Bioequivalence and Bioavailability Forum

Dear all,

on 31 May the EMA’s CHMP adopted new product-specific guidance (effective with 1 December 2018):

1. Dabigatran etexilate hard capsule 75 mg, 110 mg and 150 mg
   
2. Dimethyl fumarate gastro-resistant capsule 120 mg and 240 mg
   

On the first one only Boehringer commented. IMHO, dabigatran is a NTID but I didn’t have the time to comment.
I suggested to delete “Comparable median and range for t_lag” from the second one:

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Comment:

For gastric-resistant formulations any [sic] difference in t_lag is reflected in t_max as well. In other words: Any shift in t_lag will lead to exactly the same shift in t_max.
Whereas rich sampling close to the expected t_max likely is already applied in the study (in order to get reliable estimates of C_max) this is generally not the case around the expected t_lag. In order to get reliable estimates of t_lag, additional samples would have to be drawn in the absorption phase.

Concerns:

1. Unnecessary burden to the subjects renders this requirement ethically doubtful.
   
2. Contrary to C_max, early concentrations might be close to the analytical limit of quantification – which leads to high variability and hence, likely ill-defined estimates of t_lag.
   
3. (As in other guidelines) it is an unresolved question what a “comparable” median is.
   
4. The range has a breakdown point of one (i.e., a single extreme value distorts the estimate towards this value).
   Example: Values after both the test and reference product are identical and 1. If we add another subject with T=1 and R=24, the medians will be still 1 for both products. For T the range will be 0 but for R it will be 23. This lacks any relevance.

Proposed change:

Remove t_lag from the required PK variables.

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Was obviously accepted (even t_max removed…) but comments not published.
Am I a persona non grata?