Vioxx Fallout: Merck Officials Intervened–NYT / FDA Officials Intervened–Mother Jones

Vioxx Fallout: Merck Officials Intervened–NYT / FDA Officials Intervened–Mother Jones

Mon, 25 Apr 2005

Mother Jones and The New York Times focus on the Vioxx fall out–a case that encapsulates the corrupt practices in drug research. Merck and FDA officials intervened to conceal the lethal cardiac effect of Vioxx. Mother Jones focuses on the plight of Dr. David Graham whose moral and professional integrity collides with top FDA officials who shield drug manufacturers who don’t disclose the hazards of patented drugs to physicians and the public. Dr. Graham estimates that between 88,000 to 139,000 Americans suffered heart attacks attributable to Vioxx. “Of these, 30 to 40 percent probably died. For the survivors, their lives were changed forever.” Michael Scherer notes, “According to the top end of those projections, the toll Vioxx had already taken was comparable to the number of Americans killed in Vietnam.”

The Times focuses on the culpability of Merck officials as revealed in e-mail correspondence obtained by plaintiff’s attorneys. The Times notes that the content of the e-mail correspondence “could help plaintiffs paint a picture of the company that is at odds with Merck’s public statements that it had no evidence of Vioxx’s cardiac risks until last fall.”

A major revelation in e-mails from Dr. Edward M. Scolnick, Merck’s top scientist from 1985 until 2002, and Dr. Alise S. Reicin, a vice president for clinical research, indicates that evidence existed contradicting Merck’s claim that Vioxx was safe. Much is revealed about the unethical culture in which drug manufacturers make their decisions. For example, Merck’s marketing department had created a clinical trial “as a promotional tool, to introduce about 600 doctors to Vioxx.” But when a woman died of a heart attack in that trial, Dr. Scolnick realized it was “just stupid,” to have conducted it inasmuch as “Small marketing studies which are intellectually redundant are extremely dangerous.” In a culture of lawlessness, marketing goals trump safety considerations.

Merck documents examined by the Times also reveal the shady world of drug research. Unwanted evidence is covered-up by drug manufacturers who even threaten FDA reviewers: Dr. Scolnick indicated that “he would personally pressure senior officials at the agency if it took action unfavorable to Vioxx.” His decision not to disclose the fatal cardiac risk for Vioxx patients was that it would have “put us in a terrible situation.” Dr. Reicin concurred: “I think this should be called an unknown cause of death.” A few hours later, she wrote, “I would prefer unknown cause of death so we don’t raise concerns.” Trials that are often done – not for their scientific value–but for marketing purposes; academic researchers are shown to help drug companies manipulate and misrepresent the clinical trial findings; academics are shown to lend their names to reports that were then published in (formerly) respected scientific journals, where they misled physicians about the safety of Vioxx.

These academics aren’t even ashamed to acknowledge that they neither saw nor analyzed the original data, nor did they write the articles to which they agreed to pen their names to misinformation – thereby becoming an accomplice to (what New York State Attorney General, Eliot Spitzer called) fraud. Rheumatologist, Dr. Jeffrey Lisse who is listed as the first author of a Vioxx report in the Annals of Internal Medicine, said that Merck actually wrote the report: “Merck designed the trial, paid for the trial, ran the trial.” Dr. Lisse said. “Merck came to me after the study was completed and said, ‘We want your help to work on the paper.’ The initial paper was written at Merck, and then it was sent to me for editing.”

Contact: Vera Hassner Sharav
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THE NEW YORK TIMES
April 24, 2005, p. A-1
Evidence in Vioxx Suits Shows Intervention by Merck Officials
By ALEX BERENSON

In 2000, amid rising concerns that its painkiller Vioxx posed heart risks, Merck overruled one of its own scientists after he suggested that a patient in a clinical trial had probably died of a heart attack.

