Is Cmax 95% Upper bound 0.0024 = Zero? [RSABE / ABEL]

posted by Sereng  – USA, 2020-10-22 18:30 (35 d 19:17 ago) – Posting: # 22047
Views: 479

Dear colleagues, Quadra therapeutics is a virtual non-profit (501(c)(3)) pharmaceutical company. To support a Prior Approval Supplement for a change in formulation, we had to undertake three bioequivalence studies for a multisource products as there are several NDA's approved with different therapeutic equivalence AB codes. For two of the studies, we met the bioequivalence criteria for AUC and Cmax. For the third study, we met the bioequivalence criteria for AUC. However, for Cmax, the scaled ABE for was LCmax 95% Upper bound 0.0024.

There do not appear to be any specific FDA guidance expressly stating the number of significant figures required in the non-zero calculations for RSABE. In the FDA Draft Guidance, Bioavailability and Bioequivalence Studies for Orally Administered Drug Products – General Considerations (July 2002), I did find the following language. "If the study estimate of standard deviation is 0Tσ≤, the constant-scaled criterion and its associated confidence interval should be computed. Otherwise, the reference-scaled criterion and its confidence interval should be computed. If the upper confidence bound for the appropriate criterion is negative or zero, conclude population BE. If the upper bound is positive, do not conclude population BE."

This is uncharted territory for us. is there any precedence for this? Should we truncate our results to 0.00? Can we conclude BE in our study report? If we can conclude BE, should we truncate the Cmax value to 0.00? Any help would be appreciated.

Edit: Please don’t shout[Helmut]

Najib Babul, PharmD, MBA
Quadra Therapeutics, LLC

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