Bioequivalence and Bioavailability Forum

Dear all,

in a recently published book* I found an interesting case study. Formulation change of the innovator (mesalamine: DR tablet ⇒ DR capsule). PK endpoints C_max, AUC_0–t, AUC_8–48. Fully replicated 4-period study, 238 (‼) completers, study passed RSABE:

PK metric   sWR     PE   95% UCL
Cmax        1.231  1.11  -1.030
AUC0–t      1.439  1.10  -1.265
AUC8–48     1.360  1.08  -1.608

CVs were for C_max (R 200%, T 170%), AUC_t (R 306%, T 272%), and AUC_8-48 (R 286%, T 268%). I guess the originator was well aware about the GMRs in designing the study. For GMR 1.10, CV 300%, and a target power of 90% I got:

++++++++ Reference scaled ABE crit. +++++++++
           Sample size estimation
---------------------------------------------
Study design:  2x2x4 (full replicate)
log-transformed data (multiplicative model)
1e+05 studies for each step simulated.

alpha  = 0.05, target power = 0.9
CVw(T) = 3; CVw(R) = 3
Null (true) ratio = 1.1
ABE limits / PE constraints = 0.8 ... 1.25
Regulatory settings: FDA

Sample size
 n    power
234   0.90046

Quote:

[…] although the RSABE was implemented to promote development of generic HV drugs by easing regulatory burdens, this was the first time that the approach was successfully used to support major post-approval reformulation of an innovator’s MR drug product.

Note that in the EU scaling is acceptable only for C_max. Good luck with ABE for the AUCs.

+++++++++++ Equivalence test - TOST +++++++++++
            Sample size estimation
-----------------------------------------------
Study design:  2x2x4 replicate crossover
log-transformed data (multiplicative model)

alpha = 0.05, target power = 0.9
BE margins        = 0.8 ... 1.25
Null (true) ratio = 1.1,  CV = 3

Sample size (total)
 n     power
1208   0.900182

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• Davit BM, Patel DT. Bioequivalence of Highly Variable Drugs. In: Yu LX, Li BV (eds), FDA Bioequivalence Standards. New York: aapspress/Springer; 2014. p. 139–64. doi 10.1007/978-1-4939-1252-0