sweiner ☆ 20200630 01:07 (566 d 05:23 ago) Posting: # 21612 Views: 3,828 

Hi, In a 5way BE crossover trial, is there a methodology available that allows one to analyze 3 out of 5 sequences for BE in an interim fashion, and contingent upon results complete the remaining 2 sequences and analyze all 5 sequences at the conclusion? Could you please provide references on this subject. Thanks, Sveta Edit: Category changed; see also this post #1. [Helmut] 
Helmut ★★★ Vienna, Austria, 20200630 12:19 (565 d 18:11 ago) @ sweiner Posting: # 21615 Views: 3,058 

Hi Sveta, » In a 5way BE crossover trial, is there a methodology available that allows one to analyze 3 out of 5 sequences for BE in an interim fashion, and contingent upon results complete the remaining 2 sequences and analyze all 5 sequences at the conclusion? Once you dosed subjects (i.e., in all 5 sequences), you have to analyze them. Anything else is not ethical. Along these lines the EMA’s BEGL, section Subject accountability: Ideally, all treated subjects should be included in the statistical analysis. […]
Even if your protocol would be accepted by the IEC/IRB and agency (I hope not), your approach might lead to an inflated type I error (if you fail with 3 sequences and continue with the other 2) because at the end you will use 60% of the data twice. Calls for some kind of αadjustment (narrower CI) due to multiplicity issues. » Could you please provide references on this subject. IMHO, nothing published – and for a reason. Don’t even think about the ‘magic’ α 0.0294. In short: Forget it. — Diftor heh smusma 🖖 Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes 
sweiner ☆ 20200630 17:08 (565 d 13:22 ago) @ Helmut Posting: # 21621 Views: 2,989 

Thanks Helmut! This is very helpful. 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] 
sedhosen ☆ Iran, 20210316 08:30 (306 d 21:00 ago) @ Helmut Posting: # 22270 Views: 1,150 

Hi Helmut, Thanks for your thorough information about analyzing all dosed subjects. I read the mentioned guideline "BEGL, section Subject accountability" and I have a question about replacing people in the study. Regarding the following sentence from the guideline: "It is not acceptable to have a protocol which specifies that ‘spare’ subjects will be included in the analysis only if needed as replacements for other subjects who have been excluded." Is it also not acceptable to replace subjects even if the number of excluded subjects is more than the number of considered dropouts? For example, if 7 subjects are withdrawn during the study after receiving the dose, and the number of considered dropouts are 5 subjects, is there any way we can replace 2 subjects that were withdrawn over the number of dropouts? Thanks in advance Edit: Relax; see also this post #9. Another post with identical text deleted. [Helmut] 
Helmut ★★★ Vienna, Austria, 20210316 16:00 (306 d 13:29 ago) @ sedhosen Posting: # 22273 Views: 1,087 

Hi sedhosen, » Is it also not acceptable to replace subjects even if the number of excluded subjects is more than the number of considered dropouts? Acc. to the GL, yes. » For example, if 7 subjects are withdrawn during the study after receiving the dose, and the number of considered dropouts are 5 subjects, is there any way we can replace 2 subjects that were withdrawn over the number of dropouts? Two points:
— Diftor heh smusma 🖖 Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes 
Relaxation ★ Germany, 20200630 14:10 (565 d 16:19 ago) @ sweiner Posting: # 21618 Views: 3,030 

Dear Sveta. Nothing to add to the answer already given. I just want to ask, whether you may want to give some more background information on the situation. Because I really was not able to think of a scenario, where considering only a part of the population based on the sequences could provide a benefit (unless its a sneaky twostage, but then as said: nothing to add to the answer given). Likely just a case of limited imaginative power on my side . Best regards, Steven. 
sweiner ☆ 20200630 17:10 (565 d 13:20 ago) @ Relaxation Posting: # 21622 Views: 2,982 

» I just want to ask, whether you may want to give some more background information on the situation. » Because I really was not able to think of a scenario, where considering only a part of the population based on the sequences could provide a benefit […] Dear Steven, thanks for the feedback! Here the first part of the 5way crossover analysis (Part A 3x3 analysis) would be under fasted conditions (Tablet formulation #1 vs. Tablet formulation #2 vs. Capsule formulation), and if BE is shown for either Tablet formulation vs. Capsule formulation, same subjects would complete in a 2x2 fashion under fed conditions (Tablet #1 or #2 [depending on BE result] vs. Capsule). In the final analysis, once all 5 sequences complete all 5 periods, fasted state vs. fed state to be compared for BE. 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] 
ElMaestro ★★★ Denmark, 20200630 18:17 (565 d 12:13 ago) @ sweiner Posting: # 21623 Views: 2,984 

