pa1kumar.anna ☆ India, 20081201 10:51 (5771 d 01:09 ago) (edited by pa1kumar.anna on 20081201 13:14) Posting: # 2843 Views: 31,392 

DEAR ALL, please provide the sas code of partial replicate design.  with regards APK 
Ohlbe ★★★ France, 20081201 11:45 (5771 d 00:16 ago) (edited by Ohlbe on 20081202 09:40) @ pa1kumar.anna Posting: # 2844 Views: 28,634 

Dear pa1kumar.anna, Please read the Forum policy and instructions. For instance: Be polite! It's nice to start your post with a salutation, and include a signature as well. You may save a signature with your User's data; it will be automatically attached to your posts. This will greatly improve your chances of getting an answer. Regards Ohlbe  Edit: initial message edited by APK to add salutation and signature 
d_labes ★★★ Berlin, Germany, 20081202 10:17 (5770 d 01:44 ago) @ pa1kumar.anna Posting: # 2858 Views: 28,555 

Dear APK, ❝ please provide the sas code of partial replicate design. Be a little bit more specific. What do you mean with partial replicate design? A 3period replicate design? What SAS code do you need? Average bioequivalence? Or what else? BTW: Hope your user name is not your password ; — Regards, Detlew 
Helmut ★★★ Vienna, Austria, 20081203 16:42 (5768 d 19:19 ago) @ d_labes Posting: # 2873 Views: 28,726 

Dear DLabes, ❝ Be a little bit more specific. ❝ What do you mean with partial replicate design? A 3period replicate design? I've heard this term for the first time at the recent Workshop at Ahmedabad. Yes, it's a 3period replicate design (TRRRTRRRT). — 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 
MGR ★ India, 20081204 12:19 (5767 d 23:42 ago) @ Helmut Posting: # 2876 Views: 28,769 

Dear Helmut, We too heard this type of design and we are also planning for the study as per the sponsor's request. Here we got the type like Partial scaled average Replicate Bioequivalence study. In this study, we had two treatments forming 3 period 3 sequence design as follows: 1) T R R 2) R T R 3) R R T Now my question is: Then what is the difference between an Scaled average Replicate 3way cross over study with the above stated one? Please clarify me regarding this. Thanks in advance. — Regards, MGR 
d_labes ★★★ Berlin, Germany, 20081204 15:17 (5767 d 20:43 ago) @ Helmut Posting: # 2877 Views: 31,126 

Dear Helmut, dear all, ❝ I've heard this term for the first time at the recent Workshop at Ahmedabad. Yes, it's a 3period replicate design (TRRRTRRRT). Taking the Holy Bible^{[1]} of crossover designs the best known 3period replicate design has the name 3period dual design with the two sequences
I have found this term in discussions (FDA and others) about scaled average bioequivalence. But here it denominates a onesequence design with replication of the reference only, for instance
To answer the original question: If the design is a 3period design with more then one sequence, to my knowledge the SAS code for the evaluation of average bioequivalence does not depend on the specific design used in replicate studies, provided you will go with restricted maximum likelihood estimation (Proc MIXED in "The power to know"). The code recommended in the FDA guidance was discussed already in breadth on this forum. See for instance this thread and others (use search!). Let me give it here again for your convienience. Proc MIXED data=YourData method=REML alpha=0.1; Y is the pharmacokinetic target (eventually log transformed f.i. for AUC, Cmax). The ODS output statement saves you the least square means and the 90% confidence intervals in SAS datasets for further processing, f.i. to back transform them into the original scale if your target was logtransformed. Be aware that SAS always gives you the difference (and 90% confidence interval) in least square means in lexicographic order, namely RT if you code your treatments as R(eference) and T(est). So do not forget to change the sign in subsequent processing! But there are variants of this code (covariance structure other than FA0(2), other ddfm=denominator degrees of freedom) and there are complete other models to choose from! See for instance ^{[2]} and ^{[3]}. If it is an ominous onesequence design I think we have no sequence and period effects in the model.?
Edit: Updated URLs. [Helmut] — Regards, Detlew 
d_labes ★★★ Berlin, Germany, 20081212 11:51 (5760 d 00:09 ago) @ d_labes Posting: # 2912 Views: 29,516 