In an e-mail exchange about Vioxx, the company’s most important new drug at the time, a senior Merck scientist repeatedly urged the researcher to change his views about the death “so that we don’t raise concerns.” In later reports to the Food and Drug Administration and in a paper published in 2003, Merck listed the cause of death as “unknown” for the patient, a 73-year-old woman. The discussion of the death is contained in several previously undisclosed Merck records, including e-mail messages from Dr. Edward M. Scolnick, Merck’s top scientist from 1985 until 2002, and from Dr. Alise S. Reicin, a vice president for clinical research, that indicate Merck’s concerns about data contradicting its view that Vioxx was safe.

In one e-mail message, Dr. Scolnick said the drug trial that included the woman’s death had “put us in a terrible situation.” In others, he fiercely criticized the F.D.A. and said he would personally pressure senior officials at the agency if it took action unfavorable to Vioxx. As lawsuits against Merck over Vioxx move toward trial, the documents could help plaintiffs paint a picture of the company that is at odds with Merck’s public statements that it had no evidence of Vioxx’s cardiac risks until last fall. Theodore V. H. Mayer, a lawyer for Merck, said that it had disclosed all information from clinical trials to the F.D.A. and that Dr. Scolnick’s e-mail messages merely reflected his concern that the F.D.A. weigh Vioxx’s benefits and risks fairly. The e-mail discussion between the Merck scientists reflected an honest scientific debate over the cause of the woman’s death, Mr. Mayer said.

Merck withdrew Vioxx in September after a different clinical trial found that the drug increased the risk of heart problems. More than 25 million Americans took Vioxx between 1999 and 2004, and at least 4,600 people or their survivors are suing Merck, claiming Vioxx caused their heart attacks or strokes. The first individual cases are scheduled for trial next month in Alabama and Texas, filed by the survivors of two men who the suits say died of heart attacks after taking the drug. Merck, the nation’s third-largest drug maker, has said it plans to defend every suit. The company says it did everything reasonably possible over the years to determine whether Vioxx caused heart problems and to disclose the drug’s risks to patients and doctors. The e-mail messages and other internal Merck documents, including the report of the woman’s death, were provided to The New York Times by a person working with plaintiffs.

The death of the 73-year-old woman – who was not identified by name in the documents and whose identity has not been disclosed – occurred during a 12-week clinical trial called Advantage that covered 5,500 patients. Clinical trials are at the core of the development of new medicines, providing data that enable the F.D.A. and doctors to weigh drug risks and benefits. Mr. Mayer said the doctors involved in the e-mail exchanges could not be certain whether the woman who died was taking Vioxx or an older painkiller, naproxen, that was used in the trial, because information about which participant was taking which drugs was kept confidential. But at the time, there was widespread concern within the company about the relationship between Vioxx and heart attacks as a result of troubling earlier research.

During the Advantage trial, eight people taking Vioxx suffered heart attacks or sudden cardiac death, compared with just one taking naproxen, according to data released by the F.D.A. earlier this year. The difference was statistically significant, but Merck never disclosed the data that way. Back in 2000, Merck was already struggling to explain the results of another study, called Vigor, which also indicated that patients taking Vioxx had more heart attacks than those taking naproxen, which is found in over-the-counter drugs like Aleve. Unlike the Advantage results, the Vigor results had been publicly disclosed by Merck. Dr. Scolnick expressed his worry in e-mail messages to other senior Merck scientists that the Advantage results would encourage the F.D.A. to demand that Vioxx’s label highlight its cardiac risks. Such a change would have damaged Vioxx’s sales, especially because a competing drug, Celebrex, did not have heart risks prominently displayed on its warning label.

In e-mail messages on April 7, 2001, to Dr. Douglas A. Greene, an executive vice president at Merck Research Laboratories, Dr. Scolnick wrote that he was especially angry because the Advantage trial had no scientific purpose. In theory, Merck set up the trial to show that Vioxx caused fewer stomach problems than naproxen. But Merck had already demonstrated that with the Vigor trial, which tracked more than 8,000 patients for a year. As it turned out, Merck’s marketing department had created the Advantage trial as a promotional tool, to introduce about 600 doctors to Vioxx. “This course is just stupid,” Dr. Scolnick wrote. “Small marketing studies which are intellectually redundant are extremely dangerous.”

