Bioequivalence and Bioavailability Forum

Dear all,

we plan to perform a pilot study as 4-period BE study fed/fasting conditions.

Some issues were discusssed in:
http://forum.bebac.at/mix_entry.php?id=3820#p3820

Approach 1:
Williams Design as 4x4, 4 Sequences
- Rfe Rfa Tfa Tfe
- Tfa Rfe Tfe Rfa
- Tfe Tfa Rfa Rfe
- Rfa Tfe Tfe Tfa

T vs. R (BE): Statistical Data evaluation (ANOVA + CI) will be done separately for each conditions without the data of the other condition.
fed vs. fast (Food effect): Statistical Data evaluation (ANOVA + CI) will be done separately for each formulation withour the data of the other formulation.

pros:
- balanced design

cons:
- statistical data evaluation using only 50 % of the whole data, the influence (effects, ...) of the other 50 % of the data is lost.

Approach 2:
2x2-Design for feating conditions in Periode 1 and 2, 2x2-Design for fed conditions in Periode 1 and 2 leads to 2 sequences
- Rfa Tfa Rfe Tfe
- Tfa Rfa Tfe Rfe

T vs. R (BE): Statistical Data evaluation (ANOVA + CI) will be performed as 2x2x2-Design for each condition.
fed vs. fast: Statistical Data evaluation (ANOVA + CI) will be done separately for each formulation without the data of the other formulation.
fed vs. fast (Food effect): Statistical Data evaluation (ANOVA + CI) will be done separately for each condition withour the data of the other condition without the factor period in the ANOVA.

pros:
- 2x2-Design for each condition

cons:
- period effect could not be captured in food effect analysis

Because the pivotal studies will be perfomed in two seperate 2x2-crossover studies, one under fasting and one under fed conditions, Approach 2 would be the best for our purpose.

In the current EMA-Guideline is stated, it is acceptable to conduct either two seperate 2x2-crossover studies or a four way crosssover study. My question is, which approach is the best for a 4x4-Pivotal study in your oppinion?

Thank you in advance for your answers.

Best regards.

beman