How many subjects, and which population, are required in a bioequivalence study?

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SFDA: “In general, a number of 24 normal healthy subjects, preferably non smoking, between 18 years of age or older and within 15% of ideal body weight, height and body build (Metropolitan Life Insurance Company Statistical Bulletin, 1983) to be enrolled in a crossover bioequivalence study.” (SFDA BE v3.1 · 3.1.3 Subjects – Number of subjects) “A number of subjects of less than 24 may be accepted (with a minimum of 18 subjects) when statistically justifiable. However, in some cases (e.g., for highly variable drugs) more than 24 subjects are required for acceptable bioequivalence study.” (SFDA BE v3.1 · 3.1.3 Subjects – Number of subjects) “Subjects should be 18 years of age or older and have a Body Mass Index between 18.5 and 30 kg/Sq.m.” (SFDA BE v3.1 · 3.1.3 Subjects – Selection of subjects) EU: “The number of subjects with evaluable data for primary statistical analysis in a pivotal BE study should not be less than 12 for a crossover design or less than 12 per treatment group for a parallel design.” (ICH M13A · 2.1.3) “To reduce variability not related to differences between drug products, the studies should normally be performed in healthy subjects unless the drug carries safety concerns that make this approach unethical.” (ICH M13A · 2.1.1) “If the investigated active substance is known to have adverse effects and the pharmacological effects or risks are considered unacceptable for healthy subjects, the study may instead be conducted in a targeted patient population under suitable precautions and supervision.” (ICH M13A · 2.1.1) US FDA: “The number of evaluable subjects in a PK BE study should not be less than 12.  For highly variable drug products, a minimum of 24 subjects are recommended for BE assessment (Davit and Conner 2010).” (FDA Statistical Approaches 2026 · II.A.3) “The number of subjects with evaluable data for primary statistical analysis in a pivotal BE study should not be less than 12 for a crossover design or less than 12 per treatment group for a parallel design.” (FDA M13A · 2.1.3) “Subjects recruited for in vivo BE studies should be 18 years of age or older and preferably have a body mass index between 18.5 and 30.0 kg/m2.” (FDA ANDA BE 2026 · III.A.5) WHO: “A minimum of 12 subjects is required.” (WHO TRS 1052 Annex 8 · 7.2.1) “Bioequivalence studies should generally be performed with healthy volunteers. Clear criteria for inclusion and exclusion should be stated in the study protocol. If the pharmaceutical product is intended for use in both sexes, the sponsor should include both males and females in the study.” (WHO TRS 1052 Annex 8 · 7.2.4) “Generally, subjects should be aged between 18 and 55 years and their weight should be within the normal range, with a body mass index between 8 and 30 kilograms per square metre (kg/m²).” (WHO TRS 1052 Annex 8 · 7.2.4)

How many subjects, and which population, are required in a bioequivalence study?

SFDA Saudi Food and Drug Authority

EU European Union

US FDA US Food and Drug Administration

WHO World Health Organization

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