relax [Regulatives / Guidelines]

posted by Helmut Homepage – Vienna, Austria, 2020-01-23 11:59 (849 d 19:44 ago) – Posting: # 21082
Views: 2,133

Hi Fabrice,

» » Doesn’t matter because we are interested in PK (I) and safety (II).
»
» OK but then how to justify in the dossier the extrapolation of some early phase outcomes, e.g. a food effect or an efficacy and/or safety exposure signal... should these key findings be evaluated/demonstrated again with the final formulation?

An example: The NDA of idelalisib. A lot of Phase I/II studies (women/men, Japanese/Caucasian, food effect, DDIs, renal/hepatic impairment) were performed in 6 (six!) to 12 subjects with early formulations.
There was also a study comparing formulations (n = 15, extremely underpowered for the x̃ CV of 29% in earlier studies). Some comparisons failed (e.g., 90% CI of Cmax 106–153%). Funny:

2.5.2.2 What are the safety or efficacy issues, if any, for BE studies that fail to meet the 90% CI using equivalence limits of 80–125%?
None. The exposure for the different drug products is similar.

Quoting nobody: It’s originator, stupid!

Since idelalisib is in BCS II (where dissolution cannot predict in vivo performance), the FDA lamented about later manufacturing changes but accepted the package at the end of the day.

Dif-tor heh smusma 🖖 [image]
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes

Complete thread:

UA Flag
Activity
 Admin contact
22,091 posts in 4,630 threads, 1,566 registered users;
online 7 (0 registered, 7 guests [including 5 identified bots]).
Forum time: Sunday 08:44 CEST (Europe/Vienna)

Competence, like truth, beauty and contact lenses,
is in the eye of the beholder.    Laurence J. Peter

The Bioequivalence and Bioavailability Forum is hosted by
BEBAC Ing. Helmut Schütz
HTML5