libaiyi Junior China, 20180608 11:41 Posting: # 18870 Views: 1,092 

Hi, I am so confused about how to calculate the suitable BE limits for HVDPs based on EMA criterion since the range changes all the time. When we get a CVwr, how to get the BE limits? Thanks in advance Edit: Category changed; see also this post #1. [Helmut] 
Shuanghe Regular Spain, 20180608 12:51 @ libaiyi Posting: # 18872 Views: 973 

Hi, » I am so confused about how to calculate the suitable BE limits for HVDPs based on EMA criterion since the range changes all the time. » » When we get a CVwr, how to get the BE limits? The easiest way is using R. Some nice guy in this forum wrote a package so basically library(powerTOST) will give you whatever you want, where CV is the CV of reference. And it's not limited to EMA. you can use it for calculations according to US FDA's and Canadian's guidance too (regulator="FDA" or "HC"). e.g. scABEL(0.5, regulator="EMA") will give you lower upper and scABEL(0.4, regulator="EMA") will give lower upper If you like to reinventing the wheel then it is also pretty straightforward to do so. If your CV_{WR} is between 30% and 50%, the lower and upper limit is EXP(0.76*s_{WR}) and EXP(0.76*s_{WR}) , respectively.Relatioship between CV_{WR} and s_{WR} is described in EMA's guideline. you can check the formula there. — All the best, Shuanghe 
Helmut Hero Vienna, Austria, 20180608 13:19 @ libaiyi Posting: # 18873 Views: 976 

Hi libaiyi, » When we get a CVwr, how to get the BE limits? The switching CV_{wR} is 30% and hence, the regulatory constant k should be log(1.25)/√log(0.30²+1) or 0.7601283… In R (CVs and BE limits in %):
In its eternal wisdom (preferring “nice” numbers) the EMA demands a rounded k 0.76 (which implies a switching CV_{wR} of 30.0053%).*
More convenient by the function scABEL() of the Rpackage PowerTOST (by applying the default argument regulator="EMA" ). The function then uses k 0.76, returns the conventional ABE limits if CV_{wR} ≤30%, and observes the upper cap of CV_{wR} 50%:
Don’t apply double rounding! Round the 90% CI in percent to two decimal places but compare it to the expanded limits in full precision.
Edit: Hey Shuanghe, you were faster! — Cheers, Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes 
libaiyi Junior China, 20180611 07:21 @ Helmut Posting: # 18881 Views: 823 

Hi， I want to know how to figure out that whether the results are bioequivalence? According to CFDA (China Food and Drug Administration) guidelines, when CVwR of Cmax is larger than 0.3, BE limits are fixed at (69.83, 143.19). Can we use the results from Mixed Model by SAS directly to determine if it falls between the limits or not? 
Helmut Hero Vienna, Austria, 20180611 12:24 @ libaiyi Posting: # 18882 Views: 790 

Hi libaiyi, » I want to know how to figure out that whether the results are bioequivalence?
» According to CFDA (China Food and Drug Administration) guidelines, when CVwR of Cmax is larger than 0.3, BE limits are fixed at (69.83, 143.19). Weird – do you have a reference? Feel free to post in Chinese; we have some native speakers here. This would add another story to the two we already have (see this thread in all of its beauty). I have some doubts whether that is really what the CFDA wants. Would be a step back to what was used in some European countries 25+ years ago. » Can we use the results from Mixed Model by SAS directly to determine if it falls between the limits or not? First you have to clarify which method for HVD(P)s the CFDA accepts.
— Cheers, Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes 
libaiyi Junior China, 20180612 11:09 @ Helmut Posting: # 18887 Views: 729 

Hi Helmut, thanks for your help. CFDA has relased the draft guidance for HVBE, which follows FDA method (RSABE). I still have a question about EMA method. Do you mean if we follow EMA's guidance, the ABEL should be used rather than RSABE, please give me more advise. thanks in advance. 
Helmut Hero Vienna, Austria, 20180612 14:54 @ libaiyi Posting: # 18889 Views: 730 

Hi libaiyi, » CFDA has relased the draft guidance for HVBE, which follows FDA method (RSABE). <nitpick> There is nothing like “highly variable bioequivalence”. Either the drug itself is highly variable (if the clearance is HV already seen after an iv dose or after an oral solution the absorption is HV: HVD) or a drug product is HV: HVDP. Since it not always known whether the drug itself is HV, when talking about formulations people like me leave the question open and prefer the term HVD(P). I see. Is this link correct? Interesting the two attachments (#1, #2). When it comes to replicate designs only the lousy partial replicate (TRRRTRRRT) and one full replicate (TRTRRTRT) given in Tables 2&3. Never heard about the 3period full replicate (TRTRTR) and another 4period full replicate (TTRRRRTT)? Although not given in the tables, 4sequence 4period full replicates are also mentioned (TRTRRTRTTRRTRTTR or TRRTRTTRTTRRRRTT). Forget it; confounded effects. From #2 it is clear that the FDA’s RSABE was 1:1 copied. » I still have a question about EMA method. Do you mean if we follow EMA's guidance, the ABEL should be used rather than RSABE, … Correct. » … please give me more advise. As I wrote previously, SAScode is given in the EMA’s Q&Adocument. The EMA prefers a fixed effects model (‘Method A’). — Cheers, Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes 
libaiyi Junior China, 20180613 03:39 @ Helmut Posting: # 18895 Views: 681 

Thanks for you reply. Another question, how to write the null hypothesis and alternative hypothesis for BE based on FDA or EMA method? 
Helmut Hero Vienna, Austria, 20180613 11:39 @ libaiyi Posting: # 18897 Views: 665 

Hi libaiyi, » how to write the null hypothesis and alternative hypothesis for BE based on FDA or EMA method? That's a legitimate question. May sound strange but the hypotheses don’t exist until we have estimated s_{wR} (the extent of scaling in RSABE and the expanded limits in ABEL are random variables and not fixed like in ABE). Hence, both hypotheses are generated “in face of the data” which may lead to inflation of the type I error.^{1–7} RSABE and ABEL are frameworks^{a,b} where one cannot know beforehand which “path” to follow (see here and there). One can only specify the method and its conditions intended to follow in the protocol.
— Cheers, Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. ☼ Science Quotes 
libaiyi Junior China, 20180614 03:46 @ Helmut Posting: # 18903 Views: 612 

The replies and the materials enlighten me a lot. Thanks for your patience. 