In response to the revelation that three additional myocardial infarctions were withheld from the original Vioxx® GI Outcomes Research (VIGOR) trial submitted to the New England Journal of Medicine, the editors of the journal have called into question the integrity of the data and requested that the authors submit a correction to account for the "inaccuracies and deletions" in the original published article.1

Merck & Co, Inc, the manufacturer of Vioxx, responded to the editorial appearing in the December 29, 2005, edition of the journal by emphasizing that the company promptly and appropriately disclosed the results of VIGOR and is confident in its research.2

Citing evidence unearthed during the ongoing Vioxx litigation, the NEJM editors allege in an early-release editorial that three myocardial infarctions (MI) were not included in the data submitted to the journal, despite ample opportunity during the review and revision process prior to publication. The editors write that they first became aware of these events when the data were presented to the US Food and Drug Administration (FDA) in 2001.

Memorandum obtained by subpoena suggests subterfuge

"Until the end of November 2005, we believed that these were late events that were not known to the authors in time to be included in the article published in the Journal on November 23, 2000," they write. But "at least two of the authors knew about the three additional MIs at least 2 weeks before the authors submitted the first of two revisions and 4½ months before publication of the article."

Not including these events, the editors write, made certain calculations and conclusions of VIGOR incorrect. "In addition, the memorandom of July 5, 2000, contained other data on cardiovascular adverse events that we believe would have been relevant to the article," they charge. "We determined from a computer diskette that some of these data were deleted from the VIGOR manuscript two days before it was initially submitted."

Merck counters that the additional MI events did not alter trial conclusions

"The additional events referred to in the editorial were events that were reported after the prespecified cut-off date and therefore were not included in the primary analysis reported in the New England Journal article," Merck states in a press release. "Nevertheless, these additional events were disclosed to the FDA in 2000, presented publicly at the FDA's Advisory Committee in February 2001, included in numerous press releases subsequently issued by Merck, disclosed to physicians given a copy of the article by Merck, and detailed in the updated prescribing information for Vioxx.  We also note that these additional events did not materially change any of the conclusions in the article."

VIGOR data in public arena
 
"The VIGOR data was cardiovascular (CV)-adjudicated after the blind was broken and was fully submitted to the FDA and presented in public at the February 2001 advisory meeting, so this discrepant number of CV events was in public and fully vetted," explains Lee Simon, MD, a rheumatologist and associate clinical professor of medicine at Harvard Medical School in Boston, Massachusetts.

Dr. Simon explains that at that time, these three cardiovascular events were censored because they occurred after the trial, and therefore were not included. "The FDA then calculated a 5-fold increase over naproxen, while the paper said 4-fold, and the extra cases would have made no substantial change to the effect at that time," Dr. Simon tells CIAOMed.

Importantly, the editorial changes nothing regarding the data, he says. But "it will change much for the authors and, more importantly, probably for Merck by casting them in the light of ‘lying' when in fact there were many saying that they should have written or at least acknowledged what they found, even though these three cases were outside the parameters of the trial," Dr. Simon says. "By strict trial design, they would not be included. A trial has to stop somewhere, and only in hindsight are we really sure about what these data might have meant." 

References

  1. Curfman, GD, Morrissey S, Drazen, JM. Expression of concern: Bombardier et al, "comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis." N Engl J Med. 2000;343;1520-1528; N Engl J Med. 2005;353:26:2813-2814.
  2. Response to an editorial posted on The New England Journal of Medicine Web site [press release]. Whitehouse Station, NJ: Merck & Co, Inc; December 8, 2005.