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© Bird & Bird LLP 2010 Thanks to our Sponsors!! Bird & Bird LLP Engel & Novitt, LLP Finnegan, Henderson, Farabow, Garrett & Dunner, LLP
© Bird & Bird LLP 2010 GoToWebinar Attendee Interface 1. Viewer Window 2. Control Panel
Biosimilars Europe AIPLA Webinar-8 December, 2010 Liz Fuller, Partner
© Bird & Bird LLP 2010 Overview ● Chemicals vs. Biologics-bioequivalence and comparability ● Authorisations to date ● Biosimilars in Europe-Legal basis for authorisation ● What's New-Draft Guidelines out for Biosimilars of Monoclonal Antibodies ● Summary
© Bird & Bird LLP 2010 Generics: Chemicals vs Biologics ● Chemical products are created by mixing together well-defined chemicals under controlled circumstances. The resultant product can be analysed in a laboratory to determine that it is identical to that of an originator/innovator. Therefore easy to compare to reference product for bioequivalence. ● Biological products are alive (e.g., vaccines, mAbs, recombinant proteins). They are created by engineering living cells to produce the desired protein or antibody. As the living cells are unique, the products so produced can never be absolutely identical to that of an originator/innovator. ● “Biological medicinal products can be defined therefore largely by reference to their method of manufacture.”
© Bird & Bird LLP 2010 Biosimilars to date ● EU approvals Omnitrop-Sandoz (reference Genotropin) Binocrit, Abseamed, Epoietin Alfa Hexal-Sandoz (reference Eprex) Silapro-Stada (reference Eprex) Retacrit-Hospira (reference Eprex) Valtropin-BioPartners (reference Genotropin) Filgrastim-Sandoz/Hexal (reference Neupogen) ● EU rejections Alpheon-interferon α-2a and interferon β-BioPartners Insulin Human Marvel-Marvel LifeSciences-withdrawn ● US-Omnitrop-Sandoz (reference Genotropin)
© Bird & Bird LLP 2010 So why are Biosimilars important? ● Biosimilars have strongest growth in the pharma sector, and are not priced as are other “generics” ● They are an extremely expensive category of products used to treat very serious indications ● Many other products under development by: BioPartners, Merck BioVentures, Sandoz, Bioceuticals, Biogenerix, Ambrx, et al. Other major pharma companies have indicated they will enter this market. ● Regulatory environment and legal status in flux in EU, on a case-by-case basis In US, legal pathways created in Biologics Act in March 2010-Guidances forthcoming
© Bird & Bird LLP 2010 Biopharmaceuticals: Biogenerics, Biosimilars and Follow-on Biologics ● Biological pharmaceuticals manufactured by biotechnology methods, i.e., involving the use of living organisms (cells, bacteria, yeast) ● Biopharmaceuticals are defined by their manufacturing processes. If they originate in different cell lines, they are distinct, i.e., not bioequivalent. As such, there is technically no such thing as a biogeneric, though the term is often used. ● It is however, possible to demonstrate comparability to the originator’s product, the term “biosimilar” is used in Europe, while the terms biosimilar and “follow-on biologic” are used by the FDA.
© Bird & Bird LLP 2010 Relevance of this lack of “identicality” ● Immunogenicity-significant danger to patients ● Very difficult to develop products from a different cell line-only very large sophisticated companies can manufacture and support biotech development. ● Very minor changes in the manufacturing process can result in profound differences in safety and efficacy of the product (e.g., Eprex) ● Extensive post-marketing surveillance is required, and effects “substitutability” by physicians and pharmacists (US), problem with INN ● Perhaps particularly relevant in case of mAbs-due to multi- determined (and sometimes poorly understood) efficacy
© Bird & Bird LLP 2010 Eprex and PRCA ● J & J (Ortho Biotech/Janssen-Cilag) altered its manufacturing process (and presentation) of erythropoietin marketed in the EU, Eprex. ● On the market for 10 years, and in 2002, PRCA (pure red cell aplasia) was identified in patients with CRF and/or CRI that had received Eprex SC. MA in that indication suspended in EU for nearly 4 years. ● There were over 65 variations in the EU to the original Eprex registration. ● Significance is that problems of the RMP effect profoundly effect subsequent developments and regulatory strategies (specific exception made for Binocrit from the EPO development guideline in this case- Eprex was not used as a comparator in SC studies in renal anaemia patients and therefore no second randomised, parallel group clinical trial could be conducted). ● Regulatory Authorities far more strict on safety issues and also in imposing post-marketing obligations.
