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Karmegams ☆ India, 2011-06-10 09:54 (5072 d 13:42 ago) Posting: # 7099 Views: 6,473 |
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Dear Sir, Normally we use Expected deviation of 5% or 7.5% in sample size calculation for bioequivalence study. please suggest me the maximum Expected deviation that can be used for sample size calculation? Regards Skar |
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Dr_Dan ★★ Germany, 2011-06-10 10:51 (5072 d 12:46 ago) @ Karmegams Posting: # 7100 Views: 5,637 |
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Dear Skar What do you mean by "expected deviation"? True difference in formulation (µT/µR) or difference in number of subjects needed to demonstrate BE with a specific power and number of enrolled subjects (drop out reserve)? In both cases the answer is: it depends.... In general you calculate your sample size with a formulation difference < 5%. Assuming a greater difference will tell an assessor that you have information showing that your formulation is borderline bioequivalent (= bad formulation that can only fit in the BE acceptance range if the study is overpowered). To calculate the drop out reserve you need to know the adverse event profile of the drug and the compliance of the subjects. I hope this helps. Kind regards Dan — Kind regards and have a nice day Dr_Dan |
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Karmegams ☆ India, 2011-06-10 11:57 (5072 d 11:40 ago) @ Dr_Dan Posting: # 7101 Views: 5,647 |
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Dear Sir I meant true difference in formulation (µT/µR). Yes, you cleared my doubt. Thank you very much. Regards Skar |
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ElMaestro ★★★ Denmark, 2011-06-10 14:19 (5072 d 09:18 ago) @ Karmegams Posting: # 7103 Views: 5,641 |
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Hello Skar, ❝ Normally we use Expected deviation of 5% or 7.5% in sample size calculation for bioequivalence study. please suggest me the maximum Expected deviation that can be used for sample size calculation? EU regulators put in the sentence "Unless otherwise justified, the assayed content of the batch used as test product should not differ more than 5% from that of the batch used as reference product determined with the test procedure proposed for routine quality testing of the test product." in the 2010 guideline for BE. and from that perspective you might say that this should be reflected in the powering; at least I know of a few companies doing it this way. But I think that answering your question is not as simple as just that, mainly because real life can be rather cruel. For this reason Potvin's method for two-stage design was recently extended to T/R's of 0.9, which I see as a recognition of the fact that T/R deviating e.g. 5% from unity is not always realistic. In addition, some dosage forms do not have a well-defined release method that fit neatly into this way of thinking and for which PK may still be used to qualify BE or TE. Examples include nasal sprays and inhalation products. You have all sorts of weird parameters you could try, like delivered dose (which will vary between start and end of canister or spray-bottle) and various size partitions corresponding to what may be expected to reach the relevant sites of absorption or action. Finally, when something is BE then it is because we are 90% sure that the real T/R is within some acceptance range. A product can be shown BE even if the true T/R is terrible like 0.85. It may just cost a lot of money to prove it. I am not aware of any other strict rule regarding the maximum expected deviation, but of course some..... erm hehe.... common sense (sorry HS, I couldn't think of any other term) is needed here. If you have a good method in vitro for your expected T/R and it turns out the expected T/R is 0.85 then it might be a good idea to reformulate rather than initiate a study. From an ethics perspective I do see a bit of reason in doing so. — Pass or fail! ElMaestro |
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Helmut ★★★   Vienna, Austria, 2011-06-10 15:40 (5072 d 07:57 ago) @ ElMaestro Posting: # 7104 Views: 5,523 |
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Dear ElMaestro & Skar, ❝ ❝ Normally we use Expected deviation of 5% or 7.5% in sample size calculation for bioequivalence study. ❝ I am not aware of any other strict rule regarding the maximum expected deviation, but of course some..... erm hehe.... common sense (sorry HS, I couldn't think of any other term) is needed here. I love common sense. Maximum ±5% in EMA’s GL targets measured content of test and reference – not the expected ∆. We shouldn’t forget
The number of subjects required is determined by The number of subjects to be included in the study should be based on an appropriate sample size calculation. If you take the points mentioned on top into account, it might be reasonable to expect a larger ∆ even for measured ±≤5 %. I’m happy with Skar’s 7.5%. ❝ If you have a good method in vitro for your expected T/R and it turns out the expected T/R is 0.85 then it might be a good idea to reformulate rather than initiate a study. From an ethics perspective I do see a bit of reason in doing so. Supported. — 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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Dr_Dan ★★ Germany, 2011-06-10 17:06 (5072 d 06:31 ago) @ Helmut Posting: # 7106 Views: 5,603 |
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Dear Helmut ❝ If you take the points mentioned on top into account, it might be reasonable to expect a larger ∆ even for measured ±≤5 %. I’m happy with Skar’s 7.5%. Yes, I agree. But this is just for your own estimation. In the study protocol I would compensate a ∆ larger than ±≤5% by assuming a higher intra-individual CV% since a naive and inexperienced assessor expects an equivalent product (ideally 1:1 and if differences than not more than 5%. Do you remember the discussion about point estimators and confidence intervals? Kind regards Dan — Kind regards and have a nice day Dr_Dan |
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Karmegams ☆ India, 2011-06-13 08:05 (5069 d 15:32 ago) @ Helmut Posting: # 7110 Views: 5,419 |
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Dear Sir, Thank you very much for your clarification. The reason for my doubt (Normally we use Expected deviation of 5% or 7.5% in sample size calculation for bioequivalence study. please suggest me the maximum Expected deviation that can be used for sample size calculation?) is: In two cross over design; for 90% CI, a sample size of "40 subjects" it gives 80% power if product having CV-intra of 25% and their expected deviation is assumed as 7.5%. For 90% CI, a sample size of "40 subjects" is gives >90% power if product having CV-intra of 25% and their expected deviation is assumed as 5%. Regards, Skar |
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GSTATS ☆ India, 2011-06-13 09:36 (5069 d 14:01 ago) @ Karmegams Posting: # 7111 Views: 5,425 |
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Dear Skar ❝ The reason for my doubt (Normally we use Expected deviation of 5% or 7.5% in sample size calculation for bioequivalence study. please suggest me the maximum Expected deviation that can be used for sample size calculation?) is: Maximum Expected deviation can be used depending on the situation, literature, pilot study or sponsor's point of view. I have seen studies, accepted by regulatory, planned on sample size caculated with expected deviation of 10% or sometimes more. For example, if a pilot study shows a deviation of 10% and variability around 15%. Then one can plan a study with sample size based on 10% expected deviation, variability=15%, power=80% or 90% (on your choice). But i will suggest that if expected deviation (from pilot study) is =>15% then one should definetly go for reformulation. But if one is expecting deviation to be between 10% to 15% then variability of the molecule should be low (shown in literature or pilot study). Regards, GSTATS www.gstatsolutions.com — Let Noble Thoughts come from Every Side: RIG VEDA |
Ing. Helmut Schütz