## What is the purpose? [Design Issues]

Hi M.tareq,

» […] performing stat analysis of a 4 period 4 seq 3 treatment partial replicate Cross over study, where the ref product only replicate against t1 and t2 for a bioequivlence study of sofosbuvir?

Can you give us an example how the sequences would look like? What is the purpose of having two Test-products in the study? See also this post and followings.

» The FDA recommendation is for full replicate…

No it isn’t. The FDA recommends two conventional 2×2×2 studies (fasting and fed state).

According to the WHO’s PQTm the reference in fed state is a HVDP (Cmax CVwR 54%) whilst variability of AUC is low (CVwR 10%). In the WHO’s guidance reference-scaling for Cmax according to the EMA’s method is mentioned as an alternative.

» …and there are little information found regarding a 4 period Cross over with partial replication?

I have never heard about such a design.

» What other effects to account for beside the usual fixed effects in traditional 2x2 Cross over?

No idea.

» Within subject effect, within formulation variability, and carry over effect?

The sequence effect is confounded with
• the carry-over effect, and
• the formulation-by-period interaction.
A statistically significant sequence effect could indicate that there is
• a true sequence effect,
• a true carry-over effect,
• a true formulation-by-period interaction, or
• a failure of randomization.
It cannot be handled statistically but only avoided by design (sufficient wash-out). Including carry-over in cross-overs does not make sense.

» Newbie in stat...

You mentioned Sas proc mixed in the subject line. If you want to apply the EMA’s ABEL, a mixed-effects model is not acceptable. If you want to apply the FDA’s RSABE, the partial replicate for the unscaled PK metric (AUC) may fail to converge. Specify the covariance structure with TYPE=FA0(1) instead of TYPE=FA0(2) as given in the progesterone guidance.

Dif-tor heh smusma 🖖
Helmut Schütz

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