FDA official reviews his own prasugrel review in NEJM

Now that prasugrel has finally been approved, EF Unger, one of its chief reviewers at the FDA, is providing insight into the FDA thought process in a perspective in the New England Journal of Medicine. Along the lines of the old TV ad for EF Hutton, when EF Unger speaks, people interested in prasugrel listen. As Unger writes, the “FDA grappled with a number of complex issues during the review process.” Discussing the TRITON-TIMI 38 trial, Unger says that:

Not all observers agree that the treatment effect was important, since many of the excess myocardial infarctions in the clopidogrel group were not manifested clinically but were merely “enzyme leaks” that were detected during routine monitoring in the peri-interventional period. The agency and the advisory committee concluded, however, that such enzyme elevations indicate tissue damage and that such damage has serious long-term consequences. Moreover, there was also a significant reduction in the rate of nonfatal myocardial infarctions that occurred after the peri-interventional period.

Unger also discusses the issues of bleeding and excess neoplasms associated with prasugrel, and emphasizes the risk-mitigation strategies and followup studies that are now required.

Unger concludes by discussing the risk-benefit equation that “ultimately… will be a matter of individual clinical judgment”:

The principal advantage of prasugrel over clopidogrel appears to be the prevention of nonfatal myocardial infarctions, many of which would not have immediate overt clinical consequences. The cost of this prevention is excess bleeding — an important adverse effect, but one that is transient and does not result in increases in strokes or deaths. Ultimately, deciding which drug is preferable will be a matter of individual clinical judgment. The FDA made sure that prasugrel’s label clearly articulates the balance between efficacy and risk — a balance that physicians will need to assess carefully when choosing treatment for individual patients.

Click here for a complete chronology of the prasugrel controversy.


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  1. It is hard to reconcile the statement that the treatment with prasugrel does not “result in increases in strokes or deaths” with the observed statistically significant increase in bleeding-related deaths seen in TRITON-TIMI 38.

  2. What a sad attempt by E F Unger in trying to vindicate the FDA for making a mess of the entire approval process for prasugrel. There will be questions that will linger in everyone’s mind. Why was Sanjay Kaul and his analyses systematically excluded from the review process? Why was the neoplasm and cancer signal not given sufficient prominence in the final PI? Was sufficient care taken to warn the medical profession about the ‘real life’ bleeding risks, knowing fully well that TIMI major bleeds greatly underestimate clinically relevant bleeds? How convenient for the FDA and Unger to pass on the liability of using this drug on to the clinician by asserting that use of this drug will ultimately be a matter of individual clinical judgement..


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