Dear all, FYI: The 3sequence3period replicate design with the sequences
^{[1]} R.J. McNally Tests for Individual and Population Bioequivalence Using 3Period Crossover Designs and the 2sequence variant using only the two first sequences in ^{[2]} S.C. Chow, J. Shao and H. Wang Individual bioequivalence testing under 2×3 designs Statist. Med. 2002; 21:629–648 which can be found ^{[1]} here and ^{[2]} there. These papers deal with individual BE but the parts relevant for average BE can easily extracted. Interesting enough these papers state, that the intraindividual variance component for T(est) is not identifiable/estimable, due to the "partial" replicate nature of these designs (replicates only for R). Thus one would expect some difficulties with the FDA SAS code, which has a covariance parameter for that in the model. But my little experimentation with it and some artificial data for an extrareference design show that the code is able to deliver a value for that variance parameter s_{WT}. Black magic or some sort of perpetuum mobile of information? Because the intraindividual variance for the Reference is identifiable (regardless which method, REML or method of moments) one could go with Reference scaled ABE as described in Haidar et al. Evaluation of a scaling approach for the bioequivalence of highly variable drugs AAPS J. 2008 Sep;10(3):4504. Epub 2008 Aug 26 — Regards, Detlew 
Helmut ★★★ Vienna, Austria, 20081212 12:34 (5759 d 23:27 ago) @ d_labes Posting: # 2913 Views: 28,653 

Dear D. Labes, thanks for your references! ❝ Black magic or some sort of perpetuum mobile of information? Neither nor  just For my simple mind it seems to be quite strange to get the variance of a measurement we have performed only once. — 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 
d_labes ★★★ Berlin, Germany, 20081212 14:28 (5759 d 21:33 ago) @ Helmut Posting: # 2914 Views: 28,910 

Dear Helmut, ❝ ❝ Black magic or some sort of perpetuum mobile of information? ❝ ❝ Neither nor  just the 'power to know'! ❝ For my simple mind it seems to be quite strange to get the variance of a measurement we have performed only once. I am the last to tout "SAS all over the world" (although I have to deal with the 'power to know' most time of my working day). But here I must defend it. I guess this is not a problem of SAS. It may be a problem of what we (I) do with it. Fitting an inappropriate? or overspecified? model. Eventually anybody can fit the underlying model in WINNONLIN or R using REML to see what happens? I have taken my data to play with from example 4.2 of Patterson/Jones "Bioequivalence and Statistics in Clinical Pharmacology" (C5300.zip with data and SAS code), changed the original sequences to TRR/RTR. I place a bet that then also a fitted value for s^{2}_{WT} is obtained . Maybe it is even correct!? (I confabulate: total variability of T: estimable; variability of TR: estimable and sum of intrasubject variabilities + treatment*subject interaction; intrasubject variability of R: estimable; so ......) BTW: Simple minds are more then 30 years successful . — Regards, Detlew 
Helmut ★★★ Vienna, Austria, 20081212 15:58 (5759 d 20:03 ago) @ d_labes Posting: # 2916 Views: 28,909 

Dear D. Labes, ❝ I guess this is not a problem of SAS. It may be a problem of what we (I) do with it. Fitting an inappropriate? or overspecified? model. ❝ ❝ Eventually anybody can fit the underlying model in WINNONLIN or R using REML to see what happens? ❝ I place a bet that then also a fitted value for s^{2}_{WT} is obtained . Maybe it is even correct!? I fitted C_{max} with your modified sequences (because I didn't want to start with incomplete AUC data) in WinNonlin to PBE/IBE and obtained: SigmaR 0.9999185 (no SigmaWT!)❝ (I confabulate: total variability of T: estimable; variability of TR: estimable and sum of intrasubject variabilities + treatment*subject interaction; intrasubject variability of R: estimable; so ......) If I run ABE in WinNonlin I'm lost in the options; choosing the defaults (no time to dig into the manual right now...) fixed: sequence+treatment+period I get Final variance parameter estimates: where according to this post lambda(1,1)_11, lambda(1,2)_11 and lambda(2,2)_11 correspond to SAS' FA(1,1), FA(2,1) and FA(2,2)... — 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 
d_labes ★★★ Berlin, Germany, 20081212 16:44 (5759 d 19:17 ago) @ Helmut Posting: # 2918 Views: 29,042 

Dear Helmut, thanks for your very quick replay. ❝ I fitted C_{max} with your modified sequences (because I didn't want to start with incomplete AUC data) in WinNonlin to PBE/IBE and obtained: ❝ ❝ Seems 'Method of moments' is used here? ❝ If I run ABE in WinNonlin I'm lost in the options; choosing the defaults [...] ❝ I get ❝ ❝ ❝ ❝ ❝ ❝ Here are the covariance parameters from Proc MIXED (FDA code) Covariance Parameter Estimates With the exception of lambda(1,1) there seems no match ! Now we need someone with knowledge of relationship of SAS and WINNONLIN parameters. Is var(period*treatment*subject) the intrasubject variability? But enough to now. Have a nice weekend. — Regards, Detlew 
Helmut ★★★ Vienna, Austria, 20081212 17:33 (5759 d 18:27 ago) @ d_labes Posting: # 2919 Views: 28,594 

