SD vs. MD, partial AUCs [Regulatives / Guidelines]
some comments on this week’s workshop in Bonn.
»The BfArM still sleeping at 5 a.m.«
1. SD vs. MD
- The U.S. FDA generally does not require MD studies (exception: studies in patients under therapy due to unacceptable safety profile in healthy subjects).
- Japan’s NIHS requires SD studies, although “multiple dose studies may be employed for drugs which are repeatedly administered to patients.”
- Brazil’s ANVISA does not require MD studies.
- Canada’s HPFB/TGD requires MD studies only if substantial accumulation is expected, i.e.,
AUCt > 80% AUC∞.
- The EMA currently requires MD additionally to SD in all cases.
- According to the draft MD studies might be waived under certain circumstances:
- AUCt > 90% AUC∞ and
- BE demonstrated in SD for additional PK metrics, e.g., pAUCs (Cτ under discussion).
As Alfredo García-Arieta pointed out “The 10% residual AUC are arbitrary; we could have used 20% or 5% as well.” OK, Canada is successfully applying the 20% for more than two decades [sic] now…
I love arbitrary values.
The suggested procedure starting with the SD study is as following:
- If AUCt ≤ 90% AUC∞ target metrics are AUC∞, AUCt, and Cmax. Whether AUC∞ is primary for controlled release and AUCt for delayed release is under discussion. pAUCs for multiphasic profiles.
MD mandatory (waiving criterion not fulfilled).
- If AUCt > 90% AUC∞ target metrics as above + additional metrics describing the shape of profiles (pAUCs, t75%?).
- If additional metric(s) pass BE, a MD study might be waived.
- If the additional metric(s) fail, a MD study is required.
He was asked how achievement of steady state can be demonstrated and whether a statistical test is required. The answer was “A test is not expected. Reporting of pre-dose concentrations and plots are sufficient.” All other members of the drafting party nodded in agreement.
2. partialAUC (if applicable)
- The U.S. FDA requires pAUCTmax,ref as a measure of early exposure if clinically relevant. Tmax,ref is the population (‽) median. Conventional acceptance range.
- The U.S. FDA requires pAUCs in some product-specific guidances (methylphenidate: ER capsules, ER tablets; zolpidem ER tablets). The truncation time point ‘T’ is a priori set based on PD and might be different for fasting/fed or applicable to one state only. Example: MPH (3 h fasting, 4 h fed), zolpidem (1.5 h fasting only).
Required metrics: AUC0-T, AUCT-t, AUC0-∞, and Cmax; conventional acceptance range.
- HPFB/TGD requires pAUCTmax,ref as a measure of early exposure if clinically relevant. Tmax,ref is defined as the individual’s value. Relative mean within the conventional acceptance range (no CI).
- EMA Q&A Ref.4 (02/2012): Pre-specified truncation time point. AUC0-T, AUCT-t, Cmax,0-T, Cmax,T-t; conventional acceptance range.
- MR draft (lines 787–792): Pre-specified truncation time point. AUC0-t, AUC0-∞, Cmax, tmax, AUC0-T, AUCT-t, Cmax,0-T, Cmax,T-t, tmax,0-T, tmax,T-t. Yippee! Ten characteristics. That’s a lot. IMHO, only descriptive.
Statistical evaluation (lines 800–805): AUC0-t, AUC0-∞, Cmax, AUC0-T, AUCT-t; conventional acceptance range or scaling (lines 807–810).
Presentations of the workshop will be available for some limited time in a couple of weeks at EUFEPS’ website.
Dif-tor heh smusma 🖖🏼 Довге життя Україна!
The quality of responses received is directly proportional to the quality of the question asked. 🚮
- Draft EMA MR formulations GL published! Ohlbe 2013-03-15 12:10 [Regulatives / Guidelines]
- Housekeeping suggestions Helmut 2013-03-15 13:28
- Scaling for pAUCs Helmut 2013-03-15 14:19
- Draft EMA MR formulations GL published! ioanam 2013-03-30 17:54
- Clarity on waiving multiple dose study Tina 2013-05-15 14:19
- SD vs. MD, partial AUCsHelmut 2013-06-21 19:24
- tmax (DR & multiphasic) Helmut 2013-06-22 01:15
- Presentations of the EUFEPS meeting Helmut 2013-07-15 15:50
- ⧫ Deadline approaching ⧫ Helmut 2013-08-16 16:41
- Download comment form Helmut 2013-08-26 11:28
- Food effect Compliance 2013-08-26 12:04
- Food effect Dr_Dan 2013-08-26 16:48
- Variability (MR vs. IR) Helmut 2013-09-12 15:23