sweiner ☆ India, 20200122 21:22 (1494 d 19:46 ago) Posting: # 21081 Views: 5,022 

Hello, I would like to obtain an advice on BE study sample size estimation. Let’s say, we are planning a 2x2 crossover study for BE, and the intrasubject coefficient of variation for our test compound, from a prior study, is 23%. The assumed geometric mean ratio is 1.00, alpha is 0.05, equivalence limits are 80%125%, and we desire power of 80%. These criteria result in an overall sample size of 20 subjects, or 10 per sequence. Subsequently, we want to add 2 extra dose levels of our test drug, resulting in a 4x4 crossover trial. Let’s assume that %CV and GMR are not changing, as no further data is available. For this new scenario, is it appropriate to: 1) use the original sample size of N=20 and simply divide it over 4 sequences (5 per sequence), or 2) take the original per sequence sample size of 10 and multiply by 4 to get 40 subjects overall needed? In either case 1) or 2), is there a supporting reference you can provide? Thanks, Sveta Edit: Category and subject line changed; see also this post #1 and #2. [Helmut] 
Helmut ★★★ Vienna, Austria, 20200123 14:48 (1494 d 02:20 ago) @ sweiner Posting: # 21083 Views: 3,614 

Hi Sveta, ❝ Let’s say, we are planning a 2x2 crossover study for BE, and the intrasubject coefficient of variation for our test compound, from a prior study, is 23%. The assumed geometric mean ratio is 1.00, … Which PE did you find in the prior study? Its sample size would be helpful as well. ❝ … alpha is 0.05, equivalence limits are 80%125%, and we desire power of 80%. These criteria result in an overall sample size of 20 subjects, or 10 per sequence. Correct – if you are a believer of the ‘carved in stone’ approach (i.e., that in the planned study the CV will be exactly 23% and the PE exactly 1). I suggest to have a look at Example 3 of the ABEVignette of the R package PowerTOST to reconsider your assumptions. See also there (slide 8 and followings).❝ Subsequently, … What do you mean by ‘subsequently’? ❝ … we want to add 2 extra dose levels of our test drug, resulting in a 4x4 crossover trial. What is the purpose of the study – dose proportionality? If yes, that’s another cup of tea. ❝ Let’s assume that %CV and GMR are not changing, as no further data is available. Rather strong assumptions, right? ❝ For this new scenario, is it appropriate to: 1) use the original sample size of N=20 and simply divide it over 4 sequences (5 per sequence), or 2) take the original per sequence sample size of 10 and multiply by 4 to get 40 subjects overall needed? It depends whether you want to show dosenormalized equivalence (i.e., strict dose normality) or dose proportionality by the power model \(E[Y]=\alpha \cdot D^{\; \beta}\). Say we have four formulations ( A , the reference R , B , and C ) and three dose levels (x, y, z), where A = R = x, B = y, C = z.You randomize subjects either to the Latin Square ARBCRBCABCARCARB or any one of the six Williams’ designs ACBRRBCABARCCRAB , ARBCRCABBACRCBRA , ACRBRABCBRCACBAR , ABRCRACBBCARCRBA , ABCRRCBABRACCARB , ARCBRBACBCRACABR .
— 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 
Ihababdallah ☆ 20200930 17:17 (1243 d 00:52 ago) @ Helmut Posting: # 21952 Views: 2,467 

Hi Helmut, I have question related to this topic, if a study design is 5x5 cross over trial, reference, 3 treatments, and placebo, and I would like to estimate the sample size ? 
Helmut ★★★ Vienna, Austria, 20200930 20:08 (1242 d 22:00 ago) @ Ihababdallah Posting: # 21953 Views: 2,424 

Hi Ihababdallah, ❝ […] if a study design is 5x5 cross over trial, reference, 3 treatments, and placebo, and I would like to estimate the sample size ? See the subject line. If you will tell us the purpose of the study, we may help. What do you want to demonstrate? Equivalence of the treatments to the reference and superiority of all to placebo or what? — 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 
Ihababdallah ☆ 20200930 21:31 (1242 d 20:37 ago) @ Helmut Posting: # 21954 Views: 2,417 

