Friday, November 14, 2008

An Intriguing, and Truly-Independent, AHA Plenary Session: SEAS "Minority Report" Emerges. . . .

Dr. Allen Taylor, and Dr. Robert Califf, of Duke, made news (once again yesterday), at the close of the American Heart Association's conference in New Orleans, as reported in Medscape Today. [Do go read it all -- much more color there.]

Squarely in the cross-hairs of this plenary session was the July 21, 2008 Schering-Plough-arranged press conference, held during the NYSE trading day, by Dr. Richard Peto -- to defend Vytorin and Zetia, in the wake of the unexpected SEAS cancer signal. Let's listen in:

. . . .Large multinational clinical trials require a "global set of standards of conduct and behavior" to ensure that outcomes reflect objective, unbiased evidence, a prominent cardiology researcher said here.

Because pragmatic clinical trials provide the foundation for clinical practice, a global imperative exists to develop internationally recognized and accepted "rules of conduct," Robert Califf, M.D., of Duke in Durham, N.C., said during a plenary session at the American Heart Association meeting. . . .

. . . .In the wake of the highly publicized SEAS episode, Dr. Califf offered a list of recommendations to remove as much bias potential as possible from the clinical investigation process.
▲ A balanced executive committee that includes representatives of the sponsor but whose majority consists of investigators. Only the sponsor's representatives should have any ties to the sponsor.

Transparent reporting of financial relationships.

▲ Identification of conflicts of interest that are not directly financial in nature (deeply held professional beliefs about a scientific issue, working for competitors, previous request for funding turned down by sponsor).

▲ Commitment to publish.

▲ Appropriate airing of differences of opinion (not in the media).

Prohibition of direct-to-consumer advertising until definitive data are available.

▲ Increased public funding of clinical trials to preempt claims of bias.

. . . .The SHARP and IMPROVE-IT trials will not answer questions about the unexpected cancer risk in the SEAS trial, because neither trial was designed to address that issue, said Allen Taylor, M.D., of the Uniformed Services University of the Health Sciences in Rockville, Md.

Moreover, he continued, the two ongoing trials differ in several key respects from SEAS, including type of control (positive versus placebo), age, sex, disease spectrum, and LDL levels, and length of follow-up -- not to mention the ongoing status of IMPROVE-IT and SHARP. The differences have the effect of creating a negative bias toward cancer.

Despite the negative bias, a cancer signal has emerged from SHARP and IMPROVE-IT during relatively brief follow-up, one year in the case of IMPROVE-IT, in Dr. Taylor's estimation. The Peto analysis yielded a hazard ratio of 1.34 for cancer death in patients treated with ezetimibe/simvastatin, although the difference did not quite achieve statistical significance (95% CI 0.98 to1.84, P=0.07).

"The confidence intervals suggest as much as an 84% increased risk of cancer death," said Dr. Taylor.

"When examining possible harm, is a 5% confidence limit appropriate?" he continued. "When considering an a priori hypothesis of harm, should it be 0.1 or 0.2?"

The SEAS controversy has played out against a backdrop of what is known about ezetimibe/simvastatin, Dr. Taylor continued. Excluding aortic stenosis from the event rate would result in a 25% reduction in the ischemic event rate. Compared with other recent trials, the benefit appears modest, especially given the large reduction in LDL achieved with the drug.

"One senses that ezetimibe/simvastatin was underperforming," said Dr. Taylor.

Events of the past several months have resulted in a conundrum regarding ezetimibe's net effect on health care outcomes, he concluded. The net benefit remains unmeasured, and the absence of harm is uncertain. . . .

Indeed. I wonder whether Mike Huckman, and the various Wall Street analysts factored any of this into their reports. . . if they didn't -- they should have.

The evaluation of these rigorously-documented, but "against the grain" (or, "ambiguous", even, to be fairer to Dr. Peto's views) sorts of results -- like the SEAS cancer signal -- is far-more-properly the domain of peer-reviewed scientific journals, and not hastily-convened, company-sponsored "damage control" press conferences, with only company-retained "experts" on hand to discuss the event. Here endeth today's sermon.

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