Which reference (comparator) product must be used in a bioequivalence study?

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SFDA: “Reference Products must be the original brand-name (i.e. manufactured in the country of origin of the original brand name); if this is not available in the local market then the brand-name regarding the same company but different country of origin is used, marketed in GCC region, ICH region, or in any stringent regulatory authority.” (SFDA BE v3.1 · 3.1.2 Reference and test product – Selection of reference drug) “If the original brand-name is not available in the market or no longer produced, then the product which is the local market leader may be used as a reference product.” (SFDA BE v3.1 · 3.1.2 Reference and test product – Selection of reference drug) “The study report should include the reference product name, strength, pharmaceutical form, batch number, manufacturer, expiry date and country of purchase.” (SFDA BE v3.1 · 3.3.1 Bioequivalence study report) EU: “For Article 10(1) and 10(3) marketing authorisation applications reference must be made to the dossier of a reference medicinal product for which a marketing authorisation is or has been granted in the Union on the basis of a complete dossier in accordance with Articles 8(3), 10a, 10b or 10c of Directive 2001/83/EC, as amended.” (EMA BE guideline · 4.1.2) “Bioequivalence studies comparing the product applied for with non-EU reference products should not be submitted and do not need to be included in the list of studies.” (EMA BE guideline · 4.1) “Including comparator products from different regions in one trial is acceptable to streamline the BE demonstration by conducting one single higher-order crossover BE study with multiple comparator products.” (ICH M13A · 2.2.5.1) US FDA: “To receive approval for an ANDA, an applicant generally must demonstrate, among other things, that its proposed drug product is bioequivalent to the reference listed drug (RLD).” (FDA ANDA BE 2026 · II) “During such BE studies, an applicant compares the systemic exposure profile of a test drug product to that of the reference standard designated in FDA’s Approved Drug Products with Therapeutic Evaluations (the Orange Book).” (FDA ANDA BE 2026 · II) “As discussed further below, a comparator product used in conducting an in vivo BE study to support an ANDA in the United States is the reference standard (21 CFR 314.3(b)).” (FDA ANDA BE 2026 · II, footnote 7) WHO: “The comparator product is a pharmaceutical product with which the multisource product is intended to be interchangeable in clinical practice. The comparator product will normally be the innovator product for which efficacy, safety and quality have been established.” (WHO TRS 1052 Annex 8 · 2. Glossary — comparator product) “Preferably this will mean employing the innovator product available on the market when studying multisource products for national and regional approval. There will be situations, however, where this is not feasible. Detailed guidance for the selection of comparator products for use in national and regional applications is provided in the comparator guidance (8).” (WHO TRS 1052 Annex 8 · 7.3.2) “Content of the API of the comparator product should be close to the label claim and the difference between two products being compared should not be more than ± 5%.” (WHO TRS 1052 Annex 8 · 7.3.2)

Which reference (comparator) product must be used 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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