CEMDC-PharmaTrain, Module 8. FOLLOW-ON DRUGS: GENERIC, BIOSIMILAR & NON-BIOLOGICAL SIMILAR MEDICINAL PRODUCTS May 11th 2017 Marketing authorization of biosimilar medicinal products. Differences of the EMA and FDA regulations Ildiko Aradi, PhD Clinical Development of Biologics Biotechnology Business Unit Gedeon Richter Plc.

AGENDA Registration of biosimilars in the EU Registration of biosimilars in the US Harmonisation of regulatory requirements

Registration of biosimilars in the EU

Biosimilars Biologicals: made by or derived from living organism using biotechnology (proteins, monoclonal antibodies) Biosimilars: after patent expiry, e.g. insulin 2001, somatropin 2003, erythropoietin 2004, filgrastim 2006 Legal basis in EU -2003/2004, first biosimilar guidelines - 2005/2006 Biologicals form a significant portion of the pipelines  future for biosimilars

Biosimilars in EU First biosimilar in 2006 – somatropin (Sandoz) First biosimilar mAb in 2013 – infliximab (Remsima/Celltrion and Inflectra/Hospira) Biosimilar mAbs in focus Targeted therapies Market potential Increasing number of biologicals Access to patients Source: Evaluate Pharma, AAPS Biotechnology Conference May 2011

Focus on Biosimilars - EMA Definition A biosimilar is a biological medicinal product that contains a version of the active substance of an already authorised original biological medicinal product (reference medicinal product) in the European Economic Area (EEA). Similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise needs to be established. EMEA/CHMP/BMWP/42832/2005 Rev1

Biosimilars - Why Not Identical? MAb 150 000 Daltons Insulin 5 700 Daltons Complexity matters

Major Indications for mAb Therapy Psoriasis etanercept (Enbrel®) adalimumab (Humira®) infliximab (Remicade®) Oncology cetuximab (Erbitux®) bevacizumab (Avastin®) rituximab (MabThera®) trastuzumab (Herceptin®) Rheumatoid arthritis rituximab (MabThera®) adalimumab (Humira®) etanercept (Enbrel®) infliximab (Remicade®) Inflammatory bowel disease infliximab (Remicade®) adalimumab (Humira®) Patent protections expiring soon

Duration of procedure: Centralized Marketing Authorization procedure Day 120 List of Questions (LoQ) Day 180 List of Outstanding Issues (LoOSI) Duration of procedure: ~ 1 year Schneider 2008

Development of Biosimilar Medicines in EU – Comparability Exercise EU Reference Product Comparable Comparable Comparable Target Process Physico-chemical quality Non-clinical Clinical Risk Management Plan Similar Biological Medicinal Product

Continuous revison of guidelines EMA Biosimilar guidelines PRODUCT SPECIFIC BIOSIMILAR GUIDELINES GUIDELINES OF RELEVANCE FOR BIOSIMILAR MEDICINES OVERARCHING BIOSIMILAR GUIDELINES GENERAL - Guideline on similar biological medicinal products QUALITY ISSUES - Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues NON - CLINICAL AND CLINICAL ISSUES - Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues Insulin Somatropinn G-CSF EPO LMWH IFN -alpha IFN- beta FSH mABbs OTHER GUIDELINES RELEVANT FOR BIOSIMILARS COMPARABILITY – QUALITY ISSUES – Guideline on comparability of medicinal products containinig biotechnology derived proteins as active substance: Quality Issue COMPARABILITY – NON -CLINICAL AND CLINICAL ISSUES - Guideline on comparability of biotechnology-derived medicinal products after change in the manufacturing process: non-clinical and clinical issues IMMUNOGENICITY - Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins and Guideline on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use Continuous revison of guidelines

Comparability Exercise Comparability of different versions of the active substance of a biological Manufacturing change Versions of a product need to be comparable before and after a manufacturing change Biosimilar development Biosimilar product needs to be comparable to its reference product © Christian Schneider, presented at 25th Annual EuroMeeting, Amsterdam, 2013

Biosimilars are Systematically Engineered to Match the Reference Product Define target Confirmation: Final comparability exercise Development of Manufacturing process Target directed approach Characterize multiple lots of the Reference Product: Changes in the reference product over time provides distribution of acceptable variants Iterative optimization of all process steps using sophisticated analytical characterization to achieve biosimilarity Ranking quality attributes based on their criticality Risk based Approach

Non-clinical and Clinical Development 1 PRINCIPLES OF NON-CLINICAL DEVELOPMENT Step-wise approach – risk based panel of in vitro assays in vivo non-clinical studies – usually not needed Challenges: statistical analysis, complex panel of assays, necessity of in vivo studies in certain regions outside of EU

