Description Usage Arguments Details Value Note Author(s) References See Also Examples
The (widened) scaled BE acceptance limits are calculated according to the regulatory settings of EMA, HC, FDA or via user defined regulatory settings.
1  scABEL(CV, regulator)

CV 
Coefficient of variation (of the Reference) as ratio. 
regulator 
Regulatory body settings for the widening of the BE acceptance limits. 
The widened BE acceptance limits are calculated by the formula
[L, U] = exp(/+ r_const * sWR)
with r_const
the regulatory constant and sWR
the standard deviation of the within
subjects variability of the Reference.
regulator="EMA"
or regulator="HC"
r_const = 0.76
(~ log(1.25)/sqrt(log(0.30^2+1)))
regulator="GCC"
r_const = 0.97997...
(= log(1/0.75)/sqrt(log(0.30^2+1)))
regulator="FDA"
r_const = 0.89257...
(= log(1.25)/0.25)
If the CVwR of the Reference is < CVswitch=0.3 the conventional ABE limits
apply (mixed procedure).
In case of regulator="EMA"
a cap is placed on the widened limits if
CVwR>0.5, i.e., the widened limits are held at the value calculated for CVwR=0.5.
In case of regulator="HC"
the capping is done such that the acceptance
limits are 0.6666 ... 1.5 at maximum, i.e., CVcap=0.57382.
Literally it is given by Health Canada rounded to three significant digits as 57.4%.
Returns a vector of lenghth 2 if one CV is given or a matrix if CV is given as vector
with named components lower
and upper
of the scaled acceptance limits.
The scaled acceptance limits (coined ‘implied limits’ by Davit et al.) are not directly used in the BE evaluation for HVDP(s) recommended by the FDA. They are included here for comparative purposes. Moreover, there are controversies where to locate the ‘implied limits’ and whether the socalled ‘desired consumerrisk model’ should be used.
D. Labes
Davit BM, Chen ML, Conner DP, Haidar SH, Kim S, Lee CH, Lionberger RA, Makhlouf FT, Nwakama PE, Patel DT, Schuirmann DJ, Yu LX. Implementation of a ReferenceScaled Average Bioequivalence Approach for Highly Variable Generic Drug Products by the US Food and Drug Administration. AAPS J. 2012;14(4):915–24. doi: 10.1208/s122480129406x
Health Canada, Therapeutic Products Directorate. Guidance Document. Comparative Bioavailability Standards: Formulations Used for Systemic Effects. 2018/06/08. ISBN: 9780660255149
power.scABEL, sampleN.scABEL, reg_const
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33  scABEL(CV = 0.3, regulator = "EMA")
# should give the conventional (unscaled) BE limits:
# lower upper
# 0.80 1.25
scABEL(CV = 0.5, regulator = "EMA")
# should give the (maximum) expanded limits:
# lower upper
# 0.6983678 1.4319102
# define old ANVISA settings via reg_const()
rc < reg_const("USER", r_const = 0.76,
CVswitch = 0.4, CVcap = 0.5)
rc$name < "ANVISAold"
scABEL(CV = 0.4, regulator = rc)
# should give the conventional (not expanded) limits:
# lower upper
# 0.80 1.25
scABEL(CV = 0.55, regulator = "HC")
# should give the widened limits:
# lower upper
# 0.6765789 1.4780241
scABEL(CV = 0.55, regulator = "GCC")
# should give the widened limits:
# lower upper
# 0.750000 1.333333
scABEL(CV = 0.55, regulator = "FDA")
# should give the 'implied' limits:
# lower upper
# 0.6320032 1.5822705

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