Allegations of Conflicts of Interest and the Decision to Continue the VIGOR Trial

Last week, US National Public Radio (NPR) reported on a new twist to the tangled Vioxx controversy. Rofecoxib (Vioxx) has been taken off the market in 2004 by its manufacturer, Merck, amidst increasing evidence that the drug increased the risk of myocardial infarction (heart attack). In 2000, the results of the VIGOR trial, published in the New England Journal of Medicine, provided apparent support for the use of the drug as an anti-inflammatory pain reliever. We had posted a while back on later controversy about how the results of the VIGOR trial were reported and interpreted.

In this report, NPR focussed on the role of the data safety monitoring board (DSMB) in the conduct of the trial. NPR found that prior to the conclusion of the trial, the DSMB saw data that showed an increasing divergence as the trial went along between adverse events experienced by patients who took Vioxx (rofecoxib) and those who took the non-steroidal anti-inflammatory drug (NSAID) naproxen. Several experts interviewed by NPR, including Dr Eric Topol (previously of the Cleveland Clinic), Dr Paul Armstrong of the University of Alberta, and Professor Curt Furberg of Wake Forest University, thought in retrospect that the rising adverse event rate in the rofecoxib group should have lead to the early termination of the trial.

In a written statement, the DSMB replied to NPR that "the DSMB was unable to determine whether the difference was due to some adverse effect of Vioxx, the lack of protective anti-platelet effects of naproxen, or some combination of these factors." Yet Furberg pointed out the lack of evidence that naproxen has any beneficial anti-platelet effect.

Furthermore, NPR alleged that potential conflicts of interests affected members of the DSMB.

In 1999, Merck appointed rheumatologist Michael Weinblatt of Brigham & Women's Hospital in Boston to head the safety panel for the Vioxx study called VIGOR. When he became chair of the safety panel, Weinblatt and his wife owned $73,000 of Merck stock.

[Weinblatt replied in writing] At all times, I exercised my independent medical judgment on the issues presented to the board, uninfluenced by any other considerations or interests. I also believe I complied to the best of my ability with all applicable regulations and standards regarding financial disclosures and conflicts.

David Bjorkman, now dean of the University of Utah School of Medicine, also served on the five-member safety panel. In a written statement to NPR, Bjorkman backed up Weinblatt's assertion. Bjorkman also told NPR he didn't own any Merck stock. He added that he didn't advise or speak for Merck while he was on the safety panel, or in the following year. But Merck documents obtained by NPR show that Bjorkman did consult for Merck in that period.

[Bjorkman replied in writing] In reviewing my records for 1999, I discovered that I participated in the Merck speakers bureau and gave presentations in the summer of 1999 that I did not recall at the time of my prior email.

At its last meeting, in December 1999, when the safety panel decided the heart problems weren't serious enough to stop the study, it also said that the problems merited analysis. The panel asked Merck to do that as soon as possible. Merck sent back word that it wanted to wait.

When the safety panel's chairman Michael Weinblatt insisted, Merck proposed a plan. The company would analyze heart problems it was told about by a "cutoff" date -- one month before the study ended. Weinblatt agreed.

As a result of that cut-off date, three of the 20 heart attacks among Vioxx patients weren't included when Merck wrote up the study in the New England Journal of Medicine. And, Vioxx looked safer than it really was.

Soon after agreeing to Merck's plan, Weinblatt signed a new consulting contract to sit on a Merck advisory board. Merck agreed to pay him $5,000 a day for 12 days over a two-year period. Weinblatt received an initial check for $15,000 a few weeks later.

[At that time] The safety panel's formal meetings were done, but the study wasn't. Some patients were still taking their drugs when Weinblatt signed the new contract.

[Weinblatt's written reply] I deeply resent the suggestion that there was any conflict of interest between my brief service on the advisory board and my work as chair of the VIGOR DSMB. The DSMB had completed its task.

Curt Furberg of Wake Forest says the consulting deal calls into further question Weinblatt's independence from Merck. 'I mean you can see it as a payback for being a loyal, supportive investigator. It just looks bad.'

Additionally, NPR found that a Merck employee sat on the DSMB, and took its minutes.

Experts NPR consulted say the safety panel's capacity to protect patients in the study was compromised, not just by these financial conflicts of interest, but by the presence of a Merck employee. The employee attended all the panel's meetings -- including its private deliberations. She even wrote the meetings' minutes.

Lawyer Jim Fitzpatrick represents Merck in lawsuits brought by former Vioxx users. He says the presence of the Merck employee didn't stifle the safety panel's discussions.

This NPR report adds another piece to the complicated jigsaw puzzle of the history of the Vioxx controversy. It illustrates again how conflicts of interest became increasingly pervasive in health care in the late 20th century, and how they raise questions about how all sorts of important decisions were made.
The lessons for the 21st century are

• At a minimum, conflicts of interest affecting anyone who makes health care decisions need to be disclosed to all who may be affected by these decisions.
• Ideally, health care decision makers, whether they be physicians, researchers, executives, etc need to make every effort to divest themselves of financial relationships that could possible conflict with making the best possible decisions on behalf of patients and the public, even though, as we posted earlier, the resulting independence may be painful.