Non-clinical and Clinical Development 2 PRINCIPLES OF CLINICAL DEVELOPMENT Step-wise approach comparative pharmacokinetic (PK) and pharmacodynamic (PD) study comparative efficacy and safety study in one or more indications (extrapolation) sensitive patient population endpoint selection immunogenicity ‘specifically tailored’ clinical programs Challenges: feasibility of huge trials in oncology setting, necessity of local clinical studies in certain regions outside of EU

Biosimilars approved in the EEA have equivalent Aim of the Biosimilar Clinical Studies: Establishing Clinical Comparability Comparative PK/PD (i.e. Phase I) Comparative efficacy/safety/immunogenicity (i.e. Phase III) Equivalence trials Clinical studies single centre or multi-centre healthy volunteers or patients n ≈ 100-500 1 to 3-5 years How much clinical data is necessary? How much similarity is necessary? What should be the study population? What should be the clinical endpoint? How big safety database is needed? … Biosimilars approved in the EEA have equivalent efficacy and safety with the reference product

Weise et al. Biosimilars: What clinicians should know, Blood 2012

Weise et al. Biosimilars: Clinicians concerns addressed based on scientific principles Quality of biosimilars in EU Biosimilar – why not identical? Sufficient safety database, including immunogenicity Efficacy of biosimilars Extrapolation of indications Interchangeability/substitution

Quality of biosimilars in EU Biosimilars approved in the EU are of high quality - same quality standards for all biologicals Comprehensive guality comparability programme assessing physicochemical and functional characteristics of the biosimilar with the reference product

Biosimilar – Why not Identical? Biological products always vary In the human body From batch to batch After manufacturing changes Between manufacturers © Christian Schneider, presented at 25th Annual EuroMeeting, Amsterdam, 2013

Sufficient safety database, including immunogenicity General safety experience gained with the reference product applicable to the biosimilar based on demonstrated close similarity Demonstration of similar physicochemical characteristics, biologic activity, pharmacokinetics, pharmacodynamics/efficacy and safety data, including immunogenicity, allow reasonable reassurance for comparable safety profile Immunogenicity testing: same requirements for all biologicals, no specific concern with biosimilars

Efficacy of biosimilars Biosimilars are as efficacious as their reference products Equivalence margins for comparative efficacy studies based on statistical and clinical considerations to exclude any clinically relevant difference Biosimilars are therapeutic alternatives to their reference products using the same posology for the same indications

Extrapolation of indications Based on the totality of evidence provided by quality, non-clinical and clinical comparability data High analytical and functional similarity: If there are no differences relevant to the pharmacology of the molecule, it will behave as the reference product in all patient populations Extrapolation also applies to pre-and post-change products already on the market

Interchangeability/substitution Biosimilars are therapeutic alternatives to their reference products using the same posology for the same indications Switching: do not lead to change in clinical management Traceability: pharmacovigilance legislation in EU Recent developments, e.g. Norway and Finnland Norwegian switch study (NOR-SWITCH) – initiated in 2014; switch to biosimilar infliximab is almost complete in Norway Current position of Fimea is that ‘biosimilars are interchangeable with their reference products under the supervision of a health care person’

Registration of biosimilars in the US

Five distinct registration pathways in the US EU: Centralized procedure, interchangeability decided at national level US: Alternative pathways, interchangeability is regulated by FDA 1. NDA (505(b)1): Originator NCE ‘Original’ or‘Stand alone’ - small molecule and early biotechnology products – not a registration route for biosimilars 2. Hybrid NDA (505(b)2): Partial reference to originator NCE Example : Somatropin/Sandoz ; EU: biosimilars USA: 505(b)2 úton. No available pathway for biosimilars at that time. 3. ANDA (505(j)): Reference to originator NCE Example: LMWH /Sandoz; EU: biosimilar USA: ANDA, generic 4. BLA (PHS 351(a)) Originator biologicals Most biotechnology products registered in the US as BLA. Example: Tbo-filgrastim/Teva; EU: biosimilar (2008), FDA: BLA (submitted in 2009 and approved 2012, lack of biosimilar pathway) 5. BLA (PHS 351(k)): Reference to originator biological (2010) 1962. után (Kefauver-Harris – safety&efficacy is kell az elfogadáshoz) törzskönyvezett gyógyszerek generikumai esetében.

