Current Regulatory thinking Around Biosimilars A Regulator s Perspective

Transcription

1 Current Regulatory thinking Around Biosimilars A Regulator s Perspective Biologics and Biosimilars Symposium; 07 May, 2012 Dr. Elena Wolff-Holz Paul Ehrlich Institut Federal Agency for Vaccines and Biomedicines [email protected] The views presented here are my own and do not necessarily reflect the views of the Paul-Ehrlich-Institut.

2 Biologics have revolutionized modern medicine and will continue to do so

3 Biologics have revolutionized modern medicine By 2016, 8 of the top 10 pharmaceuticals worldwide will be Biologics

4 Some economical considerations Slide by Paul Cornes, MD

5 Some economical considerations Slide by Paul Cornes, MD

6 Could there be biogenerics? Insulin MW MAb MW ?

7 Yes, there can! 14 Biosimilars authorized under own legislation in the EU None in the US (Cave: r-insulin, somatropin, LMWH) (as of January 2012)

8 Definition of a biosimilar in EU Directive 2001/83/EC (as amended) Article 10: Generics and legal basis for biosimilars Article 10(2a): 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 referencemedicinal product, ( ). Article 10(4): Where a biological medicinal product which is similar to a reference biological product does not meet the conditions in the definition of generic medicinal products, owing to, in particular, differences relating to raw materials or differences 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.

9 Different names throughout different jurisdictions

10 Generic and biosimilar development are different The EU pioneered law to establish a regulatory pathway for bringing biosimilars to market

11 For biologics: The process is the product. Source: Talk Inger Mollerup, Novo Nordisk A/S Joint EMEA/DIA Workshop on Biosimilars, Paris 2005

12 For biologics: The process is the product. Source: Talk Inger Mollerup, Novo Nordisk A/S Joint EMEA/DIA Workshop on Biosimilars, Paris 2005

13 Complexity and multifunctionality of MAbs 1 Fab 2 Fc 3 heavy chain 4 light chain 5 antigen binding site 6 hinge MAb MW

14 Biologics are always threesome Quality - impurities - batch inconsistency - contaminants - aggregates - microheterogeneity - fragments - tissue cross-reactivity - binding - potency - toxicity - immunotoxicity Non-Clinical B R I D G I N G Clinical - efficacy data - safety data - immunogenicity data

15 Bridging is done by Comparability Exercise Necessary whenever process is the product o Pre-and Post-change product (ICH Q5E) o new manufacturing site o upscale production o new up- (fermentation, harvest) or downstream (purification) process o new filling process o Comparison of a product with Reference Product (CHMP/437/04, 2005 = overarching guideline ) Case by case assessment Based on scientific principles

16 Bridging is done by Comparability Exercise Technical term to show that two biological / biotechnological products are similar or comparable 1) Scenario 1: After a change in the manufacturing process of a given product (pre- and post-change product from the same manufacturer) 2) Scenario 2: In a biosimilarity exercise (two products from different manufacturers) Scenario 1: Manufacturer has all the data and experience Scenario 2: Manufacturer does not have the data from the originator company (intellectul property) -> reverse engineering!

17 Development of biosimilars How much similarity do we need? How much do we need to know?

18 Development of biosimilars How much similarity do we need? How much do we need to know?

19 NOT Similar are Alternative Biologics Isoelectric focussing gels of non-innovator erythropoietins NOT similar to Reference E Schellekens H, Eur J Hosp Pharm Pract 2004; 3:43-7

20 Approved true biosimilar (Binocrit ) High batch consistency and NO difference to originator in Isoelectric Focusing Gels Brockmeyer and Seidl et al., Eur J Hosp Pharm Pract 2009; 15: 34-40

21 NOT similar is product with different amino acid sequence Guideline CHMP/437/04 Overarching guideline 2.1 CHOICE OF REFERENCE PRODUCT: The active substance of a similar biological medicinal product must be similar, in molecular and biological terms, to the active substance of the reference medicinal product: o Interferon alfa 2a IS NOT Interferon alfa 2b The pharmaceutical form, strength and route of administration of the similar biological medicinal product should be the same as that of the reference medicinal product. o Otherwise additional data in the context of the comparability exercise should be provided o Any differences between the similar biological medicinal product and the reference medicinal product will have to be justified by appropriate studies on a case by-case basis.

