Bioequivalence and Bioavailability Forum

Hi Bharathi,

❝ Fed study was completed with 2 groups […] Analysis was done and proved to be bioequivalent.

❝

❝ In fasting study, only group 1 is completed and there's no time for the group 2 to be completed.

What do you mean by “there's no time”? I wouldn’t call that a reasonable justification.

❝ So can I analyze and if it is bioequivalent, will Agency accepts by proposal (deviation from the protocol that group 2 was not performed?)

Depends on the Agency. You are aware that your power (i.e., chance to demonstrate BE in only ½ of the planned sample size) will substantially drop?
Example: CV_total 20%, GMR 0.95, n_planned 36, power 81.0% ⇒ n_actual 18, power 42.7%.
OK, the patient’s risk is not affected (and this is the regulator’s main concern) – but with such a low power you are playing havoc with the producer’s risk. What does the sponsor say? Even if you pass – a posteriori power is nonsense, but well, cough… Likely you will have to face questions from some regulators.
I would expect that the chance of the study to fail is higher than to pass. Then what? You cannot post hoc switch to a Two-Stage Design. Repeat the study once you “have more time”? Remember you are treating human beings (patients?), not guinea pigs.

The only option I see is not to perform the assessment of BE of the first group. Submit a substantial amendment to the agency + IEC stating that you will perform a Two-Stage Design*. Hope for the best (there is no guarantee whether they will swallow your justification). If you get the approvals, perform the analysis of group 1 and continue according to the decision tree of the framework. Be aware that it is very likely that a second group is required (low power in the first group expected), which – in the worst case – might lead to a total sample size substantially larger compared to the one you originally planned for. Good luck!

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• Fuglsang A. Sequential Bioequivalence Approaches for Parallel Designs. AAPS J. 2014;16(3):373–8. doi 10.1208/s12248-014-9571-1