What do FDA insiders really think of prasugrel?

The benefits of prasugrel in TRITON-TIMI 38 were greatly exaggerated by the “massive inclusion of ‘MIs” unreported by the trial investigators,” according to an editorial in Cardiology by Victor Serebruany. Serebruany’s severe criticism of prasugrel and TRITON will come as no surprise to CardioBrief readers. (See our prasugrel chronology for a detailed history of the controversy).

But what is extraordinary and possibly unprecedented is Serebruany’s acknowledgment at the end of the paper (normally the least interesting part of a paper). Here is the text of the acknowledgment:

“The author wishes to thank Norman Stockbridge, MD, PhD, Director, FDA Cardiovascular and Renal Products, and Thomas Marciniak, MD, FDA Medical Team Leader, for constructive dialog.”

At the time of the original FDA hearing in February, CardioBrief and others noted a strong disconnect between the details in the lengthy briefing document prepared by FDA reviewers and the much briefer recommendations and conclusions in the summary documents. Serebruany’s editorial provides the clearest explication yet of the heart of the FDA staff’s criticism of TRITON.

At the core of the critique is the discrepancy between the number of MIs originally reported by the TRITON investigators and a greatly increased number in the final data set, a result of redefinitions of MI that occurred during the course of the trial. Serebruany’s editorial is based on the data analysis presented in the FDA’s  briefing document. According to Serebruany,

“…introduction of surrogate ‘extra’ MIs, especially late in TRITON, was a questionable strategy with no apparent clinical implication, but with the direct effect of transforming neutral into positive results by inflating the apparent prasugrel efficacy. Indeed, if the primary TRITON outcome were based on the investigator- reported events (cardiovascular death 150 vs. 142, nonfatal MI 298 vs. 226, and stroke 60 vs. 61), the prasugrel benefit would be 15.5% rather than the reported 18.2%, and statistical significance would be lost [4] . Considering extra bleeding fatalities [5] , and unexpected cancer risks after prasugrel, the benefit-to-risk relation of the experimental drug would appear far less favorable.”

CardioBrief has asked for comments from Lilly, Stockbridge, and Marciniak. Any responses we receive will be reported in future posts.

Update: You can read a response from Lilly, and Serebruany’s rebuttal, in our next post.

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  1. […] What do FDA insiders really think of prasugrel? […]

  2. […] response to Victor Serebruany’s editorial in Cardiology criticism of TRITON-TIMI 38 (see our previous post), a Lilly spokesperson sent the following statement to […]

  3. […] What do FDA insiders really think of prasugrel? […]

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