Astea
★    

Russia,
2019-06-06 01:24

Posting: # 20319
Views: 728
 

 Two-Stage Design for FDC [Two-Stage / GS Designs]

Dear Smart People!

I'm wondering what is an appropriate way to use Two-Stage Designs for FDC (two analytes, A and B, for example)? It seems we are facing several questions:
1). Initial sample size calculation - best guess of CV for two CV?
2). Initial sample size calculation - power (see this thread). So if we would not expect independent hypothesis we should use the adjusted power for calculation. Correspondingly this will lead to neccesity of using additional simulations cause we will be automatically driven from validated values of 80 and 90%.
3). Interim analyses: for 2 analytes it leads to different possibilities: pass, fail, pass for A but need the second stage for B...
4). Sample size for the next stage:
- additional subjects could cause TIE inflation (as in the example with extra drop-outs, see this thread
- is it regulatory addopted - ignoring data for the second analyte?

"We are such stuff as dreams are made on, and our little life, is rounded with a sleep"
mittyri
★★  

Russia,
2019-06-08 15:44

@ Astea
Posting: # 20320
Views: 551
 

 No simple way out

Dear Astea,

as far as I can see you made a lot of forum research already


I don't see any other method except direct simulations, but as Detlew mentioned in the link you provided: too many what if's!!!
Remember that you need to take into account not only 2 analytes, but 2 PK metrics for both of them.

» 1). Initial sample size calculation - best guess of CV for two CV?

see above - not for 2 but for 4!
Guestimation is our friend. For that particular protocol I think you can prove almost any reliable numbers. (n1 is low: well, that's a 2 Stage design, I know nothing about CV!
n1 is high: I think CV for Cmax of that analyte should go to the sky!)

» 2). Initial sample size calculation - power (see this thread: ). So if we would not expect independent hypothesis we should use the adjusted power for calculation. Correspondingly this will lead to neccesity of using additional simulations cause we will be automatically driven from validated values of 80 and 90%.

If you don't know CVs how would you estimate rho?
May you want to build a correlation matrix for all of 4 pk metrics? :cool:

» 3). Interim analyses: for 2 analytes it leads to different possibilities: pass, fail, pass for A but need the second stage for B...

Yes, end of story (again, 4 metrics!). The framework becomes absolutely crazy. So I don't see any option except independent PK metrics analysis as you did for simple analytes in 2 stage designs. Forced BE? Yes, we're gonna live with that for now...

» 4). Sample size for the next stage:
» - additional subjects could cause TIE inflation (as in the example with extra drop-outs, see this thread.

From the link provided I don't see TIE inflation (using Potvin B and Detlew's function)

» - is it regulatory addopted - ignoring data for the second analyte?

No, as Helmut mentioned in the same link. I don't think experts be happy trying to dive into so complicated framework.

Kind regards,
Mittyri
Astea
★    

Russia,
2019-06-09 22:56

@ mittyri
Posting: # 20321
Views: 508
 

 the more complicated the more interesting

Dear mittyri!

I am very grateful for your reply!

As for ρ (that is two PK metrics of the same analyte) I think that it is worth to expect correlation while for two different analytes correlation of the same PK metrics is not very likely.

» From the link provided I don't see TIE inflation (using Potvin B and Detlew's function)

Sorry, I've assumed the linked with this theme thread. Of course the theme is too complicated, but any possible affection on the TIE should be investigated, shouldn't it?

"We are such stuff as dreams are made on, and our little life, is rounded with a sleep"
Activity
 Thread view
Bioequivalence and Bioavailability Forum |  Admin contact
19,688 posts in 4,178 threads, 1,353 registered users;
online 13 (0 registered, 13 guests [including 8 identified bots]).
Forum time (Europe/Vienna): 09:44 CEST

Power. That which statisticians are always calculating
but never have.    Stephen Senn

The BIOEQUIVALENCE / BIOAVAILABILITY FORUM is hosted by
BEBAC Ing. Helmut Schütz
HTML5