Monday, December 12, 2005

The New England Journal Charges Merck Suppressed Vioxx Research Results: "One Horrible Debacle in American Medical History"

Late last week, the New England Journal of Medicine published an unusual Editorial "Expression of Concern." (Curfman GD, Morrisey 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: 1520-8. N Engl J Med 2005; 353: 26.)

The editorial stated that an article in journal which reported on VIGOR trial, which compared Merck's drug rofecoxib (Vioxx) with naproxen, omitted mention of cardiac adverse events that were known to the study's authors before the final version of the manuscript was submitted to the journal. Specifically, the editorial states that at least two of the authors knew that three patients who had received rofecoxib in the trial had suffered myocardial infarctions (heart attacks), but did not include these patients in their calculations of adverse events. Furthermore, some of the authors were apparently aware of "other data on cardiovascular adverse events that we believe would have been relevant to the article," but did not include this data in the article.

Subsequent interviews with Dr. Curfman revealed that the two authors who knew about the extra adverse events were both Merck employees (Toronto Star, Dec. 8). The only two Merck employees now known to be authors were Dr. Alise Reicin, Vice President for Clinical Research, and biostatistician Dr. Deborah Shapiro. When Curfman was giving a deposition for a case brought against Merck, he was shown a Merck internal memo dated July 5, 2000, two weeks before the VIGOR authors submitted a revised but not final version of the manuscript to the journal. The memo suggested that three patients had suffered heart attacks, yet that data was not included in the revised (or final) version of the paper. Curfman also said,

We hope by issuing the statement of concern that it will be a stark reminder to the science community, to the scholarly community, that if we don't his this principle of trust, that the whole scholarly process is just going to collapse into rubble.
Merck's response was a statement, "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. We also note that these additional events did not materially change any of the conclusions of the article."

Forbes reported that "a pre-submission version of the study from which data, including the number of heart attacks and deaths, were deleted by a Merck editor two days before submission." Forbes also quoted Dr. Eric Topol,

This is one horrible debacle in American medical history. I've never seen the likes of this.

Curfman talked more to the Boston Globe (Dec. 10, 2005), admitting that he should have been more skeptical about the VIGOR trial article. In particular, the authors of the study suggested that any apparent differences between adverse cardiac events for patients receiving rofoecoxib versus naproxen were due to a protective effect of naproxen. Curfman said, "I should have been more diligent in questioning the hypothesis at the time."
The Globe also reported that some of the plaintiffs' attorneys involved in Vioxx litigation are questioning whether Merck Vice President Reicin may have commited perjury. Attorney Mark Lanier said that he plans "on using it [the New England Journal editorial] to show that she's been less than honest with other juries." Furthermore, "What a jury is going to get is A, Merck fudged on the details, B, the fudge was in their favor, C, it was on purpose, D, Merck lied about fudging, or at least covered it up. And E, the most prestigious medical journal in the United States of America has called their hand and said this is unethical and wrong."

The evidence that Merck was reluctant about disclosing research data unfavorable to Vioxx just gets stronger and more extensive. We can only hope that this increasingly sad case will force pharmaceutical companies, and other large health care organizations, to be more open, transparent, accountable, and honest.

It would help if health care professionals united to demand these changes. Bravo, at least to Dr. Curfman and the other editors of the New England Journal, and Dr. Eric Topol, for speaking up.

[Update as of Dec 19, 2005: Merck's full statement in response to the New England Journal of Medicine editorial statement, and its news coverage, is on the Merck web-site. To quote the statement in more detail than provided above,
The article in the NEJM was based on cardiovascular data reported as of a prespecified cutoff date established by the Company. The reason for specifying a cutoff date in advance were to ensure that the data analysis could be completed in a prompt manner and to avoid any later allegation that the data were manipulated.
All potential CV serious adverse experiences eligible for adjudication that had been reported to Merck by the cutoff date, February 10, 2000, were referred for adjudication and the confirmed events formed the basis of Merck's communication on the primary study data.... The NEJM thus received the data that was part of the primary analysis.
Any additional CV events eligible for adjudication but reported to Merck after the February 10 cutoff date were subsequently adjudicated.
Merck used other means to disclose the additional information.
The statement of concern by the NEJM editors may have left the mistaken impression that the updated data, including the 3 additional MIs on rofecoxib, were in the original draft version of the manuscript submitted to the NEJM but deleted before submission. That is incorrect. The basis for this misimpression was a document submitted electronically to the NEJM that simply showed the deletion of a header and footers for a table discussion cardiovascular events in the study. There was no data in the table.
As some other bloggers might say, "read the whole thing," and see what you think.]

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