22 How much similarity do we need? Totality of the evidence obtained by evaluating more attributes and combinations of attributes at greater sensitivities with multiple complimentary methods. Clin Pharmacol Ther Mar;91(3):405-17

23 How much similarity do we need? Quality assessments Huub Schellekens & Ellen Moors; Nature Biotechnology 28,1; 2010

24 How much similarity do we need? Analytic characterization The mainstay is an extensive physicochemical and biological characterization: Form and function of the molecule Physicochemical characterisation, e.g. Capillary electrophoresis with laser-induced fluorescence detection (CE-LIF) Mass spectrometry techniques (e.g., MALDI-TOF) Nuclear magnetic resonance Antigen-antibody interaction, e.g. Surface plasmon resonance Secondary structure detection, e.g. Circular dichroism in near- and far-uv spectra Fourier transform infrared spectroscopy Combination of methodologies, e.g. liquid chromatography combined with mass spectrometry (e.g. Beck, A. et al, J Chrom B Analyt Tech Biomed Life Sci. 819(2): ; 2005)

25 How much similarity do we need? Preclinical characterization..aimed to close gaps of uncertainty Product Specificity Potency assay Comments Avastin (Bevacizumab) Anti-VEGF anti-proliferation bioassay (inhibition of rhvegf-induced proliferation of Human Umbilical Vein Endotheliae Cells HUVEC). (relative number of viable cells, quantified by fluorescence) Assay chosen as drug substance release test based on its sensitivity (ability to detect significant changes in the activity), robustness, precision (RSD<10%) and accuracy (98-102%) Simulect (Basiliximab) Anti-CD25 Inhibition of binding of radiolabelled IL-2 to IL-2 receptor expressed on T- lymphocytes (and thus inhibition of lymphocyte proliferation) Synagis (Palivizumab) Anti-RSV In vitro: RSV Microneutralisation Assay, RSV Fusion Inhibition Assay, BIAcore Analysis In vivo potency: Reduction of RSV titre in the lungs of infected cotton rats Comparison of different predecessor products with palivizumab during development Tysabri (Natalizumab) Anti-α4-integrin In vitro assay: Ability to bind α4-integrins and block its interaction with its co-receptor. Xolair (Omalizumab) Anti-IgE Inhibition of binding: Ability of omalizumab to inhibit binding of IgE to its receptor Shown to correlate to the inhibition of release of histamine

26 How much similarity do we need? Clinical comparability

27 Basic principles for Clinical Development of biosimilars The aim of a biosimilar development programme is NOT to establish benefit of a treatment for the patient (this had been done before for the reference product!) The aim is to establish biosimilarity! This means: The clinical study follows the idea that patients are models The clinical study is selected to represent the most sensitive model to study differences Thus, trial design might be (entirely) different from the normal guideline principles!

28 Basic principles for clinical development of biosimilars A clinical study in the most sensitive clinical condition as regards ability to detect differences = key principle o o o Homogeneous patient population Most sensitive endpoint (not necessarily benefit endpoint) Large efficacy difference Most likely to develop immune response (Anti Drug Abs,..) Normally: clinical equivalence Extrapolation to other indications, not formally tested but based on overall scientific evidence, is a sound principle Post-authorisation follow-up (pharmacovigilance) as needed

29 Extrapolation to other indications: What is current evidence for therapy decisions? Originator: a-tnf alpha Rheumatoid arthritis Psoriasis Psoriatric arthritis Crohn s disease Ulcerative colitis Ankylosing spondylitis Juvenile RA infliximab adalimumab golimumab certolizumab pegol EU: US: etanercept

