The vexations of Vioxx
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《加拿大医疗协会学报》
The wave of litigation surrounding rofecoxib (Vioxx) has lapped ashore at the New England Journal of Medicine (NEJM), whose oft-cited study of the drug published in 2000 appears to contain incomplete adverse event information.
Merck & Co. pulled rofecoxib off the market on Sept. 30, 2004, after finding it doubled the risk of heart attack and stroke. There are now some 9200 lawsuits pending in the US against Merck & Co, based in Whitehouse Station, NJ.
In the midst of one such suit, on Nov. 21, 2005, a Merck & Co. memo dated July 5, 2000, emerged. It indicated that at least 2 authors of the NEJM article on the VIGOR (Vioxx Gastrointestinal Outcomes Research) study (2000;343:1520-8) knew 4.5 months before publication that 20 study participants suffered myocardial infarction (MI) after taking the drug — not 17 patients, as the NEJM article reported.
In the original article, the researchers, led by Dr. Claire Bombardier, the director of rheumatology at the University of Toronto, reported a relative risk of MI while taking rofecoxib of 4.25 (95% CI 1.4–17.4). Taking into account the 3 unreported MIs, the relative risk is 5.0 (95% CI 1.7–20.1).
Merck & Co. contends in a Dec. 8, 2005, statement that the MIs in question occurred "after the pre-specified cut-off date and therefore were not included in the primary analysis."
A NEJM expression of concern (online Dec. 8, 2005; print 2005;353:2813-4) states that the editors first became aware of the additional infarctions in 2001 (see (box 1), when additional data were made public by the FDA (www.fda.gov/ohrms/dockets/ac/01/briefing/367b2_03_med.doc), but until the memo emerged on Nov. 21, 2005, "we believed that these were late events that were not known to the authors in time to be included in the article."
The expression of concern questions the validity of research and invites the authors to explain themselves. They had not done so as of this writing.
Bombardier and the NEJM declined to comment on the case. In a statement, the editors said: "Once our concerns have been fully pursued and answered, we will publish the results."
All this fuss is "somewhat surprising," says Dr. James Wright, given that NEJM was aware of the 3 additional MIs when it saw the FDA posting 5 years ago (Feb. 8, 2001); that information was reiterated in Wrights' Therapeutics Letter on Jan. 31, 2002 (www.ti.ubc.ca/PDF/43.pdf) and in CMAJ (2002;167:1131-7).
NEJM "should have reacted when the FDA put the information out there in February 2001. I don't know if the drug would have been withdrawn sooner," says Wright, who has been retained as an expert witness by 5 legal firms involved in Vioxx litigation.
Wright believes journals shouldn't publish any research article unless they get all the data. "There should be standards."(Barbara Sibbald)
Merck & Co. pulled rofecoxib off the market on Sept. 30, 2004, after finding it doubled the risk of heart attack and stroke. There are now some 9200 lawsuits pending in the US against Merck & Co, based in Whitehouse Station, NJ.
In the midst of one such suit, on Nov. 21, 2005, a Merck & Co. memo dated July 5, 2000, emerged. It indicated that at least 2 authors of the NEJM article on the VIGOR (Vioxx Gastrointestinal Outcomes Research) study (2000;343:1520-8) knew 4.5 months before publication that 20 study participants suffered myocardial infarction (MI) after taking the drug — not 17 patients, as the NEJM article reported.
In the original article, the researchers, led by Dr. Claire Bombardier, the director of rheumatology at the University of Toronto, reported a relative risk of MI while taking rofecoxib of 4.25 (95% CI 1.4–17.4). Taking into account the 3 unreported MIs, the relative risk is 5.0 (95% CI 1.7–20.1).
Merck & Co. contends in a Dec. 8, 2005, statement that the MIs in question occurred "after the pre-specified cut-off date and therefore were not included in the primary analysis."
A NEJM expression of concern (online Dec. 8, 2005; print 2005;353:2813-4) states that the editors first became aware of the additional infarctions in 2001 (see (box 1), when additional data were made public by the FDA (www.fda.gov/ohrms/dockets/ac/01/briefing/367b2_03_med.doc), but until the memo emerged on Nov. 21, 2005, "we believed that these were late events that were not known to the authors in time to be included in the article."
The expression of concern questions the validity of research and invites the authors to explain themselves. They had not done so as of this writing.
Bombardier and the NEJM declined to comment on the case. In a statement, the editors said: "Once our concerns have been fully pursued and answered, we will publish the results."
All this fuss is "somewhat surprising," says Dr. James Wright, given that NEJM was aware of the 3 additional MIs when it saw the FDA posting 5 years ago (Feb. 8, 2001); that information was reiterated in Wrights' Therapeutics Letter on Jan. 31, 2002 (www.ti.ubc.ca/PDF/43.pdf) and in CMAJ (2002;167:1131-7).
NEJM "should have reacted when the FDA put the information out there in February 2001. I don't know if the drug would have been withdrawn sooner," says Wright, who has been retained as an expert witness by 5 legal firms involved in Vioxx litigation.
Wright believes journals shouldn't publish any research article unless they get all the data. "There should be standards."(Barbara Sibbald)