The New England Journal of Medicine published today an "expression of concern" about the validity of a study it published in 2000. The study looked at the pain reliever Vioxx and is known in medical circles as the "VIGOR" trial.
The "expression of concern" is a preliminary step sometimes taken before a journal declares a scientific paper invalid and retracts it.
In a written statement, the journal said that as part of preparations for a federal trial now going on in Houston, plaintiff's attorneys subpoenaed the journal's executive editor, Dr. Gregory D. Curfman, for information and testimony regarding the 2000 paper.
The Houston jury is considering whether Vioxx caused the death of Richard Irvin, of St. Augustine, Fla., in 2001.
During the process leading up to the trial, journal editors say they learned that relevant data on cardiovascular events had been deleted from the VIGOR manuscript prior to its submission to the journal and that study authors had also concealed that three trial participants had heart attacks during the study.
The evidence has "raised questions," the statement continued, "about the integrity of the data on adverse cardiovascular events in the article and about some of the article's conclusions."
Adverse cardiovascular events refer to heart attacks, strokes and deaths.
Merck responded in a statement late Thursday to the NEJM editorial, saying that the additional heart attacks "did not materially change any of the conclusions of the article." The company also said the information was not included because the heart attacks were reported after Merck's cut-off date for collecting information on the patients in the study.
"Nevertheless, these additional events were disclosed to the FDA in 2000, presented publicly at the FDA's Advisory Committee in February 2001, and included in numerous press releases subsequently issued by Merck," the statement reads.
The journal paper has been cited numerous times by the drug's maker, Merck, as showing that Vioxx did not increase the risk of heart disease or death. Merck frequently referred to the study's publication in the New England Journal of Medicine to bolster its claims.
The journal stood by its publication of the study for years. But behind the scenes, controversy erupted in August 2001 when a paper published in the Journal of the American Medical Association indicated that Merck may not have been totally forthcoming with NEJM back in 2000.
In a July 2005 interview, NEJM's editor-in-chief, Dr. Jeffrey Drazen, told NPR that NEJM editors then investigated what might have happened. They learned that because of an unusual quirk in the design of the trial, Merck hadn't given them the data about adverse events that it received in the last weeks of the trial.
Drazen said that he felt that the journal had been "hoodwinked" by the company.
"There's a difference between the letter of the law and the spirit of the law," Drazen said in the July interview, "and what they did conformed with the letter of the law.
"But in my opinion, it broke the spirit of the law because you're using human subjects, participants in this trial, and you're putting them at risk," Drazen said. "I believe it's the responsibility of the authors to come forward with that data when they become available."
A Merck attorney, Ted Mayer, said at the time: "I believe the paper accurately disclosed the information from the VIGOR trial that was relevant to assessing the risks and benefits of the medicine.
"The few additional events that were subsequently learned about after the previously specified cutoff date," Mayer said, "did not materially change any of the conclusions in the article or any of the analysis of those conclusions."
In today's statement, the journal also says it learned in October 2004 that data had been deleted from Merck's submission. It said that in 2000, the publication was in the midst of transitioning from a paper-based system for processing manuscripts to a computerized system. The VIGOR manuscript was processed under the old paper system, even though it had been submitted in both paper and electronic form.
"We did not access the diskette until October 5, 2004," the statement reads, "several days after Vioxx was withdrawn from the market. In reviewing the diskette, we learned that data on cardiovascular events had been deleted from the manuscript before it was submitted."
Observers at the trial in Houston had expected these facts to emerge in the trial during Dr. Curfman's video deposition. But the deposition was not entered into evidence and was never played to the jury.
Before the defense rested yesterday, Dr. Alise Reicin, Merck's vice president for clinical research testified that the company never misled doctors and the public about studies linking heart attacks to Vioxx.