How to realise biosimilar’s full potential: Regulator’s view DIA 26th Annual EuroMeeting, Vienna 2014 Dr Peter Richardson Head of Quality, European Medicines Agency An agency of the European Union Disclaimer  The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to Drug Information Association, Inc. (“DIA”), its directors, officers, employees, volunteers, members, chapters, councils, Special Interest Area Communities or affiliates, or any organization with which the presenter is employed or affiliated.  These PowerPoint slides are copyright of the European Medicines Agency. Reproduction is permitted provided the source is acknowledged. 1 How to realise biosimilar’s full potential: Regulator’s view Evolution of Biosimilars in the EU Legislation Guidance Overarching guideline Directive 2001/83/EC Quality guideline & Directive 2004/27/EC Non-clinical/Clinical guideline Guideline Revision / Update Directive 2003/63/EC Product-class specific guidelines 2001 2002 Product evaluation 2 2003 2004 2005 First biosimilars authorised – Omnitrope and Valtropin 2006 2007 2008 First biosimilar epoetins authorised How to realise biosimilar’s full potential: Regulator’s view 2009 2010 First biosimilar filgrastims authorised 2011 2012 2013 First biosimilar mAbs authorised Dossier requirements for Biosimilars CTD Module Originator Biosimilar 3 4 Cross reference 5 Cross reference Cross reference – class specific Safety and Efficacy 3 How to realise biosimilar’s full potential: Regulator’s view Integrated Comparability Exercise – product specific Quality, Safety and Efficacy EU Biosimilar philosophy • Apply scientific principles • Use most sensitive methods / studies to show differences • Reduce non-clinical / clinical data requirements where appropriate • Develop EU network and facilitate global evolution of biosimilar framework 4 How to realise biosimilar’s full potential: Regulator’s view Biosimilar product experience in EU Marketing Authorisation 29 MAAs submitted 1 MAA under review 27 MAAs reviewed Insulin glargine(1) 1 Negative 19 Positive 7 Withdrawn Insulin (6) Epoetin (1) 17 Valid MAs 2 Withdrawn Filgrastim (1) Somatropin (1) Interferon alfa Somatropin (1) Epoetin (5) Filgrastim (7) Infliximab (2) Follitropin alfa (2) 5 How to realise biosimilar’s full potential: Regulator’s view Biosimilar scientific advice experience: EU 6 How to realise biosimilar’s full potential: Regulator’s view Biosimilar mAb scientific advice experience: EU 7 How to realise biosimilar’s full potential: Regulator’s view Guidelines for biosimilars Overarching Guidelines: Overarching Guideline (CHMP/437/04) “Guideline on Similar Biological Medicinal Products” Defines principles General Guidelines on Q/S/E Overarching nonclinical/clinical Guideline Overarching Quality Guideline Under Review Comments Under Review Class-specific Guidelines: non-clinical/clinical aspects Insulin 2006 Rev 2012 Somatropi n 2006 G-CSF Epoetin 2006 2006 Rev 2010 IFN-α LMWH mAbs IFN-β 2009 2009 Rev 2013 2012 2013 Public C. 8 How to realise biosimilar’s full potential: Regulator’s view Under Review Public C. Follitropin alfa 2013 Biosimilars Workshop 9 How to realise biosimilar’s full potential: Regulator’s view Overarching Guideline Main changes: • Definition of biosimilar and scope of biologicals covered • How to manage: improved efficacy or safety • Clarification regarding possibility to gain authorisation based on a PK comparative study (minimal clinical data) • Choice of reference medicinal product (global development) 10 How to realise biosimilar’s full potential: Regulator’s view Proposed Biosimilar Definition A biosimilar is a biological medicinal product containing a version of the active substance of an already authorised original biological medicinal product (reference medicinal product) (RP). A biosimilar demonstrates similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise. 11 How to realise biosimilar’s full potential: Regulator’s view Improved efficacy / safety  Intended changes to improve efficacy are not compatible with the biosimilarity approach.  Differences which could have a safety advantage (e.g., lower levels of impurities or reduced immunogenicity) should be explained but may not preclude biosimilarity. 12 How to realise biosimilar’s full potential: Regulator’s view Tailored development programme In specific circumstances, e.g. for structurally more simple biological medicinal products, a comparative clinical efficacy study may not be necessary • if similarity of physicochemical characteristics and biological activity/potency of the biosimilar and the reference product can be convincingly shown and similar efficacy and safety can clearly be deduced from these data and comparative PK data. • such an approach may have to be supported by additional data, for example in vitro and/or clinical PD data from a comprehensive comparative PD fingerprint approach. 