History Will Declare Dr. Steven Nissen Right -- About the SEAS Cancer Signal. . . .

Dr. Steve Nissen, a name near the top of the very-short-list for head of the FDA -- in the emerging Obama Administration, has done an excellent job of succinctly pointing out what was lacking -- from a scientific point of view -- from the Peto analysis of the SEAS data. After his, I'll reprint the retort from Drs. Peto and Collins, in the spirit of fairness (in dark red, below) -- but not because I endorse even one word of it. Each was just recently-released, online, at the New England Journal of Medicine [linked here].

Dr. Nissen is up first, then -- in blue:

To the Editor:

The article by Peto et al. (Sept. 25 issue), which reports cancer incidence and mortality in three clinical trials of ezetimibe, raises disturbing scientific and ethical questions. Premature unblinding of ongoing trials is not a reliable approach to the evaluation of drug safety. In their discussion of one of the trials, the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), the authors report that the mean exposure to ezetimibe was only 12 months, which is insufficient time for any hazard to emerge. Analysis of short-term trials dilutes any evidence of an excess risk. The most relevant statistical analysis is the upper 95% confidence interval for the observed relative risk. For cancer mortality in the two confirmatory trials, the Study of Heart and Renal Protection (SHARP) and IMPROVE-IT, the relative risk was 1.35 (approximate 95% confidence interval, 0.98 to 1.84), which was not reported by Peto et al. Thus, these two trials can only rule out a risk of death from cancer of 84% or more. The conclusion that there is no "credible evidence" for a cancer risk associated with ezetimibe is simply not supported by the data. The use of incomplete studies to rule out a safety hazard represents a dangerous precedent. If such a standard were widely applied, risky therapies would be routinely misclassified as safe, with potentially catastrophic public health consequences.

Steven E. Nissen, M.D.
Cleveland Clinic

And now, Collins -- Peto:

The authors reply:

It is not in the interest of public health to label potentially useful drugs as unsafe if there is no credible evidence that they are -- or, of course, to overlook reliable evidence of hazard if it does emerge. To help avoid both these serious errors, unexpected findings, such as those regarding the risk of cancer in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial, that generate but do not prove the hypothesis of a new hazard should be tested independently in a separate, substantial data set.

For ezetimibe, the only large, randomized data set is that from interim results of the SHARP and IMPROVE-IT trials. It already involves four times as many cancers as SEAS did but does not suggest any increase in cancer incidence, either overall (313 in the ezetimibe group vs. 326 in the control group) or more than 3 years after randomization (20 in the ezetimibe group vs. 24 in the control group, all in the SHARP trial; with 19 vs. 17 after year 3 in the SEAS trial). In the SHARP and IMPROVE-IT trials, a nonsignificant difference in the number of cancers that had already caused deaths (97 in the ezetimibe group vs. 72 in the control group) was counterbalanced by a nonsignificant difference in the number of cancers (216 vs. 254) that had not yet caused death. . . .

Provided an appropriate distinction is made between hypothesis-generating and hypothesis-testing findings (as in our article), the trial results provide no credible evidence of an adverse effect of ezetimibe. Continuation of the SHARP and IMPROVE-IT trials will provide further evidence about the effects of a statin plus ezetimibe (which reduces the level of low-density lipoprotein cholesterol more than monotherapy can), not only on safety but also on the major vascular outcomes this treatment may prevent.

Concerns about possible conflicts of interest were raised by the Congressional Committee on Oversight and Investigations; the response from the Clinical Trial Service Unit to the U.S. Congress is available on the unit's Web site.¹

Rory Collins, M.B., B.S.
Richard Peto, F.R.S.
Oxford University

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1. Clinical Trial Service Unit. CTSU response to U.S. Congress.

Much earlier, the New England Journal of Medicine had carried this panel reaction to SEAS, for more complete, and balanced, background.