Marcel H.N. Hoefnagel 2 November 2007 BIOSIMILARS are not Generics But similar

2/13 Content Generics and Biosimilars Review for Marketing Authorisation Efficacy and Safety Pharmacovigilance Conclusion The content of this presentation is the view of the authors and does not necessarily represent the opinion of the Dutch MEB and/or EMeA/CHMP

3/13 Generics “A generic drug is a copy that is the same as a brand-name drug in dosage, safety, strength, how it is taken, quality, performance and intended use” “before approving a generic drug product, FDA requires many rigorous tests and procedures to assure that the generic drug can be substituted for the brand name drug.”

4/13 Generics FAQ Are generic drugs as safe as brand-name drugs? Yes. FDA requires that all drugs be safe and effective. Since generics use the same active ingredients and are shown to work the same way in the body, they have the same risks and benefits as their brand- name counterparts. Are generic drugs as strong as brand-name drugs? Yes. FDA requires generic drugs to have the same quality, strength, purity and stability as brand-name drugs. Do generic drugs take longer to work in the body? No. Generic drugs work in the same way and in the same amount of time as brand-name drugs. Are brand-name drugs made in more modern facilities than generic drugs? No. Both brand-name and generic drug facilities must meet the same standards of good manufacturing practices.

5/13 Biosimilars are not generics Biological medicines produced in a living system or organism The (complex) manufacturing process is a determining factor Larger molecules, complex (three-dimensional structure ) and heterogeneous (e.g. isoforms and multimers) Difficult to characterise Impurities: Both Product-related and Process-related

6/13 Biosimilar Market Application Comparability (quality, non-clinical, clinical) EU registered reference product Same pharmaceutical form, strength, administration route Abbreviated application; Differences supported by additional data Generally same indication(s) as reference product

7/13 Biosimilar: Stepwise approach Case-by Case Qualitative Comparability Non-clinical -Toxicity studies Clinical studies -Pharmacokinetics -Pharmacodynamic studies -Efficacy studies -Immunogenicity

8/13 Comparability exercise Complete Module 3 (Quality dossier) Plus Comparability Excercise -After process change or Biosimilar Reference product Identical primary structure (AA order) Post-translational differences (incl. glycosylation) E.g. Non-PEGylated vs. PEGylated not accepted Physicochemical characterisation Biological activity Impurities

9/13 Non-clinical studies Case-by-Case dependent on physicochemical and biological characterisation (e.g. different glycosylation or impurities) Pharmacodynamic studies Toxicity studies

10/13 Clinical studies Pharmacokinetics -Phase I safety -Clinical comparability with reference product Pharmacodynamic studies Phase III Comparability -Similar efficacy pharmacodynamic markers -Similar or lower Adverse Events Incidence -Immunogenicity with or without clinical consequences

11/13 Immunogenicity and Pharmacovigilance Immunogenicity an issue for all biologicals (both innovators and biosimilars) Immunogenicity also after process change!! Minimum of 12 months data available; 24 months ongoing study post-approval Minimise unnecessary switching between products (also between innovators)! Pharmacovigilance: Traceability important

12/13 Conclusion Demonstrated Efficacy & Safety Quality ensured Pharmacovigilance: Traceability important -be perceptive for unexpected effects on both safety and efficacy of all biologicals Minimise unnecessary switching between products -switching should always be done with care

13/13 Biosimilars FAQ Are Biosimilars as safe as innovator drugs? Yes. EMEA requires that all drugs be safe and effective. Since biosimilars use the same active ingredients and are shown to work the same way in the body, they have the same risks and benefits as their innovator counterparts. Are Biosimilars drugs as strong as innovator drugs? Yes. EMEA requires biosimilars to have the same quality, strength, purity and stability as reference product. Do Biosimilars take longer to work in the body? No. biosimilars work in the same way and in the same amount of time as innovator drugs. Are innovator drugs made in more modern facilities than Biosimilars? No. Both innovator and biosimilars manufacturing facilities must meet the same standards of GMP.