1. Biosimilars – So where are we in the EU? Robert Williams, Partner, Bird & Bird LLP (London)

2. 2 EU Legislation : Basic Rules Basic Rule No medicinal product can be placed on the market without a MA Applicant must provide the results of: Pharmaceutical tests (physico-chemical, biological or microbiological tests); Pre-clinical tests (toxicological & pharmacological tests); and Clinical data Article 10.1 Directive 2001/83 Applicable to Generics Compared to the reference product : Same qualitative and quantitative composition in active substances Same pharmaceutical form Bioequivalence (demonstrated by bioavailability studies) The applicant is not required to provide the results of pre-clinical tests and of clinical trials if he can demonstrate that the medicinal product is a generic of a reference medicinal product which is or has been authorized under Article 6 for not less than 8 years in a Member State or in the Community NB “old” rules still in place for reference products applied for pre-Nov 05 (ie 10 years RDP for products applied for centrally)

3. 3 What is a biosimilar? According to article 10.4 of Directive 2001/83 Where a biological medicinal product which is similar to a reference biological product does not meet the definition of generic medicinal products, owing to, in particular, differences relating to raw materials or manufacturing processes, the results of appropriate pre-clinical tests or clinical trials relating to these conditions must be provided. Type and quantity of supplementary data provided must comply with relevant criteria stated in the Annex; and related detailed guidelines. The results of other tests and trials from the reference medicinal product's dossier cannot be provided. Consequence: a biosimilar is defined by what is accepted (or not) by the EMEA (or other competent authorities) No a priori definition of the acceptable differences between a biosimilar and the reference product

4. 4 What is a biosimilar ? “Biological medicinal product” Means that the active substance is a biological substance “Biological substance” Substance produced or extracted from a biological source Combination of physico-chemical-biological testing, production process and its control are needed for its characterization and determination of quality Examples of biological medicines: Immunological medicinal products and medicinal products derived from blood and human plasma (article 1.4 & 1.10 of Directive 2001/83) Medicinal products developed by recombinant DNA technology, controlled expression of genes coding for biologically active proteins from a cell culture, hybridoma and monoclonal antibody methods ATMP Biologicals are among best-selling/fastest growing drugs in the world Epogen/Procrit®, Enbrel®, Humira®, Remicade®, Herceptin®, Avastin®

5. 5 Active substance for biological medicinal products “ Biosimilar ” “similar” product made according to a different process For example different construct, host, cell line, protocol and/or purification steps In practice: impossible to know without access to original process But developers of biosimilars normally have no direct access to originator’s data Have to reverse engineer (i.e. made using different process): additional pre-clinical tests or clinical trials required to show similarity

6. 6 Overarching Guideline Defines basic principles, philosophy + « User guide » General Guidelines General principles for assessing quality, non-clinical, clinical aspects Product Specific Guidelines Annexes to General Guideline on (non-) clinical issues Address specific pre-clinical and clinical issues re. specific products Guidelines on biosimilars Somatropin Insulin Granulocyte-colony Erythropoietins IFN-alpha LMW heparin, etc. Quality issues (Non-) Clinical issues Apply to all biosimilars

7. 7 Information required for a biosimilar MA Quality data Complete self-standing quality dossier + Comparability exercise Complete self-standing quality dossier + Comparability exercise Non-clinical data Clinical data Pharmacovigilance Case-by-case basis Abridged programs (in vitro/in vivo) + Comparability exercise Case-by-case basis Abridged programs (in vitro/in vivo) + Comparability exercise Abridged programs but most of the time: extensive trials are required All results must be submitted ( + and -) + Comparability exercise Abridged programs but most of the time: extensive trials are required All results must be submitted ( + and -) + Comparability exercise Monitoring is necessary, as for all other medicines Monitoring is necessary, as for all other medicines