33 Extrapolation to other indications: What is current evidence for therapy decisions? Originator: a-tnf alpha Mechanism of action is same o differences may be due to soluble vs membrane bound TNF Safety profile in clinical trials very similar Prescribers often talk of TNF blockers as a class of drug (e.g. Deutsche Gesellschaft für Rheumatologie) FDA has language in the label that refers to the class of TNF blockers Same principle may apply to Biosimilars

34 How much similarity do we need: General Dossier requirements CTD Module Originator Biosimilar 3 Quality 4 Non-Clinical Cross reference 5 Clinical Cross reference Cross reference class specific Safety and Efficacy Integrated Comparability Exercise product specific Quality, Safety and Efficacy Slide by Falk Ehmann, European Medicines Agency

35 Development of biosimilar guidelines: ongoing process! Defines principles Overarching Guideline (CHMP/437/04). Guideline on Similar Biological Medicinal Products Biotechnology- derived proteins Quality General guidelines Quality / Safety Efficacy Non-clinical Clinical Insulin Somatropin GCSF Epoetin IFN-α LMWH mabs follitropin-a IFN-b Product class specific data requirements Non-clinical Clinical Non-clinical Clinical Non-clinical Clinical Non-clinical Clinical Non-clinical Clinical Non-clinical Clinical Non-clinical Clinical Non-clinical Clinical Non-clinical Clinical

36 Draft Guideline on biosimilar medicines

37 Outcome of the public consultation huge interest!!! 405 pages of comments from 22 stakeholders

38 Outcome of the public consultation Mainly: agreement with the concepts proposed Main issues raised in the comments: Guideline should include a chapter on Quality Guideline should be clear on the degree of similarity (and not allow differences in the amino acid sequence) Guideline should not mention next generation mabs Non-clinical part: Guideline should ask for comparative toxicity study/ off-target toxicity Guideline should prohibit substitution / interchangeability

39 Outcome of the public consultation Main issues raised in the comments (continued): Extrapolation of indications only based on clinical data Define minimally acceptable programme for biosimilars whether licensed or not : Should not be allowed Product-/indication specific guidance should be prepared Guideline should advocate clear labelling / branding / INN, also necessary for traceability Guideline should include SmPC guidance / clarity Only surrogate PD markers to be accepted or no acceptance at all of PD markers as substitute for efficacy

40 Outcome of the public consultation! Disclaimer: Not yet final! May change! Draft guideline as published Current draft revised guideline

41 Approval of biosimilars in Europe requires thorough review

42 .and should lead to some investment and time savings mod. slide bythomas Kirchlechner, Sandoz

43 US Biosimilar Regulatory Framework: In 2009: Biologics Price Competition & Innovation (=BPCI) Act by Congress o FDA may oversee abbreviated pathway for approval of biosimilars but these are viewed as NDA products (r-insulin, LMWH, somatropin). o No legal pathway for EPO, filgastrim, mabs) In 2010: Patient Protection and Affordable Care Act passed by Congress Feb 2012: US Dept of Health published Draft Guidance for Industry: Scientific/Quality considerations in demostrating biosimilarity to a reference product Biosimilars newly defined class, based on analytics, (pre)-clinical studies plus Interchangeability meaning switching/alternating Interchangeability meaning substitution by pharmacist But hurdles remain: o Congress mandates user-fee program for FDA review o Legislation protecting intellectual property rights

44 Current EU issues -possible next steps: Continued improvement of regulatory framework for Biosimilars o use of PD parameters Development of new regulatory framework for Biobetters o Improved manufacturing (glycosylation, analytics,..) o Drug product (form, strength, iv/sc,..) o Improved proteins (T1/2, efficacy, penetration, safety, immunogenicity,..) Removal of barriers for global development of biosimilars o Feb 2012: US Dept of Health published Draft guidance for industry: one comparator in clin. trial (vs: US+EUR+Jap Originator+Biosimilar) is enough! o Apr 2012, EGA: original EU Dir. 2001/83 allows sufficient flexibility..removal of barriers for global development bringing down development cost Wider use of biosimilars

45 Thank you for your attention!!