abew4me
Nicely done, but my first reaction is that "flexibility" and "bureaucracy" are oxymorons.LOL
Still, I do think, when you are dealing with a bureaucracy, there is often a way to get a job done, if you have enough experience and know the "key" that can open the door. Hopefully, AVXL can use flexibility with the FDA in an expert manner and maybe your pitch works.
The place where I find your argument unconvincing, and the heart of the problem for me, is whether the "evidence" developed in a 7 week trial gives them the fundamental information that they will consider sufficient to fall within their range of possible flexibility.
Another word for flexibility in this context is "discretion." Who will be in charge of the issue and what discretion that leader in the FDA will have may decide the issue, even if they might have some flexibility in how the handle issues.
These labels (flexibility, and discretion) are no substitute for expertise in evaluation of the quality of evidence issues. So, where is the weak link?
I think the weakest link is the limited data for only 7 weeks on a chronic condition that does not have urgency as part of the problem.
To employ flexibility, the FDA must balance using an experimental drug on a long term chronic problem which could worsen it, a safety issue, where the only proven upside is of limited duration.
It is one thing to be safe on someone older with AD versus someone younger with Rett Syndrome, and for kids it is even more unknown.
I would not guarantee the FDA will consider safety to be sufficiently shown with only 7 weeks of data. At a minimum, I would think the FDA would want to see the OL data, since it is going to be available.
How "flexible" they are will depend, I suppose, on how convinced that the effect size tends to guarantee that, despite the small sample, the data shows a genuine clincal benefit that makes a difference in the life of a rett's patient. They must be convinced that the drug works and that the endpoint proposed is a valid test of efficacy (unless it is like Aduhelm and they want to grant AA.)
All that said, I concede that you may indeed by correct that it is possible. But is it probable? Will AVXL make this NDA filing if they are risking a Complete Response Letter (CRL)? Would it be safer to wait for the Excellence results? I don't know, but I trust Missling will have an informed opinion.
I will read the link you provided and get back to you if I see other things that worry me.
Since I have never presented an NDA application to the FDA, I would not want anyone to think my opinion would be worth much, expecially on how to use the key that will unlock FDA flexibility.
Hopefully, AVXL's former FDA managers will have expert knowledge and experience, and know how to accomplish the goal they select.
Thanks for your imput.
If they do file an adult NDA, I think that will mean they believe that they can get it accepted.
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