8. 8 Experience so far: Overview of EU authorized biosimilars Somatropin INN Biosimilar Epoetin alfa Epoetin zeta Filgrastim Omnitrope® (Sandoz) Valtropin® (BioPartners) Binocrit® (Sandoz) Epoetin alfa Hexal® Abseamed® (MAP) Silapo® (Stade Arzneimittel) Retacrit® (Hospira) Biograstim® (CT Arzneimittel) Filgrastim Ratiopharm®, Ratiogastim®, Tevagrastim® Biograstim® (CT Arzneimittel) Filgrastim Ratiopharm®, Ratiogastim®, Tevagrastim® Reference Product Genotropin® (Pfizer) Humatrope® (Eli Lilly) Eprex®/ Erypo® (J&J) Neupogen® (Amgen) Filgrastim Hexal®, Zarzio® (Sandoz) Nivestim ® (Hospira) Filgrastim Hexal®, Zarzio® (Sandoz) Nivestim ® (Hospira)

9. 9 Experience so far: Refusal/Withdrawals of biosimilars Interferon alfa INN Biosimilar Human insulin Alpheon (Biopartners) Insulin Marvel short Insulin Marvel Intermediate Insulin Marvel long Status Refused in June 2006 Withdrawn Not all biosimilar applications have been successful

10. 10 Acceptable differences between biosimilars and reference product Different host cells Differences between biosimilars and reference drug products Different levels of impurities Different levels of impurities Different formulation Different formulation Different glycosylation Different glycosylation Valtropin Abseamed, Binocrit, Epoetin alfa Hexal Abseamed, Binocrit, Epoetin alfa Hexal Retacrit and Silap Source: H. Schellekens & E. Moors, « Clinical comparability and European biosimilar regulations », in Nature Biotechnology January 2010nr. 1, vol. 28, p. 29 Zarzio and Filgrastim Hexal Zarzio and Filgrastim Hexal Biograstim, Filgrastim, Ratiopharm, Ratiograstim and Tevagrastim Biograstim, Filgrastim, Ratiopharm, Ratiograstim and Tevagrastim Abseamed, Binocrit, Epoetin alfa Hexal Abseamed, Binocrit, Epoetin alfa Hexal Retacrit and Silap Zarzio and Filgrastim Hexal Zarzio and Filgrastim Hexal

11. 11 Acceptable differences between biosimilars and reference product These variations can have a potential major effect on a product's safety and efficacy So far: clinical studies show no negative effect The differences have not compromised the efficacy or increased the level of adverse effects compared with the reference product Raise the question of the relevance of the comparison exercice Comparison of quality characteristics between biosimilar and reference product will always show differences (product is the process) Comparative clinical data is mandatory

12. 12 Biosimilars: specific RDP rules Usually requires data from a bio-assay (set by EMEA) Which may again not be available to the generic And will data from another (similar) bio-assay be accepted ? Choice of comparator is crucial Reference product should be approved in the EU and not be changed during development New technical assay and analytical tools may mean that more “differences” between the reference product and the biosimilar can be detected Regulators will need to decide how relevant they are

13. 13 Biosimilars: the next steps Application of the current regulatory framework to monoclonal antibodies (MAbs)? In principle: the "biosimilar" approach applies to any biological medicine Overarching guideline only excludes blood or plasma-derived products No exclusion regarding development of biosimilars mAbs But comparablity exercise is more easily applied to highly purified products (easy to characterize, >< more complex biologics) So: in reality will it depend on the ability to characterize the product? Feasibility? High molecular weight proteins Considerably more complex molecules than the currently developed biosimilars Contain process and product related impurities

14. 14 Further Guidelines..... “Biosimilar antibodies”: concept paper by CHMP dated 22 October 2009 Deadline for comments has expired and draft guideline due out in November 2010 (hopefully) May be different guidelines for cytotoxic and immunomodulatory MAb’s ? Other pending concept papers by CHMP (dated 18 March 2010) Recombinant follicle stimulation hormone Deadline for comments expired on 1st June 2010 Recombinant interferon beta Deadline for comments expired on 11 June 2010