5% Cmax-rule only in SD [Study As­sess­ment]

posted by Helmut Homepage – Vienna, Austria, 2019-03-31 12:52 (603 d 06:08 ago) – Posting: # 20107
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Hi Hiren,

please see this post (#3 and #5). Without knowing the regulation you are bound to and more details about the study we are fishing in the dark.

» We did a multiple dose (5 weeks, 1 TDS patch every week) bioequivalence study. The BE was assessed at week 5 at steady state. It was a 3-period study. In period 2 and 3, we observed some carry-over from the previous period treatments. I remember, the 5% of Cmax rule for single-dose studies.

Correct (EMA, FDA). Equal carry-over does not bias the estimated treatment effect, whereas unequal carry-over will (to an unknown degree). Since no statistical method exists to correct the later, it has to be avoided by design (in SD sufficiently long washout or – in the case of steady state / switch-over – washout from one treatment overlapping built-up of steady state of the other).

» But, can someone please throw some light on how to handle this carry-over in multiple dose steady state studies?

Since you mentioned steady state, I assume relevant accumulation (otherwise, f.i. according to the EMA’s GL the multiple dose study can be waived). By definition (superposition principle of linear PK) you will observe residual concentrations from earlier doses. Hence, the exclusion-rule does not make any sense. I hope you didn’t state it in the protocol.

» Does the carry-over in week 1 pre-dose really impact week 5 steady state parameters?

Don’t understand what you mean.

@Nirali: Why should that matter?

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