The Advantage trial was completed in 2000, but its results were not published until 2003, when they appeared in the Annals of Internal Medicine, a well-regarded journal. Dr. Jeffrey R. Lisse, a rheumatologist at the University of Arizona who is listed as the study’s first author, said in an interview that at least two other journals had rejected the study because its results were not novel. In the published study, Dr. Lisse reported that five patients taking Vioxx had suffered heart attacks during the trial, compared with one taking naproxen, a difference that did not reach statistical significance. But the paper never mentioned the three additional cardiac deaths of patients taking Vioxx, including the 73-year-old woman. Dr. Lisse said that while he was listed as the paper’s first author, Merck actually wrote the report, an unusual practice. “Merck designed the trial, paid for the trial, ran the trial,” Dr. Lisse said.

“Merck came to me after the study was completed and said, ‘We want your help to work on the paper.’ The initial paper was written at Merck, and then it was sent to me for editing.”Dr. Lisse said he had never heard of the case of the woman who died, until told of it by a reporter. “Basically, I went with the cardiovascular data that was presented to me,” he said.

The 73-year-old woman who became the subject of the debate inside Merck died on Oct. 21, 1999, a few minutes after calling her son to tell him she felt short of breath. By the time her son reached her house, she was dead. Records show that she had been taking 25 milligrams of Vioxx a day as part of the clinical trial. Both the Advantage and Vigor trials were “double-blinded,” a common practice in drug research. Neither patients nor their doctors were aware whether patients were receiving Vioxx or naproxen. Results from the trials were also supposed to be blinded when they were examined, so that Merck researchers could not bias the results.

In 1998, Merck had created a committee of academic researchers to review the case reports for many patients who had suffered suspected heart problems in clinical trials of Vioxx or Arcoxia, a Merck arthritis drug that has still not been approved. But the woman’s case never reached the outside committee because the cause of death listed on the death certificate from an independent autopsy – hypertensive heart disease – did not fall into a category that would automatically prompt Merck to refer the case. As a result, Merck reviewed the case internally. After examining the case, Dr. Eliav Barr, a Merck scientist, initially judged that the woman had probably died of a heart attack. “Common things being common, the clinical scenario is likely to be MI,” Dr. Barr wrote in an e-mail message in November 2000 to Dr. Reicin, the clinical research executive. MI is an abbreviation for myocardial infarction, or heart attack. “Certainly, it is not definitive. I just used my clinical judgment.” Dr. Reicin quickly responded, “I think this should be called an unknown cause of death.” A few hours later, she wrote, “I would prefer unknown cause of death so we don’t raise concerns.” Mr. Mayer, Merck’s lawyer, said the exchange reflected that the scientists were working to classify the death properly, and probably did not know whether the woman had been taking Vioxx or naproxen. But the scientists did already have the results of the Vigor trial, which had shown that Vioxx was associated with an increased risk of cardiovascular death compared with naproxen.

Dr. Robert J. Myerburg, director of cardiology at the University of Miami medical school, said he was taken aback by Merck’s decision to reclassify the woman’s case. Dr. Myerburg, a prominent cardiologist who is not involved in the Vioxx litigation, reviewed the e-mail exchanges at the request of The Times. “A fatal event not being treated as objectively as possible surprises me,” he said. “It looks like they’re playing around with this death.” When Merck presented the data from the Advantage trial to the F.D.A., it classified the woman’s death as unknown. But in November 2001, an F.D.A. reviewer who had examined all the company’s data concluded in a report to other agency officials that Merck had misclassified the death and should have referred the case to its outside committee. In her report, the reviewer, Dr. Maria Lourdes Villalba, said that the heart attacks and sudden cardiac deaths during the Advantage trial had heightened her concerns about Vioxx, because the participating patients were taking only 25 milligrams of the drug, the usual daily dose. In addition, many patients were also taking aspirin, which helps protect against heart attacks. But the F.D.A. never publicly disclosed its concerns about the Advantage trial. And Merck discussed the results of the trial only once, at a conference in 2001, before the publication of Dr. Lisse’s paper in 2003.

