Bioequivalence and Bioavailability Forum

Dear Sir
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You can use the following design


1 B-A-C-D-A-C

2 A-D-B-C-C-A

3 D-C-A-A-B-C

4 C-A-D-C-A-B

5 A-C-C-B-D-A

6 C-B-A-A-C-D


SABE for fast and food accepted by FDA

Six period with six sequences

B= Test under fast

A= Ref under fast

D= Test under fed

C= Ref under fed

Dear Sereng,

From my understanding, this is not a replicate study. 4-ways is not always a replicate. There can be 4 periods but with 4 different formulations, or in different administration conditions, and in those cases it would not be a "full replicate". In your case, according to my humble opinion it is not a "full replicate" since they are administered in different conditions (fast VS fed). In your case, I think it would be more accurate to call it "4-ways food effects". At least in our own previous experiences, this is the way we have approached it.

Best regards,

Hi Sereng,

❝ … my associate is using the term "full replicate" to describe a four-way crossover BE study of Test (Fed), Test (Fasted), Reference (Fed) and Reference (Fasted), with each treatment given only once. In my view, this is not an appropriate us of the term "full replicate" but I want to be certain.

You are right. For some of the designs see the vignette of the R package replicateBE.
For the named food-interaction study you have three options. Primarily you are interested to demonstrate BE in fasted and fed state. The assessment of food effects of test and reference is just ‘nice to know’.

1. Two separate 2×2×2 studies AB|BA and CD|DC, where A = T_fed, B = R_fed, C = T_fasting, D = R_fasting. Esp. for controlled release products BE in fed state is more difficult due to potentially different food effects of T and R. Hence, I suggest to perform this study first.
   
2. A higher-order crossover in a Williams’s design. You can use any of the six designs ADBC|BACD|CBDA|DCAB, ADCB|BCDA|CABD|DBAC, ACDB|BDCA|CBAD|DABC, ACBD|BADC|CDAB|DBCA, ABDC|BCAD|CDBA|DACB, or ABCD|BDAC|CADB|DCBA. What you must not use is the Latin Square ABCD|BCDA|CDAB|DABC. Only from a Williams’ design you can extract balanced pairwise comparisons (see there).
   
3. Like #1 but in the same subjects and the second following immediately after the first. Essentially it’s one study with two parts.

#1 is most simple and allows to perform both studies in either fixed-sample or adaptive two stage designs. However, assessment of food effects is done in parallel groups and therefore, has low power.
Whilst #2 is popular, there are drawbacks. If variabilities in fasted and fed state are different (commonly fed > fasted), you have to base the sample size on the worst case.
#3 is for the courageous ones (though all of my studies were accepted by European agencies ). Both parts (fed and fasting) are TSDs like in #1. You start with a best guess sample size for the condition with lower variability. Food effects can by assessed as paired comparisons (assuming identical period effects), which is much more powerful than the parallel comparison in #1.

❝ Additionally, what is the appropriate term, "Full Replicate" or "Fully Replicate"?

You can either say “full replicate design” or “fully replicated design”. In the former term you use an adjective and in the latter adverbs.