What next? Manufacture the biosimilar product

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1 What next? Manufacture the biosimilar product Design manufacturing process to match QTPP Full quality dossier required. Use state of the art technologies In accordance with relevant ICH and CHMP guidelines Targeted development of biosimilar to match the reference product Careful consideration to the manufacturing process as the process defines the product e.g. host cell line, transfection process, cell culture media, hold times, drug product excipients, primary packaging

2 And then Demonstrate Comparability? Comprehensive analysis of the biosimilar and the reference product Designed to show similarities and potential differences in quality Side by side analysis using sensitive and orthogonal methods Final commercial product Not expected that all quality attributes of biosimilar will be identical to reference product but: Differences need to be justified Only acceptable if no impact on clinical performance Particular attention to attributes that impact potency and immunogenicity Ultimate objective: demonstrate similarity to the reference product

3 Assessing biosimilarity protein structure Protein structure Primary amino acid sequence should be the same as the reference Comparable higher order structure

4 Protein heterogeneity Amino acid substitution N- and C- terminal changes Mismatched S-S bonds Altered folding Truncation Aggregation Multimer dissociation Denaturation Assessing biosimilarity O- linked glycosylation N-linked glycosylation Methylation Oxidation Acetylation Deamidation Carboxylation Post translational modifications need to be characterized Presence of glycosylation structures/variants may be

5 Typical physiochemical biosimilarity exercise

6 Biological activity Variety of different assays should be used Complementary or orthogonal approaches to overcome limitations of single bioassay Assays sensitive, specific and discriminatory If product has more than one mechanism of action all functional activities should be evaluated e.g. receptor binding and activation Biological assays confirm Quality of product Integrity of higher order structure Mechanisms of action (Presence of expected functions, absence of new functions) Potential effects of post-translational modifications Receptor binding (ELISA/SPR) Cell based assays Functional assays Apoptosis ADCC C1q binding CDC FcyRI binding FcyRII binding FcyRIII binding FcRn binding

7 Quality comparability exercise : case study

8 Non-clinical studies required for Biosimilars Non-clinical studies performed before clinical trials Commence with in-vitro studies and then, if necessary, continue with in-vivo studies Studies required will depend on the number of relevant quality differences observed

9 Clinical studies required for Biosimilars Tailored clinical testing programme Stepwise approach: PK/PD followed by clinical efficacy and safety Choice of population for PK studies must be justified Comparative PK/PD studies may be sufficient along with immunogenicity data (e.g. surrogate marker)

10 Efficacy trials Efficacy trials are designed to investigate if there are no clinically meaningful differences between the biosimilar and reference, they are not designed to establish patient benefit Patient benefit established by reference product, need to demonstrate similar safety and efficacy Equivalence design Most sensitive patient population (in order to detect differences) Confirmatory clinical efficacy may not always be a prerequisite (e.g. concept paper for Filgrastim)

11 Clinical safety Captured during initial PK/PD studies and pivotal efficacy studies Immunogenicity of biologicals well known Product related causes include protein aggregates, attachment of sugars that are not present in humans, host cell proteins Safety data includes immunogenicity testing of biosimilar and reference (up to 1 year in a chronic condition) in order to identify any differences between the biosimilar and reference Pharmacovigilance and risk management activities necessary during the post-authorisation phase

12 Indication extrapolation Reference product usually has more than one indication When biosimilar comparability has been shown in one indication, extrapolation of clinical data to other indications possible if justified Consider in light of totality of data, mechanism of action and potential risks in patient populations Extrapolation of immunogenicity data from studied indication/route of admin must be justified HCPs should consult EPAR for details on clinical data provided

13 EMA concluded assay was not representative of physiological situation and allowed extrapolation to UC, CD, PsA and PsO Health Canada: ADCC may be an active mechanism in IBD but not in rheumatic diseases - extrapolation not recommended for UC and CD FDA: Accepted extrapolation to all indications approved for the reference product Remicade Indication extrapolation: Controversies Infliximab biosimilar (CT-P13) Differences in afucosylated glycan structures, FcyRIIIa binding, and in a highly sensitive antibody-dependent cell mediated toxicity assay (ADCC) Clinical studies: patients with RA and AS

14 Pharmacovigilance of Biosimilars As with any new medicine additional PV monitoring applies Remains under additional monitoring for ~5 years or until the EMA s Pharmacovigilance Risk Assessment Committee (PRAC) decides to remove it from the list. Biological medicines should be identified in suspected adverse reaction reports with respect to name and batch number

15 Pharmacovigilance: Importance of traceability for all biological medicines Inherent variability in large molecular weight structurally complex protein molecules (batch to batch from same manufacturer) Complex manufacturing process is specific to each manufacturer and will shape quality, safety and efficacy profile Changes in manufacturing processes may impact product quality. Not always possible to predict immunogenicity as a result of manufacturing change

16 Naming of biosimilars In the EU, biosimilars have the same INN as their reference Any biological medicine prescribed, dispensed or sold should be clearly identifiable (brand name or INN plus name of MAH). This will also ensure substitution by pharmacists does not inadvertently occur when the medicine is dispensed by a pharmacist Biological medicines can exhibit variability and therefore biological medicines which have the same INN should not be considered to be identical

17 Naming of Biosimilars WHO - INN biological qualifier proposal Voluntary scheme Random code follows INN Code - differentiate biological drug substances manufactured by different processes Aims to aid in the minimisation of errors in prescription, dispensing, pharmacovigilance and international transfer of Rxs Will prevent proliferation of national qualifier systems Scheme has generated controversy Impact assessment on scheme implementation to be carried out FDA draft guidance on Nonproprietary naming of biological products Shared non-proprietary names not appropriate for all biological products Non-proprietary name will include FDA designated suffix Aims to identify biological products to prevent inadvertent substitution and improve pharmacovigilance?? if interchangeable products will share same suffix as reference Public consultation now closed - no update so far!

18 Biological Medicinal Products sales and patent expiry USD$ billion EU Expiry date Ranibizumab (Lucentis) Pegfilgrastim (Neulasta) Glatiramer Acetate (Copaxone) 4.7 Expired Trastuzumab (Herceptin) 5.1 Expired Interferon Beta-1A (Avonex, Rebif) 5.4 Expired Insulin Aspart (Novomix, Novorapid) 5.4 Expired Bevacizumab (Avastin) Rituximab (Mabthera) Insulin Glargine (Lantus) Infliximab (Remicade) Etanercept (Enbrel) Adalimumab (Humira) Expired Expired Expired Expired USD$ billion

19 Slide by Peter Richardson, EMA, EBG Conference London 2016

20 Biosimilars in the pipeline

21 Regulatory Science Ireland: Biosimilar Research Project

22 RSI: Biosimilar Project Research activities: HPRA and UCC Objectives Peer reviewed scientific publications (practical considerations for HCPs) Survey perspectives and understanding of biosimilars Comparative studies of international models for providing safe and effective use of biosimilars Develop training activities and online resources Outreach activities Publications to date Biosimilar Medicines: Opportunities and Challenges in the clinical use and supply of Biosimilars Biosimilar Medicines: Recent Developments

23 Any questions?????????????