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Regulatory framework constants for bioequivalence assessment

Source: R/bioequivalence.R
be_regulator.Rd

be_regulator() returns the scaling type, switching and capping rules, and regulatory constants that define a bioequivalence (BE) assessment framework. It is the single source of truth for these values: be_assess() and the internal decision functions pull every constant from here rather than hard-coding it.

Usage

be_regulator(name = c("ABE", "EMA", "HC", "GCC", "FDA", "NTID", "HVNTID"))

Arguments

name

The regulatory framework, one of "ABE", "EMA", "HC", "GCC", "FDA", "NTID", or "HVNTID".

Value

An object of class be_regulator: a list with elements name, scaling (one of "none", "abel", "rsabe", "ntid", "hvntid"), cvswitch, r_const, cvcap, switch_swr, pe_constr, est_method ("anova" or "isc"), and switch_basis.

Details

The supported frameworks and their constants are:

  • ABE – average bioequivalence; the universal unscaled criterion that the 90% confidence interval fall within 80.00-125.00%. No reference scaling.

  • EMA – average bioequivalence with expanding limits (ABEL). Scaling begins when the within-reference coefficient of variation (CVwR) exceeds 30% (cvswitch = 0.30); the limits widen as exp(+/- k * swR) with the regulatory constant k = 0.76 and the expansion is capped at CVwR = 50% (limits 69.84-143.19%). The constant 0.76 is log(1.25) / sqrt(log(1 + 0.30^2)) rounded to two decimals, as fixed by the EMA bioequivalence guideline.

  • HC – Health Canada; ABEL with the same k = 0.76 but the expansion is capped at CVwR = 57.382% (upper limit 150%).

  • GCC – Gulf Cooperation Council; fixed widened limits of 75.00-133.33% whenever CVwR > 30% (not CV-dependent).

  • FDA – reference-scaled average bioequivalence (RSABE). The linearized (Howe/Hyslop) criterion uses r_const = log(1.25) / 0.25 = 0.8926 (theta = r_const^2) and switches from unscaled ABE when swR >= 0.294 (CVwR of about 30%).

  • NTID – FDA narrow therapeutic index drugs; uses r_const = -log(0.9) / 0.1 = 1.0536 and always applies the scaled criterion (a fully replicated design is required).

  • HVNTID – FDA highly variable narrow therapeutic index drugs; the RSABE-style scaled criterion with the NTID constant and the within-subject standard deviation ratio constraint.

All frameworks additionally impose the point-estimate constraint that the geometric mean ratio fall within 80.00-125.00%.

See also

be_expand_limits() for the ABEL acceptance limits and be_assess() for the full assessment.

Other Bioequivalence: be_assess(), be_compare(), be_dataset(), be_design(), be_expand_limits(), be_extract_param(), be_fit_model_single(), be_fit_models(), be_table(), be_within_var()

Examples

be_regulator("EMA")
#> Bioequivalence regulator: EMA
#>   Scaling:            abel
#>   CV switch:          30%
#>   Regulatory const.:  0.76
#>   CV cap:             50%
#>   PE constraint:      80.00-125.00%
#>   Point estimate:     anova
be_regulator("FDA")
#> Bioequivalence regulator: FDA
#>   Scaling:            rsabe
#>   CV switch:          30%
#>   swR switch:         0.294
#>   Regulatory const.:  0.8925742
#>   PE constraint:      80.00-125.00%
#>   Point estimate:     isc