13 How to realise biosimilar’s full potential: Regulator’s view Choice of Reference Product (RP) Facilitation of global development  A non EEA-authorized version of the RP may be used for certain clinical and in vivo non-clinical studies (where needed) if - authorisation based on similar regulatory standards - representative of the RP in the EEA  Bridging data will typically include - 3-way quality comparison (e.g., structural / functional data) And may include - 3-way PK and/or PD comparison 14 How to realise biosimilar’s full potential: Regulator’s view General Non-clinical / Clinical Guideline Main changes: • Risk-based approach: extent and nature of studies dependent on – product complexity – ability to characterise at quality level – differences at quality level (active substance and formulation (excipients, impurities)) • Non-clinical : step-wise approach (in vitro, need for in vivo, in vivo) • Clinical: PD markers and surrogate endpoints, safety, study design to test immunogenicity, extrapolation of indication 15 How to realise biosimilar’s full potential: Regulator’s view General Quality Guideline Main changes, elaboration / clarification of: • Quality target product profile (QTPP) • Evolution of quality profile through life-cycles • Comparability at the level of the finished product • Amino acid sequence expected to be the same as reference product • Additional testing expected for monoclonal antibodies • Different expression system 16 How to realise biosimilar’s full potential: Regulator’s view 1st Biosimilar Mab – Remsima / Inflectra • • • Remsima (duplicate Inflectra) : first biosimilar mAbs to be approved in Europe. European Commission Decision – 10th September 2013. Active substance: INN infliximab Reference product Remicade (authorised 1999). Further details – see comprehensive EPAR. 17 How to realise biosimilar’s full potential: Regulator’s view • Remsima Comparability (bioactivity) Extensive information Table continued in EPAR 18 How to realise biosimilar’s full potential: Regulator’s view Remsima - Learnings •Extensive comparability exercise: quality and non-clinical (in-vitro). This provided robust assurance on clinical performance and the extrapolation of indications. •Difference in quality profile - reduced afucosylation, translating into a lower binding affinity towards specific FcγRIIIa receptors→ lower ADCC activity ? Resolved by extended testing: physicochemical / bioactivity and consideration of mechanism of action. 19 How to realise biosimilar’s full potential: Regulator’s view EC: Market access to biosimilars • Sep 2010 project launch • Review availability of biosimilars in EU market • Define the necessary conditions for patient access – Current experience with access and uptake of biosimilars – Effects and consequences from the uptake of biosimilars – How to promote uptake of biosimilars • Deliverables -> 22th April 2013 – – – – Consensus doc: “What you need to know about Biosimilars” Information on reimbursement in EEA countries Study on “biosimilar market access” prepared by IMS Survey conducted by EGA to identify good practices, obstacles related to biosimilar uptake http://ec.europa.eu/enterprise/sectors/healthcare/files/docs/biosimilars_report_en.pdf 20 How to realise biosimilar’s full potential: Regulator’s view INN Aspects • EMA uses INN according to WHO policy • Biosimilar can use Reference Product INN - EMA: robust assessment of biosimilarity • WHO Consultation – 2006 / 2013 • What can be expected from INN ? - WHO Biological Qualifier • Coding of active substance in biosimilar - TGA Policy : 21 How to realise biosimilar’s full potential: Regulator’s view For further details on the discussion at the 57th Consultation on INN for Pharmaceutical Substances in October 2013, please see the Executive Summary: http://www.who.int/medicines/services/inn/57th_Executive_Summary.pdf International Pharmaceutical Regulators Forum - IPRF The IPRF will meet initially in conjunction with ICH Steering Committee meetings. Switzerland chair, Japan co-chair. The first goal is to enable all parties to identify new approaches and specific best practices, and develop smart strategies for dealing with the challenges of the globalization of the pharmaceutical industry. The second goal is to provide a global overview of the different regulatory developments at national and international level and enable open sharing of information and ideas among regulatory leaders with hands-on operational responsibilities. This information sharing will allow the forum participants to discuss issues at an actionable level of detail. The third goal is to support international regulatory cooperation in areas which are not covered by existing initiatives. http://ec.europa.eu/health/files/committee/71meeting/pharm636.pdf IPRF Working Group on Biosimilars – Chair: MFDS, Rep. Korea. Meetings are convening 1Q 2014 IPRF - further information, contact: secretariat.IPRF@swissmedic.ch 22 How to realise biosimilar’s full potential: Regulator’s view Thank you Peter Richardson Head of Quality Specialised Scientific Disciplines Department European Medicines Agency peter.richardson@ema.europa.eu | www.ema.europa.eu • Acknowledgements – Martina Weise (BMWP) – Camille Vleminckx (EMA) 23 How to realise biosimilar’s full potential: Regulator’s view