pa1kumar.anna ☆ India, 2008-12-01 10:51 (5618 d 11:58 ago) (edited by pa1kumar.anna on 2008-12-01 13:14) Posting: # 2843 Views: 28,100 |
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DEAR ALL, please provide the sas code of partial replicate design. -- with regards APK |
Ohlbe ★★★ France, 2008-12-01 11:45 (5618 d 11:05 ago) (edited by Ohlbe on 2008-12-02 09:40) @ pa1kumar.anna Posting: # 2844 Views: 25,577 |
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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, 2008-12-02 10:17 (5617 d 12:33 ago) @ pa1kumar.anna Posting: # 2858 Views: 25,506 |
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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 3-period 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, 2008-12-03 16:42 (5616 d 06:08 ago) @ d_labes Posting: # 2873 Views: 25,687 |
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Dear DLabes, ❝ Be a little bit more specific. ❝ What do you mean with partial replicate design? A 3-period replicate design? I've heard this term for the first time at the recent Workshop at Ahmedabad. Yes, it's a 3-period replicate design. — 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 |
MGR ★ India, 2008-12-04 12:19 (5615 d 10:31 ago) @ Helmut Posting: # 2876 Views: 25,716 |
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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 3-way cross over study with the above stated one? Please clarify me regarding this. Thanks in advance. — Regards, MGR |
d_labes ★★★ Berlin, Germany, 2008-12-04 15:17 (5615 d 07:33 ago) @ Helmut Posting: # 2877 Views: 28,046 |
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Dear Helmut, dear all, ❝ I've heard this term for the first time at the recent Workshop at Ahmedabad. Yes, it's a 3-period replicate design. Taking the Holy Bible[1] of cross-over designs the best known 3-period replicate design has the name 3-period 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 one-sequence design with replication of the reference only, for instance
To answer the original question: If the design is a 3-period 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 log-transformed. Be aware that SAS always gives you the difference (and 90% confidence interval) in least square means in lexicographic order, namely R-T 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 one-sequence design I think we have no sequence and period effects in the model.?
Edit: Updated URLs. [Helmut] — Regards, Detlew |
d_labes ★★★ Berlin, Germany, 2008-12-12 11:51 (5607 d 10:59 ago) @ d_labes Posting: # 2912 Views: 26,437 |
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Dear all, FYI: The 3-sequence-3-period replicate design with the sequences
[1] R.J. McNally Tests for Individual and Population Bioequivalence Using 3-Period Crossover Designs and the 2-sequence 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 intra-individual 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 extra-reference design show that the code is able to deliver a value for that variance parameter sWT. Black magic or some sort of perpetuum mobile of information? Because the intra-individual 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):450-4. Epub 2008 Aug 26 — Regards, Detlew |
Helmut ★★★ Vienna, Austria, 2008-12-12 12:34 (5607 d 10:16 ago) @ d_labes Posting: # 2913 Views: 25,605 |
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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. — 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 |
d_labes ★★★ Berlin, Germany, 2008-12-12 14:28 (5607 d 08:22 ago) @ Helmut Posting: # 2914 Views: 25,854 |
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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 over-specified? 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 s2WT is obtained . Maybe it is even correct!? (I confabulate: total variability of T: estimable; variability of T-R: estimable and sum of intra-subject variabilities + treatment*subject interaction; intra-subject variability of R: estimable; so ......) BTW: Simple minds are more then 30 years successful . — Regards, Detlew |
Helmut ★★★ Vienna, Austria, 2008-12-12 15:58 (5607 d 06:52 ago) @ d_labes Posting: # 2916 Views: 25,828 |
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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 over-specified? 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 s2WT is obtained . Maybe it is even correct!? I fitted Cmax 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 T-R: estimable and sum of intra-subject variabilities + treatment*subject interaction; intra-subject 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)... — 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 |
d_labes ★★★ Berlin, Germany, 2008-12-12 16:44 (5607 d 06:06 ago) @ Helmut Posting: # 2918 Views: 25,979 |
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Dear Helmut, thanks for your very quick replay. ❝ I fitted Cmax 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 intra-subject variability? But enough to now. Have a nice weekend. — Regards, Detlew |
Helmut ★★★ Vienna, Austria, 2008-12-12 17:33 (5607 d 05:16 ago) @ d_labes Posting: # 2919 Views: 25,542 |
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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 intra-subject variability? Yes, well the variance (and you get the CV in the usual way; not built-in in WinNonlin: pocket-calculator business): Var(period*treatment*subject)_21 sigma²reference Var(period*treatment*subject)_22 sigma²test — 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 |
MGR ★ India, 2008-12-30 11:12 (5589 d 11:38 ago) @ Helmut Posting: # 2985 Views: 25,456 |
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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, 2008-12-30 17:04 (5589 d 05:46 ago) @ MGR Posting: # 2991 Views: 26,082 |
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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 WW Hauck and S. Anderson Just run the BE Wizard. For lnCmax 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. — 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 |
MGR ★ India, 2008-12-31 08:52 (5588 d 13:58 ago) @ Helmut Posting: # 2994 Views: 25,413 |
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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, 2009-01-12 14:10 (5576 d 08:40 ago) @ MGR Posting: # 3021 Views: 25,215 |
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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 post above. [Helmut] — Regards, Pavan |