More on prasugrel: what the FDA doesn’t want you to know

The FDA appears to have incompletely scrubbed redacted text from the PDF documents posted on its web site. Two major issues:
the formulation of prasugrel and an increased incidence of cancer observed in clinical trials, appear to have raised concerns among FDA reviewers.
The FDA reviewers originally proposed that prasugrel gain approval without undergoing an advisory board meeting, “in light of what appeared to be robust efficacy findings.” Furthermore: “Given that prasugrel appeared to be superior to established treatment for the prevention of nonfatal MI, this approach was planned in the interest of public health, so that regulatory action would not be unnecessarily delayed.”
The briefing document doesn’t appear to answer this question. The space following this paragraph is blank, apparently redacted. But the content has been incompletely scrubbed from the PDF file, and CardioBrief was able to recover the missing text:
Two unanticipated issues came to light during the review process: 1) the imbalance in neoplasms between the prasugrel and clopidogrel groups; and 2) form conversion from salt to base, with bioinequivalence between the forms in the presence of a PPI. In addition, other individuals thought that a public discussion of the bleeding risk would be of value. Ultimately, the Office reached the conclusion that a public presentation of these issues to the Cardiovascular and Renal Drugs Advisory Committee would be advisable, and such is planned for February 3, 2009. [page 77 of the PDF document]
CardioBrief was also able to recover from the PDF document a long passage, which we won’t even begin to claim we understand, about the drug’s formulation. The newsworthy information buried here is that “many on the review team have recommended that the sponsor reformulate the product.”
In light of the above considerations, and in light of the public health implications of a product that has been shown to be superior to established therapy on an important outcome measure, the Division does not wish to deny or delay approval of prasugrel on the basis of this product issue. Many on the review team have recommended that the sponsor reformulate the product, and characterize safety and efficacy of the reformulated product in Study TABY, with additional characterization in bioequivalence studies, as appropriate.
Although reformulation seems desirable (even if only for the sake of product purity), the issue is extremely complex and lacks a straightforward solution:
• Reformulation requires technical advances, and neither the sponsor nor we can be certain
that they are feasible. Thus, we can not require the sponsor to “improve” the product.
• The sponsor has already altered the manufacturing process to limit form conversion to some extent. The ramifications of this are two-fold:
1) If we were to grant approval of the product today, the marketed product would differ
somewhat from the product studied in TAAL.
2) If the sponsor were to develop a second generation reformulated product and we were to require them to compare it to the product evaluated in TAAL, they might not be able to
produce reference product lots similar to those studied in TAAL. Thus, such a study
might not be feasible.
Finally, some reviewers have expressed concern that a reformulated product could lead to
higher plasma concentrations of the active metabolite, and thereby excess bleeding. If fact, the “best case” scenario for bioavailability, i.e., no effect of form conversion, has already been studied. In Study TAAL, prasugrel’s bioavailability would not have been diminished in subjects who were not taking gastric pH-altering medications. Thus, the present consensus within the Division is that a large safety outcome study would not necessarily be requisite to support a new formulation. A final decision on appropriate studies would need to await information on the actual formulation change, assuming that the sponsor is able to achieve this. [page 80 of the PDF document]
Update (9:45 PM):
Harlan Krumholz gave a comment to CardioBrief:
The information from the FDA documents appears to explain, at least in part, the delay in approval for prasugrel. I am disappointed that these concerns were not in the public domain and that there was not an opportunity for public scrutiny and review. In particular, the public should be given the opportunity to review the data and understand the strength of evidence behind these concerns. It would be best if all the safety and efficacy data were made public.

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