Iman Barilero, PhD, PharmD Associate Director, European Regulatory Affairs

1. Current Regulations and Guidelines in Europe on Approval of Similar Biological Medicinal Products “Biosimilars”Malaysia National Regulatory SeminarSubang Jaya, Selangor, 6-7 September, 2005 Iman Barilero, PhD, PharmD Associate Director, European Regulatory Affairs Global Regulatory Policy and Intelligence Johnson & Johnson Pharmaceutical R&D, United Kingdom September 7, 2005

2. Driving forces for emerging biosimilars • The potential increase for the biopharmaceutical market, as innovative science is targeting a huge range of diseases from growth deficiency to arthritis, to multiple sclerosis, to cancer and orphan diseases, etc • The patents of several biopharmaceuticals have expired, or are about to expire opening a new market sector • Pressure to reduce healthcare expenditure and increase patient access to treatment will drive the development of cheaper biosimilars How will emerging biosimilars be evaluated by regulators, pharmacists and physicians?

3. Scientific framework development • Biopharmaceuticals as compared to chemical low molecular weight drugs: • Size and Complexity • High molecular weight with complex three-dimensional structure • Production process • Recombinant DNA technology with complex manufacturing process • Produced by living organisms, therefore often heterogeneous • Small changes in the process may affect safety and efficacy • Characterization and analytical methods • Difficult to characterize completely by physico-chemical analytical methods or bioassays • Current analytical methods do not detect all product variations that can affect clinical efficacy, side effects or immunogenicity • Biological activity • Depends on reproducibility of the production process, in-house standards, and maintaining cold chain integrity • Immunogenicity • Proteins known to induce a specific immune response with clinical implications

4. Regulatory framework development • Regulatory authorities in the EU (EMEA), the USA (FDA) and scientific community have recognized that biosimilars (as new biopharmaceuticals) differ from generic low molecular weight drugs in several important ways (scientific considerations) • Not possible at present for two different manufacturers to manufacture two identical biopharmaceuticals (similar at best) • Can a generic approach be used for marketing approval of biosimilars? The legal and regulatory principles of ‘essential similarity’ (EU) or ‘bioequivalence’ (USA) cannot be applied to biosimilars

5. Regulatory status in EuropeSeptember 2005 • Review of Pharmaceutical legislation in EU since 2001 after proposal from EU Commission • Part of the New Medicines Legislation in EU (comes into force in 2005) • The first legal basis in the EU for biosimilars has been established1 • Directive 2004/27/EC of 31 March 2004 (amending Directive 2001/83/EC): to come into force in EU members states by 30 October 2005 • Directive 2003/63/EC of 25 June 2003 (Annex I): already came into force in EU member states on 1 July 2003 There is a clearly defined legal/regulatory framework in the EU 1http://pharmacos.eudra.org/F2/review/index.htm

6. Legal framework for biosimilars (1) • Directive 2004/27/EC – Article 10.4 • Where a biological medicinal product which is similar to a reference biological product does not meet the definition of a generic medicinal product • Owing to, in particular, differences in raw material or differences in manufacturing processes • The results of appropriate pre-clinical tests or clinical trials must be provided, in accordance with the relevant criteria stated in Annex I and the related detailed guidelines Concept of ‘biosimilarity’  from concept of ‘essential similarity’

7. Legal framework for biosimilars (2) • Directive 2003/63/EC - Part II, Section 4 of Annex I • Information required for ‘essentially similar‘ products (generics) not sufficient • Data requirements • Pharmaceutical, chemical, and biological data (+ Quality comparability studies) • Bio-equivalence and bio-availability data • Other comparative data (on a case by case basis) • Toxicological, other non-clinical • Appropriate and clinical data • Extrapolation of efficacy and safety to other indications to be justified or demonstrated separately • The general principles are (to be) addressed in agency guideline The same reference product should be used in all studies

8. Key aspects of the new EU legislation on biosimilars (1) • The CentralisedProcedure is obligatory for biopharmaceuticals and biosimilars • Recognition of high standard data package to evaluate biosimilars based upon fundamental criteria of quality, safety, and efficacy • Reference product to be authorized in the EU • The new legislation places a strong emphasis on safety when assessing and approving biosimilars • Framework for general and product specific case-by-case approachto assess biosimilars, taking into account current scientific knowledge and guideline to be developed by agency

