## tlag‽ [Regulatives / Guidelines]

❝ ...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 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:

- Unnecessary burden to the subjects renders this requirement ethically doubtful.

- 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}.

- (As in other guidelines) it is an unresolved question what a “comparable” median is.

- 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.

*Dif-tor heh smusma*🖖🏼 Довге життя Україна!

_{}

Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮

Science Quotes

### Complete thread:

- EMA Product Specific GL mmw 2017-07-14 14:50 [Regulatives / Guidelines]