Copyright 2005 The New York Times Company

http://www.motherjones.com/news/feature/2005/05/david_graham.html

The Side Effects of Truth
In exposing the deadly threat posed by Vioxx, FDA researcher David Graham was serving the public interest. His bosses had other interests in mind.
Michael Scherer
May 01 , 2005

DR. DAVID GRAHAM IS LOSING WEIGHT AGAIN. His wife noticed first, then his colleagues at the Food and Drug Administration. Graham is a skinny man, and when he drops weight, his cheekbones seem to sit higher on his face. His striped cotton shirts, the frumpy uniform of a government scientist, hang more loosely on his narrow frame. But he isn’t eating, and no wonder: Graham, the scientist who brought the Vioxx scandal to the nation’s attention, feels like a marked man.

“I’m no longer welcome,” he says, sitting in a Rockville, Maryland, coffee shop in early February. He has just left another frustrating day at work, where his boss warned him not to disclose new safety findings about a popular class of painkillers called Cox-2 inhibitors. In a few minutes, he is due at his son’s Boy Scout meeting, but all he can talk about now is the exhaustion of working in a drug-safety system in turmoil. “I’m hoping things will calm down, but I don’t think the FDA will let that happen,” he says. “How do you get off the merry-go-round?”

In August 2004, Graham told his supervisors that, in light of his research, high-dose prescriptions of the painkiller Vioxx, which appeared to triple heart attack rates, should be banned. They told him to be quiet. Their reasoning was circular: That’s not the FDA’s position; you work here; it can’t be yours. Dr. John Jenkins, the FDA director of new drugs, argued that because Graham’s findings didn’t replicate the drug’s warning label, Graham shouldn’t be raising the warning. Another supervisor, Anne Trontrell, called Graham’s position “particularly problematic since FDA funded this study.” Days after Graham’s pronouncement, the agency approved Vioxx for use in children. But Graham was right. The following month, Merck pulled Vioxx from the market after its own research found that the drug, even when taken at low dosages, doubled the risk of heart attack. The announcement provided Graham no vindication. With a scandal on the horizon, the FDA brass now saw him as a danger. They couldn’t silence the message, so they tried to take out the messenger.

Dr. Steven K. Galson, the acting director of the drug-evaluation division at the FDA, told reporters that Graham’s work “constitutes junk science.” Then he sent an email to an editor at the prestigious British medical journal The Lancet, questioning the “integrity” of Graham’s data – a suspicion that proved baseless. The FDA’s acting commissioner, Dr. Lester Crawford, criticized Graham for evading the agency’s “long-established peer review and clearance process.” Another official made calls to at least one Senate staffer, disparaging Graham personally and professionally.

Eventually, he was heard. In November he went before the Senate Finance Committee hearing on Vioxx. Gaunt (he’d lost 12 pounds over three months) but very lucid, Graham took his place before a bank of cameras, wearing his only sport coat, a 20-year-old blue blazer with brass buttons. He explained his conclusion that patients taking high doses of Vioxx were suffering heart attacks. “The estimates range from 88,000 to 139,000 Americans,” he said. “Of these, 30 to 40 percent probably died. For the survivors, their lives were changed forever.” According to the top end of those projections, the toll Vioxx had already taken was comparable to the number of Americans killed in Vietnam. “The FDA, as currently configured,” Graham told the committee, “is incapable of protecting America against another Vioxx. We are virtually defenseless.”

