What is the standard bioequivalence study design?

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SFDA: “If two formulations are compared, a randomized, two-period, two-sequence single dose crossover design is recommended.” (SFDA BE v3.1 · 3.1.1 Study design – Standard design) “The treatment periods should be separated by a wash out period sufficient to ensure that drug concentrations are below the lower limit of bioanalytical quantification in all subjects at the beginning of the second period. Normally at least 5 elimination longest half-lives are necessary to achieve this.” (SFDA BE v3.1 · 3.1.1 Study design – Standard design) “In order to reduce variability not related to differences between products, the studies should normally be performed in healthy volunteers unless the drug carries safety concerns that make this unethical.” (SFDA BE v3.1 · 3.1.3 Subjects – Selection of subjects) EU: “A randomised, single-dose, crossover study design is recommended when comparing test and comparator formulations, as single-dose studies provide the most sensitive conditions to detect differences in the rate and extent of absorption. Treatment periods should be separated by a sufficiently long washout period, e.g., at least 5 elimination half-lives (see Section 2.2.3.3).” (ICH M13A · 2.1.2) “For drugs with long elimination half-lives, a randomised parallel design may be employed when a crossover design is impractical due to the need for a prolonged washout period.” (ICH M13A · 2.1.2) “A multiple-dose study may be conducted in patients if a single-dose study cannot be conducted in either healthy subjects for safety and/or tolerability reasons or in patients for ethical reasons.” (ICH M13A · 2.1.2) US FDA: “A randomized, single-dose, crossover study design is recommended when comparing test and comparator formulations, as single-dose studies provide the most sensitive conditions to detect differences in the rate and extent of absorption.  Treatment periods should be separated by a sufficiently long washout period, e.g., at least 5 elimination half-lives (see section 2.2.3.3).” (FDA M13A · 2.1.2) “For most dosage forms that release a drug intended to be systemically available, FDA recommends that applicants perform a single-dose, crossover study using either healthy subjects or other populations, as appropriate.  In this design, each subject should receive each treatment (the test product and the reference standard) in a random order.” (FDA ANDA BE 2026 · III.A.4) “FDA recommends that applicants use (1) a single-dose, nonreplicate crossover study design, (2) a single-dose, parallel study design, or (3) a single-dose, replicate crossover study design for BE studies.” (FDA ANDA BE 2026 · III.A.4) WHO: “In general, for a bioequivalence study involving a multisource product and a comparator product, a randomized, two-period, two-sequence, single-dose, crossover study conducted with healthy volunteers is the preferred study design. In this design each subject is given the multisource product and the comparator product in randomized order. An adequate washout period should follow the administration of each product.” (WHO TRS 1052 Annex 8 · 7.1) “The washout period should be the same for all subjects and should normally be more than five times the median terminal half-life of the API.” (WHO TRS 1052 Annex 8 · 7.4.5) “The minimum washout period should be at least seven days unless a shorter period is justified by a short half-life.” (WHO TRS 1052 Annex 8 · 7.4.5)

What is the standard bioequivalence study design?

SFDA Saudi Food and Drug Authority

EU European Union

US FDA US Food and Drug Administration

WHO World Health Organization

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