9. Key aspects of the new EU legislation on biosimilars (2) • When developing a biosimilar, it is important for the Marketing Authorization Holder (MAH) to consider whether each individual indication should be studied • The Committee for Human Medicinal Products (CHMP) of the EMEA will decide what kind of tests and data will be needed to assess the safety and efficacy of biosimilars • EMEA/CHMP scientific advice EMEA/CHMP guidelines on Comparability

10. EMEA/CHMP guidelines on comparability • Since 2002 EMEA/CHMP have been developing a set of guidelines on "comparability issues" covering • Quality • Preclinical • Clinical aspects • Applying to • Change to a manufacturing process of a biological medicinal product • Similar biological medicinal products "biosimilars"

11. www.emea.eu.int EMEA/CHMP guidelines on comparability

12. Need for biosimilar guidelines • Need to support legislation • Annex I *: General (Overarching) Guideline • “The general principles to be applied are addressed in a guideline taking into account the characteristics of the concerned biological medicinal product published by the Agency.” • Need to focus on Comparability Exercise versus Reference Product • Specific Quality / Safety / Efficacy guidelines • * 2003/63/EC, Annex I, Part II, Section 4 Dr John Purves, EMEA – DIA Euro meeting Lisbon, 8 March 2005

13. EMEA/CHMP new biosimilar guidelines • 16 November 2004, the EMEA issued new guidance documents for the development and approval of biosimilar products • EMEA/CHMP overarching guideline to address general principles for development of biosimilars • Fourconcept papers that will lead to product-class specific guidelinesfor four biosimilar products (insulin, somatropin, epoetin, G-CSF) • Plan to revise existing EMEA/CHMP guidelines on Comparability • separation of biosimilarity and comparabilityguidelines for biotechnology-derived proteins More comprehensive and evolving EMEA/CHMP guidelines for biosimilars taking into consideration the clinical and regulatory experiences to date

14. Comparability guidelines: separation of comparability and biosimilarity Guidelines on Comparability Quality issues (non)- clinical issues Comparability of biotech-derived proteins: Quality ICH Q5E Comparability of biotech-derived proteins S&E (?) Biosimilar biotech-derived proteins CHMP-BWP Biosimilar biotech-derived proteins: S&E CHMP BMWP Dr Pekka Kurki, Chair CHMP Biosimilar WP – DIA Euro meeting Lisbon, 8 March 2005

15. Biosimilar guidelines Biosimilar biotechnology-derived proteins (S&E) Product-class-specific annexes Somato-tropins Epoietins Insulins rhG-CSF Others? Dr Pekka Kurki, Chair CHMP Biosimilar WP – DIA Euro meeting Lisbon, 8 March 2005

16. Biosimilar guidelines – current status (1) • Overarching guideline on biosimilars (EMEA/CHMP/437/04) released November 2004 for public consultation by February 2005 • Guideline on similar biological medicinal products containing biotechnology derived proteins as active substance • Quality (EMEA/CHMP/49348/05) released March 2005 for public consultation by June 2005 • Non-clinical / Clinical (EMEA/CHMP/42832/05) released June 2005 for public consultation by October 2005

17. Biosimilar guidelines – current status (2) • Product-class specific guidelines on biosimilars - (non)clinical annexes • Insulin (EMEA/CHMP 32775/05) released May 2005 for public consultation by October 2005 • Somatropin (EMEA/CHMP/94528/05) released May 2005 for public consultation by October 2005 • Erythropoietin (EMEA/CHMP/94526/05) released June 2005 for public consultation by October 2005 • Granulocyte colony stimulating factors (EMEA/CHMP/31329/05) released June 2005 for public consultation by October 2005

18. Biosimilar overarching guideline(EMEA/CHMP/437/04) • Outline concepts and basic principles (Annex I, Part II, Section 4) • In principle, concept of “biosimilarity” applicable to any biological product . In practice, highly purified products, which can be thoroughly characterised (some biotech products) • Due to the complexity of biotechnology derived products the generic approach is scientifically not appropriate • Biosimilar considerations: analytical methods, ability to characterize the product, manufacturing process, clinical and regulatory experience • Choice of Reference Product • Authorized in EU • Similar in molecular and biological terms • Same reference product used in quality, safety and efficacy studies • Same pharmaceutical form, strength and route of administration • Specific biosimilar product given to patient should be clearly identified to support Pharmacovigilance monitoring post-marketing

