What bioequivalence acceptance limits apply to narrow therapeutic index drugs?

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SFDA: “In specific cases of products with a narrow therapeutic index, the acceptance interval for AUC should be tightened to 90.00-111.11%. Where Cmax is of particular importance for safety, efficacy or drug level monitoring the 90.00-111.11% acceptance interval should also be applied for this parameter.” (SFDA BE v3.1 · 3.1.9 Narrow therapeutic index drugs) “It is not possible to define a set of criteria to categorize drugs as narrow therapeutic index drugs (NTIDs) and it must be decided case by case if an active substance is an NTID based on clinical considerations.” (SFDA BE v3.1 · 3.1.9 Narrow therapeutic index drugs) EU: “In specific cases of products with a narrow therapeutic index, the acceptance interval for AUC should be tightened to 90.00-111.11%. Where Cmax is of particular importance for safety, efficacy or drug level monitoring the 90.00-111.11% acceptance interval should also be applied for this parameter.” (EMA BE guideline · 4.1.9) “It is not possible to define a set of criteria to categorise drugs as narrow therapeutic index drugs (NTIDs) and it must be decided case by case if an active substance is an NTID based on clinical considerations.” (EMA BE guideline · 4.1.9) “It is, therefore, highlighted that the requirements of both ICH M13A and the existing EMA Guideline read in conjunction may be applicable to e.g., • BE studies with highly variable drugs (replicate design) • drugs with narrow therapeutic index, and • complex BE study designs and data analysis e.g., • adaptive design.” (EMA M13A implementation · Implementation) US FDA: “NTI drugs are those drugs where small differences in dose or blood concentration may lead to serious therapeutic failures and/or adverse drug reactions that are life-threatening or result in persistent or significant disability or incapacity.  For NTI drugs, a fully replicate crossover design should be used.  The statistical analysis should be carried out using both the average BE and the reference-scaled average BE tests for both AUC and Cmax.” (FDA Statistical Approaches 2026 · III.B) “NTI BE studies should pass both the reference-scaled average BE criteria and the unscaled average BE limits of 80.00 percent to 125.00 percent.” (FDA Statistical Approaches 2026 · III.B) “In addition, the test/reference ratio of the within-subject standard deviation should be evaluated.  The within-subject variability comparison of T and R is carried out by a one-sided F test.” (FDA Statistical Approaches 2026 · III.B) WHO: “If the API is determined to possess a narrow therapeutic index, the bioequivalence acceptance range should be restricted to 90.00–111.11%.” (WHO TRS 1052 Annex 8 · 7.7 — AUC0–t ratio) “If the API is determined to possess a narrow therapeutic index, the bioequivalence acceptance range may need to be restricted to 90.00–111.11%, if appropriate.” (WHO TRS 1052 Annex 8 · 7.7 — Cmax ratio)

What bioequivalence acceptance limits apply to narrow therapeutic index drugs?

SFDA Saudi Food and Drug Authority

EU European Union

US FDA US Food and Drug Administration

WHO World Health Organization

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