Bioequivalence and Bioavailability Forum

Hi Felipe,

❝ Since the drug is a HVD:

❝ Their reccomendation is to use a 3-sequence 3-period or a 2-sequence 4 period design.

❝

❝ Could anybody explain the main differences between them and when should I use each one? Go easy, I'm not a biostatistician

When you do a replicated study for the purpose of proving BE by means of reference scaling it is of primary interest to you to have two administrations on Ref. and one administration of Test within each subjects.
Thus it isn't necessary to have two administrations of Test within each subject. Therefore I would personally prefer a 3-period, 3-sequence study. That designs is also lighter on the subjects - they undergo treatment (exposure) only in three periods and not four and that is arguably an ethical advantage.

I'll say this a little differently (principle applies to both the EU and US version, although there are subtle other difference in how it works under the hood, especially since the CI is implicit in the US). The three period design gives you:

1. The treatment effects of Test and Ref. You use this to derive the point estimate.
   
2. The variability of the point estimate. This determines the width of your CI.
   
3. The within-subject variability associated with the reference product. This one determines the acceptance range for the confidence interval.
   The four-period design gives you all of the above plus
   
4. The within-subject variability for the Test product. No-one asks for this and to the best of my knowledge there is no way to use that estimate towards proving BE.