2000 Study by Merck Showed Vioxx Risk: Results Not Given to FDA – Star Ledger

Sun, 3 Jul 2005

News reports reveal that Merck failed to disclose Vioxx lethal effects to the FDA.

Sheldon Krimsky, a science policy expert at Tufts University states: “if there was evidence the drug was dangerous and they didn’t report it, they violated their fiduciary responsibility to consumers.”

The Star Ledger reports that Dr. Krimsky noted that the issue “is an extension of the recent debate over disclosing clinical-trial data. A controversy arose last year after it became known that some drug makers failed to report adverse events in their clinical trials for antidepressants.”

Lost in this unravelling of trust in medicine is a matter of possible criminal responsibility.

According to FDA’s Dr. Robert Temple–failure to disclose a drug’s lethal effects to the FDA is a criminal offense for which executives can go to prison.

At least that’s what Dr. Temple told me personally on January 8, 2002 when I suggested that the FDA may have mistakenly approved Prozac for pediatric depression without having ALLl the evidence of its harmful effects in children.

Indeed, when the FDA finally got around to examining the clinical trial data from Prozac and the other SSRI antideprssants, the agency was compelled to issue black box warnings about a twofold increased suicidee risk.

Does no one bear responsibility for 38,000 preventable deaths because the lethal effect of Vioxx was undisclosed?

If the FDA fails to use its authority to enforce the law, then the onus is left to civil litigators.

The Star-Ledger reports that “lawyers are expected to argue that Merck manipulated clinical trial designs and outcomes, concealed unfavorable findings, improperly promoted the drug to doctors and attempted to silence critics, such as academics who raised safety questions.”

However, as has been amply demonstrated, companies whose sales for a single drug can bring in $2 to $4 billion annualy, are not deterred from concealing a drug’s hazards– even if their actions result in multi-million dollar settlements. A simple cost-benefit calculation reveals why drug companies fall into th ecategory of recidivist violators–there’s more to be gained financially by hiding a drug’s adverse effects that it will cost in settlements.

Contact: Vera Hassner Sharav
212-595-8974

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2000 study by Merck showed Vioxx risk Results not given to FDA
Sunday, July 03, 2005
BY ED SILVERMAN
Star-Ledger Staff

Merck officials five years ago conducted an internal analysis that revealed patients taking Vioxx were twice as likely to suffer heart attacks as those on similar painkillers, but the giant drug maker never reported its finding to federal regulators.

Merck’s analysis included the review of more than 20,000 study patients from five trials. Other findings from the study were provided to the Food and Drug Administration in January 2001 in preparation for a regulatory meeting. Merck, however, did not include the portion that measured the rate at which Vioxx users suffered heart attacks.

Ted Mayer, an attorney who represents Merck, said the analysis was not given to the FDA because it was not statistically sound. He also said regulators were given a broader overall analysis that, at the time, found no excessive risk associated with Vioxx.

“It was not a statistically valid pooling,” Mayer said. “You don’t disclose every single piece of data or the way you think about it. You disclose your best analysis of the data.”

The existence of this previously unreported analysis surfaced last week when it was disclosed during a hearing in state court in Atlantic City, where more than 2,000 lawsuits have been filed against the Whitehouse Station drug maker over Vioxx.

The company’s findings five years ago were part of a larger scientific review of Vioxx called a meta-analysis — a common practice in the pharmaceutical industry in which companies pool results from previous patient trials and study the combined data. Merck launched its meta-analysis of Vioxx after concerns were raised in 2000 that the medicine was linked to heart attacks.

The result places Merck’s own review among the first scientific confirmations that Vioxx held a greater risk than competing medicines. The drug, which once was used by millions of Americans, ultimately was pulled from the market last fall, and the company now faces billions of dollars in potential damages from lawsuits.

A spokeswoman for the FDA, Laura Alvey, said a company isn’t required to submit every single analysis, but the agency would want to see a danger signal.

