Achievwin ★ US, 20220520 06:44 (701 d 14:47 ago) Posting: # 23005 Views: 2,357 

Question for study design experts. If we want to introduce assessment or claim using BE study which design is more appropriate? 3way cross over partial study or 4way cross full replicate design. Please share your experience. Sincerely, Achiewin Edit: Category changed; see also this post #1. [Helmut] 
Helmut ★★★ Vienna, Austria, 20220520 11:17 (701 d 10:14 ago) @ Achievwin Posting: # 23006 Views: 2,014 

Hi Achievwin, population BE (prescribability) and individual BE (switchability) are of historic interest only. Both are not assessed in any of the currently recommended approaches (average BE, referencescaled BE, average BE with expanding limits). ❝ If we want to introduce assessment or claim using BE study which design is more appropriate? Define ‘appropriate’. An appetizer. — Diftor heh smusma 🖖🏼 Довге життя Україна! _{} Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes 
Achievwin ★ US, 20220520 16:19 (701 d 05:12 ago) @ Helmut Posting: # 23007 Views: 1,932 

❝ population BE (prescribability) and individual BE (switchability) are of historic interest only. Both are not assessed in any of the currently recommended approaches (average BE, referencescaled BE, average BE with expanding limits). Thanks for the clarification I vaguely recall when you don't have subject by formulation interaction in a replicate study design (4period full replicate design???) you can request switchability (Metadate ANDA I guess) My question is can we assess this subject by formulation interaction in a 3period partial replicate design?) what additional statistical test one needs for documenting this? 
Helmut ★★★ Vienna, Austria, 20220520 17:33 (701 d 03:58 ago) @ Achievwin Posting: # 23008 Views: 2,073 

Hi Achievwin, ❝ I vaguely recall when you don't have subject by formulation interaction in a replicate study design (4period full replicate design???) you can request switchability (Metadate ANDA I guess) No idea (too lazy to search). ❝ […] can we assess this subject by formulation interaction in a 3period partial replicate design?) what additional statistical test one needs for documenting this? Not sure whether it will work. The partial replicate is a nasty beast (for potential problems see there). IIRC, in the late 1990s concerns about the SubjectbyFormulation interaction emerged. Temporarily studies had to be performed in a replicated design. After assessing the results, the FDA concluded that the S × F interaction is practically not relevant and the temporary requirement was lifted. Furthermore, none of the simulations performed by various authors or by the FDA which lead to RSABE contained an S × Finteraction term in the model. — Diftor heh smusma 🖖🏼 Довге життя Україна! _{} Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes 
Achievwin ★ US, 20220521 01:32 (700 d 19:59 ago) @ Helmut Posting: # 23010 Views: 1,989 

Thanks Helmut 
Brus ★ Spain, 20230606 13:02 (319 d 08:29 ago) @ Helmut Posting: # 23577 Views: 1,188 

Dear Helmut, I don't understand the subjectbyformulation effect, can it only be studied in full replicated designs? If the subjectbyformulation effect is the change between test and reference difference means from one subject to another, in a 2x2 design it should be possible to study it. Right? And in that case it could also be measured in partial replicate. Right? Maybe I'm confused or don't understand something. Thank you so much Best regards, 
Helmut ★★★ Vienna, Austria, 20230607 12:34 (318 d 08:57 ago) @ Brus Posting: # 23580 Views: 1,167 

Hi Brus, ❝ I don't understand the subjectbyformulation effect, … ❝ … can it only be studied in full replicated designs? ❝ If the subjectbyformulation effect is the change between test and reference difference means from one subject to another, in a 2x2 design it should be possible to study it. Right? Adding S × F will not work. Didn’t try it yet. Either you get zero degrees of freedom in a fixed effects model or a mixedeffects model will collapse. ❝ And in that case it could also be measured in partial replicate. Right? — Diftor heh smusma 🖖🏼 Довге життя Україна! _{} Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes 
Achievwin ★ US, 20230608 12:21 (317 d 09:10 ago) @ Helmut Posting: # 23581 Views: 1,140 

I agree switchability can only be studied by full replicate design, follow up question is now that partial replicate or reference replicate are GONE (??? really) in the new statistics guidance can we study switchability by 3period replicate design (as it is balanced).... and Can we measure the additional parameter needed for NTIDs by 3period replicate (balanced design) "Applicants should use the average bioequivalence approach with BE limits of 80125%. The withinsubject variability of test and reference products should be compared and the upper limit of the 90% confidence interval for the testtoreference ratio of the withinsubject variability should be ≤ 2.5. For details about the Method for Statistical Analysis comparing withinsubject variability of test and reference products, refer to Guidance on Warfarin Sodium." Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post #5! [Helmut] 