Rofecoxib (Vioxx) Studies on Mortality Were Controlled by Drug Company

By Peggy Peck
NEW YORK, 15 april 2008 -- Ongoing litigation about rofecoxib (Vioxx) has provided confirmation that Merck employees or hired ghostwriters were the true authors of manuscripts about the drug published as the work of academic researchers.That finding was published in the April 16 issue of the Journal of the American Medical Association along with a second study -- also mined from a paper flood uncovered by lawyers -- that suggests Merck manipulated data to hide an increased mortality risk with rofecoxib.Bruce M. Psaty, M.D., Ph.D., and Richard A. Kronmal, Ph.D., of the University of Washington in Seattle, said Merck told the FDA that an intention-to-treat analysis of data from three trials designed to assess the effects of rofecoxib on the occurrence or progression of Alzheimer's disease revealed an increased mortality risk with the drug.
But Merck, according to Drs. Psaty and Kronmal, told the FDA there was no increased mortality, a conclusion the company reached by using an on-treatment rather than intention-to-treat analysis.
As early as Dec. 5, 2001, the FDA raised the question of mortality risk in a letter to Merck that asked "about the ethics of continuing study 078 [an Alzheimer's disease study] based on the excess mortality seen in study 091 [another Alzheimer's disease trial]."
Merck, in its response, reiterated the mortality data derived from the on-treatment analysis, adding that the difference between rofecoxib and placebo represented "small numeric differences … most consistent with chance fluctuations." Merck said, too, that the study had no data safety monitoring board and the company had not supplied the mortality data to institutional review boards at the study sites because the company "does not believe that a safety issue has been identified."
Rofecoxib was not removed from the market until Sept. 30, 2004, when the data safety monitoring board of a colorectal cancer trial reported an increased risk of cardiovascular events associated with long-term, high-dose rofecoxib use.
The two JAMA papers not only call into question the integrity of the drug company, but also of the researchers, who posed as authors for money or prestige, or both, and the integrity of JAMA itself.
Catherine D. DeAngelis, M.D., JAMA's editor-in-chief, and Phil B. Fontanarosa, M.D., M.B.A., the executive deputy editor, took themselves as well as industry and academia to task in an editorial, writing that even though the two studies document the actions of a single company, "the manipulation of study results, authors, editors, and reviewers is not the sole purview of one company."
Joseph S. Ross, M.D., M.H.S., of Mount Sinai School of Medicine in New York, and colleagues turned up 250 documents by searching court documents for these words: clinical trial, author, authorship, review, manuscript, and publication. The court documents were part of the legal files compiled for two New Jersey Vioxx trials.
The search uncovered a Merck publications status report, which revealed that 24 of the early clinical trials of rofecoxib -- which were eventually published as 20 manuscripts when some of the trial protocols were combined for publication -- had a Merck employee "designated within the report as author of the first draft of the manuscript."
When those 20 trials were matched with published papers, Dr. Ross discovered that in 16 cases the listed first author was "an external academically affiliated investigator."
A Merck employee, who was designated as author in the company's internal document, was listed as an author -- usually the final author -- in 14 of the studies.
Dr. Ross and colleagues included examples of communications between Merck and medical publishing companies that were hired to write manuscripts that were then shopped around to academic researchers as Merck sought high-profile authors.
In one case -- which was especially embarrassing for the JAMA editors -- Grace E. Johnson, Pharm.D., a senior editor at Scientific Therapeutics Information, Inc., sent Merck a first draft of "A Randomized, Placebo-Controlled, Parallel-Group, Double-Blind Study to Evaluate the Safety and Efficacy of Rofecoxib 25 mg and Celecoxib 200 mg in Patients with Osteoarthritis of the Knee and Hip," which she said had been prepared for submission to JAMA Express.
Drs. DeAngelis and Fontanarosa wrote that the study "was, indeed, published in JAMA (in January 2002), but not as an Express (online publication) article." They added that when the paper was published, "it was disclosed that Merck sponsored the trial; that three of the five authors (including the first and corresponding author) were employees of Merck; and that the other two authors (who were identified as co-principal investigators) disclosed receiving funding from Merck."
But there was no disclosure that the paper was written by Scientific Therapeutics Information, Inc.
In their editorial, the JAMA editors proposed an 11-point plan of action to clean up medical publishing.
Those recommendations include:
Requiring that all clinical trials be prospectively listed in registries accepted by the International Committee of Medical Journal Editors prior to patient enrollment, and the names of the principal investigators included in that registration.
Require that all authors report their specific contribution to the manuscript, and also require the listing by name of all individuals who "do not qualify for authorship" but who had a role in the manuscript development.
Journals should seriously consider funding sources and authors' disclosed financial conflicts of interest and financial relationship when deciding whether to publish a study or review.
Academic investigators who are not in the employ of trial sponsors should be responsible for collecting and monitoring data and preparing the manuscript reporting study results.
All journals "must require a statistical analysis of clinical trial data conducted by a statistician who is not an employee of a for-profit company" (JAMA already does this).
An author who fails to disclose financial relationships or other conflicts of interest should be punished by both his or her academic institution and by the journal, which should consider banning the author from publishing in the journal.
Peer reviewers who leak confidential information about studies under review should likewise be punished by their institutions and by the journals.
Any editor who knowingly allows (or is party to allowing) for-profit companies to manipulate the journal "must be relieved of the editorship."
Continuing medical education providers "should not condone or tolerate for-profit companies having any input into the content of educational materials or providing funding or sponsorship for medical education programs.
And finally, the JAMA editors recommended this sweeping rule: "Individual physicians must be free of financial influence of pharmaceutical and medical device companies including serving on speaker's bureaus or accepting gifts."
Dr. Psaty reported that he testified at a Senate hearing titled "FDA, Merck, and Vioxx: Putting Patients First," Dr. Kronmal said that he was retained by plaintiff attorneys in Merck litigation from 2005 to 2007. There was no funding organization or sponsor for the Psaty/Kronmal paper.

Primary source: Journal of the American Medical AssociationSource reference:Ross JS, et al "Guest authorship and ghostwriting in publications related to rofecoxib: A case study of industry documents from rofecoxib litigation" JAMA 2008; 299: 1800-1812. Additional source: Journal of the American Medical AssociationSource reference: Psaty BM, Kronmal RA "Reporting mortality findings in trials of rofecoxib for Alzheimer disease or cognitive impairment: A case study based on documents from rofecoxib litigation" JAMA 2008; 299: 1813-1817. Additional source: Journal of the American Medical AssociationSource reference: DeAngelis CD, Fontanarosa PB "Impugning the integrity of medical science: The adverse effects of industry influence" JAMA 2008; 299: 1833-35