BEQool ★ 20240129 12:53 (77 d 01:21 ago) Posting: # 23845 Views: 1,288 

Hello! I have searched the forum but couldn't find the answer to the following question: why does the sample size estimation with R with package PowerTOST differ between sampleN.TOST and sampleN.scABEL when CV=30%?Lets take a look at the following example: a) Sample size estimation with sampleN.TOST sampleN.TOST(CV=0.3, theta0=0.95, design="2x3x3") b) Sample size estimation with sampleN.scABEL sampleN.scABEL(CV=0.3, theta0=0.95, design="2x3x3") So why do the sample size estimations differ? They have the same arguments (design="2x3x3", theta0=0.95 ...). CV is 30% so there should be no scaling (conventional BE limits, i.e., 80.00125.00). Does it have to do anything with simulations? But even when I increase number of simulations, the differences aren't that big. Or if I reformulate the question, why dont the following powers match: a) power.TOST(CV=0.3, theta0=0.95,design="2x3x3", n=30) b) power.scABEL(CV=0.3, theta0=0.95, design="2x3x3", n=30) Regards BEQool Edit: Category changed. [Helmut] 
Helmut ★★★ Vienna, Austria, 20240129 14:52 (76 d 23:22 ago) @ BEQool Posting: # 23846 Views: 1,105 

Hi BEQool, ❝ […]: why does the sample size estimation with R with package PowerTOST differ between Therefore, simulations are needed. At a true CV_{wR} = 30% we have – roughly* – a 50% chance that in the actual study CV_{wR} > 30%. Then we could expand the limits, gain power for a given sample size, or need less subjects for a certain power than we would need in ABE. ❝ So why do the sample size estimations differ? They have the same arguments (design="2x3x3", theta0=0.95 ...). CV is 30% so there should be no scaling (conventional BE limits, i.e., 80.00125.00). You could also remove all scaling conditions. Then you get the same sample size than with sampleN.TOST() :reg < reg_const(regulator = "USER", r_const = 1, CVswitch = Inf, CVcap = Inf, pe_constr = FALSE) ❝ Does it have to do anything with simulations? But even when I increase number of simulations, the differences aren't that big. ❝ Or if I reformulate the question, why dont the following powers match: ❝ a)
❝ b)
You asked the wrong question in b) because power.scABEL(CV=0.3, theta0=0.95, design="2x3x3", n=27) Let’s consider an example where expanding the limits is less likely.
BTW, I would never ever assume theta = 0.95 for a HVD(P). That’s why in the referencescaling functions of PowerTOST theta = 0.90 is the default.
— 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 
BEQool ★ 20240130 11:52 (76 d 02:22 ago) @ Helmut Posting: # 23851 Views: 1,027 

Thank you for the explanation, it seems I havent taken the distribution of CV into account (jumping over and below the limit CV=30%). ❝ Therefore, simulations are needed. At a true CV_{wR} = 30% we have – roughly* – a 50% chance that in the actual study CV_{wR} > 30%. Then we could expand the limits, gain power for a given sample size, or need less subjects for a certain power than we would need in ABE. ❝ […] Now the sample sizes are identical. Power for ABEL is slightly larger than for ABE because there is a certain – while small – chance to expand the limits. So the sample size with ABEL is always smaller or equal to ABE right (with the same arguments)? Similarly, power for the same number of subjects is always higher (or equal) with ABEL than with ABE (as shown in my reformulated question at the end of the first post or in your example with n=21 for ABE vs. ABEL)? Additional 2 questions popped into my head while thinking about this:
BEQool 
Helmut ★★★ Vienna, Austria, 20240130 14:08 (76 d 00:06 ago) @ BEQool Posting: # 23852 Views: 1,015 