LEGAL FIGHT TAKING SHAPE

The disclosure is the latest episode in a mounting battle between Merck and a cadre of lawyers from around the country who claim the company failed to properly disclose cardiovascular side effects caused by Vioxx.

“You don’t find this (analysis) on the product label,” David Buchanan, a lawyer who represents a union that claims it was overcharged for an unsafe drug, said during a hearing last week. He cited the previously undisclosed analysis in his argument.

The first trial is slated to begin later this month in Texas, where a 60-year-old woman says Vioxx caused her husband’s heart attack and death. The implications for Merck are enormous.

Many Wall Street analysts estimate Merck faces liability from $4 billion to $30 billion, depending upon the outcome of the first few trials. If Merck loses those trials, analysts say, others may be encouraged to file lawsuits.

To make their point, lawyers are expected to argue that Merck manipulated clinical trial designs and outcomes, concealed unfavorable findings, improperly promoted the drug to doctors and attempted to silence critics, such as academics who raised safety questions.

For its part, Merck maintains it promptly investigated questions about heart problems linked to Vioxx and disclosed all pertinent material to the FDA. The company also argues that internal memos are being leaked to the media and taken out of context.

THE NAPROXEN EFFECT

In discussing the newly disclosed analysis and why it wasn’t submitted to the FDA, Mayer explained the trial results included some studies that were skewed by the use of naproxen by some patients.

Since questions about Vioxx first arose, Merck has explained that clinical trials showed a higher incidence of cardiovascular side effects among Vioxx patients, compared with those given naproxen, an older painkiller. Merck hypothesized that naproxen benefits the heart.

This explanation was cited when in 2000 the company reported the results of its so-called Vigor trial, which found that Vioxx patients were five times as likely to suffer heart attacks as were patients on naproxen, which is another type of non-steroidal anti-inflammatory.

For this reason, Mayer said, using the newly disclosed analysis to measure the risk of heart attacks among all clinical-trial patients was not useful. He said this conclusion was backed by a team of outside consultants, although he declined to identify them.

“This analysis was done in the course of doing a reality check,” Mayer said. “They went where the statistical rules told them to go. But the tests showed you couldn’t combine (the different Vioxx trials) and get proper results” due to the naproxen effect.

Chris Seeger, another attorney who represents the union as well as individuals suing Merck, said this wasn’t the only instance in which Merck didn’t disclose the five-year-old analysis. He pointed to an October 2001 article in Circulation, a medical journal that discussed risks but not the specific findings.

Several authors were Merck employees.

“If the findings were so benign, why didn’t they just disclose it to the FDA?” Seeger said. “If Merck thought it was meaningful for their scientists to run data on only heart attacks, I think that data would also have been meaningful to the FDA and doctors.”

RESPONDING TO RED FLAGS

Experts note that large-scale reviews of clinical trials — the meta-analyses — can be imperfect, likening the effect to mixing apples and oranges. But these experts also said the results can be meaningful and that worrisome signals shouldn’t be ignored.

“There’s no reason why a company can’t play around with its internal data for its own benefit,” said Sheldon Krimsky, a science policy expert at Tufts University. “But if there was evidence the drug was dangerous and they didn’t report it, they violated their fiduciary responsibility to consumers.”

The issue, he added, is an extension of the recent debate over disclosing clinical-trial data. A controversy arose last year after it became known that some drug makers failed to report adverse events in their clinical trials for antidepressants.

Another expert, Arthur Caplan, who heads the Center for Bioethics at the University of Pennsylvania, noted that such concerns should extend to a drug maker’s meta-analysis, even though current FDA regulations do not require a company to report such findings.

“In this case,” Caplan said, Merck had “an ethical duty to report the data. If we’re talking about deaths, it’s serious. The stakes are higher.”

Ed Silverman may be reached at (973) 392-1542

© 2005 The Star Ledger

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