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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", "descriptive")
)

Arguments

name

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

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, est_method ("anova" or "isc"), widen_like (for the expanding-limits frameworks, whether the endpoints judged like "cmax" or like "auc" widen), pe_only_like (those judged by the point estimate alone), reference (the source guidance, or NA), pe_constr, decision (FALSE only for "descriptive"), sw_ratio_cap, and switch_basis.

Details

The supported frameworks, the acceptance limits each applies to each endpoint, and their sources are:

  • ABE – average bioequivalence; the 90% confidence interval of the geometric mean ratio within 80.00-125.00% for Cmax and AUC, with no reference scaling (ICH M13A, section 2.2.4).

  • EMA – average bioequivalence with expanding limits (ABEL) for Cmax and the parameters judged like it (see below); AUC and the parameters judged like it keep the 90% confidence interval within 80.00-125.00% whatever their variability (EMA Guideline on the Investigation of Bioequivalence, Rev. 1, sections 4.1.8 and 4.1.10). Cmax limits widen when the within-reference coefficient of variation (CVwR) exceeds 30% (cvswitch = 0.30), as exp(+/- k * swR) with the regulatory constant k = 0.760, capped at CVwR = 50% (limits 69.84-143.19%), and the geometric mean ratio must lie within 80.00-125.00%. The constant is log(1.25) / sqrt(log(1 + 0.30^2)) rounded to three decimals. For modified-release products the EMA also allows the same widening for Cmax,ss, Ctau,ss, and partial AUCs (EMA Guideline on the Pharmacokinetic and Clinical Evaluation of Modified Release Dosage Forms, section 6.8.2.2). Cmax,ss and Ctau,ss are judged like Cmax; PKNCA cannot tell a partial AUC from AUC(0-tau) by its name, so name it in the widen_endpoints argument of be_assess().

  • HC – Health Canada. ABEL for AUC and the parameters judged like it: the 90% confidence interval within limits widened as exp(+/- 0.76 * swR) when swR > 0.294 (CVwR > 30%), capped at 66.7-150.0% (CVwR = 57.4%), with the ratio of geometric means within 80.0-125.0% (Policy on Bioequivalence Standards for Highly Variable Drug Products, effective 2018). Cmax, and the parameters judged like it, is judged by its point estimate alone: the ratio of geometric means within 80.0-125.0%, with no requirement on its confidence interval (Comparative Bioavailability Standards: Formulations Used for Systemic Effects, sections 2.1 and 2.1.1.1). Health Canada requires the relative mean Cmin at steady state to be at least 80.0%, with no upper limit; judged like Cmax, it must also be at most 125.0%. Health Canada no longer uses urinary data. These are the standards for drugs that are not critical dose drugs.

  • GCC – Gulf Cooperation Council; the EMA rules: ABEL for Cmax and the parameters judged like it, with k = 0.760, the 30% switch, the 69.84-143.19% cap, and the geometric mean ratio within 80.00-125.00%; AUC and the parameters judged like it keep 80.00-125.00% (GCC Guidelines for Bioequivalence, version 3.2, sections 3.1.8 and 3.1.10).

  • FDA – reference-scaled average bioequivalence (RSABE) for both AUC and Cmax (FDA Draft Guidance on Progesterone). The linearized (Howe/Hyslop) criterion uses r_const = log(1.25) / 0.25 = 0.8926 (theta = r_const^2) and switches from unscaled ABE (90% confidence interval within 80.00-125.00%) when swR >= 0.294 (CVwR of about 30%).

  • NTID – FDA narrow therapeutic index drugs, for both AUC and Cmax (FDA Draft Guidance on Warfarin Sodium): the scaled criterion with r_const = -log(0.9) / 0.1 = 1.0536 (always applied), the 90% confidence interval within 80.00-125.00%, and the upper 90% confidence bound of swT/swR at most 2.5 (a fully replicated design is required).

  • HVNTID – FDA highly variable narrow therapeutic index drugs, for both AUC and Cmax (FDA Draft Guidance on Dabigatran Etexilate Mesylate): unscaled, with the 90% confidence interval within 80.00-125.00% and the upper 90% confidence bound of swT/swR at most 2.5.

  • descriptive – no regulatory decision. The geometric means, their ratio, and its confidence interval are estimated exactly as for ABE, but no acceptance limits are applied and no pass/fail is reported. Use it for comparisons that are estimated rather than judged, such as food effect and drug-drug interaction studies.