Dear D. Labes, thanks for SAS' output! ❝ Seems 'Method of moments' is used here? Yes – but only to get initial variance estimates. ❝ With the exception of lambda(1,1) there seems no match ! Yes. ❝ Now we need someone with knowledge of relationship of SAS and WINNONLIN parameters. We should wait for Simon Davis coming by (he has also experience with SAS)... ❝ Is var(period*treatment*subject) the intrasubject variability? Yes, well the variance (and you get the CV in the usual way; not builtin in WinNonlin: pocketcalculator business): Var(period*treatment*subject)_21 sigma²_{reference} Var(period*treatment*subject)_22 sigma²_{test} — 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 ★ 20240729 11:38 (52 d 01:23 ago) @ Helmut Posting: # 24101 Views: 2,405 

❝ Yes, well the variance (and you get the CV in the usual way; not builtin in WinNonlin: pocketcalculator business): ❝ Var(period*treatment*subject)_21 ❝ Var(period*treatment*subject)_22 Hello, probably a very basic question but I cannot find this anywhere. I understand that one gets CVwr from Var(period*treatment*subject)_21 and CVwt from Var(period*treatment*subject)_22 but how does one get CV from Phoenix WinNonlin output for FDA fullreplicate model? Regards BEQool 
Helmut ★★★ Vienna, Austria, 20240729 15:29 (51 d 21:31 ago) @ BEQool Posting: # 24102 Views: 2,343 

Hi BEQool, I suggest to use the RSABEtemplate for Phoenix, because it deals with incomplete data, etc and was crossvalidated against SAS . The latest version 1.4 of February 2014 works in all Phoenix releases 6.4+ (I tested it with 8.4.0). Unfortunately the link in Certara’s support forum is not valid any more. Either ask there for an update of contact me directly.— 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 ★ 20240729 21:47 (51 d 15:13 ago) (edited by on 20240730 09:27) @ Helmut Posting: # 24103 Views: 2,315 

Hello Helmut, thank you, I have managed to find a newer version of this RSABE template for Phoenix here: RSABE for HDV Templates for PHX 8.3.3. ([106FL] Free Phoenix Templates for Bioequivalence Regulatory Guidances). I assume this version is good as well. But I still cannot find an object where I would find CVw: Edit: link to the Screenshot Where am I supposed to get it? Edit: If I am not wrong, confidence interval is calculated using MSE/CVintra/CVw even in RSABE so it must be displayed somewhere? BEQool 
Helmut ★★★ Vienna, Austria, 20240730 11:15 (51 d 01:45 ago) @ BEQool Posting: # 24104 Views: 2,251 

Hi BEQool, ❝ I still cannot find an object where I would find CVw: FDA RSABE Project template_ v8_3_3
— 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 ★ 20240730 12:56 (51 d 00:05 ago) @ Helmut Posting: # 24105 Views: 2,249 

❝ Do I get you right that you want to get the withinsubject withinsubject \(\small{CV_\text{w}}\)? Yes you are right. ❝ [...] I got for the EMA’s Example Data Set I: 41.620277 Thank you for the explanation and equations, I get the same CVw for the EMA Data Set I. ❝ BTW, why do you need it? Because I want to get CVw from a full replicate (n=10) pilot study and the a) CVw obtained with your equation (1) does not match (not even close) b) CVw obtained from the 90% CI with CVfromCI (PowerTOST in R).a ) Var(Period*Formulation*Subject)_21=0.020549392 Var(Period*Formulation*Subject)_22=0.18248611 CVw=SQRT(EXP((0.020549392+0.18248611)/2)1)= 32.7% b) Lower=80.633903 Upper=122.74948 CVfromCI(lower=.80633903,upper=1.2274948,design="2x2x4",n=10) > 40.5%Why is there such a difference here between the two CVw? The study is balanced with complete data. Can the reason be a relatively big difference between variability of test and reference? BEQool BTW ❝ $$s_\text{w}^2=\frac{s_\text{wR}^2+s_\text{wR}^2}{2}\tag{1}$$ ❝ You should get a table with the estimated \(\small{s_\text{wR}^2}\) in the first row and \(\small{s_\text{wR}^2}\) in the second. 
Helmut ★★★ Vienna, Austria, 20240730 13:23 (50 d 23:37 ago) @ BEQool Posting: # 24106 Views: 2,239 

