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ramgopi ☆ India, 2018-03-14 12:29 (2598 d 05:04 ago) Posting: # 18533 Views: 6,924 |
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Dear All, Greetings! We have discussed enough regarding discordant outliers in BE study in the past, but we have struct with typical situation and i would like to know experts opinion on this regard. we have a done a BE study for GCC submission with two way crossover, here one subject shows less concentration in reference product and the T/R ratio for Cmax 2.43 and AUCt 2.35, because of this subject the study failed in border, if we excluded this as a outlier the 90% CI is within the acceptance limit. 90% CI before excluding particular subject Dependent Ratio_ %RefCI_90_Lower CI_90_Upper CV%90% CI After excluding particular subject Dependent Ratio_ %RefCI_90_Lower CI_90_Upper CV%It is evident that something happen for this subject during clinical phase but the CRO failed to notify the incident. GCC just following EMA guidance so as per EMA this is failed study, but out of my curiosity Is there any way to scientifically justify and exclude this subject from statistical calculation. please let me know your opinion thanks & Regards  Gopinath Edit: Category changed; see also this post #1. Tabulators changed to spaces and BBcoded; see also this post #6. [Helmut] |
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Helmut ★★★   Vienna, Austria, 2018-03-14 17:38 (2597 d 23:55 ago) @ ramgopi Posting: # 18546 Views: 5,869 |
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Hi Gopinath, ❝ we have a done a BE study for GCC submission with two way crossover, here one subject shows less concentration in reference product and the T/R ratio for Cmax 2.43 and AUCt 2.35, … The GCC-Guidelines are practically identical to the EMA’s when it comes to exclusion of subjects. A subject is considered to have very low plasma concentrations if its AUC is less than 5% of reference medicinal product geometric mean AUC (which should be calculated without inclusion of data from the outlying subject). ❝ … because of this subject the study failed in border, if we excluded this as a outlier the 90% CI is within the acceptance limit. ❝ It is evident that something happen for this subject during clinical phase but the CRO failed to notify the incident. Why is it evident? The staff of the CRO couldn’t look into the GIT of the subject. You cannot exclude a product failure. ❝ GCC just following EMA guidance so as per EMA this is failed study, … Correct – if you didn’t state such a possible reason for exclusion it in the protocol. Post hoc exclusion (the study failed, let’s try something else) is rarely accepted. ❝ … but out of my curiosity Is there any way to scientifically justify and exclude this subject from statistical calculation. No. You can only try to refer in the report to the GL and cross fingers. — 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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mittyri ★★ Russia, 2018-03-15 11:56 (2597 d 05:37 ago) @ Helmut Posting: # 18550 Views: 5,778 |
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Hi Helmut, ❝ Correct – if you didn’t state such a possible reason for exclusion it in the protocol. If 5% GMR for ref is not mentioned in the Protocol isn't possible just to refer to EMA or other appropriate GL (depending on the jurisdiction)? Have you ever seen lucky guys in EMA jurisdiction who stated in the protocol some additional reasons for exclusion (not mentioned in GL) after ending the bioanalytical part and successfully applied them in borderline case like that? — Kind regards, Mittyri |
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ramgopi ☆ India, 2018-03-18 08:44 (2594 d 08:50 ago) @ ramgopi Posting: # 18567 Views: 5,634 |
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Thank you HS, we will see the possibility of repeating the study. Thanks & Reagrds Gopinath |
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ElMaestro ★★★ Denmark, 2018-03-18 15:43 (2594 d 01:50 ago) @ ramgopi Posting: # 18570 Views: 5,721 |
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Hi Gopinath, how about auditing the study before you take any further decisions? I am hearing you more or less say that you think the products in spite of the data are BE. That's why you want to exclude the subject in question, and that's why you think there is a grounds to believe the subject in question does not reflect the product's average performance, variance taken into consideration . Therefore, a for-cause audit might have merit. If your audit illustrates a general issue at the CRO then that's some pretty valuable knowledge to have prior to deciding on a repeat study (and especially where it is to take place). — Pass or fail! ElMaestro |
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ramgopi ☆ India, 2018-03-19 11:55 (2593 d 05:38 ago) @ ElMaestro Posting: # 18573 Views: 5,430 |
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Hi ElMaestro Thank you for your response We didn’t took any decision and still data under scrutinization Your point is well taken, auditing the facility would suffice the purpose definitely we will think over it. Regards Gopinath |
Ing. Helmut Schütz