I think that comments in the initiating E & P report on Neuren...

I think that comments in the initiating E & P report on Neuren (Nov. 2021, the month before the Phase 3 Rett results were released) provide some further insight.

Given there is no gold standard assessment in Rett syndrome and other RNDDs (rare neurodevelopmental disorders) to benchmark against, the FDA requested the co-primary endpoints of CGI-I and RSBQ for their Phase 3 (Trofinetide) Rett syndrome study. The CGI-I acts as a clinical validation of the more contentious RSBQ caregiver rating. In order to receive approval, Acadia need to demonstrate a significant improvement in mean scores for both the CGI-I and the RSBQ using a standard double-tailed statistical-test. This sets a higher bar on the likelihood of success.

… unlike the CGI, RSBQ is not an FDA approved endpoint and its utility as a trial endpoint is contentious, with a recent study concluding that the RSBQ could lead to either type 1 or type 2 errors in clinical trial — and thus may represent a poor choice as a primary outcome measure.

It seems to me that the recent manuscript draft has further heightened the analysts’ concern about the validity of the RSBQ as a primary outcome measure. Hence, they are allowing for an increased chance of the FDA saying “Yeah, nah…. we wanted clear evidence of improvement on two primary outcome measures but, sorry, we’re not going to accept your RSBQ evidence as valid.”

Now, in my opinion, that would be exceedingly poor form on the part of the FDA but it wouldn’t be the first time that the FDA has been accused of poor form (and worse!) on the issuing of a CRL (drug approval rejection).

I take comfort in the fact that the FDA is compelled by law to exercise its scientific judgment on a case-by-case basis in reviewing each rare disease NDA. That exercise of judgment can be affected by many factors, including the rarity and severity of the condition and the availability of other satisfactory therapies.

https://www.fdanews.com/articles/171126-study-fda-flexibility-helps-with-orphan-drug-approvals