BE assessment regarding first time point Cmax [Study As­sess­ment]

posted by Ohlbe – France, 2018-12-09 23:46  – Posting: # 19672
Views: 1,366

Dear Mann,

First of all, thanks for providing all information needed in this very detailed post :-)

» 1. Whether final selection of the subjects for BE assessment is correct or not?

IMHO, no.

» [...] as per the guidelines, these subjects are not considered for the analysis as there was no reliable Cmax appearance and no single sampling time between 0 to Cmax point.

That's not what the EMA guideline says. What's written is that the sampling schedule should be planned to avoid Cmax being the first point of a concentration time curve. But first point Cmax is not listed in section 4.1.8 as one of the possible reasons to exclude subjects.

» An outliers analysis (Lund's) confirmed two subjects with an outlier concentration levels. [...] Hence, we have considered that the overall eligible subjects are 13 of 38 (2 outliers, 23 with first time point Cmax)

Read again the guideline section 4.1.8:
Exclusion of data cannot be accepted on the basis of statistical analysis or for pharmacokinetic reasons alone, because it is impossible to distinguish the formulation effects from other effects influencing the pharmacokinetics.

The only two exceptions listed in the guideline are for lack of measurable concentrations (or very low concentrations) after administration of the reference product, and concentrations higher than 5 % of Cmax in period 2. Full stop.

» 2. The final positive BE result (Total transparent reflection of overall assessment of the analysis in CSR) with 13 subjects with slightly less power for Cmax is acceptable for MHRA?

They will not care about the decreased power for Cmax, which is irrelevant (have a look at Helmut's lectures if you want to know why). But they will not accept the exclusion of 25 subjects out of 38.

» 3. What other points we need to consider [...]
Obviously you have a shorter Tmax with your formulation compared to the reference. Hence a higher Cmax, this is why you get
» Cmax is out of the boundary (96.56 -133.45)

If you remove all subjects with a shorter Cmax and only keep those with a longer Cmax, you will mask this potential difference... which is why regulators will not accept to remove those subjects.

The reason why the guideline asks to plan the sampling schedule in order to avoid first point Cmax is that Cmax is likely to be underestimated if it comes as the first point. In your case, even if underestimated it is higher than with the reference product. It would be even worse with a sample collected at 5 or 10 minutes.

There is no way out. Reformulate. Sorry...


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