Bioequivalence and Bioavailability Forum

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

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