Which strength must be tested in a bioequivalence study?

Question

Accepted Answer

SFDA: “The bioequivalence study should in general be conducted at the highest strength. For products with linear pharmacokinetics and where the drug substance is highly soluble (see Appendix III), selection of a lower strength than the highest is also acceptable.” (SFDA BE v3.1 · 3.1.6 Strength to be investigated – Linear pharmacokinetics) “Selection of a lower strength may also be justified if the highest strength cannot be administered to healthy volunteers for safety/tolerability reasons.” (SFDA BE v3.1 · 3.1.6 Strength to be investigated – Linear pharmacokinetics) “For drugs with a less than proportional increase in AUC with increasing dose over the therapeutic dose range, bioequivalence should in most cases be established both at the highest strength and at the lowest strength (or a strength in the linear range), i.e. in this situation two bioequivalence studies are needed.” (SFDA BE v3.1 · 3.1.6 Strength to be investigated – Non-linear pharmacokinetics) EU: “In general, the highest to-be-marketed strength should be used in a BE study (see Section 2.1.6).” (ICH M13A · 2.1.2) “In cases of documented less than proportional increases in AUC and/or Cmax with increasing dose over the range of strengths proposed, BE should be established with the lowest strength if this is due to saturation of absorption.” (ICH M13A · 2.1.6) “If data are not available to establish dose proportionality, then BE studies should be conducted with the lowest and highest strengths of the proposed series of strengths.” (ICH M13A · 2.1.6) US FDA: “In general, BE studies should be conducted in healthy subjects (see section III.A.5, Study Population) and should be conducted on the highest to-be-marketed strength.” (FDA ANDA BE 2026 · III.A.4) “If an applicant does not intend to submit an ANDA for the highest strength of the RLD, then FDA generally recommends using the highest to-be-marketed strength for BE studies.” (FDA ANDA BE 2026 · IV.B.1) “In cases of documented less than proportional increases in AUC and/or Cmax with increasing dose over the range of strengths proposed, BE should be established with the lowest strength if this is due to saturation of absorption. If the less than proportional increase in AUC and/or Cmax with increasing dose is due to limited drug solubility, BE studies should be conducted with both the lowest and highest strengths.” (FDA M13A · 2.1.6) WHO: “In bioequivalence studies, the molar equivalent dose of multisource and comparator product must be used. For a series of strengths that can be considered proportionally formulated (see subsection 10.3), the strength with the greatest sensitivity for bioequivalence assessment should be administered as a single unit. This will usually be the highest marketed strength.” (WHO TRS 1052 Annex 8 · 7.4.1) “In certain cases, a study performed with a lower strength can be considered acceptable if this lower strength is chosen for reasons of safety or if the API is highly soluble and its pharmacokinetics are linear over the therapeutic range.” (WHO TRS 1052 Annex 8 · 7.4.1) “For APIs with non-linear pharmacokinetics within the range of strengths due to saturable absorption and resulting in less than proportional increases in AUC with increasing dose, the bioequivalence study should be conducted on at least the lowest strength (or a strength in the linear range).” (WHO TRS 1052 Annex 8 · 7.4.2)

Which strength must be tested in a bioequivalence study?

SFDA Saudi Food and Drug Authority

EU European Union

US FDA US Food and Drug Administration

WHO World Health Organization

Other questions in Bioequivalence & biowaivers