Xinlay Comments
I have to admit that I was very surprised when Abbott announced that they would pursue an NDA based on the results of a single Phase 3 study that failed to meet its primary endpoint. My surprise came despite a “heads up” from a hedge fund manager who told me that word on the Street was that an NDA would be filed. In the intervening months I had forgotten the many reasons for my surprise. They came rushing back to me as I reviewed FDA’s medical review of the NDA. Let’s recount some of them: A single Phase 3 study was performed to serve as the basis for approval without supporting evidence from another study or an internal substudy. In the Phase 3 study the primary endpoint was time to disease progression, a common endpoint for prostate cancer trials. The primary endpoint was not met with statistical significance, not even close. Four of the five pre-defined secondary endpoints also were not met. Abbott decided to rely on the “per-protocol” population for evidence of efficacy when they filed the NDA (they later changed their minds and decided that a different subset of subjects would constitute the efficacy population). This population excluded the 17% of major protocol violators; 17% major violators is a red flag. Finally, the improvement in time to progression for the per-protocol population was minimally better in the treated versus placebo group. It was small enough, in fact, that it was less than the number of days between measurements to confirm disease progression, raising the possibility that it was a spurious outcome biased by differential measurements between groups. The above concerns and others have led the FDA’s medical reviewer to comment that: “The results and conduct of phase III study do not provide convincing evidence of efficacy….There are some serious cardiovascular safety issues observed in both major randomized trials. Atrasentan does not demonstrate any clear evidence of clinical efficacy in men with hormone refractory prostate cancer in the only major trial of design adequate for a registration study.”
I couldn’t have said it better. I would be very surprised if ODAC concludes differently tomorrow. But then I’ve already been surprised once by this drug.
