Visión Global de la Regulación de Productos Biológicos y Biotecnológicos

1. Visión Global de la Regulación de ProductosBiológicos y Biotecnológicos Dr. Elwyn Griffiths Health Canada, Ottawa Buenos Aires 2008

2. Outline • Regulation of Biologics / Biotechnology Products • Fundamental issues with biotechnology products • Biosimilars / subsequent entry biologics

3. What are they- terminolgy? • Biologics (North America) • Biological medicines • Biologicals • Include Biotechnology Products • Used in prophylaxis, therapy or diagnosisof human diseases (in vitro diagnostics)

4. History • Traditional Biologicals - include vaccines, products isolated from biological materials (eg plasma -FactorViii) • Early 1980s rDNA derived products came on to the market called Biotechnology products, including products from novel cell lines (monoclonal antibodies) • Regulated as biologicals

5. Regulatory oversight • REGULATORY MEASURES put in place veryearly on in development of biotechnology medicinal products - regulated as biologicals (eg Canada, Europe, USA) • GUIDELINES on production and quality control rDNA derived proteins also developed early on (EMEA, FDA,WHO, ICH) • Provided framework for moving forward with the newer technologies

6. BiotechnologyProducts: What are the issues? • Differ from Chemical Drugsin many ways • Biological starting materials and /or manufacturing process - inherently variable • Highly complex products – large protein molecules • Test methods needed to characterize product are biological in nature (bioassays) – potency (activity), immunogenicity, safety

7. Biotechnology Products- regulatory issues cover Development genetics Cell substrates Cultivation and harvesting Downstream processing Viral validation studies Detailed product characterization Testing and release Pre-clinical studies/toxicology Clinical studies/several lots to be used

8. Critical Points • Cell bank / bacterial host / other expression system • Cell culture / fermentation • Sequence/translation of gene • Separation and purification of product • Bulk product testing • Characterization of resulting protein + glycosylation or other modifications • Final product testing

9. Product characterization • Means more than simple quality control tests • Expect several parameters to be evaluated by different techniques, not just one • Protein sequence, secondary / tertiary aspects, glycosylation, phosphorylation, oxidation, lipidation, etc • Product / host cell related impurities ( quantity, identification) • Formulation implications and Stability

10. Biotechnology products- other issues • Residual host cell DNA from transformed (continuous ) cell lines • Concern - transfer of oncogenic DNA to recipients • WHO recommendations as to allowable levels of DNA • Viral safety- cell banks screened / validation virus removal or clearance

11. Biologics production - In process controls critical • Need to understand origin of materials (production cells, seeds) • Tests on starting materials • Tests on intermediates • Tests on final product

12. Biotechnology derived products • Led to concept of “well characterized biologics” • Best characterized biological products • Safe and effective medicines • But control procedures still in place cannot FULLY predict biological properties and clinical performance • Consistency of production critical • Production changes can lead to major adverse effects

13. Biotechnology products • Very sensitive to production parameters • Nature of cell substrate and growth conditions / downstream processing • Minor changes can have major effects on biological activity: scale up major issue • Key issue potential immunogenicity

14. Potential immunogenicity-impactsproduct safety • Most biologicals induce some antibodies • Foreign proteins (streptokinase) induce antibodies via classical vaccine-type reaction • Human homologue proteins( interferon, cytokines) induce antibodies by breaking B-cell tolerance • Various factors involved- impurities and aggregates considered to be major cause • Single or multiple dose also a consideration

15. Potential immunogenicity - key event 2002 • Pure red cell aplasia related to use of Erythropoetin (epoetin) – a major event • In 2002 , 13 cases noted all associated with epoetin treatment – Antibodies to epoetin • Product Eprex had been safely used for many years. • Factors thought involved formation of micelles associated with epoetin, silicon droplets in prefilled syringes • Major changes in formulation

16. Potential immunogenicity • Such adverse events cannot be predicted • Need for vigilance especially after manufacturing changes or new products

17. Biotechnology Products • On the market since the early 1980s (rDNA derived medicinal products / products from novel cell lines) • Regulatory oversight (guidelines) put in place early on during their development- maximized their safety and efficacy • Best characterized biological medicines • Much production and clinical experience

18. Recent Developments • Increasing number of patents/data protection expiring • Products “similar” to the originals (innovator) coming to the market • Intention that licensing rely, in part, on data from an approved innovator product • Much manufacturer and regulatory interest worldwide

19. Drivers • Alternatives to innovator products expected more affordable – may contribute to increased access • Global markets for biologicals growing and attractive - so considerable global interest • Difficult and contentious issues • Key question is how to handle the licensing of these products if relying, in part, on data from innovator product

20. Request to WHO for Action • International Conference of Drug Regulatory Authorities , Seoul, 2006 • WHO requested to develop globalregulatoryconsensus and guidance • WHO Consultations on nomenclature and regulatory evaluation for “Biosimilars” 2006, 2007,2008- regulators and manufacturers • WHO Expert Committee on Biological Standardization (2006, 2007)

21. WHO Consultations outcomes • Better understanding of directions and challenges in the regulatory evaluation of the quality, safety and efficacy of “biosimilars” • Exchange of information between regulators, the identification of key issues and gaps, and recommendations on the next steps • Wide range of regulatory preparedness • Clear need for global road map • Decision on INNs • WHO Guideline Drafting Group established

22. What should they be called? • Different NAMES given by different jurisdictions • Follow-on Biologics/protein products (USA, Japan) • Biosimilar Products (EU) • Subsequent-entry Biologics (Canada) • Biogeneric products(others)

23. Not Generics • Agreed – biotechonolgy products do not meet criteria for true GENERICS - should not be regulated under generic (chemical ) drugs regulations • Biologicals / biotechnology products, by definition, are not “identical” • They are highly complex in nature and production

24. Key Consensus Points • Possibility of licensing a new biotechnology product on basis of “similarity” with a well established licensed product agreed • Extensive characterization of new product • Abridged non clinical and clinical data package possible (case by case) • But what type of regulatory pathway to use?

