Bioequivalence and Bioavailability Forum

Dear Ratnakar & Ohlbe,

❝ Also regarding the FDA guidance, I just wanted to highlight that as per FDA guideline data can be excluded if the vomiting occurs before two times median Tmax and very few references mention median Tmax.

@Ohlbe: I think you mixed up FDA’s Guidance and EMA’s draft GL. FDA’s states on early exposure:

We recommend that the partial area be truncated at the population median of Tmax values for the reference formulation.

And on vomiting:

We recommend that data from subjects who experience emesis during the course of a BE study for immediate-release products be deleted from statistical analysis if vomiting occurs at or before 2 times median Tmax. In the case of modified-release products, the data from subjects who experience emesis any time during the labeled dosing interval can be deleted.

Since in FDA’s terminology ‘population’ is always referring to subjects in a particular study, no reference is made to the label (median t_max, which is rarely – if ever – given).

EMA’s draft was confusing, since it stated about early exposure:

For products where rapid absorption is of importance, partial AUCs can be used as a measure of early exposure. The partial area can in most cases be truncated at the population median of t_max values for the reference formulation. However, an alternative time point for truncating the partial AUC can be used when clinically relevant. The time point for truncating the partial AUC should be pre-specified and justified in the study protocol.

Whilst the second sentence call for a truncation time obtained from study’s data, the third called for a prespecification (from the SmPC‽). The entire section was dropped in the final GL (see also the commentary document pp87-89).
When it comes to exclusion, it’s up to the applicant to specify limits in the protocol:

Examples of reasons to exclude the results from a subject in a particular period are events such as vomiting and diarrhoea which could render the plasma concentration-time profile unreliable. […] The permitted reasons for exclusion must be pre-specified in the protocol. If one of these events occurs it should be noted in the CRF as the study is being conducted. Exclusion of subjects based on these pre-specified criteria should be clearly described and listed in the study report.

In my studies for EMA I’m using FDA’s rules (IR: 2× t_max,ref, MR: τ) and never had any problems.

❝ Further I had discussed this issue with FDA and I got in writing from FDA that the median Tmax should be considered from the study (for that treatment) and not from the literature as the Tmax depend upon the time points in the study which may vary from study to study. I do have the letter from FDA regarding the same.

Yes, this is consistent with their guidance, IMHO.