April 15, 2008 — Two studies appearing in Tuesday’s Journal of theAmerican Medical Association have prompted the journal’s editors to callfor “drastic action” to prevent drug companies from misrepresentingdata from clinical trials.
The two investigations involve the painmedication Vioxx, which was taken off the market in2004 after being linked to an increased risk of heart attacks and strokes amonglong-term users. The revelations are the latest to come to light from lawsuitsbrought by people who claimed they’d been harmed by Vioxx.
Researchers charged that the drug’s manufacturer, Merck, withheld key datafrom Vioxx trials from federal regulators and misrepresented the Vioxxresearch. The JAMA editors agreed, but they added that the problems arepervasive within the industry and not confined to Merck.
“The (two studies) document how one company, Merck & Co. Inc.,apparently manipulated dozens of publications to promote one of itsproducts,” the journal’s editor in chief and executive deputy editor write.”But make no mistake — the manipulation of study results, authors,editors, and reviews is not the sole purview of one company.”
Merck Responds to Criticism
In one of the JAMA articles, researchers charge that data fromclinical trials showing a threefold increase in deaths among Vioxx users werewithheld from the FDA for more than two years.
In their review of the data and internal company documents made publicduring civil litigation against Vioxx, the two researchers from the Universityof Washington, Seattle say the company appears to have misrepresented Vioxx’ssafety profile in studies involving Alzheimer’s patients. One of those researchers, RichardA. Kronmal, PhD, was retained as an expert witness by plaintiffs’ attorneys inVioxx litigation.
In a separate analysis of the court documents, another group of researchersconcluded that Merck misled federal regulators and the public about its role inthe Vioxx studies by naming outside investigators who had little to do withthose studies as principal investigators. All of these researchers served aspaid consultants to plantiffs in Vioxx litigation.
A spokesman for the company tells WebMD that both charges are unfoundedand that the company plans to formally respond to the JAMAeditorial.
“All of Merck’s disclosures to the FDA and the medical community wereproper and appropriate,” Merck legal spokesman Kent Jarrell says.
“We heard the points presented in these articles during the litigationand we rebutted them with evidence,” Jarrell says. “It was a case oftrial lawyer’s antic masquerading as scientific substance.”
JAMA Calls for Reforms
The JAMA editorial notes that the “manipulation of studies andmisrepresentation of study results could not have occurred without thecooperation (active and tacit) of clinical researchers, other authors, journaleditors, peer reviewer, and the FDA.”
It further noted that the public’s trust in clinical research is in greatjeopardy because the extent of the problem is not known.
“Although we truly believe that the vast majority of researchers andother authors are honest and have the highest scientific integrity,manipulation of studies and publications by the pharmaceutical and medicaldevice industries is either increasing or there has been more exposure of thesepractices,” JAMA editors Catherine D DeAngelis, MD, and Phil B.Fontanarosa, MD, write.
They go on to propose reforms aimed at minimizing the influence of thepharmaceutical industry on the clinical trials process, including registeringall clinical trials prior to patient enrollment and full disclosure of the relationships of study authors with the companies payingfor the research.
Vioxx Study Deaths Underreported
The University of Washington review included data from two studies designedto determine if Vioxx had a role in the treatment of Alzheimer’s disease.
Researchers Bruce M. Psaty, MD, PhD, and Richard A. Kronmal, PhD, comparedthe two published trials to internal Merck documents about the studies madepublic during the court trials.
Psaty tells WebMD that internal documents show that as early as spring 2001Merck identified a threefold increase in the risk of death among Vioxx usersvs. patients taking placebo, but the information was not given to federalregulators.
“These analyses were not submitted to the FDA or the public in a timelyfashion, and when Merck did submit the data to the FDA, they used accountingmethods that minimized the appearance of risk,” he says.
Specifically, Psaty says the company’s April 2001 analysis of pooled datafrom two trials identified 34 deaths among 1,069 Vioxx patients and 12 deathsamong 1,078 patients in the placebo arms of the studies.
“If you were to ask independent scientists whether a threefold increasein mortality represented a safety problem, I think you would be hard pressed tofind many, if any, who would say no,” Psaty says.
But Psaty says safety data submitted by Merck to the FDA a few months latershowed a smaller difference in deaths between the Vioxx and placebo-treatedpatients because the company included only the patients who were actuallytaking the treatment they were assigned to take.
“This on-treatment approach to reporting minimized the appearance of anymortality risk,” Psaty and Kronmal write.
In the other review of the court documents, Joseph Ross, MD, of New York’sMount Sinai School of Medicine, and colleagues conclude that Merckmisrepresented the authorship of many Vioxx studies by recruiting outsideinvestigators with impressive academic affiliations.
These investigators were often listed in the published studies as first,second, and third authors, even though they had little active role in theresearch, which was done internally by Merck, Ross tells WebMD.
“This gave the appearance of more academic rigor and more objectivitythan there actually was in these studies,” Ross says.
Merck Calls Reports Misleading
In a written statement, the company says it is the authors of the twoJAMA studies who misrepresented the facts by failing to provideappropriate context for their claims.
“Merck is disappointed that we did not have an opportunity to respond tothe misleading claims made in these articles prior to their publication,”the statement reads. “We believe that a full, unbiased evaluation of theMerck papers shows that many of the conclusions put forward by the authors ofthe JAMA papers are incorrect.”
In the statement, Merck officials say the review of deaths in theAlzheimer’s trials was misleading because it failed to include informationabout the causes of death among the patients in the Alzheimer’s studies.
“Merck carefully analyzed the data and found that there was no patternsuggesting the deaths had any connection to Vioxx; some of the deaths werecaused by car accidents, poisonings, infections, and other causes that are notrelated to Vioxx,” the statement reads.
Jarrell says the authorship review misrepresented the role of the academicauthors involved with the studies.
“We certainly feel that our actions on disclosure were appropriate andin line with industry practice,” Jarrell tells WebMD. “And, mostimportantly, the data in the articles were completely accurate.”
Merck agreed to pay $4.85 billion last November to settle lawsuits broughtby people who claimed to have been harmed by Vioxx.