Bioequivalence and Bioavailability Forum

Hi everyone,

I have a question about BE study design for an inhaled product planned for EMA submission.

With EMA OIP Guideline Revision 2 coming into effect yesterday (1 February 2026), truncated AUC is mentioned as an acceptable option for drugs with a long terminal half-life.

In our case, the drug has a very long half-life, but in practice, plasma concentrations are not measurable beyond 48–72 hours (sometimes even less than 24 hours), although the LLOQ is below 5% of Cmax for all subjects.

According to the guideline, the sampling schedule should allow AUC₀–t to cover at least 80% of AUC₀–∞. If justified, a truncated AUC can be used instead for drugs with long half-life.

This creates a practical issue in the study design:

If we plan a truncated design (for example AUC₀–72h), many subjects may have BLQ samples before 72 hours, leading to missing AUC₀–72h data.

If we extend sampling to cover about 3 half-lives to meet the AUC₀–t / AUC₀–∞ ≥80% rule, concentrations will still be BLQ at late time points, and many subjects may not meet this criterion.

In this situation, what would be more appropriate for EMA?

Should we extend sampling to theoretically cover 3 half-lives even if late samples are mostly BLQ?

Or should we predefine a truncated AUC window (e.g., AUC₀–72h) and avoid relying on AUC₀–t and AUC₀–∞?

Thanks in advance