Bioequivalence and Bioavailability Forum

Hi Yura,

since Belarus as a member of the EAEU (which in its GL closely followed the EMA’s rules for reference-scaling by Average Bioquivalence with Expanding Limits – ABEL), according “to the book” no adjustment of α is required (i.e., 90% CI of T vs. R).
However, when you suspect multiplicity issues – which might lead to an inflation of the Type I Error – you are right (Labes and Schütz¹, Muñoz et al.², Wonnemann et al.³)! Adjusting α in such a way that the consumer risk is preserved at 0.05 is provided in the open-source package PowerTOST, function scABEL.ad().
No adjustment of α is required for PK metrics assessed by (conventional unscaled) ABE (like AUC). Adjustment for PK metrics intended for reference-scaling (like C_max) depends on the CV_wR and – to a minor degree – on the sample size. I would not recommend Bon­ferroni’s correction (i.e., α 0.025) because generally it is unnecessarily conservative and negatively impacts power. BTW, in rare cases (extremely high sample sizes) you would have to go below 0.025…

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1. Labes D, Schütz H. Inflation of Type I Error in the Evaluation of Scaled Average Bioequivalence, and a Method for its Control. Pharm Res. 2016;33(11):2805–14. doi:10.1007/s11095-016-2006-1. full-text view-only.
   
2. Muñoz J, Alcaide D, Ocaña J. Consumer's risk in the EMA and FDA regulatory approaches for bioequivalence in highly variable drugs. Stat Med. 2016;35(12):1933–43. doi:10.1002/sim.6834.
   
3. Wonnemann M, Frömke C, Koch A. Inflation of the Type I Error: Investigations on Regulatory Recommendations for Bioequivalence of Highly Variable Drugs. Pharm Res. 2015;32(1):135–43. doi:10.1007/s11095-014-1450-z.