A new study alleges that the manufacturer of the anti-inflammatory drug Vioxx did not disclose to authorities or the public that the medication was linked to a higher death rate.

A second study claims that employees of the manufacturer, Merck, had written studies about the drug and put scientists' names on them, even if they had little or no involvement in the research.

Both studies were published in the Journal of the American Medical Association.

Researchers came to their conclusions after analyzing court documents filed in lawsuits on behalf of patients who had taken Vioxx.

Lawsuits against Merck are currently underway in both Canada and the United States. They were filed after Vioxx was removed from the market in 2004 following studies showing it doubles the risk of heart problems.

Vioxx is a non-steroidal, anti-inflammatory drug that was used to treat rheumatoid and osteoarthritis, migraines and other pain conditions. More than 20 million people worldwide used the drug.

Researchers allege that, during 2001 trials to determine if Vioxx alleviated symptoms in Alzheimer's patients, officials at Merck discovered that the drug in fact led to a three-fold increase in a patient's risk of death. This data was never made public.

Dr. Bruce Psaty of the University of Washington and one of the authors of the study, said: "If these findings had been made public back in 2001, many fewer people would have taken Vioxx and because it is associated with an increased risk of mortality and of heart attacks, many fewer people would have been harmed."

Merck responded to the findings by saying that the studies are "false, misleading or lack context," and that it had, in fact, made the data about the risks of Vioxx public.

Greg Montforton, a Windsor lawyer who represents 350 Canadians who are suing Merck, says this incident will make the public wary of trusting information about new medications, and may not even have faith in the recommendations of their doctors.

"I think it will also serve to undermine the public's confidence in the honesty and integrity of the research that this company, Merck, and in most cases other companies offer in support of the medication they are trying to bring to the market," Montforton said.

Calgary resident John Venables would like to see the drug approval system overhauled completely, because his faith has been compromised.

Venables had a heart attack in July 2000 after taking Vioxx to ease pain in an arthritic heel. He ended up with damage to 75 per cent of his heart, and he went off the drug when it was recalled in 2004.

He didn't have heart problems before taking Vioxx and is now unable to work.

"You have to wonder about the safety of a lot of drugs," Venables said.

"I'm jaded enough and I don't think my confidence can be restored."

The study's authors believe that so-called "ghostwriting" practices are widespread throughout the pharmaceutical industry. They recommend some stricter regulations to be put in place to ensure the public has confidence in information about new drugs.

Based on a report by CTV's medical correspondent Avis Favaro and producer Elizabeth St. Philip.

Abstracts:

Reporting Mortality Findings in Trials of Rofecoxib for Alzheimer Disease or Cognitive Impairment

A Case Study Based on Documents From Rofecoxib Litigation

Bruce M. Psaty, MD, PhD

Richard A. Kronmal, PhD

Sponsors have a marketing interest to represent their products in the best light. This approach conflicts with scientific standards that require the symmetric and comparable reporting of safety and efficacy data. Selective reporting of the results of clinical trials can misrepresent the risk-benefit profile of drugs. We summarize how the sponsor represented mortality findings associated with rofecoxib in clinical trials of patients with Alzheimer disease or cognitive impairment. We reviewed documents that became available during litigation related to rofecoxib involving Merck & Co, including internal company analyses and information provided by the sponsor to the FDA.Wealso evaluated information in 2 published articles that reported results of these trials. In one article (reporting results of protocol 091) published in 2004,11"non-drug related deaths" were reported (9 deaths among 346 rofecoxib patients and 2 deaths among 346 placebo patients). In another article (reporting results of protocol 078) published in 2005,39deathswerereportedamong patients taking study treatment or within 14 days of the last dose (24 among 725 rofecoxib patients and 15 among 732 placebo patients) and an additional 22 deaths in the off-drug period (17 in rofecoxib patients and 5 in placebo patients). However, these articles did not include analyses or statistical tests of the mortality data, and the 2 articles concluded that regarding safety, rofecoxib is "well tolerated."

In contrast, in April 2001, the company's internal intention-to-treat analyses of pooled data from these 2 trials identified a significant increase in total mortality (hazard ratio [HR], 4.43; 95% CI, 1.26-15.53 for protocol 091, and HR, 2.55; 95% CI, 1.17-5.56 for protocol 078), with overall mortality of 34 deaths among 1069 rofecoxib patients and 12 deaths among 1078 placebo patients (HR, 2.99; 95% CI, 1.55-5.77). These mortality analyses were neither provided to the FDA nor made public in a timely fashion. The data submitted by the sponsor to the FDA in a Safety Update Report in July 2001 used on-treatment analysis methods and reported 29 deaths (2.7%) among 1067 rofecoxib patients and 17 deaths (1.6%) among 1075 placebo patients. This on-treatment approach to reporting minimized the appearance of any mortality risk. In December 2001, when the FDA raised safety questions about the submitted safety data, the sponsor did not bring these issues to an institutional review board for review and revealed that there was no data and safety monitoring board for the protocol 078 study. The findings from this case study suggest that additional protections for human research participants, including new approaches for the conduct, oversight, and reporting of industry sponsored trials, are necessary.

Guest Authorship and Ghostwriting in Publications Related to Rofecoxib

A Case Study of Industry Documents From Rofecoxib Litigation

Joseph S. Ross, MD, MHS; Kevin P. Hill, MD, MHS; David S. Egilman, MD, MPH; Harlan M. Krumholz, MD, SM

Context: Authorship in biomedical publication provides recognition and establishes accountability and responsibility. Recent litigation related to rofecoxib provided a unique opportunity to examine guest authorship and ghostwriting, practices that have been suspected in biomedical publication but for which there is little documentation.

Objective: To characterize different types and the extent of guest authorship and ghostwriting in 1 case study.

Data Sources: Court documents originally obtained during litigation related to rofecoxib against Merck & Co Inc. Documents were created predominantly between 1996 and 2004. In addition, publicly available articles related to rofecoxib identified via MEDLINE.

Data Extraction: All documents were reviewed by one author, with selected review by coauthors, using an iterative process of review, discussion, and rereview of documents to identify information related to guest authorship or ghostwriting.

Data Synthesis: Approximately 250 documents were relevant to our review. For the publication of clinical trials, documents were found describing Merck employees working either independently or in collaboration with medical publishing companies to prepare manuscripts and subsequently recruiting external, academically affiliated investigators to be authors. Recruited authors were frequently placed in the first and second positions of the authorship list. For the publication of scientific review papers, documents were found describing Merck marketing employees developing plans for manuscripts, contracting with medical publishing companies to ghostwrite manuscripts, and recruiting external, academically affiliated investigators to be authors. Recruited authors were commonly the sole author on the manuscript and offered honoraria for their participation. Among 96 relevant published articles, we found that 92% (22 of 24) of clinical trial articles published a disclosure of Merck's financial support, but only 50% (36 of 72) of review articles published either a disclosure of Merck sponsorship or a disclosure of whether the author had received any financial compensation from the company.

Conclusions: This case-study review of industry documents demonstrates that clinical trial manuscripts related to rofecoxib were authored by sponsor employees but often attributed first authorship to academically affiliated investigators who did not always disclose industry financial support. Review manuscripts were often prepared by unacknowledged authors and subsequently attributed authorship to academically affiliated investigators who often did not disclose industry financial support.