ElMaestro ★★★ Denmark, 20210823 14:42 (24 d 06:07 ago) Posting: # 22532 Views: 867 

— Pass or fail! ElMaestro 
Helmut ★★★ Vienna, Austria, 20210823 15:31 (24 d 05:19 ago) @ ElMaestro Posting: # 22533 Views: 756 

Hi ElMaestro, » FDA updated the canonical BE guideline for ANDAs. THX, had a quick look. » Draft. What else… Main difference is that referencescaling is detailed and not just mentioning the progesterone guidance in a footnote – like in the draft of 2013. Interesting difference: Progesterone guidance \(\small{\text{a. the 95% upper confidence bound for }\left(\widehat{Y}_T\widehat{Y}_R\right)^2\theta s_{wR}^2\text{ must be}\leq 0}\) New ANDA draft \(\small{\text{a. The 95% upper confidence bound for }\left(\widehat{Y}_T\widehat{Y}_R\right)^2\theta s_{wR}^2\text{ must be}\leq 0}\) We had a few discussions about rounding in RSABE in the past (here and there). In both guidances the formula is confusing. The regulatory limit \(\small{\sigma_\textrm{w0}=0.25}\) leads to the regulatory constant $$\small{\theta_\textrm{s}=\frac{\log_{e}1.25}{\sigma_\textrm{w0}}=0.89257\ldots}$$Furthermore, we need the standard error \(\small{s_\textrm{d}}\) of the point estimate \(\small{PE=\widehat{Y}_\textrm{T}\widehat{Y}_\textrm{R}}\) given by $$\small{s_\textrm{d}=\sqrt{\frac{MSE}{seq^2}\sum{\frac{1}{n_i}}},}$$ where \(\small{MSE}\) is the residual Mean Squares Error, \(\small{seq}\) the number of sequences, and \(\small{n_i}\) are the number of subjects in sequence \(\small{i}\). According to the SAScode (without an explanation) \(\small{s_\textrm{d}}\) acts as a bias correction and therefore,$$\small{crit=PE^2s_\textrm{d}^2\theta_\textrm{s}^2\cdot s_\textrm{wR}^2.}$$ Referencescaling for NTIDs is also outlined. Again, a statement about rounding (contrary to the warfarin guidance). — Diftor heh smusma 🖖 Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes 
Achievwin ★ US, 20210908 04:09 (8 d 16:41 ago) @ Helmut Posting: # 22560 Views: 356 

» Furthermore, we need the standard error \(\small{s_\textrm{d}}\) of the point estimate I did not find this one in the guidance can you point out to me what line number this is in the new guidance? Edit: quote restored [Ohlbe] 
Helmut ★★★ Vienna, Austria, 20210910 20:47 (6 d 00:03 ago) @ Achievwin Posting: # 22567 Views: 248 

Hi Achievwin, » » Furthermore, we need the standard error \(\small{s_\textrm{d}}\) of the point estimate » » I did not find this one in the guidance can you point out to me what line number this is in the new guidance? That’s a little bit tricky. I’ll try again. We have the regulatory constant $$\small{\theta_\textrm{s}=\frac{\log_{e}1.25}{\sigma_\textrm{w0}}=0.89257\ldots}\tag{1}$$ In the guidance line 998 the scaled average BE limit is given by $$\small{\theta\equiv\left(\frac{\log_{e}1.25}{\sigma_\textrm{w0}}\right)^2\tag{2}}$$which is simply what I used in my previous post by $$\small{\theta=\theta_\textrm{s}^2}\tag{3}$$ Of course, $$\small{\left(\widehat{Y}_T\widehat{Y}_R\right)^2=PE^2}\tag{4}$$ In the guidance line 1003 we have $$\small{crit=\left(\widehat{Y}_T\widehat{Y}_R\right)^2\theta\cdot s_\textrm{wR}^2}\tag{5}$$ That’s the same as $$\small{crit=PE^2\theta_\textrm{s}^2\cdot s_\textrm{wR}^2}\tag{6}$$Here the confusion starts. You find my \({\color{Red}{s_\textrm{d}}} \) in lines 1083 and 1219 as the stderr of the difference.In the respective next lines you find
Hence, actually not \((5)\) or \((6)\) has to be used but $$\small{\begin{matrix} crit=PE^2{\color{Red}{s_\textrm{d}^2}}\theta_\textrm{s}^2\cdot s_\textrm{wR}^2 =\\ \left(\widehat{Y}_T\widehat{Y}_R\right)^2{\color{Red}{se^2}}\theta \cdot s_\textrm{wR}^2 \end{matrix}}\tag{7}$$ The bias correction is not mentioned anywhere in the guidance and therefore, \((5)\) without one is extremely misleading.^{1,2} It is evident only if you inspect the SAS code. See Detlew’s post about the background given by Donald Schuirmann in 2016.
— Diftor heh smusma 🖖 Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes 
Achievwin ★ US, 20210823 21:35 (23 d 23:14 ago) @ ElMaestro Posting: # 22534 Views: 693 

» FDA updated the canonical BE guideline for ANDAs. Draft. Comments period is open till October 22, 2021, Therefore any issues bothering/benefit ANDA folks can be sent to FDA as comments for consideration. FDA decided to split BA/BE guidance into two guidance 1) for ANDA filings and 2) for IND/NDAs More elaborate explanations of each aspect. 
Helmut ★★★ Vienna, Austria, 20210823 23:46 (23 d 21:04 ago) @ Achievwin Posting: # 22535 Views: 695 

Hi Achievwin, » FDA decided to split BA/BE guidance into two guidance 1) for ANDA filings and 2) for IND/NDAs Already in 2013/2014. » More elaborate explanations of each aspect. I expect to see an update of #2 (current draft of Feb 2019) as well. — Diftor heh smusma 🖖 Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes 