International Evolution

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1 EMA Biosimilar update: International Regulatory Convergence Presented by: Peter Richardson, 29 April 2016 Head of Quality Office Specialised Scientific Disciplines Department, EMA An agency of the European Union Contents International Evolution EU Update: products & guidelines Transparency IPRF Biosimilar Working Group Quality characterisation Training / communication 1 1

2 Biosimilars: Surfing the wave 80 s : rdna insulin 90 s : Comparability guidelines 00 s : EU + WHO Biosimilar guidelines 2016 : Strong global interest in biosimilars Global implementation Major regions have developed and adopted guidelines to WHO standard (not all represented) 3 2

3 Biosimilars WHO international role ICDRA 2006 Implementation meetings : SBP Guideline review WHO guideline: very important tool to assist global convergence 4 Biosimilars / Similar Biotherapeutic Products Key learning during WHO implementation Biosimilar (SBP) Generic (not BE study or repeat of benefit / risk) Comparability v RBP (head to head required) Terminology important (e.g. not biogenerics) Quality is foundation of SBP (a key communication message) Biosimilarity: Stepwise approach (start with quality: Totality of Evidence) Experience has refined approach (efficient / science based data requirements) 5 3

4 Additional effort required (WHO Implementation) 6 International Pharmaceutical Regulators Forum Biosimilars Working Group (BWG) 7 4

5 Contents International Evolution EU Update: products & guidelines Transparency IPRF Biosimilar Working Group Quality characterisation Training / communication 8 General Guidelines: Guidelines for biosimilars Overarching Guideline (CHMP/437/04 Rev. 1) Guideline on Similar Biological Medicinal Products Non-clinical/clinical Guideline Quality Guideline Class-specific Guidelines: non-clinical/clinical aspects: Insulin Somatropin G-CSF Epoetin IFN-α LMWH mabs IFN-β Follitropin 2006 Rev Revision ongoing 2006 Rev CP(RP): Jan16 Revision ongoing 5

6 EU Scientific advice for biosimilars FU First Around 75% of scientific advice requests are for monoclonal antibodies 10 EU Biosimilar product review (Mar 2016) 44 MAAs submitted 31 MAAs reviewed 13 MAAs under review 2 Negative 22 Positive 7 Withdrawn Interferon alfa Insulin human Valid MAs Somatropin (1) Epoetin (5) Etanercept (1) Filgrastim (8) Infliximab (2) Follitropin (2) Insulin glargine (1) Pre-authorisaton Insulin (6) Epoetin (1) 2 Withdrawn Post-authorisaton Filgrastim (1) Somatropin (1) Adalimumab (2) Enoxaparin sodium (2) Etanercept (1) Insulin glargine (1) PEG-filgrastim (3) Rituximab (1) Teriparatide (2) EC Decision Infliximab (1) 6

7 Business Pipeline Forecast and business intelligence BP dialogue with companies companies actively participating in the BP activity Internal discussion - Contributions to the EMA planning and reporting cycle Business intelligence - 20/25 BP meetings per year Forecast - increase in biosimilar MAAs in 2015: realised & continuing in Immunogenicity Guideline: Workshop (9 March 2016)

8 Statistical methodology for quality comparability 14 Contents International Evolution EU Update: products & Guidelines Transparency: IPRF Biosimilar Working Group Quality characterisation Training / communication 15 8

9 IPRF: Biosimilar Working Group Chair: Yeowon Sohn (Younjoo Park) MFDS; Co-chair: Peter Richardson EMA 3 rd Face-to-Face meeting: 27 th June Work plan and mandate adopted ICH June Public Assessment Summary Information for Biosimilars (PASIB) - Reflection paper Synergy with WHO Training 16 PASIB PASIB : Aim is to increase transparency Concise summary of the review of a biosimilar application in a common language (e.g. English) PASIB is an optional tool and has been designed to reduce local translation effort by the NRA Template + Guidance + 4 examples 17 9

10 IPRF BWG - PASIB 18 PASIB 19 10

11 PASIB PASIB : Can be used for lifecycle NRA may ask applicant to compile data (optional): NRA to decide how to use NRA compiles review summary and controls final document NRA free to compile as required IPRF encourage consistency and transparency Aim for < 10 pages 20 PASIB Remsima (EMA) 21 11

12 Availability of PASIB Aim is to provide directory via IPRF website PASIB: local NRA EPAR (EU) Other Assessment Report formats 22 Contents International Evolution EU Update: products & guidelines Transparency: IPRF Biosimilar Working Group Quality characterisation Training / communication 23 12

13 Transparency Quality aspects Substantial increase in transparency for quality aspects relating to biosimilars, e.g. PASIB EPAR FDA Advisory Committee EU examples 24 PASIB Herzuma, quality part (MFDS) 25 13

14 Benepali EPAR: Quality characterisation 26 FDA - Arthritis Advisory Committee Meeting: CTP-13, February 9,

15 Biosimilar mabs - physical-chemical methods Biosimilar example / function Example 1 Example 2 Characterisation AS specifications ESI-MS (mass, glycation) Peptide map (MS/MS / Peptide map (MS/MS / HPLC) N-terminal / C-terminal sequencing MS Disulphide bonds / Free thiol analysis FTIR / CD DSC (thermal stability) SEC-HPLC CE-SDS (purity) IEF (charge heterogeneity) IEC-HPLC LC-MS/ UV HPAEC-PAD (Oligosaccharide, monosaccharide, Sialic acid content) Identity (IEF) Identity/Purity (IEC-HPLC) Purity reduced/non-reduced (CE-SDS) Purity(SEC-HPLC) Content (UV) Oligosaccharide profiling (Bio-LC) MS (mass) Peptide map (LC-MS) N- / C-terminal sequence (peptide map) Disulphide bonds / Free thiol analysis (FLP) Methionine oxidation (LC-MS) Deamidation (LC-MS) N- glycan profile (LC-ESI-MS/MS, HILIC-UPLC) N-linked glycosylation site analysis SEC-HPLC icief / CEX (charge heterogeneity) FTIR / CD / HDX-MS DSC (thermal stability) Aggregates (SEC/MALLS / SV-AUC) CE-SDS (purity) Protein size (DLS) UV Subvisible particles (MFI) Content (UV) Identity (icief) HMW (SEC) Non-reduced (CE-SDS) FP specifications 28 Particulate matter Content (UV) Identity (IEF) Purity(SEC-HPLC) Identity/Purity (IEC-HPLC) Purity reduced/non-reduced (CE-SDS) Particulate matter Content (UV) Identity (icief) HMW (SEC) Non-reduced (CE-SDS) Regulatory considerations on HOS V Jekerle Biosimilar mabs - biological methods Biosimilar example / function Example 1 Example 2 Characterisation Substrate binding affinity (SPR, ELISA) Fc binding (FcγRI, FcγRIIa, FcγRIIb, FcRn, FcγRIIIa/b) C1q binding (ELISA) Ex vivo cell binding Transmembrane substrate binding Substrate specificity In vitro neutralisation assay Substrate effect blockage (in vitro) Apoptosis (FACS) CDC ADCC Effector function in vitro Substrate binding affinity (FRET, FACS, SRP) 6 x Fc domain binding C1q binding (ELISA) In vitro assay (neutralisation) Apoptosis assay CDC ADCC Effector function in vitro Biological activity (cell-based disease model) Inhibitory apoptosis assay AS specifications In vitro assay (substrate neutralisation) Competitive inhibition (FRET) In vitro assay (neutralisation) FP specifications In vitro assay (substrate neutralisation) Competitive inhibition (FRET) In vitro assay (neutralisation) 29 Regulatory considerations on HOS V Jekerle 15

16 Contents International Evolution EU Update: products & guidelines Transparency IPRF Biosimilar Working Group Quality characterisation Training / Communication 30 European Medicines Regulatory Network (Regulator s view) 31 16

17 TRAINING - International Agency is proposing to run a training event for international regulators in 4Q 2016 Multiple requests from external NRAs and EU MS IPRF BWG identify training as a key aspect at this stage of biosimilars implementation Aim is also to complement WHO initiatives 32 EC communication: DG GROW Workshop - 06 Oct EC: yearly report on market access for biosimilars Yearly multi-stakeholder workshop Focus: Patients, Physicians, Payers 33 17

18 EC communication: DG GROW Workshop - 20 June 2016 = Patients & Physicians 34 EMA communication activities Agency is... Participating at Conferences particularly to communicate with patients / physicians, e.g. European Medical Societies Roundtable on Biosimilars, January 2016 EC Workshop : June

19 Thank you for your attention Peter Richardson, Head of Quality Office Specialised Scientific Disciplines Department, EMA 36 19