Tabak & Co.
“Post fen-phen, things tightened up for about 18 months”, Funtleyder says. “This regulation tends to be cyclical. They'll tend to get tighter for a while and after we've gone a few years without a major safety scandal, they'll go laissez-faire again”, he says.
Steven Galson, director of the FDA's centre for drug evaluation and research, says that companies have become concerned about more FDA scrutiny and that officials may be looking more closely at industry applications. But he denied in an interview that the agency's decision-making process has changed.
“You can't avoid some of FDA's reviewers taking a harder look at safety info but that doesn't mean were going to be stricter in our safety decisions”, Galson said. “I object to the notion that there's any evidence that we've become stricter in the last few months.”
Kuhlik maintains that Merck has not altered the way it interacts with FDA. “I just don't see that changing”, he says.
The FDA has reacted in other, more obvious ways. The agency has vastly increased the amount of safety-report information it shares with the press and the public, regularly publicising minor drug-label changes and other safety information. An independent review of how the agency monitors drugs already on the market is underway, and over the summer the agency created a new board to help monitor drug safety.
Wood, who in 2002 was a candidate to take over as FDA commissioner, takes a dim view of the agency's recent moves. He likens the organisational changes to “shuffling the deck chairs on the Titanic” and says that the FDA should instead lower its threshold for compelling companies to conduct safety trials involving already-common side-effects like the heart attacks suspected with Vioxx. “The place to make the change is the FDA, not to ratchet up the tort system”, Wood says.
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