Bioequivalence and Bioavailability Forum

Hi NK,

❝ In our BE study, We observed C_max at 0.25 hours (15 minutes) which is our first post dose time point.

❝ Do we need to exclude those subjects with C_max at 15 min for statistical analysis?

According to the FDA’s guidance of August 2012 you quoted, yes. Note that the first paragraph of “Section V.C.” states:

The first point of a concentration-time curve in a BE study, based on blood or plasma measurements, is sometimes the highest point, which raises questions of bias in the estimation of C_max because of insufficient early sampling times. A carefully conducted pilot study can enable an applicant to avoid this problem.

Did you perform a pilot study or were you fishing in the dark? With a pilot study you would have an argument.
You may provide the complete data as a sensitivity analysis, though I strongly doubt that the FDA will give much – if any – weight to it, especially without a pilot where no first point C_max was observed.

The ICH M13A is only a little bit more permissive in “Section 2.1.8.1”.

The sampling schedule should include frequent sampling around the anticipated t_max to provide a reliable estimate of C_max. In particular, the occurrence of C_max at the first post-dose sampling time point should be avoided by careful consideration of the known PK properties of the drug and selection of a suitable early sampling schedule. For example, for drug products with rapid absorption, collection of blood samples at an early time point, between 5 and 15 minutes after dosing, followed by additional sample collections, e.g., two to five samples in the first hour after dosing, is usually sufficient to assess peak drug concentrations. When absorption is rapid, time points earlier than 5 minutes are generally not expected.
For subjects where C_max occurs at the first post-dose sampling time, the actual C_max may have been missed as it could have occurred at an earlier time point. When this occurs, the robustness of the study results in relation to the potential missed C_max should be discussed. This could include additional analysis where data from the affected subjects are removed from the analysis.

In other words, it is the other way around than for the FDA. Keep the subject(s) in the primary analysis and exclude them in a sensitivity analysis.

❝ To avoid exclusion of subject for statistical analysis, do we need to keep first point "at 15 minutes" or "between 5 and 15 minutes eg. 10 minutes"?

What do you mean by that? You wrote that

❝ … (15 minutes) which is our first post dose time point.

❝ Is it applicable for modified Release product also?

For the FDA, yes. ICH M13A deals only with IR products. However, a first point C_max at 15 minutes is unlikely for MR products.