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

The guidances name more parameters than Cmax and AUC and judge each like one of them. An endpoint is matched by its PKNCA parameter name or its CDISC PPTESTCD code (see pknca_cdisc_codes()). Judged like Cmax:

  • cmax: Cmax, and Cmax,ss at steady state (EMA section 4.1.8);

  • cmin and ctrough: Cmin,ss and Ctau,ss (EMA modified-release guideline section 6.8.2.2; Health Canada section 2.1.1.1);

  • ermax: Rmax, the maximal rate of urinary excretion, "analysed using the same acceptance interval as for Cmax" (EMA section 4.1.8; GCC section 3.1.8);

  • and their dose-normalized forms.

Judged like AUC:

  • the AUCs: auclast (AUC(0-t)), aucall, aucinf.obs and aucinf.pred (AUC(0-inf)), aucint.* (for example AUC(0-tau) at steady state and AUC(0-72h); EMA section 4.1.8, Health Canada section 2.1.1.4), the IV-extrapolated auciv*, and sparse_auclast;

  • cav*: the average concentration at steady state, AUC(0-tau)/tau;

  • ae: Ae(0-t), the amount excreted in urine, "analysed using the same acceptance interval as stated above for AUC(0-t)" (EMA section 4.1.8; GCC section 3.1.8), and fe, Ae as a fraction of the dose;

  • and their dose-normalized forms.

Other endpoints, such as tmax, use the 90% confidence interval within 80.00-125.00%. An endpoint that is neither a PKNCA parameter nor a CDISC code keeps 80.00-125.00% under the expanding-limits frameworks, with a warning, unless it is named in widen_endpoints.

References

International Council for Harmonisation. ICH M13A: Bioequivalence for immediate-release solid oral dosage forms. Step 4, 23 July 2024. https://database.ich.org/sites/default/files/ICH_M13A_Step4_Final_Guideline_2024_0723.pdf

European Medicines Agency. Guideline on the investigation of bioequivalence. CPMP/EWP/QWP/1401/98 Rev. 1/Corr**, 2010. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-bioequivalence-rev1_en.pdf

European Medicines Agency. Guideline on the pharmacokinetic and clinical evaluation of modified release dosage forms. EMA/CHMP/EWP/280/96 Rev1, 2014. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-pharmacokinetic-and-clinical-evaluation-modified-release-dosage-forms_en.pdf

Health Canada. Comparative bioavailability standards: Formulations used for systemic effects. Revised 8 June 2018, effective 1 September 2018. https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/bioavailability-bioequivalence/comparative-bioavailability-standards-formulations-used-systemic-effects.html

Health Canada. Notice: Policy on bioequivalence standards for highly variable drug products. Effective 1 September 2018. https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/announcements/notice-policy-bioequivalence-standards-highly-variable-drug-products.html

Gulf Cooperation Council. The GCC guidelines for bioequivalence. Version 3.2, 2024. https://sfda.gov.sa/sites/default/files/2024-05/GCC_Guidelines_Bioequivalence32.pdf

US Food and Drug Administration. Draft guidance on progesterone. 2011. https://www.accessdata.fda.gov/drugsatfda_docs/psg/Progesterone_caps_19781_RC02-11.pdf

US Food and Drug Administration. Draft guidance on warfarin sodium. 2012. https://www.accessdata.fda.gov/drugsatfda_docs/psg/Warfarin_Sodium_tab_09218_RC12-12.pdf

US Food and Drug Administration. Draft guidance on dabigatran etexilate mesylate. 2012, revised 2017. https://www.accessdata.fda.gov/drugsatfda_docs/psg/Dabigatran%20etexilate%20mesylate_oral%20capsule_NDA%20022512_RV05-17.pdf

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%
#>   Widened endpoints:  Cmax and the parameters judged like it
#>   PE constraint:      80.00-125.00%
#>   Point estimate:     anova
#>   Reference:          EMA Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1), sections 4.1.8 and 4.1.10
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
#>   Reference:          FDA Draft Guidance on Progesterone (2011)
be_regulator("descriptive")
#> Bioequivalence regulator: descriptive
#>   Scaling:            none
#>   PE constraint:      none
#>   Point estimate:     anova
#>   Decision:           none (descriptive; no acceptance limits or pass/fail)