mittyri ★★ Russia, 20140320 20:55 Posting: # 12681 Views: 5,946 

Dear All, I would like to discuss some issues in FDC studies design. For examle, we have FDC with 2 APIs. Let's say we know that no PK interaction is expected and the intraCVs in the pilot study were similar to the single dosage forms. If we calculate the sample size for the first API (ABC) and the second API (XYZ) with a power 80%, we'll get some values. So... We have only 80% of probability to prove BEQ for ABC (20% of II type error) and 80% for XYZ. Final probability is 80%*80%=64%! Should we use another power for calculations (89%*89%=80%)? Can someone correct or comment my statistical calculations? What about triple FDC (92.8%*92.8%*92.8%=80%)? — Kind regards, Mittyri 
Helmut ★★★ Vienna, Austria, 20140320 21:49 @ mittyri Posting: # 12682 Views: 5,150 

Hi Mittyri, » I would like to discuss some issues in FDC studies design. » So... We have only 80% of probability to prove BEQ for ABC (20% of II type error) and 80% for XYZ. » Final probability is 80%*80%=64%! » Should we use another power for calculations (89%*89%=80%)? You are thinking into the right direction. See also this thread. The question is: Are the two tests independent? — Cheers, Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes 
mittyri ★★ Russia, 20140326 19:47 @ Helmut Posting: # 12719 Views: 5,005 

Hi Helmut, » The question is: Are the two tests independent? I think two tests aren't independent. Let's say we calculated the II type errors for both APIs, ABC and XYZ  15% and 20% accordingly. There is an information that API XYZ is bioequivalent. What is the likelihood of the bioequvalence for ABC? I think more than 85%. In such a circumstance should I use Bonferronicorrection? (according to the CPMP’s ’Points to Consider on Multiplicity Issues in Clinical Trials’) By the way I cannot find a prime example in EPAR where both APIs would have same ISV. Isn't it a keypoint? See below... In this case (Irbesartan/Hydrochlorothiazide) Irbesartan and Hydrochlorothiazide had ISVs 20.13% and 15.31% accordingly. The requiring sample size for Irbesartan (with Ratio 92%) is calculated as 27=>28 (the power 81.85%, II type error 18.15%). With 28 subjects the power for Hydrochlorothiazide is 95.54%, (II type error 4.46%). So overall power would be 77.39%... — Kind regards, Mittyri 
d_labes ★★★ Berlin, Germany, 20140327 08:47 @ mittyri Posting: # 12723 Views: 4,997 

Dear mittyri, have a look at: Kem Philips "Power for Testing Multiple Instances of the Two Onesided Tests Procedure" The International Journal of Biostatistics Band 5, Heft 1, ISSN (Online) 15574679, DOI: 10.2202/15574679.1169, May 2009 Contains Rcode to play with, but unfortunately only for 2 instances of TOST. Eventually this helps, at least for FDC with two active moieties and one PK metric only . As Helmut already pointed out, the power of the combined TOST's depends crucial on the assumptions about independence of the tests instances aka correlation of the data. Just to cite from the abstract of the paper: "The power of testing two or more equivalence hypotheses simultaneously is less than the power to test any one hypothesis separately, and depends on the correlations of the measurements." — Regards, Detlew 
d_labes ★★★ Berlin, Germany, 20140327 13:27 @ fno Posting: # 12727 Views: 4,958 

Dear Fabrice, » The impact would become more relevant if both compounds have a ratio far from unity and/or high variability. The impact is also relevant if you don't think extremes. Lets assume CV=0.2 for both ingredients and GMR=0.95 also for both. That gives: Sample size n=20 with actual power = 0.834680 for each. That lets to an overall power (assuming independence) of only 0.6966907 ~ 70%. We have to plan for a power of 90% to assure overall power around 80%, which gives n=26, a 30% increase. Not so small IMHO. — Regards, Detlew 