19. Biosimilar quality guideline(EMEA/CHMP/49348/05) • Specific for rDNA derived proteins • Full quality dossier (CTD Model 3) • Extensive comparability exercise • Main issues • Comparison to EU Pharmacopoieastandard as reference is not sufficient • Drug substance/product • State-of-art analytical methodology to characterize both biosimilar and reference products • Biosimilar process should be well developed, i.e. avoid additional comparability exercises • Product produced with final manufacturing process to be used in clinical trials (close to batches intended for marketing) • Differences to be addressed in the (non)clinical program

20. Biosimilar (non)clinical guideline(EMEA/CHMP/42832/05) • Guideline on general principles • Toxicological and other non-clinical • Clinical equivalence • Safety studies • Immunogenicity • Pharmacovigilance and risk mangement • Product class specific Guidelines • As above, additional detail: case-by-case

21. Biosimilars (non)clinical guideline Principles (1) • Extensive comparability studies required to show similarity in terms of quality, safety and efficacy • Company should justify the approach taken during the development of the product and contact EMEA for scientifc and regulatory advice • Full quality dossier and equivalent safety and efficacy profiles • Same EU reference product for all aspects of the comparability studies • Same pharmaceutical form, strength and route of administration • Data requirements are guided on a case-by-case basis by • Type of product and claimed therapeutic indication(s) • Extent of characterisation possible by analytical methods (complexity of molecule, state of the art analytical procedure) • Observed / potential differences between biosimilar and originator, and the impact on quality, safety, and efficacy • Clinical experience with substance class

22. Biosimilars (non)clinical guideline Principles (2) • The more complex the production process, the more scientific studies required to establish ‘similarity’ • The required clinical data for the comparability study with test product as produced with the final manufacturing process …. (otherwise justification and adequate additional data needed) • Extrapolation to other indications • Extrapolation of efficacy and safety to other indications of the reference product must be justified or demonstrated separately • Justification dependent on e.g. • Clinical experience with the reference product • Whether same mechanism of action involved • Whether immunogenicity is disease specific, dependent on route of administration or duration of treatment Dr Martina Weise, BfArM, Member CHMP Biosimilar WP – DIA Annual Meeting, Washington, June 2005

23. Biosimilars (non)clinical guidelines Non-clinical studies (1) • Should be performed before going into clinical development • Should be designed to detect differences in response and not the response per se • Their design requires a clear understanding of the product characteristics • Physico-chemical and biological studies should be reviewed from the point of view of potential impact on efficacy and safety • Approach taken will need to be fully justified in the non-clinical overview • General principles to be followed and tailored to the specific product on a case-by-case (as per product class specifc guidelines) • Pharmacodynamics studies • Toxicological studies Dr Hans-Karl Heim, Non-clinical Assessor, BfArM– EGA Meeting on Biosimilars, London, May 2005

24. Biosimilars (non)clinical guidelines Non-clinical studies (2) • Pharmacodynamics studies • In vitro studies: a battery of receptor binding studies or cell-based assays • many of which may already be available from quality-related bioassays • in order to assess if any differences in reactivity are present and to determine the likely causative factors • In vivo studies: animal studies shouldbe designed to maximise the information obtained • preferablycompare reference and claimed ‘biosimilar‘ products in the pharmaceutical form intended to be used in the clinical trials • be performed in (a) relevant species • employ state of the art technology

25. Biosimilars (non)clinical guidelines Non-clinical studies (3) • Limitted Toxicological studies • Repeat dose toxicity study • at least one study in relevent species, including toxicokinetic and immunological measurements • study duration should be sufficiently long to detection of relevant differences in toxicity • Specific safety concerns (e.g. local tolerance, antigenicity) • might be addressed in the same repeat dose study

26. Biosimilars (non)clinical guidelines Clinical studies (1) • The clinical comparability exercise is a stepwise procedure • Comparative PK study • Absorption and clearance and/or half life (e.g elimination rate may be different) • Equivalence margin must be based on clinical judgement (acceptance range for generics may not be applicable) • Clinical efficacy • In principle, confirmatory comparative trial(s) to demonstrate therapeutic equivalence and assay sensitivity (ICH E9, ICH E10) • Equivalence margins justified primarily on clinical grounds (review of the clinical trials performed with reference drug)

27. Biosimilars (non)clinical guidelines Clinical studies (2) • Comparative PK/PD studies may suffice if • The reference product is well characterised • PK and PD • Relationship PK – PD – clinical effect (exposure/effect) • PD marker(s) accepted surrogate marker(s) for efficacy (most relevant PD marker to be tested) • Equivalence margin pre-defined and justified • Comparison within the linear/”sensitive” part of the dose-response curve (more than one dose may be needed)

