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EMA: 2 product-specific guidances adopted [BE/BA News]

posted by Helmut Homepage - Vienna, Austria, 2018-06-26 14:40  - Posting: # 18968
Views: 1,708

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 tlag” from the second one:


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


  1. Unnecessary burden to the subjects renders this requirement ethically doubtful.
  2. Contrary to Cmax, early concentrations might be close to the analytical limit of quantification – which leads to high variability and hence, likely ill-defined estimates of tlag.
  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 tlag from the required PK variables.

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

Helmut Schütz

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