25. Which regulatory pathway? • Some authorities already established regulatory pathway (Europe/EMEA) • Others close to doing so (Canada) • Yet others do not have a regulatory framework for such products • Sometimes legal framework problem • Generally same issues highlighted

26. Issues • Definitions and terminology • Type of regulatory pathway • Scope of products – only rDNA proteins ? monclonals? Polysaccharides (Heparins)? • Degree of “similarity” – potential immunogenicity • Demonstration of “similarity” • Defined comparator / reference product • Extrapolation of indications from originator • Interchangeability / substitutability

27. WHO Draft Guidelines developed • By WHO Drafting Group • Consultation, Seoul, May 2008, public consultation/comments • PAHO Consultation of Regulatory Authorities, Dominican Republic, June 2008 • Presented to WHO Expert Committee on Biological Standardization, October 2008 • Immense global interest – regulatory agencies, industry, media

28. WHO Draft Guidelines • Intention- globally acceptable set of principles for abbreviated/abridged licensing pathways for biological therapeutic products • Intention - not to resolve all issues • Need for implementation strategy • Need for transition period

29. Current WHO Draft Guideline Considered 3Regulatory Pathways • Full license application : no reliance on any data from already licensed product • TwoAbbreviated licensing approaches: -reliance on demonstrated “similarity” of new product with an innovator product : -reliance on knowledge and experience of product class • Both have extensive quality dossier

30. Abbreviated pathway 1 Biosimilar approach (like EMEA) • Reliance on head to headdemonstration of “similarity” of new product characteristics (physico chemical / biological activity) to a chosen licensed reference product (innovator product) • Reduced non-clinical and clinical data but including head to head comparison with the same reference product

31. Biosimilar Approach Choice of Reference Product • Reference must be a licensed product • Object of comparability studies is to demonstrate product “similarity” • Same reference throughout studies • Extrapolation- of indications of the Reference Product to the biosimilar possible on basis of one clinical study on justification

32. Biosimilar Approach Choice of Reference Product • Unavailability of reference drug substance, only formulated product • Need to extract from formulated product for physico chemical studies • Verification that extraction does not affect drug substance properties

33. Abbreviated pathway 2 Clinical comparability approach • Reliance on belonging to product class; no head to head quality comparison with a reference product • Reduced non-clinical data package • Reduced clinical data possible on justification but including head to head comparison with reference product

34. Clinical comparability approach Reference Product • No need to extract drug substance since formulated product used in clinical studies • Comparator should be well established product in product class • Extrapolation- of indications of the Reference Product to the new one notto be considered on basis of one clinical study

35. WHO Guidelines -Abbreviated licensing approaches • Both approaches have same requirement for an extensive immunogenicity studies in comparison with the reference products prior to licensing. • Both require a post marketing pharmacovigilance plan to be developed

36. Regulatory approaches for biotherapeutics following licensing of the originator Abbreviated licensing pathways Full licensing application • Biosimilar approach • Full quality dossier with a comparability exercise • Reduced non-clinical and clinical data (comparative) • Clinical comparability approach • Full Quality dossier • Reduced nonclinical data • Clinical data (head to head comparison with reference product) Full dossier (no data reduction) Stand alone product Biosimilar product Clinically comparable product Extrapolation of indications possible on justification No extrapolation of indication(s) To be considered

37. WHO Expert Committee - Concerns expressed over first official draft • Concerns of IFPMA, manufacturers, number of regulatory agencies (FDA,EMEA,TGA) • Perception Clinical Comparability approach lower standard than “biosimilar pathway”. Two standards which may compromise safety • Agreed parts of a complete/full licensing approach can be reduced on consideration of knowledge and experience of product class (IFPMA letter to WHO)

38. WHO Expert Committee 2008 Proposed Guidelines • Intensive discussion over several sessions • Document not adopted • Many proposals made for improvements • Document now being revised • To be submitted to Expert Committee in draft for general agreement prior to posting on internet in first quarter 2009. • To undergo further public consultation; revised version will go to the WHO Expert Committee in 2009

39. WHO Expert Committee 2009 Proposed Revised Guidelines • Issues to be reviewed/revised: Scope (agreed not vaccines); Non-inferiority/clinical equivalence; extrapolation of indications • To cover “biosimilar” approach and full licensing approach with considerations for reduction of non-clinical and clinical package based on knowledge of product class and experience of use. • Focus on principles not regulatory pathways

40. WHO Expert Committee 2009 Proposed Revised Guidelines • Possibility of further consultation in 2009 being considered prior to ECBS • Need for clarity • Difficulties will be terminology / nomenclature • Time to prepare/brief manufacturers and National Regulatory Authorities (NRAs) regarding future developments and directions – feedback on revision

41. Preparation and Implementation • Additional consultations with other stakeholders (relevant government representatives, physicians, patients groups) also needed concerning • adoption of “biosimilars” by drug formularies • Interchangeability and substitutability • Post-market surveillance issues which are an important component of the draft guideline

42. Next 12 months • Share information on issues and options with national regulatory authoriites • Stimulate broad discssion as ot how to handle licensing in PAHO countries • Need for expertise • Feedback to WHO on next draft of guidelines – clear ? useful?