Critical review of EU BE guideline (Rev.1) [Regulatives / Guidelines]

posted by Helmut Homepage – Vienna, Austria, 2008-08-22 16:30 (5697 d 05:39 ago) – Posting: # 2233
Views: 25,210

Dear all!

After the draft was published yesterday for a consultation period until January 31st, 2009 I want to start a discussion of critical points.
Some of them are already given in this thread. Feel free to join the party.

Acceptance limits, page 14 (lines 553-554)
'Confidence intervals should be presented to two decimal places. To be inside the acceptance interval the lower bound should be ≥ 80.00 and the upper bound should be ≤ 125.00.'
Wonderful. All the software I know performs a comparison of the CI with the acceptance range internally in full precision and prints out something like 'BE demonstrated at alpha=0.05' or 'Failed to demonstrate BE', or - if the entire CI is outside the AR – 'BioINequivalence demonstrated…'. It's easy to round the CI for the presentation, but it's not possible to change the internal algorithm of a commercial program. If following this logic one should come up with, let's say a lower CL of 79.995 (from the calculation), the sentence 'Failed to show average bioequivalence for confidence=90.00 and percent=20.0.' (WinNonlin) and a rounded result of 80.00 which supports BE??

Acceptance limits, page 14 (lines 555-557)
Target parameter of early exposure (if clinically relevant) is partial AUC truncated at the median tmax of the reference (lines 718-719). tmax is dropped from evaluation. This is in accordance with FDA’s guideline. Same goalposts as for Cmax apply (i.e., widening should be possible for HVDs in a replicate design study only; see Section 4.1.10, page 16, lines 631-641).
This is funny, because one will rarely find any reference giving values for the partial AUC truncated at tmax in the literature (at least I don’t remember any). So if you have a claim on early exposure, a pilot study is mandatory for sample size planning (preferrably in a replicated design - variability may hit you). Endrényi, Tóthfalusi, and Midha have shown that Cmax is a lously metric for the rate of absorption (based on simulations) - but on the other hand I haven't seen any study demonstrating that truncated AUC performs ‘better’ than tmax. So what’s the rationale - except harmonization with the FDA?
Since I do have a large database of studies I’m in the mood of reanalysing them and become famous. :-D

Acceptance limits, page 14 (lines 558-559)
‘[…] at steady state AUCtau, Cmax,ss, and Cmin,ss should be analysed using the same acceptance interval as stated above.’
Cmin,ss was added probably after concerns for oxycodone, but this metric will be rather tough to meet for some drugs. Since scaling is not allowed sample sizes are expected to be very high (for HVDs even in steady state the variability of Css,min » Css,max).

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