How are bioequivalence acceptance limits widened for highly variable drugs?

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SFDA: “Highly variable drug products (HVDP) are those whose intra-subject variability for a parameter is larger than 30%. If an applicant suspects that a drug product can be considered as highly variable in its rate and/or extent of absorption, a replicate cross-over design study can be carried out.” (SFDA BE v3.1 · 3.1.10 Highly variable drugs or drug products) “Those HVDP for which a wider difference in Cmax is considered clinically irrelevant based on a sound clinical justification can be assessed with a widened acceptance range. If this is the case the acceptance criteria for Cmax can be widened to a maximum of 69.84 – 143.19%. For the acceptance interval to be widened the bioequivalence study must be of a replicate design where it has been demonstrated that the within-subject variability for Cmax of the reference compound in the study is >30%.” (SFDA BE v3.1 · 3.1.10 Highly variable drugs or drug products) “The geometric mean ratio (GMR) should lie within the conventional acceptance range 80.00-125.00%. The possibility to widen the acceptance criteria based on high intra-subject variability does not apply to AUC where the acceptance range should remain at 80.00 – 125.00% regardless of variability.” (SFDA BE v3.1 · 3.1.10 Highly variable drugs or drug products) EU: “Those HVDP for which a wider difference in Cmax is considered clinically irrelevant based on a sound clinical justification can be assessed with a widened acceptance range. If this is the case the acceptance criteria for Cmax can be widened to a maximum of 69.84 – 143.19%. For the acceptance interval to be widened the bioequivalence study must be of a replicate design where it has been demonstrated that the within-subject variability for Cmax of the reference compound in the study is >30%.” (EMA BE guideline · 4.1.10) “The geometric mean ratio (GMR) should lie within the conventional acceptance range 80.00-125.00%. The possibility to widen the acceptance criteria based on high intra-subject variability does not apply to AUC where the acceptance range should remain at 80.00 – 125.00% regardless of variability.” (EMA BE guideline · 4.1.10) “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: “Highly variable drugs are drugs for which within subject variability (%CV) in BE measures 30 percent or greater and that are not considered NTI drugs.  In order to use the reference-scaled average BE approach for highly variable drugs, a partial or fully replicate crossover design should be used.  The statistical analysis should be carried out using the mixed scaling approach below for both AUC and Cmax.” (FDA Statistical Approaches 2026 · III.C) “If the estimated within-subject standard deviation of the reference is < 0.294, the average BE two one-sided test procedure should be used to determine BE for the individual PK parameter.  Otherwise, the reference-scaled average BE procedure should be used to determine BE for the individual PK parameter together with a point estimate constraint for the estimated test/reference geometric mean ratio, which should be bounded by 80.00 percent to 125.00 percent.” (FDA Statistical Approaches 2026 · III.C) “A replicate design is advantageous over a nonreplicate design for non-narrow therapeutic index (NTI) drugs with a high intrasubject variability.  Either a partial or fully replicate design may be used, but a reference-scaled BE analysis approach should only be applied to specific PK metrics that exhibit a high within-subject variability for the reference standard in the pivotal BE study.” (FDA ANDA BE 2026 · III.A.4) WHO: “A “highly variable API” has been defined as an API with an intrasubject variability of > 30% in terms

How are bioequivalence acceptance limits widened for highly variable 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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