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joyjac ★ Philippines, 2006-05-18 10:13 (6921 d 04:51 ago) Posting: # 125 Views: 23,040 |
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Before proceeding with a full-scale BE, we do pilot or trial study to validate the bioanalytical method and optimize sampling time intervals. We would also want to assess the variability i.e. intra-subject that would help us determine the best sample size for the full-scale BE. Can anyone suggest what should be the sample size for a pilot BE to obtain the above objectives. Thanks. |
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Helmut ★★★   Vienna, Austria, 2006-05-18 15:17 (6920 d 23:47 ago) @ joyjac Posting: # 126 Views: 24,707 |
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Hello Joy! ❝ Before proceeding with a full-scale BE, we do pilot or trial study to validate the bioanalytical method and optimize sampling time intervals. We would also want to assess the variability i.e. intra-subject that would help us determine the best sample size for the full-scale BE. This is a very good idea! ❝ Can anyone suggest what should be the sample size for a pilot BE to obtain the above objectives. Bad news CV-estimates from pilot studies, or values from the literature have a high degree of uncertainty (in the actual study it is much more likely that you will be able to reproduce the point estimate, than the CV). Good news It is possible to calculate a Confidence Interval on CVs; therefore, if you want to be on the safe side, you can use the upper limit in sample size estimation. Bad news Such a CI is never published (at least I haven’t seen a single one). Good news Help is on the way; just use following formulas (according to Chow/Liu, Design and Analysis of Bioavailability and Bioequivalence Studies, Marcel Dekker 2000, p.193-6) df = n1+n2-2 (n1/n2 = number of subjects in sequences 1/2, or in the balanced case df = sample size-2)alpha = 0.05 (95% confidence interval)chi²L = chi²(alpha/2,df)A numerical example: n1 = n2 = 8 (pilot study’s sample size 16)df = 14Therefore, the upper 95% confidence limit of the 16% intra-subject CV from your pilot study is almost 24%; if your pilot study has a sample size of 12, the upper limit is 26.6% (and 44.9% for n=6…) This echoes the trivial statement that the bigger your pilot study is, the higher will be your certainty about CV. According to my experience I would not recommend performing a pilot study with a sample of less then 16 subjects. Important is also the expected deviation from the reference. Another example: acceptance range 80%–125%, CV=20%, n=24. You will have 90% power to demonstrate BE for an expected deviation of ca. 5%, but if the actual deviation is ca. 7%, power will drop to 80%… Good luck! — Dif-tor heh smusma 🖖🏼 Довге життя Україна! ![[image]](https://static.bebac.at/pics/Blue_and_yellow_ribbon_UA.png) Helmut Schütz ![[image]](https://static.bebac.at/img/CC by.png) The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes |
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Helmut ★★★ Vienna, Austria, 2006-05-18 16:36 (6920 d 22:27 ago) @ Helmut Posting: # 127 Views: 19,423 |
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Hello Joy! Since we are interested only in the upper limit of CV – if CV in the main study is lower than predicted, we are only gaining power – it may be better to apply a one-side approach instead: df = n1+n2-2 (n1/n2 = number of subjects in sequences 1/2, or in the balanced case df = sample size-2)alpha = 0.05 (95% confidence interval)chi2 = chi2(1-alpha,df)![[image]](img/uploaded/CV Confidence Limit.png) Unfortunately the function is a little bit nasty (depending on the sample size and the CV). The upper 95% confidence is given on the z-axis as a percentage of the CV (x-axis: sample size, and y-axis: CV found in pilot study). A numerical example: n1 = n2 = 8 (pilot study's sample size 16)df = 14 (147% of the CV found in the pilot study)Therefore the one-sided 95% confidence limit of the 15% intra-subject CV from your pilot study is about 22%; if your pilot study has a sample size of 12, the 95% CL of the CV is 24.1% (161% of pilot study), and 36.5% (243%) for n=6... Bottom line: the smaller the sample size of you pilot study is, the higher is the uncertainty of the estimated CV. — 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 |
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joyjac ★ Philippines, 2006-05-19 03:22 (6920 d 11:42 ago) @ Helmut Posting: # 128 Views: 19,074 |
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Dear HS, Thanks for your kind and prompt attention. I understand we cannot get a reliable estimate of the CV by using a small sample size i.e. 6 subjects; but using 16 subjects for a pilot BE is analogous to doing a full-scale BE. What if the pilot BE using 16 indicates bioequivalence for the test product versus the reference product based on the 90% CI for Cmax and AUC - would this mean a full-scale BE is no longer needed? |
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Helmut ★★★ Vienna, Austria, 2006-05-19 15:02 (6920 d 00:01 ago) @ joyjac Posting: # 130 Views: 19,362 |
