Bioequivalence and Bioavailability Forum

Dear all,

given the occasion, a clarification regarding the comparator (prior to ICH M13 called reference product) in bioequivalence.

Only with a few exceptions (i.e., in Australia, Canada, New Zealand, Singapore, South Africa, Switzerland, Taiwan, the UK, and in countries following the WHO’s guidelines^1–3) under certain conditions, the local comparator must be used in comparative BA studies. Accepting a foreign comparator or – even better – a ‘Global Comparator’ would be desirable in order to reduce the number of studies.^4–8
Under current legislation, this is not possible in most countries.⁹

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1. WHO Expert Committee on Specifications for Pharmaceutical Preparations. Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability. Fifty-first report. Technical Report Series, No. 992, Annex 6. Geneva. April 2017. Online.
   
2. WHO. List of International Comparator products. Geneva. 11 December 2024. Online.
   
3. Freitas Fernandes EA, van Oudtshoorn J, Tam A, Arévalo González LA, Aurela EG, Potthast H, Mettke K, Kuribayashi R, Shimojo K, Kasuga M, Morales L, Rodríguez Z, Jones B, Ahn C, Yun E, Kim SH, Rodrigues C, Tiong T, Crane C, Walther C, Roost MS, Chen T-L, Hsu L-f, Braddy AC, García-Arieta A, Abalos I, Divinsky M, Alsuwyeh A, Alzenaidy B, Alhar A. The bioequivalence study design recommendations for immediate-release solid oral dosage forms in the international pharmaceutical regulators programme participating regulators and organisations: differences and commonalities. J Pharm Pharmaceut Sci. 2024; 27: 12398. doi:10.3389/jpps.2024.12398.
   
4. ICH. M13A Step 4 Presentation. Geneva. 23 July 2024. Online.
   
5. Wang YL, Hsu LF. Evaluating the Feasibility of Use of a Foreign Reference Product for Generic Drug Applications: A Retrospective Pilot Study. Eur J Drug Metab Pharmacokinet. 2017; 42(6): 935–42. doi:10.1007/s13318-017-0409-y.
   
6. Gwaza L, Gordon J, Leufkens H, Stahl M, García-Arieta A. Global Harmonization of Comparator Products for Bioequivalence Studies. AAPS J. 2017; 19(3): 603–6. doi:10.1208/s12248-017-0068-6.
   
7. Almeida S. An opportunity or a mirage: Single global development for generic products. Presentation at: BioBridges; Prague. 27 September 2019. Online.
   
8. Almeida S. Harmonis(z)ation of BE and beyond. Presentation at: BioBridges; Prague. 22 September 2022. Online.
   
9. Tam A, García-Arieta A, Abalos I, Freitas Fernandes EA, Mendes Lima Santos G, Rodríguez Martínez Z, Divinsky M, Kariv R, Potthast H, Braddy AC, Rodrigues C, Guzman Aurela E, Arévalo González LC, Gutierrez Triana D, Jones B, Ahn C, Kim H, Kim SH, Kuribayashi R, Myoenzono A, Shimojo K, van Oudtshoorn J, Bigler C, Meincke R, Roost MS, Walther C, Hsu L-f, Crane C, Jarman T. A Survey of the Criteria Used for the Selection of Alternative Comparator Products by Participating Regulators and Organizations of the International Pharmaceutical Regulators Programme. J Pharm Pharmaceut Sci. 2022; 25: 323–39. doi:10.18433/jpps33081.