Studies suggest drugmaker skewed clinical trial reports

Washington -- Recent studies detailing an alleged maneuver by pharmaceutical giant Merck in the promotion of its now-withdrawn pain reliever Vioxx are sounding alarms throughout the medical community -- sweeping in researchers, journal editors and clinicians who look to the studies for up-to-the-minute practice advice.

The authors of two studies in the April 16 Journal of the American Medical Association analyzed documents that came to light during ongoing litigation of thousands of cases filed after Vioxx, or rofecoxib, was found to raise the risk of heart attacks and stroke. Merck voluntarily withdrew the drug from the market in September 2004.

One study contended that Merck downplayed the drug's risk of death in trials involving patients with cognitive impairments or Alzheimer's disease. The second charged that the firm concealed the true authorship of articles by either naming as lead authors prestigious academic researchers or guest authors who had done little actual work on the trial, or by hiring outside consultants to "ghostwrite" studies without revealing this relationship.

Merck said the charges in the JAMA studies were "false, misleading or lack context." Contrary to the assertions, complete mortality data from the Alzheimer's study were provided to the Food and Drug Administration, said Peter S. Kim, PhD, president of Merck Research Laboratories. The outside authors also were intimately involved, he said, noting that Merck's authorship policies were followed.

Steven Ferris, PhD, executive director of New York University's Silberstein Aging and Dementia Research Center, was named as a guest author in an illustration accompanying the JAMA article on that topic and denies the allegation of wrongdoing. He said he actually had played a substantial role in preparing the cited manuscript.

While the JAMA authors may have a valid point in their criticism, Dr. Ferris said, they picked the wrong example. "I neither condone nor participate in guest authorship."

Dr. Kim also noted that several JAMA authors had served as paid consultants to plaintiffs in the lawsuits against Merck, a fact disclosed in the journal.

A pervasive problem?

Although the current controversy centers onMerck, the studies' findings can be applied more broadly, the authors said. "I do not think Merck is the only company doing this," said Joseph Ross, MD, instructor in the Dept. of Geriatrics and Adult Development at Mount Sinai School of Medicine in New York City. He was the lead author on the guest authorship and ghostwriting study.

"Our study raises questions about the wisdom of allowing the sponsor to control the data and the analysis," said Bruce Psaty, MD, PhD, lead author of the mortality findings study and a professor of medicine, epidemiology and health services at the University of Washington. "The integrity of medical research is an effort based largely on trust."

Although observers of drug safety thought that Merck's actions as portrayed in the studies betrayed that trust, they were not surprised by the findings. Some had long suspected that drugmakers skewed study results or delayed negative findings.

"We've all known these things are true. They've come out in bits and pieces over the past 20 years or so," said Kay Dickersin, PhD, professor of epidemiology and director of the Center for Clinical Trials at Johns Hopkins University's Bloomberg School of Public Health in Baltimore.

"What's different this time is you can see exactly what [evidence] was submitted," she said. "It makes it more difficult [for Merck] to refute."

And the repercussions were seen as serious. "If research findings are altered and/or misrepresented in medical journals, both patients and physicians could suffer severe consequences," said AMA President Ron Davis, MD. "Physicians rely on peer-reviewed literature as accurate, unbiased information to aid in clinical decision-making."

The AMA has clear ethical guidelines to help minimize potential conflicts of interest when physicians work with pharmaceutical companies, Dr. Davis said. They recommend that physicians ensure that an institutional review board examines the protocol and that the research conforms to government regulations. Neither of these precautions apparently was followed in research examined by Dr. Psaty and colleagues. He reported that one study had no safety monitoring board. The guidelines also urge physicians to make certain that results will be reported without delay.

In an editorial in the same JAMA issue, Editor-in-Chief Catherine D. DeAngelis, MD, MPH, and Executive Deputy Editor Phil B. Fontanarosa, MD, set out an 11-point agenda to address the issues raised by the two articles. It includes requirements that all those named as authors fulfill authorship criteria and that all clinical trials be listed prospectively in registries before patient enrollment. The editors also caution against accepting any gifts from pharmaceutical companies.

JAMA has instituted numerous safeguards to try to avoid the publication of studies that include manipulated data, inappropriate analyses and selective reporting of results. The JAMA editors urge other journal editors to adopt the same practices.

The editors also noted that lessons have been learned from these and other studies. One lesson is that manipulation of studies and their results could not occur without the cooperation of researchers, authors, journal editors, peer reviewers and the FDA. Another is that public trust in clinical research is in great jeopardy.

As to whether improvements are ahead? "I'm an optimist," Dr. DeAngelis responded. "I'm surprised that this happened in the first place, and I think people are getting fed up."

She also warned that if physicians don't step up and make necessary changes, the "feds are going to do it for us. Why would you want a group of people in Washington telling you how to run a profession? But if we do a better job, they won't want to get involved in this. Why would they?"