University of Washington statistician Thomas Fleming in today's New England Journal of Medicine challenges Richard Peto's study that claims ezetimibe (trade name Zetia and included in the combo pill Vytorin, made by Merck/Schering-Plough Pharmaceuticals) is unlikely to cause cancer. Fleming argues that the large increases in cancer cases and deaths in the SEAS clinical trial and the biological plausibility of ezetimibe causing cancer (see these Gooznews posts for background, here and here) demands an independent clinical trial to determine if an unacceptable cancer risk is associated with prolonged use of the drug.

Examining the Peto analysis of the SHARP and IMPROVE-IT trials, Fleming states that while the analysis appears to rule out a large increase in cancer cases from Vytorin, it also shows an increase in risk of cancer death of 34 percent and does not exclude an increased risk of cancer death as high as 84 percent.

Moreover, in Fleming's view the Peto analysis of interim data from two clinical trials that are still in progress raises "additional important concerns." First, interim data can be easily misinterpreted. Second, the release of interim data can disturb the integrity of a clinical trial, making the final results less valid. In addition, he writes that it is impossible based on currently available information to determine the extent to which the SHARP and IMPROVE-IT trials meet the standards for safety trials (i.e., trials designed to rule out an unacceptable safety risk). These standards include, among other things, the selection of patients who are at sufficiently high risk of the type of harm being tested, the enrollment of a large enough number of patients, and long-term follow-up of almost all of the patients.

In conclusion, Fleming states the following:

Additional data are needed to adequately address the signal that simvastatin–ezetimibe is associated with an increased risk of death from cancer. Such data should be provided by completed randomized trials that have been prospectively designed and conducted to meet the performance standards for safety trials. Such confirmation is especially important in the case of agents, such as ezetimibe, for which there are safety signals of major illness or death and evidence of efficacy that is limited to documented effects on a biomarker.

I agree.

-- PM