Generic vs biosimilar registration in the US

Biosimilar (BLA 351(k)) legislation in the USA Public Health Service Act - Amended by the Biologic Price Competition and Innovation Act of 2010 Section 351(k) abbreviated pathway for the approval of biosimilars Section 351(i) definition of biosimilarity Biosimilar Interchangeable biosimilar Definition of biological product redefined to include “protein”. For proteins, BLA 351(k) can be followed. Chemically synthesized polypeptides with more than 100 amino acids are proteins Recombinant biologicals with less then 40 amino acids are not proteins but peptides (consequently suitable for ANDA and not for BLA 351(a or k)) Highly similar (USA) used instead of comparable (EU) ICH Q5E: comparability defined as highly similar quality attributes

FDA Definition of biosimilarity Biosimilar or Biosimilarity means: that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; and there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.

Definition: Reference Product Reference Product means: the single biological product, licensed under section 351(a) of the PHS Act, against which a biological product is evaluated in an application submitted under section 351(k) of the PHS Act. Note: A biological product, in a 351(k) application, may not be evaluated against more than 1 reference product.

Definition: Interchangeability Interchangeable or Interchangeability means: the biological product is biosimilar to the reference product; it can be expected to produce the same clinical result as the reference product in any given patient; and for a product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the product and its reference product is not greater than the risk of using the reference product without such alternation or switch. Note: The interchangeable product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.

FDA guidelines Category Title Type Date Procedural; Biosimilarity Reference Product Exclusivity for Biological Products Filed Under (PDF - 99KB) Draft Guidance 08/04/14 Biosimilarity Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (PDF - 169KB) Final Guidance 04/28/15 Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product (PDF - 144KB) Biosimilars Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 Guidance for Industry (PDF - 107KB) Biosimilars: Additional Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 (PDF - 104KB) 05/12/15 Biosimilarity; Procedural Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants (PDF - 306KB) 11/17/15 Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product (PDF - 150KB) 12/28/16 Considerations in Demonstrating Interchangeability With a Reference Product Guidance for Industry (PDF - 229KB) 01/17/17

BLA 351(k): general concept and issues Scientific/clinical issue: biosimilar vs interchangeable biosimilar Biosimilar – no interchangeability Interchangeable biosimilar – additional clinical studies BUT first, almost all products will become biosimilar only Biosimilar – new active ingredient New INN for biosimilar (originator’s strategy, branded product) just like for BLA Consequences for pharmacovigilance Because of new INN PREA requires PK and/or PD study in pediatric population; Solution: FDA meeting, waiver, or postpone EU biosimilar dossier could be submitted as BLA 351(a) see example of tbo-filgrastim Patent issues

Biosimilar approvals in the US INN Trade name Company Date of approval pegfilgrastim   Mylan/Biocon adalimumab Boehringer Ingelheim bevacizumab Amgen/Allergan trastuzumab Coherus infliximab Flixabi Samsung/Merck Amjevita Amgen 2016 Sandoz complete response letter etanercept Erelzi epoetin alfa Retacrit Pfizer/Hospira filgrastim Apotex Inflectra Pfizer/Celltrion Zarxio 2015

Biosimilars under FDA review 351(k) Applications Under First-Cycle Review Goal Date Proposed Biosimilar Reference Product January 2017 Samsung Bioepis' SB2 Janssen Biotech's Remicade(infliximab) June 2017 Coherus’ CHS-1701 Amgen's Neulasta (pegfilgrastim) September 2017 Mylan and Biocon's MYL-1401O Genentech's Herceptin (trastuzumab) Amgen and Allergan's ABP 215 Genentech's Avastin (bevacizumab) September 2017 (estimated) Boehringer Ingelheim’s BI 695501 AbbVie’s Humira (adalimumab)

Global harmonisation of reguatory requirements Challenges - need for comparability with reference product sourced locally in vivo studies efficacy data local studies Interchangeability INN name issue Comparability at clinicallevel is not expcted to be affected by ethnic factors – acceptance of trials from different regions/populations should be justified.

Global harmonisation of reguatory requirements Global harmonisation efforts WHO IPRF: International Pharmaceutical Regulators Forum Biosimilar Cluster: EMA, FDA, HC, PMDA Global development can be facilitated by acceptance of reference products and clinical data from different regions Goal: faster access of patients to affordable medicines at sustainable price Comparability at clinical level is not expcted to be affected by ethnic factors – acceptance of trials from different regions/populations should be justified.

European markets - 10 years experience with biosimilars Clinicians confidence to be further increased to ensure biosimilars can keep their promise of improving patient access and affordability 10 years of experience with biosimilars in the EU: physicians and patients are becoming more confident and less concerned Education and unbiased information on biosimilars are important 2013: European Commission consensus information document 2016: Medicines for Europe, Biosimilar Medicines Handbook

Limited patient access to biologics

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