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Dear Joy! ❝ Thanks for your kind and prompt attention. You’re welcome! ❝ I understand we cannot get a reliable estimate of the CV by using a small sample size i.e. 6 subjects; […] Not only the CV, but also the point estimate… ❝ […] but using 16 subjects for a pilot BE is analogous to doing a full-scale BE. Only for CV<18.9%, ±5% deviation from the reference, 80% power  Seriously: as you have stated in your original post, the purpose of a pilot study is not solely statistical, but also to get information on the suitability of the sampling schedule and the appropriateness of the analytical method. ❝ What if the pilot BE using 16 indicates bioequivalence for the test product versus the reference product based on the 90% CI for Cmax and AUC - would this mean a full-scale BE is no longer needed? No, since – strictly speaking - the purpose of the study was to get estimates of CV and the deviation from the reference, you should not even calculate the CI… Less strictly speaking, the outcome is a serendipitous result and only descriptive, since the main target was estimating CV and PE – and not demonstration of BE. Just to stay with yesterday’s example of 15% CV, n=16: 90% CI will be within 0.8-1.25, but you have a study with no sample size estimation, and an undefined target. OK, now comes the courage of the sponsor in - and the country you are aiming at. According to current guidelines you have to have information on variability and the expected deviation from the reference in order to perform a proper sample size estimation (otherwise it’s considered unethical to dose subjects with an unclear chance of outcome). If you are quite sure that clinics/analytics are not in question – and the primary target in the pilot study is a statistical one – you may try to go for an add-on design (though personally I’m not happy with the potentially inflated patients’ risk). Add-on designs are standard in Canada (since 1992) and Japan (since at least 1997), but are not acceptable according to some other regulations (e.g., USA, Brazil). The European Union lies somewhere in between, deciding on a case-to-case basis (not covered in the guideline), but the general practice is very restrictive. It’s part of the job of a CRO to explain to sponsors that they must not only look at the budget for BE-studies, but also avoid time-delays in the approval process (which very often easily outweigh additional costs). If you have a pilot study which ‘demonstrated BE’ this is not a BE study. Full stop. — 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 |
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H_Rotter ★ Germany, 2006-05-20 15:56 (6918 d 23:07 ago) @ joyjac Posting: # 132 Views: 18,964 |
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Hi Joy, at least for the USA it should be possible to show BE in a pilot study, because III.A.2. Pilot study: “[…] A pilot study that documents BE can be appropriate, provided its design and execution are suitable and a sufficient number of subjects (e.g., 12) have completed the study.” But don’t ask me, what ‘sufficient number’ actually means.  Best regards, Hermann Edit: Link corrected to latest archived copy. [Helmut] |
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intuitivepharma ☆ India, 2013-05-06 14:31 (4376 d 00:33 ago) @ Helmut Posting: # 10545 Views: 12,762 |
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Dear Helmut, Really sorry if I am too elementary, Kindly let me know from where can I get the below mentioned parameters. I use Winnonlin for my BE calculations. chi²Can I do the CI calculations for ISCV in Excel? * Is it the MSE # Is it (MSE/2)*DF Thanks & regards, IP. — Thanks & Regards, IP. |
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Helmut ★★★ Vienna, Austria, 2013-05-06 15:09 (4375 d 23:55 ago) @ intuitivepharma Posting: # 10546 Views: 12,920 |
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Hi IP, ❝ Kindly let me know from where can I get the below mentioned parameters. I use Winnonlin for my BE calculations. CVintra is already given in WinNonlin’s standard output for 2×2 cross-over studies. For higher-order cross-over calculate it from the Var(residual) as
MSintra=log(CVintra²+1). You also need the degrees of freedom. Get them from the Partial Tests, row sequence*subject. The inverse χ² is not available in PHX/WNL’s custom transformations (a request is scheduled for the next revision of PHX).❝ Can I do the CI calculations for ISCV in Excel? Yes, but I would not recommend it (M$ Excel’s CINV() is known to be buggy; see also this post). I would suggest the free software ![[image]](img/uploaded/Rlogo_15_12.svg) and the famous package PowerTOST.Example: 2×2 cross-over, 20 subjects balanced (n1=n2=10; df=n1+n2-2=18), CVintra 20%.
lower CL upper CLThe example in the previous posts
lower CL upper CL (![[image]](img/uploaded/image28.png) post #126)or better (since I would not use a two-sided interval any more)
lower CL upper CL ( post #127)— 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 |
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intuitivepharma ☆ India, 2013-05-07 10:52 (4375 d 04:11 ago) @ Helmut Posting: # 10550 Views: 12,494 |
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Dear Helmut,  Thanks & Regards, IP. — Thanks & Regards, IP. |
Ing. Helmut Schütz