28. Biosimilars (non)clinical guidelines Clinical safety and pharmacovigilance • Pre-licensing • Clinical safety data always required, even if efficacy is shown to be comparable • Sufficient number of patients to compare common ADRs between reference and claimed ’biosimilar’ products: type, severity, frequency • Risk specification and pharmacovigilance plan part of the application dossier, as per EU legislation and guidelines • Pharmacovigilance systems/procedures should be in place (traceability as per current EU guidelines) • Post-marketing • Benefit/risk assessment on ongoing basis • Risk management programme may be required if rare but serious adverse reactions (e.g Epoetin/PRCA)

29. Biosimilars (non)clinical guidelines Immunogenicity (1) • Factors affecting immunogenicity • The immune response against therapeutic proteins differs between products …… • There is considerable inter-individual variability in antibody response in terms of different antibody classes, affinities, and specificities • Data should be collected from a sufficient number of patients (and appropriate duration) to characterise the variability in antibody response • Consequences of an immune response • An immune response to the product may have a significant impact on its clinical safety and efficacy…….

30. Biosimilars (non)clinical guidelines Immunogenicity (2) • Principles for evaluation of immunogenicity • The immunogenicity of a similar biological medicinal product must always be investigated • Normally an antibody response in humans cannot be predicted from animal studies • Only clinical trials are decisive to reveal immunogenicity • The assessment of immunogenicity requires an optimal antibody testing strategy • Characterisation of the observed immune response, as well as evaluation of the correlation between antibodies and pharmacokinetics or pharmacodynamics, relevant for clinical safety and efficacy in all aspects

31. Biosimilars (non)clinical guidelines Immunogenicity (3) • Testing • The applicant should present a rationale for the proposed antibody-testing strategy • Testing for immunogenicity should be performed by state of the art methods … • The screening assays should be validated and sensitive enough • An assay for neutralising antibodies should be available for further characterisation of antibodies detected by the screening assays • The periodicity and timing of sampling for testing of antibodies should be justified • In case of chronic administration, one-year follow up data will be required pre-licensing. • In view of the unpredictability of the onset and incidence of immunogenicity, long term results of monitoring of antibodies at predetermined intervals will be required (post-marketing)

32. Points to consider (1) • Today, EU legal/regulatory framework is in place to approve biosimilars • Essential similarity does not apply to biosimilars • Product complexity/limitation of analytical methods – major factor • Current and evolving EMEA/CHMP guidelines to support biosimilar applications • Case by case approach and product-specific approach for the "biosimilar situation" although general principles apply • Importance of ongoing regulatory experience with the assessment of biosimilar applications via the CHMP scientific advice • Importance of clinical experience with biologics (2–3 years after market approval to adequately validate risk/benefit profile) • A post-licensing risk management program (ongoing B/R assessment, PSURs, Phase IV trials, Registries?) will be a crucial element of the approval process if safety concerns

33. Points to consider (2) • Immunogenicity is still a ‘black box’ because onset and incidence are difficult to predict • Most of the severe immune-mediated adverse events are rare and may only become evident post-approval • The question occurs all along the life cycle of the product, and particularly when • A change is introduced to the manufacturing process, the formulation, the storage conditions, etc…. • A new manufacturer proposes a "biosimilar" product • Importance of progress made with quality tools and methods • Choice of antibody assays and their standardisation are important for comprehension and interpretation of the "immunogenicity profile" at any stage of the life cycle of a product • Issue of tracking biosimilar products given to patients to ensure post-marketing surveillance?

34. Emerging biosimilars Evolving and rapidly expanding field following different rules and dynamics than generic drugs Awareness Education Alertness

35. The way forward ? The way forward ? • How to build a collaborative approaches with stakeholders, experience sharing • those who have experience should share it • unexpected immunogenicity • assay strategies for different product classes • role for Eur. Pharmacopoiea and OMCLs? • standards (antibodies, assays) • Conferences, public meetings (e.g EMEA/DIA WS on biosimilar guidelines, Dec 8-9, 2005, Paris) • Opening the immunogenicity ‘black box’? • Any further guidance is warranted? • assays? • risk management? Dr Pekka Kurki, Chair CHMP Biosimilar WP – DIA Euro meeting Lisbon, 8 March 2005