Hi BEQool, ❝ So the sample size with ABEL is always smaller or equal to ABE right (with the same arguments)? Similarly, power for the same number of subjects is always higher (or equal) with ABEL than with ABE (as shown in my reformulated question at the end of the first post or in your example with n=21 for ABE vs. ABEL)? ❝ 1. So in case regulators (EMA region) ask us to calculate post hoc power (regardless of how irrelevant it is) … ❝ … of a study with 2x3x3 design with CVwr=25%, we should calculate it with ❝ And on the other hand, for Cmax we should calculate it with ❝ 2. Another hypothetical scenario: If we get information from the literature about a drug's CVw (Cmax) of around 30% (lets say a range of 2535%) and if we get a drug's CVw of 22% from our pilot study, can we then do a regular study with design 2x3x3 (in case we get CVw for Cmax 35% so then we could widen the limits and use ABEL)? BTW, why do you want to use a partial replicate design and not one of the 2sequence 3period full replicate designs (TRTRTR or TRRRTT)? Acceptable for the EMA (see the Q&A document and this post for examples). Same degrees of freedom and similar sample sizes. More informative because you can also estimate CV_{wT}, which is useful in designing other studies (quite often CV_{wT} < CV_{wR} and you need a smaller sample size). In the partial replicate you have to assume CV_{wT} = CV_{wR}, which is often wrong. ❝ And if then our drug's CVw from this regular study is lets say 21%, can agencies ask us to justify replicate 2x3x3 design as if why didnt we use conventional 2x2x2 design if we got CVw=22% in our pilot study? There is nothing to justify. Any study in a replicate design can also be assessed for ABE. My – former – best enemy once said »From a purely statistical perspective, all studies should be performed in a replicate design.« One of the rare occasions I agree with him. — 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 
BEQool ★ 20240204 20:24 (70 d 17:50 ago) @ Helmut Posting: # 23853 Views: 923 

Sorry for my late response. ❝ Oh dear! EMA region, really‽ Outright bizarre. ❝ BTW, why do you want to use a partial replicate design and not one of the 2sequence 3period full replicate designs (TRTRTR or TRRRTT)? Acceptable for the EMA (see the Q&A document and this post for examples). Same degrees of freedom and similar sample sizes. More informative because you can also estimate CV_{wT}, which is useful in designing other studies (quite often CV_{wT} < CV_{wR} and you need a smaller sample size). In the partial replicate you have to assume CV_{wT} = CV_{wR}, which is often wrong. Nevertheless, a deficiency letter regarding 2sequence 3period full replicate design from an European agency was already received (it was answered successfully) so 3sequence 3period partial replicate design is now used sometimes instead. ❝ By ‘regular study’ are you meaning a simple crossover? Even if you observed CV_{w} ≥30% I would be cautious. That’s only a hint of a highly variable reference. See this article for details. ❝ There is nothing to justify. Any study in a replicate design can also be assessed for ABE. My – former – best enemy once said »From a purely statistical perspective, all studies should be performed in a replicate design.« One of the rare occasions I agree with him. BEQool 
Helmut ★★★ Vienna, Austria, 20240204 22:12 (70 d 16:02 ago) @ BEQool Posting: # 23854 Views: 912 

HI BEQool, ❝ Sorry for my late response. ❝ […] a deficiency letter regarding 2sequence 3period full replicate design from an European agency was already received (it was answered successfully) so 3sequence 3period partial replicate design is now used sometimes instead. — 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 
BEQool ★ 20240205 14:20 (69 d 23:54 ago) @ Helmut Posting: # 23855 Views: 855 

❝ Fantastic! The European agency (which one?) should read – and accept – what is stated in the EMA’s Q&Adocument. France and Ireland  however, it was for veterinary product 
Helmut ★★★ Vienna, Austria, 20240205 17:01 (69 d 21:13 ago) @ BEQool Posting: # 23856 Views: 870 

Hi BEQool, ❝ France and Ireland  however, it was for veterinary product — 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 
mittyri ★★ Russia, 20240205 17:49 (69 d 20:25 ago) @ Helmut Posting: # 23857 Views: 862 

Hi Helmut and BEQool! ❝ ❝ France and Ireland  however, it was for veterinary product ❝ This might explain it. The last time I read the vetGL it was crap (politely speaking). That's interesting how CHMP EMA Guidelines invade CVMP Guidelines. I am trying to catch the logic: For substances with highly variable disposition where it is difficult to show bioequivalence due to high intraindividual variability, different alternative designs have been suggested in the literature (e.g. replicate study design). A replicate crossover study design using 3 periods (partial replication where only the reference product is replicated in all animals) or 4 periods (full replication, where each subject receives the test and reference products twice) can be carried out. So CVMP people have some concerns about other designs we don't know yet. — Kind regards, Mittyri 