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Michael Marshall Ph D Regulatory Affairs Novo Nordisk A/S

BioSimilars in EU and US Scientific, Legal and Regulatory Issues. Michael Marshall Ph D Regulatory Affairs Novo Nordisk A/S. Whats in the name?. Generics. Biogenerics. Generic biotech products. Similar biological medicinal products. Follow-On Biologicals. Generic Product.

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Michael Marshall Ph D Regulatory Affairs Novo Nordisk A/S

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  1. BioSimilars in EU and USScientific, Legal and Regulatory Issues Michael Marshall Ph DRegulatoryAffairsNovo Nordisk A/S

  2. Whats in the name? Generics Biogenerics Generic biotech products Similar biological medicinal products Follow-On Biologicals

  3. GenericProduct InnovatorProduct Quality Non-clinical Clinical Bioequivalence

  4. Directive 2004/27/EC amending 2001/83/EC Article 10 “Generic medicinal product” shall mean a medicinal product which has the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies Note: Directive 2003/63/EC refers to generics as “essentially similar”

  5. BioSimilarProduct InnovatorProduct ? Quality Non-clinical Clinical Bioequivalence

  6. Structure of Biologicals is complex Factor VII Insulin Aspirin

  7. No clinical effect Clinical effect Antibodies to drug Impurities Active Substance Formulation Impurities Purification Recovery Fermentation Cell Bank Host Cell

  8. Directive 2004/27/EC amending 2001/83/EC Whereas (15) Biological medicinal products similar to a reference medicinal productdo not usually meet all the conditions to be considered as a generic medicinal productmaínly due to manufacturing process characteristics, raw materials used, molecular characteristics and therapeutic modes of action. When a biological medicinal product does not meet all the conditions to be considered as a generic medicinal product theresults of appropriate tests should be provided in order to meet the requirements related to safety (pre-clinical) or efficacy (clinical), or both.

  9. Directive 2004/27/EC amending 2001/83/EC ‘ Article 10 Where abiological medicinal productwhich is similar to a reference biological productdoes not meet the conditions in the definition of generic medicinal products, owing to, in particular, differences relating to raw materials or in manufacturing processes of the biological medicinal product and the reference biological medicinal product, the results of appropriate pre-clinical tests or clinical trials relating to these conditions must be provided.  The type and quantity of supplementary data to be provided must comply with the relevant criteria stated in Annex I and the related detailed guidelines. The results of other tests and trials from the reference medicinal product's dossier shall not be provided.’

  10. Directive 2003/63/EC amending 2001/83/EC Annex 1 relating to documentation requirementsPart II.4: Similar Biological Medicinal Products • When a biological medicinal product, which refers to an original medicinal product having been granted a marketing authorisation in the Community, is submitted for a marketing authorisation by an independent applicantafter the expiry of data protection period, the following approach shall be applied • If the information required in the case of essentially similar products (generics) does not permit the demonstration of the similar nature of the two biological medicinal products, additional data, in particular, the toxicological and clinical profile shall be provided. • Modules 1, 2, 3 plus bioequivalence/bioavailability.Additional data (non-clinical/clinical: case by case basis in accordance with relevant scientific guidelines

  11. The Guidelines BioSimilars Comparability General (437) General (ICH) General (3207)Non-clinical/clinical (3097) Non-clinical/clinical (42832) Quality (49348) Annexes G-CSF (31329) Insulin (32775) h-GH (94528) EPO (94526)

  12. Guideline on Similar Biological Medicinal Products (CHMP/437/04) The standard generic approach (demonstration of bioequivalence with a reference medicinal product by appropriate bioavailability studies) is normally applied to chemically derived medicinal products. Due to the complexity of biological/biotechnology derived products, the generic approach is scientifically not appropriate for these products. The “similar biological medicinal products” approach, based on a comparability exercise, will then have to be followed.

  13. Clinical Quality Non Clinical Comparability Data

  14. Scope of Non-clinical and Clinical Studies RegulatorInnovator BioSimilarManufacturer Reduced testingjustified Safety and Efficacy must be ensured

  15. The Quality Guideline ReferenceMedicinalProduct BioSimilarMedicinalProduct Comparability • Characterisation of DS • Structure • PTM • Physicochemical • Impurities- Product related • Accelerated stability Validate Validate ActiveSubstance ActiveSubstance Process related Impurities

  16. Comparative Non-Clinical and Clinical studies

  17. Status in U.S. • Strong legal and political struggle both for and against FOBs • No FOB guidelines yet • FDA workshops have been held • Two legal systems for approval of drugs • Food, Drug and Cosmetic Act • Public Health and Safety Act • Only FDCA has regulatory route available for generics

  18. Regulatory legislation in US • Food, Drug and Cosmetic Act • Insulin, h-GH • Hatch Waxman Act 1985: • Abridged regulatory route • for Generics • FD&C Act Section 505 (b)(2) • FD&C Act Section 505 (j) • Not decided if FOBs can use • these routes Public Health Service Act Most Biologicals No Regulatory route for FOBs

  19. FD&C Act Section 505 (b)(2) • Provides for data on safety and efficacy • May rely in part on literature or on an earlier finding by FDA that a drug is safe and effective • Typically used for changes in dosage form, strength or route of administration, new indication, change to excipient • Potentially applicable for FOBs but this is being challenged legally (by interests of the innovator companies)

  20. FD&C Act Section 505(j) • “Sameness” • “An abbreviated application for a new drug shall contain information to show that the active ingredient of the new drug is the same as that of the listed drug….” • Unlikely or impossible to prove for a biotech derived product

  21. Conclusions • BioSimilars are not generics • Scientific barriers to demonstration of Comparability • EU • The legislation and regulatory guidelines are in place • One BioSimilar has already been approved and more approvals are in the pipeline • US • Scientific, legal and political issues not yet resolved • Slower than EU but FOBs will eventually come

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