Biosimilars -

Biosimilars -

1 BIOSIMILARS & EU REGULATION Alice DOMINIQUE - M2 AREIPS 2 Content 1 Definitions 2 Regulation in EU 3 Biosimilars in practice

3 DEFINITIONS 4 What is a biological medicine ? Biological medicine = Biologic medical product = Biological = Biologic Medicine made by or derived from a biological source (human, animal or microorganism), using biotechnology Active substance larger and more complex than chemical medicine Degree of variability Examples Vaccines:

Blood and blood products Allergenic extracts Gene therapies d Human cells and tissues used for transplantation Cellular therapies 5 What is a biosimilar ? Similar biological = biosimilar medicine A biological medicine developed to be similar to an existing biological medicine that has already been authorized for use. (Reference medicine) Active substance: essentially the same But minor differences due to their complex nature and production methods

Degree of natural variability When approved, its variability and any differences between it and its reference medicine will have been shown not to affect safety or effectiveness 6 Biosimilars Generics PROPERTIES GENERICS BIOSIMILARS SIZE Small Large

MOLECULAR WEIGHT < 500-900 Daltons 4000 to >140,000 Daltons STRUCTURE Simple and well-defined Complex with potential structural variations MANUFACTURING Predictable chemical process to make identical copy Specialized biological process to make similar

copy COMPLEXITY Easy to fully characterize Difficult to characterize due to heterogeneity APPROVAL REQUIREMENTS Quality information + Bioequivalence Full quality dossier + Comparability exercise (quality, safety, efficacy) 7 EU REGULATION

8 Regulation in EU EU = first region to have set up a legal framework Concept of biosimilar adopted in EU legislation in 2004 Directive 2001/83/EC, as amended by Directive 2003/63/EG and Directive 2004/27/EC First biosimilar medicine : approved by the EC in 2006 Marketing authorisation application: Centralised Procedure Only authorized once the period of data exclusivity has expired 9 EMA guidelines relevant for biosimilars

OVERARCHING BIOSIMILAR MEDICINES GUIDELINES General Quality Nonclinical and Clinical PRODUCT-SPECIFIC BIOSIMILAR MEDICINES GUIDELINES Recombinant human insulin and insulin analogues Somatropin GCSF Recombinant erythropoietins Low-molecular-weight heparins Interferon IFN FSH Monoclonal antibodies


Omnitrope Sandoz 12/04/2006 Genotropin Human Growth Hormone Abseamed Binocrit Epoetin Alfa Hexal Retacrit Silapo Ratiograstim Tevagrastim Biograstim Filgrastim Hexal Zarzio

Nivestim Grastofil Accofil Inflectra Remsima Flixabi Bemfola Ovaleap Abasaglar Benepali Inhixa Thorinane Medice Sandoz Hexal Hospira Stada Ratiopharm Teva AbZ-Pharma Hexal

Sandoz Hospira Apotex Accord Healthcare Hospira Celltrion Samsung Bioepis Finox Biotech Teva Eli Lilly Samsung Bioepis Techdow Europe AB Pharmathen S.A. 28/08/2007 28/08/2007 28/08/2007 18/12/2007 18/12/2007 15/09/2008 15/09/2008 15/09/2008

06/02/2009 06/02/2009 08/06/2010 18/10/2013 18/09/2014 10/09/2013 10/09/2013 26/05/2016 27/03/2014 27/09/2013 09/09/2014 14/01/2016 15/09/2016 15/09/2016 Eprex Erythropoeitin Neupogen G-CSF

Remicade Monoclonal antibody Gonal-ff FSH Lantus Enbrel Insulin TNF inhibitor Low molecular weight heparin EPOETIN FILGRASTIM

INFLIXIMAB FOLLITROPIN ALFA INSULIN GLARGINE ETANERCEPT ENOXAPARIN SODIUM Clexane 11 How to demonstrate biosimilarity? Similarity to the reference medicinal product in terms of: quality characteristics safety biological activity efficacy based on a comprehensive comparability Similar active substance, in molecular and biological terms For example: for a protein, same amino acid sequence Same posology and route of administration Deviations from the reference product as regards strength,

pharmaceutical form, formulation, excipients or presentation require justifications Any difference should not compromise safety Intended changes to improve efficacy are not compatible with the biosimilarity approach. 12 Marketing Autorisation application dossier 13 BIOSIMILARS IN PRACTICE 14 Why do we use biosimilars? In EU, in 2014 : 7/10 of the most sold medicines

Biological costs > Chemical medicines costs Biosimilars: More cost-effective alternative Offer a major opportunity to provide greater access to affordable healthcare Difficult production methods Supply difficulties Stock-outs 15 Interchangeability Medical practice of changing one medicine for another that is equivalent, in a given clinical setting on the initiative, or with the agreement of the prescriber EMA: Decisions on interchangeability : Outside its remit No recommendations Rely on national competent authority

For questions related to switching from one biological medicine to another, patients should speak to their doctor or pharmacist 16 Interchangeability ANSM: According to the evolution of the knowledge and the continuous analysis of efficiency and safety data of biosimilars in EU, it appears that a position excluding formally any interchangeability during the treatment is no longer justified But, for security and traceability reasons its not recommended to modify the initial prescription FIMEA: Biosimilars are interchangeable with their reference products under the supervision of a health care person 17

CONCLUSION 18 Conclusion Important sub-category of biologics One the fastest growing segments of pharmaceutical industry 2014: worldwide sales US$200 billion Importance in healthcare budget Complex structure Small differences can result in a significant impact on quality, safety & efficacy Importance of legislation and harmonisation 19 20 Bibliography

general/general_content_000529.jsp&mid=WC0b01ac0580533e0b Guideline on similar biological medicinal products CHMP/437/04 Rev 1, 2014 Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues, EMEA/CHMP/BMWP/42832/2005 Rev1, 2014 Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (revision 1), EMA/CHMP/BWP/247713/2012 , 2014 Biosimilar medicines handbook, 3rd edition - 2016, The Biosimilar Medicines Group tat des lieux sur les mdicaments biosimilaires, Mai 2016, ANSM

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