A Survey of the Regulatory Requirements for the Acceptance of Foreign Comparator Products by Participating Regulators and Organizations of the International Generic Drug Regulators Programme

Alfredo Garcia Arieta1, Craig Simon2, Gustavo Mendes Lima Santos3, Iván Omar Calderón Lojero4, Zulema Rodríguez Martínez4, Clare Rodrigues5, Sang Aeh Park6, Ji Myoung Kim6, Ryosuke Kuribayashi7, Yusuke Okada7, Arno Nolting8, Chantal Pfäffli8, Wen-Yi Hung9, Christopher Crane10, April C Braddy11, Joy van Oudtshoorn12, Diego Gutierrez Triana13, Mitch Clarke14

1Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), C/ Campezo 1. Edificio 8. Madrid, 28022, Spain
2Health Canada, 101 Tunney's Pasture Driveway, Ottawa ON, Canada K1A 0K9
3Agência Nacional de Vigilância Sanitária (ANVISA). SIA Trecho 5, Área Especial 54, Bloco B, Brasília, Brazil
4Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS), Oklahoma No. 14, Colonia Nápoles, Delegación Benito Juárez, 03810, Ciudad de México, México
5Health Sciences Authority (HSA), Health Products Regulation Group, Pre-Marketing Cluster, Therapeutic Products Branch. 11 Biopolis Way, Helios #11-01, Singapore 138667, Singapore
6Ministry of Food and Drug Safety (MFDS). Osong-eup Heungdeok-gu, Cheongju-si, Chungcheongbuk-do, South Korea
7Pharmaceuticals and Medical Devices Agency (PMDA), Shin-kasumigaseki Building 3-3-2, Kasumigaseki, Chiyoda-ku, Tokyo, Japan
8Swissmedic, Schweizerisches Heilmittelinstitut, Hallerstrasse 7, 3000 Bern 9, Switzerland
9Taiwan Food and Drug Administration (TFDA). 161-2, Kunyang St., Nangang, Taipei, 11561 Taiwan, R.O.C.
10Therapeutic Goods Administration (TGA). PO Box 100, Woden ACT 2606, Australia
11U.S. Department of Health and Human Services, Food and Drug Administration (US FDA), Center for Drug Evaluation and Research, Office of Generic Drugs, 10903 New Hampshire Avenue, Silver Spring, MD 20993
12South African Health Products Regulatory Authority (SAHPRA)Medicines Control Council (MCC). Civitas Building, 42 Thabo Sehume Street, Pretoria, South Africa
13Instituto Nacional de Vigilancia de Medicamentos y Alimentos (INVIMA). Carrera 10 No. 64-28. Bogotá. Colombia
14New Zealand Medicines and Medical Devices Safety Authority (Medsafe), Ministry of Health, 133 Molesworth Street, Thorndon, Wellington, 6011, New Zealand


The acceptance of foreign comparator products is the most limiting factor for the development and regulatory assessment of generic medicines marketed globally. Bioequivalence studies have to be repeated with the local comparator products of each jurisdiction because it is unknown if the comparators of the different countries are the same product, with the consequent duplication of efforts by regulators and industry alike. The regulatory requirements on the acceptability of foreign comparator products of oral dosage forms differ between countries participating in the Bioequivalence Working Group for Generics of the International Pharmaceutical Regulators Programme. Brazil, Colombia, the European Union member States, Japan, Mexico, South Korea and the United States only accept bioequivalence studies with their local comparator. In contrast, Australia, Canada, New Zealand, Singapore, South Africa, Switzerland and Taiwan accept studies with foreign comparators under certain conditions. Canada limits its use to highly soluble drugs with a wide therapeutic range in immediate release products. Australia requires a comparison of the quantitative composition. In contrast, there are fewer restrictions on the acceptance of foreign comparators in New Zealand, Singapore, South Africa, Switzerland and Taiwan. For the WHO Prequalification of Medicines and for developing generics of the essential medicines the WHO lists comparators from different countries. In conclusion, there is currently no consensus amongst regulators on the acceptability of foreign comparator products.

J Pharm Pharm Sci, 22 (1): 28-36, 2019

Full Text:



Van Oudtshoorn et al. A Survey of the Regulatory Requirements for BCS-Based Biowaivers for Solid Oral Dosage Forms by Participating Regulators and Organisations of the International Generic Drug Regulators Programme. J Pharm Pharm Sci. 2018;21(1):27-37. doi: 10.18433/J3X93K. https://journals.library.ualberta.ca/jpps/index.php/JPPS/article/view/29579

Therapeutic Goods Administration (Australia). Part 6, Guidance 15 Biopharmaceutic Studies of the Australian Regulatory Guidelines for Prescription Medicines (April 2015). Available from: https://www.tga.gov.au/book/156-choice-reference-product-bioequivalence-generic-medicines. Accessed on 8 November 2017.

Health Canada. Guidance Document: Use of a Foreign-sourced Reference Product as a Canadian Reference Product. Available from https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/canadian-reference-product-guidance.html. Accessed on 31 January 2018.

Agência Nacional de Vigilância Sanitária (ANVISA) (Brazil). Law n. 9787, of 10th February 1999. Establishes the generic drugs in Brazil (1999). Available from: http://www2.camara.leg.br/legin/fed/lei/1999/lei-9787-10-fevereiro-1999-351613-normaatualizada-pl.pdf. Accessed on 14 November 2017.

Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS). Article 2, fraction XIV Bis, of the Reglamento de Insumos Para la Salud, (Health Products Regulation). Available from: http://www.diputados.gob.mx/LeyesBiblio/regley/Reg_LGS_MIS.pdf. http://www.cofepris.gob.mx/MJ/Documents/Reglamentos/rtoinsumos.pdf. Accessed on 29 November 2017.

Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human. Question 8 of CMDh Questions and Answers. Generic Applications (CMDh/272/2012, Rev. 2) April 2017. Available from: http://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/Questions_Answers/CMDh_272_2012_clean.pdf. Accessed 29 November 2017.

Health Sciences Authority (Singapore). Appendix 10 Product Interchangeability and Biowaiver Request for Chemical Generic Applications, Guidance on Medicinal Product Registration in Singapore (November 2016). Available from:

http://www.hsa.gov.sg/content/dam/HSA/HPRG/Western_Medicine/Overview_Framework_Policies/Guidelines_on_Drug_Registration/DR_Guide_2016/DR%20guide%202016%20final/Appendix%2010_Product%20Interchangeability%20and%20Biowaiver%20Request%20for%20Chemical%20Generic%20Drug%20Applications_30Nov16.pdf. Accessed on 8 November 2017.

Instituto Nacional de Vigilancia de Medicamentos y Alimentos (Colombia). Resolución 1124 de 2016. Por la cual se establece la Guía que contiene los criterios y requisitos para el estudio de Biodisponibilidad y Bioequivalencia de medicamentos, se define el listado de los que deben presentarlos y se establecen las condiciones de las Instituciones que los realicen (April 2016). Available from: https://www.invima.gov.co/images/bioequivalencia/Resolución%201124%20de%202016.pdf. Accessed on 8 November 2017.

South African Health Products Regulatory Authority (SAHPRA). General Information – Registration of Medicines (August 2012). Available from: http://www.mccza.com/documents/1d9c57df2.01_General_information_Jul12_v8_showing_changes.pdf. Accessed on 8 November 2017.

South African Health Products Regulatory Authority (SAHPRA). Pharmaceutical and Analytical CTD/eCTD (August 2014). Available from: http://www.mccza.com/documents/751d10ba2.25_PA_CTD_Aug14_v4.pdf. Accessed on 29 November 2017.

South African Health Products Regulatory Authority (SAHPRA). Biostudies (June 2015). Available from: http://www.mccza.com/documents/61de452d2.06_Biostudies_Jun15_v6.pdf. Accessed on 29 November 2017.

South African Health Products Regulatory Authority (SAHPRA). Dissolution (June 2015). Available from: http://www.mccza.com/documents/0ca3cfe72.07_Dissolution_Jun15_v5.pdf. Accessed on 29 November 2017.

Medsafe (New Zealand). Part 6: Bioequivalence of medicines, Guideline on the Regulation of Therapeutic Products in New Zealand (June 2015). Available from: http://www.medsafe.govt.nz/regulatory/Guideline/GRTPNZ/bioequivalence-of-medicines.pdf. Accessed on 8 November 2017.

Ministry of Food and Drug Safety (South Korea). Standard on Pharmaceutical Equivalence Study; Notification No. 2017-28 (Apr. 19, 2017, Amended)].

Swissmedic (Switzerland) Instructions: Applications and authorisation for human medicines for known substances (May 2017). Available from: https://www.swissmedic.ch/ZL000_00_008e_VV. Accessed on 8 November 2017.

Taiwan Food and Drug Administration (Taiwan). Regulation of Bioavailability and Bioequivalence Studies, Ministry of Health and Welfare, Taiwan (March 2015). Available from: http://law.moj.gov.tw/Eng//LawClass/LawContent.aspx?pcode=L0030065. Accessed on 8 November 2017.

USFDA Draft Guidance for Industry: Referencing Approved Drug Products in ANDA submissions, January 2017. Available from: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM536962.pdf.

The Drug Price Competition and Patent Term Restoration Act of 1984 (Pub. L. 98-417) (Hatch-Waxman Amendments) for generics

Title 21- Food and Drugs, 21 USC 355, (505(j), abbreviated new drug applications. Available from: http://uscode.house.gov/view.xhtml?req=%28abbreviated+new+drug+applications%29&f=treesort&fq=true&num=2&hl=true&edition=prelim&granuleId=USC-prelim-title21-section355. Accessed on 14 November 2017.

WHO Essential Medicines and Health Products: Prequalification of Medicines. Bioequivalence: Guidance Documents, Application Forms & Templates – Comparator products. Available from: https://extranet.who.int/prequal/content/who-medicines-prequalification-guidance. Accessed on 8 November 2017.

WHO Expert Committee on Specifications for Pharmaceutical Preparations. International Comparator Products List for equivalence assessment of interchangeable multisource (generic) products. In: Annex 11 Guidance on the selection of comparator pharmaceutical products for equivalence assessment of interchangeable multisource (generic) products. WHO Technical Report Series, No. 902, 2002. Available from: http://apps.who.int/medicinedocs/en/d/Jh3009e/9.5.html. Accessed on 8 November 2017.

Gwaza L, Gordon J, Leufkens H, Stahl M, García-Arieta A. Global Harmonization of Comparator Products for Bioequivalence Studies. AAPS J. 2017; 19(3):603-606. doi: 10.1208/s12248-017-0068-6.

DOI: http://dx.doi.org/10.18433/jpps30215