libaiyi ★ China, 2018-06-08 13:41 (2518 d 05:09 ago) Posting: # 18870 Views: 8,796 |
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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 ★★ Spain, 2018-06-08 14:51 (2518 d 03:59 ago) @ libaiyi Posting: # 18872 Views: 7,693 |
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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 ![]() 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 CVWR is between 30% and 50%, the lower and upper limit is EXP(-0.76*sWR) and EXP(0.76*sWR) , respectively.Relatioship between CVWR and sWR is described in EMA's guideline. you can check the formula there. — All the best, Shuanghe |
Helmut ★★★ ![]() ![]() Vienna, Austria, 2018-06-08 15:19 (2518 d 03:31 ago) @ libaiyi Posting: # 18873 Views: 7,808 |
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Hi libaiyi, ❝ When we get a CVwr, how to get the BE limits? The switching CVwR is 30% and hence, the regulatory constant k should be \(\log{(1.25)}/\sqrt{\log{(0.30^2+1)}} = 0.7601283\ldots \) 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 CVwR of 30.0053%).*
More convenient by the function scABEL() of the R-package PowerTOST (by applying the default argument regulator="EMA" ). The function then uses k 0.76, returns the conventional ABE limits if CVwR ≤30%, and observes the upper cap of CVwR 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! — 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 |
libaiyi ★ China, 2018-06-11 09:21 (2515 d 09:28 ago) @ Helmut Posting: # 18881 Views: 7,446 |
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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 ★★★ ![]() ![]() Vienna, Austria, 2018-06-11 14:24 (2515 d 04:25 ago) @ libaiyi Posting: # 18882 Views: 7,623 |
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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.
— 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 |
libaiyi ★ China, 2018-06-12 13:09 (2514 d 05:41 ago) @ Helmut Posting: # 18887 Views: 7,538 |
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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 ★★★ ![]() ![]() Vienna, Austria, 2018-06-12 16:54 (2514 d 01:56 ago) @ libaiyi Posting: # 18889 Views: 7,647 |
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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 (TRR|RTR|RRT) and one full replicate (TRTR|RTRT) given in Tables 2&3. Never heard about the 3-period full replicate (TRT|RTR) and another 4-period full replicate (TTRR|RRTT)? Although not given in the tables, 4-sequence 4-period full replicates are also mentioned (TRTR|RTRT|TRRT|RTTR or TRRT|RTTR|TTRR|RRTT). 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, SAS-code is given in the EMA’s Q&A-document. The EMA prefers a fixed effects model (‘Method A’). — 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 |
libaiyi ★ China, 2018-06-13 05:39 (2513 d 13:11 ago) @ Helmut Posting: # 18895 Views: 7,332 |
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Thanks for you reply. Another question, how to write the null hypothesis and alternative hypothesis for BE based on FDA or EMA method? |
Helmut ★★★ ![]() ![]() Vienna, Austria, 2018-06-13 13:39 (2513 d 05:11 ago) @ libaiyi Posting: # 18897 Views: 7,399 |
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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 swR (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 frameworksa,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.
— 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 |
libaiyi ★ China, 2018-06-14 05:46 (2512 d 13:04 ago) @ Helmut Posting: # 18903 Views: 7,297 |
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The replies and the materials enlighten me a lot. Thanks for your patience. ![]() ![]() ![]() |