By David Brown
Washington Post Staff Writer
Wednesday, April 16, 2008
Two teams of researchers with access to thousands of documents gathered for lawsuits over the painkiller Vioxx allege that Merck waged a campaign of deception to promote its drug, moving slowly to warn of possible hazards while at the same time dressing up in-house studies as the work of independent academic researchers.
The reports in today's Journal of the American Medical Association in effect accuse one of the world's biggest pharmaceutical makers of various forms of scientific fraud.
One study alleges that Merck gave the Food and Drug Administration an incomplete accounting of deaths in a clinical trial of Vioxx in people with mild dementia. Federal regulators eventually received the data, which added to growing evidence that Vioxx increased the risk of heart attacks and strokes.
Simultaneously, Merck was using what the JAMA authors call "guest authorship and ghostwriting" to make it appear that research done by its employees or contractors was the work of scientists at medical schools and universities. That presumably gave the findings more credibility when they were published, in medical journals, boosting Vioxx's profile in the crowded painkiller market.
Vioxx, whose generic name is rofecoxib, went on the market in 1999. It became a "blockbuster," with $2.3 billion in sales in 2003, but Merck voluntarily withdrew it in September 2004 after several studies showed that it increased the risk of heart attacks and strokes.
Since then, Merck has been named in 26,500 lawsuits by people who say the drug harmed them. Last fall, the company created a $4.85 billion fund to settle the claims while not admitting that Vioxx caused heart attacks, strokes or deaths.
The two JAMA papers -- which were based on access to company documents made public through the lawsuits -- say they provide a look at widespread practices in the pharmaceutical industry. This view was endorsed in an editorial signed by Catherine D. DeAngelis, the journal's editor, who wrote: "But make no mistake -- the manipulation of study results, authors, editors, and reviewers is not the sole purview of one company."
Although the two studies question the integrity of dozens of physicians and scientists, the JAMA authors did not seek responses from them. Several of those people yesterday called the conclusions incorrect, incomplete or unfair.
A spokesman for Merck's legal team dismissed the JAMA authors as "people in the pay of trial lawyers."
In the study questioning Merck's reporting of deaths, Bruce M. Psaty, a physician and epidemiologist at the University of Washington, examined documents from two clinical trials testing the theory that Vioxx could slow the progress of dementia in elderly people.
In July 2001, Merck filed a report with the FDA saying that out of the roughly 1,000 people in each "arm" of the study, 29 who were taking Vioxx had died, compared with 17 taking a placebo. An internal company document three months earlier, however, contained a more ominous and lopsided report -- 34 deaths in the Vioxx group compared with 12 deaths in the placebo group.
The difference in the numbers apparently resulted from two ways of counting the deaths.
In the in-house document, the Merck researchers included people who died while taking either Vioxx or a placebo as well as people who died after stopping, as quite a few did because they had side effects, changed their minds or moved away. This method of accounting automatically captures any delayed effects of a drug (sometimes measured in months), although it unavoidably includes deaths that are very unlikely to be linked to the drug, such as a car accident occurring a year after a person stops taking a medicine.
In its FDA filing, however, Merck reported only deaths that occurred while "on treatment" and up to two weeks later (for one arm of the study) or three months later (for the other). This gave a mortality risk that was less dramatic than the 3 to 1 ratio calculated with the method the company used in-house.
Merck reported all the mortality data to the FDA two years later, and the information appeared in journal articles in 2004 and 2005. Psaty thinks it should have been done earlier.
"This was a large 'safety signal,' " said Psaty, who has received no payments from plaintiffs' attorneys. "If this had been made public in a timely fashion, many fewer patients would have used Vioxx, and fewer might have been harmed by it."
James Fitzpatrick, a lawyer at the New York firm handling Merck's Vioxx defense, said that in the 2001 report, the company was not hiding anything and that it told the FDA it was still collecting data.
"The disparity in mortality was quite clear if you looked at the on-drug data. Adding some off-drug mortality would not have changed the analysis in any way," he said.
In many clinical trials that carry a risk of death, researchers create a "data monitoring committee" of outside experts who are empowered to look at a study's interim results and stop the study if evidence of harm is found.
The FDA did not require such a committee for the Merck studies, but Psaty said the company should have had one. "That protection wasn't there. You'll have to ask Merck why it wasn't," he said.
Kent Jarrell, a spokesman for the company, said Merck opted for in-house monitoring because Vioxx was already on the market and being taken, apparently safely, by many elderly people.
"With Vioxx, the safety profile had already been studied in thousands of patients," he said.
The evidence that Merck had research papers ghostwritten is circumstantial and indirect.
It includes an e-mail from Scientific Therapeutics Information of Springfield, N.J., which Merck paid to write eight articles reviewing the usefulness of Vioxx in various types of patients. The message notes the "intended author" and "intended journal" for each paper, as well as the delivery date.
A later message to Merck from the same contractor noted that the journal had sent back one of those articles with a request for revisions, and that the author was forwarding "the entire packet" to Scientific Therapeutics Information to do the rewrite.
A letter to Merck from Health Science Communications of New York contains an invoice for a 20-page manuscript of a review "for Cardiology Audience" with authors "TBD" -- to be determined -- and a charge of $23,841.
Together, the documents suggest that Merck or its contractors ran studies and wrote review papers, and then recruited high-profile academic physicians to be the main authors even though they did only a small amount of work. Some received honoraria for this service.
"The idea is, 'We'll supply the review paper and you can edit it,' " said Joseph S. Ross, a physician at Mount Sinai School of Medicine in New York, who did the analysis (and who has been paid by plaintiffs suing Merck). "I think it is scientific fraud. The important thing is the medical profession needs to decide for itself whether it is fraud."
Fitzpatrick, Merck's attorney, said: "It is correct that Merck would sometimes use an outside company to compile the literature in a field and do the first draft, much the way a professor would use a research assistant to do the same thing."
Neither contractor responded to requests for comment, but several authors defended their work.
A draft of one of the dementia papers found in the court documents listed nine Merck employees and the notation "External author?" The version published in a medical journal was very similar -- which Ross took as indirect evidence that the paper was essentially finished before the "external authors" were recruited.
But Steven H. Ferris, a neuropsychologist at New York University School of Medicine who is listed as the second author, said it is not true. He said he was on a committee that reviewed the clinical records of 195 patients who received diagnoses of Alzheimer's during the study -- a task that took many hours, and for which he was paid.
"I was directly involved in a very substantive way," he said this week. "If an entity like JAMA is going to make an effort to expose a problem, they better get their facts straight. It is harmful if they don't."