Replies to post #115343 on Biotech Values

[DewDiligence]

In clinical-trial design, the qualifier pivotal is not well-defined. The term is often by investors to describe phase-2 trials that might lead to regulatory approval; however, when such a trial does not have an SPA, referring to it as pivotal is more an expression of hope than a commitment by regulatory agencies.

p.s. Strictly speaking, pivotal is the wrong word for the meaning described above. Literally, a pivotal trial would be one that turns a failing program into a success as opposed to a trial that builds on prior successes. A better word for the meaning in question would be decisive or dispositive.

[AlpineBV_Miller]

If you design a Phase 2 to be a Pivotal Phase 2, is this type of trial to be considered to be a Phase 3 final result trial by the FDA, or do they consider this to be some sort of play on an accelerated approval?

If it is a non-randomized Phase II trial, the only thing that would persuade me to label it as "pivotal" is if it had a SPA. I think that's one thing we learned from the T-DM1 debacle.

I guess what I'm trying to get at is there an "overlap" in what is considered accelerated approval and can the FDA simply say, after results of a Pivotal Phase 2, "no. we need more. Spend another $20 million and 3 years and get back to us later."

The FDA can always back away from a Phase II SPA, particularly in terms of safety or scant clinically relevant efficacy. In cancer, the FDA hedges its bets in Phase II SPAs by never agreeing to a "sutiable" response rate (for example). Company's always say it needs to be "robust" and that the FDA never gave them a threshold. Perhaps coincidentally, most management teams describe a threshold above 25-30% as "robust".

From what I can recall, IMGN (with T-DM1) tried to get accelerated approval, I think? However, that trial, by design, wasn't a Pivotal Phase 2, it was just a wide randomized trial. The FDA declined approval and now results will not be out (in a drug which clearly worked) til 2012.

IMGN just licensed the technology to Roche Genentech, who was responsible for development and regulatory. Roche chose to not get a SPA on the single-arm Phase II and was rebuffed by the FDA via a Refuse To file (RTF) letter. I believe that was a BS decision demonstrating Pazdur's misunderstanding of personalized medicine. Further the RTF was not a regulatory issue, but a scintific and clinical issue that should have been addressed by ODAC.

So, even you design a huge Phase 2 double-blind, randomized trial (not a Pivotal), and results are overwhelming, would you be better off "calling" it a PIVOTAL trial (instead of just a regular P2), or do you need to talk to the FDA about this before hand?

Again, IMO it shouldn't be considered pivotal unless there is a SPA. I can see some limited exceptions in the orphan space.