The risk-benefit profile of rofecoxib (marketed under the names Vioxx, Ceoxx and Ceeoxx) may be have been misrepresented by the study sponsor, Merck, in clinical trials with patients with cognitive impairment. This was the result of a comparison of internal company documents, data submitted by the company to the Food and Drug Administration (FDA,) and published clinical trial results, according to an article in the April 16 issues of JAMA.
Sponsors have a financial interest in representing their products in the most favorable way possible. This is often in direct conflict with scientific standards, which demand unbiased and comparable reports of safety and efficacy data. By selectively reporting the results of clinical trials, the risk-benefit profile of drugs can be misrepresented.
Bruce M. Psaty, M.D., Ph.D., and Richard A. Kronmal, Ph.D., of the University of Washington, Seattle, reviewed documents with the goal of summarizing how findings were represented by the study sponsor, Merck, specifically regarding the risk of death associated with rofecoxib in clinical trials of patients with Alzheimer’s disease or cognitive impairment. These documents were made available during litigation related to rofecoxib and Merck, including internal company analyses and information provided by the sponsor to the Food and Drug Administration. Additionally, they evaluated information from two published articles reporting the results of these trials.
In an article which reported the results of protocol 091, published in 2004, 11 “non-drug related deaths” were reported among patients. 9 of these were in the group of 346 rofecoxib patients, and 2 were among the same number of placebo patients. In another article, reporting the results of protocol 078, which was published in 2005, 39 deaths were reported among patients taking a study treatment or within 14 days of the last dose. This was 24 patients in the 725 strong rofecoxib group and 15 among the 732 placebo patients. Additionally, there were 22 deaths in the off-drug period (17 in rofecoxib patients and 5 placebo patients.) These articles, according to the reviewers, included no analysis or statistical tests of the mortality data. The studies then concluded that rofecoxib is “well tolerated” regarding safety.
April 2001 marks the company’s internal intention-to-treat analyses, a technique based on the evaluation of patients in the group to which they were randomly assigned, pooled data from these two trials and found a significant three-fold increase in total mortality. This was indicated by an overall mortality of 34 deaths in 1,069 rofecoxib patients and onle 12 deaths among 1,078 placebo patients. “These mortality analyses were neither provided to the FDA nor made public in a timely fashion,” write the authors of the review.
Instead, the data submitted by Merck to the FDA in a Safety Update Report in July 2001 used an on-treatment analysis, in which patients who were actually taking the drug or placebo they were assigned, reported 29 deaths among 1,067 rofecoxib patients and 17 deaths among 1,075 placebo patients. This minimized the appearance of a mortality risk, according to the review writers. Apparently, deaths that had occurred more than 14 days after discontinuation of the drug trial were apparently not included.
When the FDA raised safety questions about the submitted safety data in December 2001, the sponsor did not bring the issues to an institutional review board for review. They revealed that there was no data and safety monitoring board (DSMB) for the protocol 078 study. During additional follow-up time for the 078 study, there were approximately 8 excess deaths among those randomly assigned to receive rofecoxib, which was associated with an increased risk of progression to Alzheimer’s disease. This was, according to the review authors, “a finding that was apparent early in the trial. The mortality findings and the Alzheimer disease findings would, in our judgment, have prompted a DSMB, if it had existed, to stop the trial early.”
“The only human-subjects protections available to the study participants were those provided by the investigators who were blind not only to the treatment allocation but also to the findings for study-wide adverse events, and by the unblinded Merck investigators, who did not discern a safety issue. The sponsor’s submission of individual adverse event reports over time to the FDA is not adequate for active trial monitoring. The FDA depends on the sponsor and the DSMB to alert the agency about any evidence of harm that may be associated with the drug.” They continue, adding that all large clinical trials, especially when related to drugs with serious known risks, should have a DSMB.
“Sponsors have a direct financial interest in their products and a fiduciary duty to shareholders to provide a return on their investment. These interests disqualify sponsors from other important duties, including those normally accorded to DSMBs and institutional review boards (IRBs). Failure of the sponsor to inform IRBs of a safety issue violates the trust of those human participants who volunteered to advance science, medicine, and public health.”
The authors conclude with scathing remarks regarding the influence of industry on clinical studies. “For sponsors that conduct their own studies or use contract research organizations to conduct studies, it is not clear how transparency in the reporting of results can be achieved if a sponsor chooses to represent its products in the best possible light. The commercialization of clinical trials has neither improved the quality of the science nor enhanced the protection of human research participants. 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. A clinical trials system in which sponsors fund the trials that are conducted by independent investigators would provide additional protections.”
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
JAMA. 2008;299(15):1813-1817.
Written by Anna Sophia McKenney