Hi BEQool, ❝ ❝ BTW, why do you need it? ❝ ❝ Because I want to get CVw from a full replicate (n=10) pilot study and the a) CVw obtained with your equation (1) does not match (not even close) b) CVw obtained from the 90% CI with ❝ CVw=SQRT(EXP((0.020549392+0.18248611)/2)1)= 32.7% ❝ ❝ ❝ ❝ Why is there such a difference here between the two CVw? The study is balanced with complete data. Can the reason be a relatively big difference between variability of test and reference?
Typo in my original post corrected. THX! I still don’t understand why you need \(\small{CV_\text{w}}\). Do you plan a study for ABE?
— 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 ★ 20240731 07:49 (50 d 05:12 ago) @ Helmut Posting: # 24107 Views: 2,118 

❝ ❝ ❝ ❝ Thanks, I didnt know that robust = TRUE has to be used for mixed model. Will come in useful.❝ I still don’t understand why you need \(\small{CV_\text{w}}\). Do you plan a study for ABE? Yes because like you said: ❝ Since \(\small{CV_\text{wR}\ll 30\%}\), referencescaling is not applicable and you get for RSABE and ABEL the same sample sizes like for ABE. BEQool 
mittyri ★★ Russia, 20240731 20:25 (49 d 16:36 ago) @ BEQool Posting: # 24116 Views: 2,077 

Hi BEQool, ❝ ❝ I still don’t understand why you need \(\small{CV_\text{w}}\). Do you plan a study for ABE? ❝ ❝ Yes because like you said: ❝ ❝ ❝ Since \(\small{CV_\text{wR}\ll 30\%}\), referencescaling is not applicable and you get for RSABE and ABEL the same sample sizes like for ABE. Don't you want to apply average ABE approach (GLM) for the current dataset to get the average CVintra? I think this approach would be fair enough. — Kind regards, Mittyri 
BEQool ★ 20240801 07:45 (49 d 05:15 ago) @ mittyri Posting: # 24117 Views: 2,015 

Hello Mittyri ❝ Don't you want to apply average ABE approach (GLM) for the current dataset to get the average CVintra? I think this approach would be fair enough. In this case I get CVw of 34.5% which is somewhere between CVw = 36.90% (obtained with CI2CV ) and the "correct" CVw of 32.69% (obtained with SQRT(EXP((0.020549392+0.18248611)/2)1) ).BEQool 
MGR ★ India, 20081230 11:12 (5742 d 00:48 ago) @ Helmut Posting: # 2985 Views: 28,507 

Dear Helmut, In the previous reply, you have given the output of WinNonlin like, ❝ ❝ ❝ ❝ ❝ ❝ But my doubt is that, Can we find the Switchability, Prescribability and Global Variance from the above data in WinNonlin? If so can you please give me the formulas to calculate these parameters? As we are dealing a project of replicate, in the protocol they had mentioned these parameters. Thanks in advance. — Regards, MGR 
Helmut ★★★ Vienna, Austria, 20081230 17:04 (5741 d 18:57 ago) @ MGR Posting: # 2991 Views: 29,160 

Dear MGR! ❝ In the previous reply, you have given the output of WinNonlin like […], This was the evaluation for Average Bioequivalence (ABE). In WinNonlin’s BE Wizard entry window: Type of Bioequivalence ❝ […] Can we find the Switchability, Prescribability and Global Variance from the above data in Winnonlin? Prescribability is assessed by Population Bioequivalence (PBE); Switchability by Individual Bioequivalence (IBE). In WinNonlin's BE Wizard entry window: Type of Bioequivalence ❝ If so can you please give me the formulas to calculate these parameters? For a basic reference see Hauck WW, Andersons. Measuring Switchability and Prescribability: When Is Average Bioequivalence Sufficient? J Pharmacokin Biopharm. 1994; 22(6), 551–64 Just run the BE Wizard. For lnC_{max} of the example data set we get:
Population Bioequivalence Statistics ❝ […] in the protocol they had mentioned these parameters. Not knowing how to evaluate the study? IMHO both PBE and IBE are of historic interest only. — 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 
MGR ★ India, 20081231 08:52 (5741 d 03:09 ago) @ Helmut Posting: # 2994 Views: 28,490 

Dear Helmut, Thanks for the Reply. The exact doubt is that these three (Switchability,) terms are mentioned in the average bioequivalence study protocol but not in the Ind/Pop BE study. So i got confused with the protocol So i want to find these terms according to the Average BE Study not by using Ind/Pop BE study. Thank you, — Regards, MGR 
NPavan ☆ India, 20090112 14:10 (5728 d 21:51 ago) @ MGR Posting: # 3021 Views: 28,258 

Dear all, I am new to this field. I am a bio statistician. These forums are very helpful to beginners like me. I have seen in a protocol regarding switchability concept in average bioequivalence. Can anybody please give me formula/reference/website for calculating switchability. Thanks in advance. Regards Pavan See the reference in the post above. [Helmut] — Regards, Pavan 