But three months later, as Graham sips iced tea in a Rockville café, the FDA is again trying to suppress his research, this time on the effects of pain medications similar to Vioxx. “I think we’ve already articulated our preference,” his supervisor, Dr. Paul Seligman, wrote him in a terse email. The agency doesn’t want Graham presenting his latest research to scientists who will be meeting in a few days to discuss the drugs. David Graham is headstrong, but not insubordinate. He cannot afford to lose his job. His family has just moved to a new house. His wife, Nancy, stopped working as a lawyer so she could homeschool their six children. Really, though, he has no more time to sit here worrying. The Boy Scouts are competing for their merit badges this evening. He finishes his iced tea.

“I’ve made a commitment,” he says, before walking out the door. “I’ll weigh myself this evening.”

WE LIVE IN THE pharmaceutical era of medicine, a time of tablet-sized miracles and blockbuster serums. More than 70 new drugs are approved every year, adding to the thousands for which American doctors already write some 3 billion annual prescriptions. The medications prolong countless lives and cause millions of harmful side effects. For most patients, the benefits far outweigh the dangers. An aging man will risk diarrhea to restore his virility. A cancer patient will lose her hair in the hope that chemotherapy will save her life. FDA safety officers like Graham spend their lives searching out the other type of pills, the unexpected killers that harm patients after the FDA has approved them.

Since 1988, Graham has called for the removal of 12 drugs from pharmacy shelves, leading to 10 recalls that have likely saved hundreds, if not thousands, of lives. Each recall is an embarrassment for Graham’s employer, the FDA’s Center for Drug Evaluation and Research, which approved the drugs in the first place. The trouble is that the roughly 2,300 staffers who support the approval process, and the 109, like Graham, who study the safety of drugs after their release, all fall under the same leadership, and that leadership is highly responsive to industry. In recent years, nearly half of the center’s $400 million budget has been paid for by drug companies. This arrangement stems from a 1992 agreement, made partly at the urging of AIDS activists, that the FDA would speed up approvals in exchange for “user fees” from industry. “The focus at FDA is efficacy,” says Dr. Curt Furberg, a scientist at Wake Forest University who advises the agency. “Safety is a stepchild.”

For the pharmaceutical companies the system works just fine. “The drug-approval process [in the United States] is second to none,” says Jeff Trewhitt, a spokesman for PHRMA, the drug industry’s trade group. “This is an exhaustive process.” Companies eventually recall about 3 percent of their drugs for safety reasons. Behind many of these recalls are scientists like Graham, who often find themselves pitted against their own supervisors. “If you say something negative about a drug, they try to shut you up,” says Dr. Sidney Wolfe, an FDA watchdog for the group Public Citizen, which has been exposing dangerous drugs for three decades. “David is not the only one, by any means, who has raised issues that later proved to be correct.”

In 1998, for instance, an FDA drug reviewer named Dr. Robert Misbin wrote a paper showing that the diabetes drug Rezulin had caused liver failure in a patient during a controlled study. When his bosses tried to prevent him from publishing, Misbin saw firsthand how the system encouraged the sacrifice of public health to the interests of the industry. “One of my supervisors said something to me that I have never forgotten,” Misbin says, “that we have to maintain good relations with the drug companies because they are our customers.” Misbin eventually went public with his concerns, and the drug was pulled a year later. But he has paid for sticking to his principles. “I am no longer given any good projects,” he says.

Dr. Andrew Mosholder, another FDA reviewer, faced similar pressures last year when he completed a study showing that antidepressants increased suicidal behavior in children. Further studies proved that Mosholder’s science was spot on. But his bosses told him not to report the findings. When someone with access to the study passed his results to the press, the FDA launched an investigation into the leak. According to Tom Devine at the Government Accountability Project, who later became Graham’s lawyer, several scientists were interrogated and threatened with possible jail time. Such intimidation has worked. In 2002, about one in five FDA scientists told federal investigators that they felt pressure to approve drugs despite reservations about safety and efficacy. Two-thirds said they lacked confidence that the agency adequately monitors drug safety after approval.

Michael Scherer is the Washington correspondent for Mother Jones.

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