❝ See the subject line. If you will tell us the purpose of the study, we may help. ❝ What do you want to demonstrate? Equivalence of the treatments to the reference and superiority of all to placebo or what? yes I am looking to see the equivalence of 3 different treatments to the reference. 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. Please follow the Forum’s Policy. [Helmut] 
Helmut ★★★ Vienna, Austria, 20201001 12:28 (1242 d 05:40 ago) @ Ihababdallah Posting: # 21955 Views: 2,375 

Hi Ihababdallah, ❝ ❝ What do you want to demonstrate? Equivalence of the treatments to the reference and superiority of all to placebo or what? ❝ ❝ yes I am looking to see the equivalence of 3 different treatments to the reference. Do we need to worm the information out of you bit by bit?
— 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 
sweiner ☆ India, 20200126 17:50 (1490 d 23:18 ago) @ sweiner Posting: # 21086 Views: 3,524 

Helmut, thank you for the detailed response, examples in R, and references! I put the answers to the questions below (I tried to change color on responses, but not sure if that worked). Thanks. Sveta ❝ Which PE did you find in the prior study? Its sample size would be helpful as well. This is more a hypothetical example, so really not known ❝ ❝ … alpha is 0.05, equivalence limits are 80%125%, and we desire power of 80%. These criteria result in an overall sample size of 20 subjects, or 10 per sequence. ❝ Correct – if you are a believer of the ‘carved in stone’ approach (i.e., that in the planned study the CV will be exactly 23% and the PE exactly 1). I suggest to have a look at Example 3 of the ABEVignette of the R package PowerTOST to reconsider your assumptions. See also there (slide 8 and followings). ❝ ❝ Subsequently, … ❝ What do you mean by ‘subsequently’? ‘Subsequently’ here refers to the next study on somewhat different population (where we expect smaller value of CV), with higher order of crossover ❝ ❝ … we want to add 2 extra dose levels of our test drug, resulting in a 4x4 crossover trial. ❝ What is the purpose of the study – dose proportionality? If yes, that’s another cup of tea. The purpose is to show dosenormalized equivalence ❝ ❝ Let’s assume that %CV and GMR are not changing, as no further data is available. ❝ Rather strong assumptions, right? We actually expect a smaller value of %CV, not sure on GMR though ❝ ❝ For this new scenario, is it appropriate to: 1) use the original sample size of N=20 and simply divide it over 4 sequences (5 per sequence), or 2) take the original per sequence sample size of 10 and multiply by 4 to get 40 subjects overall needed? ❝ It depends whether you want to show dosenormalized equivalence (i.e., strict dose normality) or dose proportionality by the power model \(E[Y]=\alpha \cdot D^{\; \beta}\). ❝ Say we have four formulations ( ❝ You randomize subjects either to the Latin Square ❝ — If you want to assess dosenormalized equivalence, follow the ‘Two‐at‐a‐Time Principle’, i.e., perform pairwise comparisons whilst excluding the others.^{1} Do not use a pooled ANOVA because it may give biased estimates and/or inflate the Type I Error.^{2,3} ❝ That means your first scenario is correct (you estimate the sample size like a 2×2×2 crossover) and get three incomplete block designs to evaluate: ❝ If you insist in a pooled ANOVA for any reasons, you end up with 20 subjects as well (though with slightly higher power due to the higher degrees of freedom 3n–6 compared to the n–2 in the 2×2×2): ❝ ❝ ❝ ❝ ❝ ❝ ❝ ❝ ❝ ❝ ❝ This is what we are trying to do, so this is exactly the response I was looking for. I used the following example in R with CV=1.04 and got similar overall SS from either 2x2 or 4x4, so then the overall SS will just need to be split to higher order crossover – about 67 subjects per sequence for 2x2 and about 34 per sequence for 4x4. I assume that if we had to do even higher order crossover, then we would follow similar approach. R does not support 5x5 for example, but if we had to use 5x5 it would be about 26 subjects per sequence, it seems to be,is it correct? CV=1.04, design = 2x2: sampleN.TOST(CV = 1.04, theta1=0.67, theta2 = 1.5, theta0 = 1.1, design = "2x2", print = FALSE, logscale=TRUE, targetpower=0.9)[7:8]
CV=1.04, design = 4x4 sampleN.TOST(CV = 1.04, theta1=0.67, theta2 = 1.5, theta0 = 1.1, design = "4x4", print = FALSE, logscale=TRUE, targetpower=0.9)[7:8]
Edit: Standard quotes restored; see also this post #8. [Helmut] 