Bioequivalence and Bioavailability Forum

Dear Dan!

❝ […] I would suggest to do two studies:

❝ Fasting: two way cross-over study

❝ Fed: replicate study

Right (that’s a ‘need to know’).* But EMA is interested in the comparison of T_fed vs. T_fasted and R_fed vs. R_fasted as well (that’s the ‘nice to know’ part).* If you run two 2×2 studies you can perform such a comparison only between these studies - which is lacking power.
Therefore EMA stated in the draft GL:

In cases where information is required in both the fed and fasted states, it is preferable to conduct a four-period single dose crossover design study (both products fed and fasted) rather than conducting two separate bioequivalence studies in fed and fasted state, respectively. In a four-period crossover design study, the food effect on test and reference product can be evaluated which is not the case when conducting two separate two-period, two-sequence single dose crossover design studies under fasting and fed conditions, respectively. In addition to the bioequivalence evaluation of test/reference in fasting and in fed state, the food effect can be presented for test and reference, i.e. the ratio food/fasting and 90% confidence interval for test and reference, respectively.

(my emphases) Of course the text in red in nonsense – such a comparison is just based on a parallel design. If the usual precautions (polymorphism, etc.) are followed in designing these studies, unbiased estimates and CIs may be obtained.

Following comments (p. 78-83) on the draft this paragraph was simplified; the final GL states only:

In cases where information is required in both the fed and fasted states, it is acceptable to conduct either two separate two-way cross-over studies or a four-way cross-over study.

(my emphases)

---

• These terms where extensively discussed at the BioInternational Conference 1994 in Munich and are used ever since in that context.