Bioequivalence and Bioavailability Forum

Dear Andrew!

❝ At present all our BE protocols stick with the old guideline and require non-parametric assessment of Tmax.

Even according to the current guideline assessment of t_max was mandatory only if

• either a clinical claim was made (e.g., rapid onset like for some analgetics),
  
• or based on safety grounds (e.g., IR nifedipine).

Therefore t_max should only be reported in the majority of cases - not compared and assessed for BE.

❝ I can foresee a time in 2 years when we'll have to repeat part of every analysis to provide parametric results.

Theoretically it should be evident to any regulator that the study was performed according to the current NfG on BA/BE and the Q&A-document. We have no time machine at our disposal for planing our studies - so they should this take into account…
In my experience it will be almost impossible to show BE retrospectively by the partial AUC method proposed in the drafted guideline. The intrasubject-variability of this metric is just scary. I worked like a Trojan at the recent EUFEPS workshop to convince the PK group that it simply doesn’t make sense. Kamal Midha showed nice slides, there are papers published on the topic,… But: If we don’t like it, we have to send comments to EMEA. The clock is ticking. Deadline is this Saturday, 11:59 p.m.

❝ Are you sure that this aspect of the new guideline will stick?

You never can be sure...
I’ll give you my personal impressions. I guess there are two reasons why the drafted guideline suggested a switch from nonparametric testing of t_max to parametric testing of partial AUC truncated at median t_max of the reference.

• “Harmonization” with the FDA and Canada (you may also read this as copy-and-paste).
  
• A deep dislike of nonparametrics by UK’s statisticians.