Bioequivalence and Bioavailability Forum

Dear all
"In general, a bioequivalence study should be conducted under fasting conditions as this is considered to be the most sensitive condition to detect a potential difference between formulations." (CPMP/QWP/EWP/1401/98 Rev. 1). The drug under discussion can not be administered in the fasted state due to gastro-intestinal complications. The SmPC does not contain any information about the composition of a meal to be taken. When given with a high-fat meal, the rate of absorption of the drug under discussion was reduced (11% decrease in Cmax and prolongation of tmax by 1.5 h), with a reduction in AUC (7.4%) compared to fasting conditions. The Q&A document points out that: "The composition of the meal should be described and taken into account, since a light meal might sometimes be preferable to mimic clinical conditions, especially when the fed state is expected to be less sensitive to differences in pharmacokinetics."
We performed a BE study: two-way cross-over single dose after administration of a light meal in 28 subjects. The results show perfect bioequivalence, low inter-subject (ca. 25%) and low intra-subject (>10%) variability.
At time of clinical conduct the old Guideline CPMP/QWP/EWP/1401/98 with the respective Q&A document EMEA/CHMP/EWP/40326/2006 was effective. The study was performed in accordance with these guidelines. At time of clinical conduct the revision of above mentioned guideline was plannned and a draft version already existed. The study was also performed in accordance with this draft guideline. Only after clinical conduct the revised version of Guideline CPMP/QWP/EWP/1401/98 Rev. 1 was published. In fact now a high-fat and high-calorie meal is demanded.
Therefore we performed a second BE study: two-way cross-over single dose after administration of a high-fat and high-calorie meal in 18 subjects. The results show again perfect bioequivalence with nearly exact the same results, approximately the same low inter-subject and low intra-subject variability.
The studies were performed by the same CRO with the same test and reference batches.
Now my question: Would it be possible to evaluate both studies together to show retrospectively that (at least in case of the drug under discussion) the demand for a high-fat and high-calorie meal is unnecessary (as I predicted a priori)? Could I use an inbalanced parallel design approach?
I am looking forward to your replies.
Kind regards
Dan