First, apologies for the late response. Your pointing to approvals circa 1990 hung me up (there is essentially none of the now normal documentation available) until i forgot about this. Regardless a response is owed.
Adagen, approved in 1990 on the basis of a 6 (six) patient study for the treatment of SCID, severe combined immunodeficiency. Lots of other drugs have been approved by FDA on the basis of exceedingly small studies or no studies at all. Cytovene was approved for CMV in immunocompromised patients in ’89 on post hoc review of subjects treated by one physician at Johns Hopkins
Congrats on finding some new interesting cases - and i would agree that they provide some support to the inconsistency of the FDA and thus support the case that it is *possible* (however unlikely) that SRPT gets approved. Let me discuss them (as best i can given essentially no FDA data on the 1990 approvals) in the context of the two important factors ive discussed before with regards to orphans:
A) size of the patient pool. The regulatory agencies are more lenient the smaller the pool. The adagen pool is much much smaller than exon 51 DMD (~1 in 500,000 and the prevalence was much lower since they died quickly. Probably about 1/50th the prevalence of exon 51 DMD.).
B) strength of efficacy (against historical controls if single armed it has to be very very strong). Cytovene has much stronger ITT efficacy than any of the DMD drugs has shown to date with a subsequent trial showing about risk ratio of about 0.35 ish. That said, i will acknowledge some surprise that they approved based upon a post hoc with only an efficacy risk ratio of about 0.35 ish - but that is probably explained by the HIV panic (similar to the recent ebola panic). Regardless the efficacy in the papers i can see show it getting an efficacy a lot better than the ITT efficacies shown by any of the DMD drugs.
As for Atryn, i agree that is an odd approval (although even it was based on 30 patients, not 18). I think this is your strongest case for the FDA behaving inconsistently and irrationally. I'll give you that one. It is a non-inferiority with a very oddly large non-inferiority margin. I wouldn't take it as precedence of much other than the inconsistency of the FDA, but i concede that is a drug that was approved despite having very crappy evidence of benefit and no particular extenuating circumstances (see A and B above). That said, non-inferiorities seem to be a weak spot in the industry - often poorly done. Not as likely to repeat in a superiority.
<< Eteplirsen has dosed for three years in these kids with nada reactions. >>
And Dris probably wouldn't show adverse reactions had they tested in just 12 kids. The point of a large database is to catch the rare events - and Dris events are common enough that they need to be addressed, but rare enough that they might not show up in just 12 patients.
So you’re suggesting that FDA is just yanking around SRPT, playing some kind of game with them and an extremely vocal and influential advocacy group? That the agency has no intention of accepting or approving an NDA even after the FDA has made a point of saying that the agency is doing everything it can to cooperate with the sponsor?
No. Not a "game". A virtually inevitable result of what happens when you bully someone and they are not allowed to defend themselves (as the FDA cannot, by statute, publicly comment before the AdComm). You will get much less open dialog - and thus much more surprise at the AdComm. The CEO was actually/effectively censured by the board for his interactions with the FDA. And, as i noted elsewhere, the "DMD Moms" seem to have been more SRPT Moms. I doubt that is a coincidence.
As for drisapersen, it will be interesting to see how an Adcom handles a phosphorothioate when it comes to the safety show of hands. In large enough doses drisapersen may very well skip targeted exons but not in the doses that RNA has been limited to
Suggest this is silly. First, Dris was stat sig on one RCT and close on another. About a 1 in 10,000 chance. Second, they have assay results similar to SRPTs. And, apparently their assay is getting less flack from the FDA than SRPTs.
that is unless Jesus was performing miracles at Nationwide Children’s Hospital in Columbus
That is the point. No miracles are required if you are allowed to just throw out the inconvenient patients. And compare to non-comparable populations (see my earlier posts). And even after all that, it would take only the mildest luck to pick 6 patients from the Mercuri population, give them sugar water, and have them get the result seen in the mITT population of SRPTs trial. The best evidence of SRPTs efficacy is the Dris data and that is a very sorry state.
PS this is no Dendreon. In the rejected DNDN BLA they had one stat sig ITT RCT - albeit to a marginally post hoc endpoint. (marginal because it was the real endpoint for the which the formal prespecified endpoint was a surrogate)
PPS << I really have to wonder about your motivation especially given that you show up on this board after FDA asked SRPT for more data.>> Really? I've been posting on them for a while on other boards. And ive never been short a stock ever - although i am always surprised by who will revert to that explanation. Nor have i ever been an RNA shareholder. As i stated in an earlier post my motivation is shear disgust for the SRPT management and political/bullying approach etc - to the detriment of the patient population they so disingenuously claim to serve.