tlag‽ [Regulatives / Guidelines]

posted by Helmut Homepage – Vienna, Austria, 2017-12-21 15:43 (2108 d 03:22 ago) – Posting: # 18074
Views: 7,362

Hi nobody,

❝ ...backdoor? These are REALY ugly times we life in...

IMHO, just crazy: This is the comment I’ve send to the EMA on 31 October:

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. Concerns:

  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 (if any):
Remove tlag from the required PK variables.

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