Jay Junior India, 20180326 13:31 (edited by Jay on 20180326 13:50) Posting: # 18595 Views: 2,605 

Dear all, In one of the full replicate study of NTID the results are as per below, Parameters Swr 95%CI The ABE results are as below, Parameters T/R 90%CIL 90%CIU The point estimate is near to 100 and ABE is also within 80% to 125%. But in SABE, the Cmax criteria is more than 0 i.e. 0.0001 which leads to bioinequivalence. So can it be scientifically justified the 95%CI of Cmax value as its very borderline to 0 and T/R shows less difference between test and reference. Thanks Jay Edit: Category and subject line changed; see also this post #1 and #2. [Helmut] 
jag009 Hero NJ, 20180326 17:57 @ Jay Posting: # 18596 Views: 2,251 

Did you check individual data? Any strange ones? If FDA, "no" As in good luck in trying to convince them. John 
Jay Junior India, 20180402 06:28 @ jag009 Posting: # 18628 Views: 1,819 

Thanks, John for the reply... I would like to understand that how come the study passing in ABE within 80% to 125%, low T/R and low ISCV would not meet the BE criteria of scaled average bioequivalence. As we generally proceed with scaled approach when the ISCV is high (more than 30%) and would not meet BE criteria with ABE approach. Please let me know your views on the same. Regards, Jay 
pjs Regular India, 20180402 15:07 (edited by pjs on 20180402 15:17) @ Jay Posting: # 18633 Views: 1,773 

Dear Jay, » I would like to understand that how come the study passing in ABE within 80% to 125%, low T/R and low ISCV would not meet the BE criteria of scaled average bioequivalence. As per the Swr data shared scaled BE limits would be 95.87104.30%. Now as per the ABE data you shared lower limit is mentioned to be 95%. Now please note that variability in ABE and SABE would be different as there will be different models for the estimation. Also for SABE only subjects who had completed all four Periods would be included and in ABE any subject with atleast one reference and one test product would be included. You may refer the lower limit for the ilat output in SABE approach which would be outside 95.87%. This could be reason behind the upper bound value marginally more than 0. Just one quick question in the outputs for upper bound, value to be rounded off till which decimal? If you consider three decimals study is passing and with four decimals same is failing. Also with variability as low as 4%, you also need to check test product variability to comply with variability comparison criteria. Just to check with forum members is there any method for outlier detection in such full replicate studies? In one of the earlier posts there was discussion for use of method proposed by Lazlo for the same. Any further update for the acceptability of this approach. Can you pls confirm how many subjects were included in the study and how sample size was defined. Regards Pjs 
Jay Junior India, 20180404 14:24 @ pjs Posting: # 18639 Views: 1,495 

Dear pjs, Thanks for the reply. In any two way ABE study, if the 90%CI is not within the range of 80125%, most of time the same is reflected in the T/R and also the dissolution graphs. For highly variable product, if the 95% CI is not ≤0, the T/R ratio would be very high and beyond the range of 80 to 125%. For NTID as per USFDAs GL below three criteria should be followed,  Upper 95% CI ≤0 (SABE)  90% CI should be within 80125%  UL of 90% CI for σWT/σWR should be ≤ 2.5 (ABE) As per the case mentioned in above post, the ISCV of test and ref is very low (around 67), T/R is near to 100 and also meeting BE criteria in ABE. So if only 95% CI in SABE does not meet criteria (0.0001) so how the reason for the difference between test and reference can be interpreted. Thanks in advance. Jay 
Helmut Hero Vienna, Austria, 20180404 15:03 @ Jay Posting: # 18640 Views: 1,538 

Hi Jay, » In any two way ABE study, if the 90%CI is not within the range of 80125%, most of time the same is reflected in the T/R … Well, the CI is constructed around the GMR. _{} » … and also the dissolution graphs. Nope. Only if dissolution would be the ratelimiting step. Otherwise in vitro cannot (!) be predictive of in vivo. There a tons of studies with completely dissimilar dissolution profiles which passed BE easily. » For NTID as per USFDAs GL below three criteria should be followed, »  Upper 95% CI ≤0 (SABE) »  90% CI should be within 80125% »  UL of 90% CI for σWT/σWR should be ≤ 2.5 (ABE) You are mixing something up. Actually:  Upper 95% CI ≤0 (SABE)  90% CI should be within 80125% (ABE)  UL of 90% CI for σ_{wT}/σ_{wR} should be ≤ 2.5 (comparison of variabilities) » As per the case mentioned in above post, the ISCV of test and ref is very low (around 67), T/R is near to 100 and also meeting BE criteria in ABE. So if only 95% CI in SABE does not meet criteria (0.0001) so how the reason for the difference between test and reference can be interpreted. The FDA’s “implied BE limits” can be calculated by ℯ^{∓log(1.11111) · √log(CV²+1)/0.1} which are in your case:
These three tests are not directly related. Fine if you pass the latter two. Bad luck if you fail the first by a small margin. How was the study powered? If you targeted a power of 80–90%, the chance of failing for a product which is BE would be 10–20%. Daily life. See John’s reply above. Counterquestion: Did you ever succeed in convincing the FDA to accept a conventional BE study which showed a 90% CI of 79.99–125.01%? — Cheers, Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes 
Nirali Regular India, 20190130 15:38 @ Helmut Posting: # 19830 Views: 334 

Dear Helmut, I need the same guidance for Warfarin Sodium case. If the 95% upper bound for Cmax parameter is 0.002, should we conclude this study as a bioequivalent for Cmax? There is no specific criteria given for 95% upper bound in the OGD of Warfarin Sodium. Regards Nirali 
Helmut Hero Vienna, Austria, 20190202 14:15 @ Nirali Posting: # 19844 Views: 214 

Hi Nirali, » If the 95% upper bound for Cmax parameter is 0.002, should we conclude this study as a bioequivalent for Cmax? No, since the upper bound has to be less or equal to zero. No rounding here … » There is no specific criteria given for 95% upper bound in the OGD of Warfarin Sodium. ≤0 is the general rule for the FDA’s RSABE. See also Jay’s post above, this thread, and a paper of the two Lászlós.*
— Cheers, Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes 
Nirali Regular India, 20190212 07:10 @ Helmut Posting: # 19902 Views: 107 

Thank you Helmut. Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post #5! [Helmut] — Nirali Mehta (PHARMASTATS) 