Darborn ☆ Taiwan, 2023-08-22 04:24 (449 d 07:01 ago) Posting: # 23704 Views: 4,043 |
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Dear all, Normally we use 2x3x3 or 2x2x4 replicated design for RSABE, but it needs only one test drug. When design a crossover trial with two test drug (or one ODT given with/without water), I run into confusion about how to give a balanced design for the trial. Furthermore, which make things even worse, I always get confused by "variance-balanced" and "carryover-balance" design. I came out with the following design, but I'm not sure if it is suitable to use when analyzed with FDA RSABE approach.
Thank you! Darborn Edit: Tabulators changed to spaces and BBcoded; see also this post #6. [Helmut] |
Helmut ★★★ Vienna, Austria, 2023-08-23 12:01 (447 d 23:24 ago) @ Darborn Posting: # 23705 Views: 3,377 |
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Hi Darborn, ❝ When design a crossover trial with two test drug (or one ODT given with/without water), I run into confusion about how to give a balanced design for the trial. If the design is not reference-replicated, easy. See this article. ❝ Furthermore, which make things even worse, I always get confused by "variance-balanced" and "carryover-balance" design. True unequal carryover will bias the treatment effect. It cannot be “corrected” statistically. It can only be avoided by sufficiently long washouts. See this article. Carryover is not included in the current models for BE. Since sample sizes for a conventional Latin Squares and (variance-balanced) Williams’ designs are similar,* you can use any of them. ❝ I came out with the following design, but I'm not sure if it is suitable to use when analyzed with FDA RSABE approach. ❝ ❝ ❝ ❝ First of all you have to receive a positive statement from the FDA in a “Controlled Correspondence” because this is not one of the recommended designs for RSABE. According to ICH M13A you have to exclude treatments ( T1 or T2 ) and perform two separate analyses on the respective others (T1 vs R and T2 vs R ). Your design will lead to two partial replicate designs with missing observations (denoted with • below):
— Dif-tor heh smusma 🖖🏼 Довге життя Україна! Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
Darborn ☆ Taiwan, 2023-08-23 13:13 (447 d 22:12 ago) @ Helmut Posting: # 23706 Views: 3,401 |
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Thank your reply Helmut! ❝ According to ICH M13A you have to exclude treatments ( ❝ 1. ❝ ❝ R T1 R • ❝ • R T1 R ❝ R • R T1 ❝ ❝ 2. ❝ ❝ R • R T2 ❝ T2 R • R ❝ R T2 R • I tried to read your article about replicate crossover, and now I know it is so called "incomplete block design" (am I right?). However, the true nightmare comes, how can I estimate the sample size required for a power of 80%. I guess that using the design of 2x3x3 or 2x2x4 in powerTOST is a big NO… |
Helmut ★★★ Vienna, Austria, 2023-08-23 13:51 (447 d 21:34 ago) @ Darborn Posting: # 23707 Views: 3,343 |
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Hi Darborn, ❝ I tried to read your article about replicate crossover, and now I know it is so called "incomplete block design" (am I right?). ❝ However, the true nightmare comes, how can I estimate the sample size required for a power of 80%. ❝ I guess that using the design of 2x3x3 or 2x2x4 in powerTOST is a big NO… sampleN.RSABE() , but the argument design = "2x4x4" is not implemented. Sorry.— Dif-tor heh smusma 🖖🏼 Довге життя Україна! Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
Darborn ☆ Taiwan, 2023-08-30 10:07 (441 d 01:18 ago) @ Helmut Posting: # 23709 Views: 3,234 |
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Thank you Helmut for answering the question |
BEQool ★ 2024-02-22 10:15 (265 d 00:10 ago) @ Darborn Posting: # 23870 Views: 2,359 |
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Hello, so the most appropriate design for 2 test treatments and replicated reference is a below one? ❝ ❝ ❝ ❝ Do you think EMA regulators would have any objections if this is was pivotal study (of course bearing Bonferroni adjustment in mind)? Probably following designs would be worse?: a) EMA suggested replicate design with additional test treatment TRR|T2 b) 3x6x3 Williams design with additional reference treatment ABC|C Best regards BEQool |
Helmut ★★★ Vienna, Austria, 2024-02-23 10:25 (264 d 00:00 ago) @ BEQool Posting: # 23876 Views: 2,314 |
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Hi BEQool, ❝ so the most appropriate design for 2 test treatments and replicated reference is a below one? ❝ ❝ ❝ ❝ ❝ ❝ ❝ ❝ ❝ Do you think EMA regulators would have any objections if this is was pivotal study (of course bearing Bonferroni adjustment in mind)? ❝ Probably following designs would be worse?: ❝ a) EMA suggested replicate design with additional test treatment ❝ ❝ ❝ ❝ b) 3x6x3 Williams design with additional reference treatment ❝ ❝ ❝ ❝ ❝ ❝ That’s the same idea as in the so-called ‘extra-reference design’2 (a two-sequence partial replicate TRR|RTR ). This design – like both of yours – is biased in the presence of true period effects.
— Dif-tor heh smusma 🖖🏼 Довге життя Україна! Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
BEQool ★ 2024-02-25 10:59 (261 d 23:26 ago) @ Helmut Posting: # 23881 Views: 2,200 |
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Dear Helmut, thank you for your explanations. Useful as always BEQool |