Ah, it is all coming together now. Thanks sweiner, this is a great question. » In a 5way BE crossover trial, is there a methodology available that allows one to analyze 3 out of 5 sequences for BE in an interim fashion, and contingent upon results complete the remaining 2 sequences and analyze all 5 sequences at the conclusion? Should read: "In a 5way BE crossover trial, is there a methodology available that allows one to analyze 3 out of 5 periods for BE in an interim fashion, and contingent upon results complete the remaining 2 periods and analyze all 5 periods at the conclusion?" This is an interesting idea, one that has not been explored much yet in the public domain; I think a few other sponsors have used it. It is definitely doable as a single protocol. It is in fact what other companies / sponsors are achieving with two separate studies. Just do it, I think it may not require much operational adjustment or statistical fiddling, unless you can say you will switch to another formulation and restart another 5period trial once the first formulation fails after 3 periods. A great post, in my opinion. — Pass or fail! ElMaestro 
Helmut ★★★ Vienna, Austria, 20200701 11:14 (564 d 19:16 ago) @ ElMaestro Posting: # 21630 Views: 2,994 

Hi ElMaestro & Sveta, » Should read: "In a 5way BE crossover trial, is there a methodology available that allows one to analyze 3 out of 5 periods for BE in an interim fashion, and contingent upon results complete the remaining 2 periods and analyze all 5 periods at the conclusion?" » » It is definitely doable as a single protocol. […] I think it may not require much operational adjustment or statistical fiddling, … @ElMaestro: Operational – no. Statistical – likely yes. The current regulatory thinking expressed at numerous conferences (nothing published) is that one still has to adjust α because in the first part one gets two chances to demonstrate BE (see this presentation, slide 23). I belonged to the first church (90% CI) for decades though now I’m a convert. I would not try to find an ‘optimal’^{ 1} adjusted α. I regolatori stanno bene con Signor Bonferroni. @Sveta: For most drugs it is more difficult to demonstrate BE in fed state (true fooddrug interaction, higher variability) than in fasted state. Consider to switch your approach (fed followed by fasted). I haven’t seen a single case where the fed study passed and the fasted one failed, but a lot of cases the other way ’round – which required reformulation. Unfortunately many companies start with the fasted study (hey, that’s standard) only to be hit in fed state. I recommend also to evaluate the first part according to the “Two at a Time” principle (two separate analyses^{ 2} as Incomplete Block Designs, i.e., T_{1} vs R and T_{2} vs R) and not “All at Once” (by one – pooled – ANOVA).^{ 3} For details and references see the vignette of PowerTOST .Note that the EMA’s BEGL states: In studies with more than two treatment arms (e.g. […] a four period study including test and reference in fed and fasted states), the analysis for each comparison should be conducted excluding the data from the treatments that are not relevant for the comparison in question. (my emphasis)
— Diftor heh smusma 🖖 Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes 
sweiner ☆ 20200707 03:00 (559 d 03:30 ago) @ Helmut Posting: # 21654 Views: 2,668 

Helmut, thank you very much for the reply related to the adjustment of alpha, testing of fed vs. fasted, as well as the detailed sample size discussion with R code provided. Can you please also provide feedback on one more scenario: 6way crossover, with the following treatments A) tablet formulation #1 fasted, B) tablet formulation #2 fasted, C) capsule formulation fasted, D) tablet formulation #1 fed, E) tablet formulation #2 fed, F) capsule formulation fed. Is there an approach that can be used to test only the first 3 treatments (all fasted) in an interim fashion, and contingent upon the results continue to test the final 3 treatments (all fed)? We are assuming a typical Latin Square such as: A B C D E F B C D E F A C D E F A B D E F A B C E F A B C D F A B C D E To allow the proposed interim analysis (all fasted), is it possible to execute only the first necessary part of the Latin Square, such as: A B C x x x B C x x x A C x x x A B x x x A B C x x A B C x x A B C x x With completion of the remaining parts (all fed) after the interim analysis: x x x D E F x x D E F x x D E F x x D E F x x x x x A B C x F x x x D E 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! [Ohlbe] 