© Bird & Bird LLP 2010 Pharmaceutical Regulation in Europe ● Most chemical products-National Regulatory Authorities either individually or through DCP or MRP ● Biotech products (e.g., recombinants, mAbs, transgenic products), orphan medicinal products and products for the treatment of certain types of disease (e.g., autoimmune, cancer and diabetes)-mandatory that they obtain regulatory approval at the EMEA (European Medicines Agency-London)
© Bird & Bird LLP 2010 Biosimilar MA Route-EU Legal Basis ● Amendments to Annex I of Directive 2001/83 (2003/63/EC) ● CPMP Guidance Notes (2003) ● Amendments to text of Directive 2001/83 (2004/27/EC) ● Various CHMP Guidelines in ● Various Product-specific CHMP Guidelines (G-CSF, Somatropin, human soluble insulin, Erythropoietins, alpha interferon and LMW heparins (draft))
© Bird & Bird LLP 2010 Amendment to Directive 2001/83 (2003/27/EC) 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. The type and quantity of supplementary data to be provided must comply with the relevant criteria stated in Annex I and the related detailed guidelines. The results of other tests and trials from the reference medicinal product’s dossier shall not be provided.” In force as from 30 October 2005.
© Bird & Bird LLP 2010 Draft Guideline on biosimilar medicines containing monoclonal antibodies ● Released for Consultation 26 November 2010 until 31 May 2010 ● Addresses Non-clinical, Clinical and Post-marketing issues (both PV and post-marketing clinical requirements) ● Quality issues are not addressed-rather the reader is referred to existing Guidances EC/CHMP/49348/05 (which is soon to be revised) and CHMP/BWP/15753/07 ● To be read in conjunction with the general guidelines set forth in the "Guideline on similar biological medicinal products containing biotechnology –derived proteins as active substance: non-clinical and clinical issues (EMEA/CPMP/42832/05)
© Bird & Bird LLP 2010 Non-clinical development for biosimilar mAbs ● Scientific Advice strongly recommended ● Risk-based approach to be evaluated on a case-by-case basis in the choice and extent of in vitro and in vivo studies ● Determination as to whether in vivo studies are required will depend on the availability of a relevant animal model-large comparative tox studies in non-human primates are not recommended, though, due to the specificity of mAbs, the relevant species for tox studies is in most cases a a non-human primate. ● If the conduct of the in vitro studies raises no specific safety concerns, it is possible that no in vivo animal studies will be required.
© Bird & Bird LLP 2010 Clinical development of biosimilar mAbs ● Again, close collaboration with EMEA through scientific advice is strongly recommended. ● A comparative PK study in a sufficiently sensitive and homogeneous population forms an integral part of biosimilar mAb development, usually in a parallel-group design due to the long half-life of mAbs and potential interference of immunogenicity. ● PK data can be used to extrapolate data on both safety and efficacy to other indications-generally most sensitive to immunogenicity must be used. ● Dose-concentration-response studies will always be required ● Specific considerations for extrapolation to additional oncological indications. ● Focus of exercise is to demonstrate similar efficacy and safety relative to the reference product, not to patient benefit, per se
© Bird & Bird LLP 2010 Biologic patents to expire-according to BIO Humira (Abbot) 2016Neulasta (Amgen) 2015 Aranesp (Amgen) 2014Enbrel (Amgen) 2012 Myozyme (Genzyme) 2016Fabrazyme (Genzyme) 2015 Herceptin (Roche) 2018Avastin (Roche) 2018 Rituxan (Roche) 2018Lucentis (Roche) 2018 Erbitux (Eli Lilly) 2017Remicade (J & J) 2014 Synagis (AZ) 2018
© Bird & Bird LLP 2010 Questions and answers
Thank you Liz Fuller Partner Bird & Bird is an international legal practice comprising Bird & Bird LLP and its affiliated businesses.
Biosimilars – So where are we in the EU? Robert Williams, Partner, Bird & Bird LLP (London)
Biosimilars in Canada and Europe AIPLA Biotechnology Committee Webinar Noel Courage September 25, 2012.
WHAT IS A BIOSIMILAR? Philip D. Home, DM, DPhil Professor of Diabetes Medicine Newcastle University Consultant Diabetologist Newcastle Diabetes Centre.
Date of preparation: May 2015 | UK/GLA/00030 An introduction to biosimilar medicines Adverse events should be reported. Reporting forms and further information.
The role of biosimilars in BMT Dr Bronwen Shaw Chief Medical Officer, Anthony Nolan Consultant in haematopoietic cell transplantation, Royal Marsden.
Structural Change in Pharmaceuticals: The Growth of Biologics and Emergence of Biosimilars Henry Grabowski Duke University Conference on Structural Change,
© Copyright 2014 Quintiles Comparison of US/EU Biosimilar Guidelines Kamali Chance, MPH, PhD, RAC Senior Director Head, Global Biosimilars Regulatory Strategy.
UNITED SPINAL ASSOCIATION AUGUST, 2014 Biologics & Biosimilars: An Overview 1.
Regulatory workflow for Registration of Biosimilar products in Egypt Biologicals Registration Directorate Central Administration for Pharmaceutical Affairs.
PhAMA Position on Biosimilar Medicines Ms. Leah Goodman.
WHO Workshop on Assessment of Bioequivalence Data Addis Ababa, 31. August – 3. September 2010 Selection of comparators Compiled by Jan Welink WHO Workshop.
FDA’s Biosimilars Guidance -- Legal and Regulatory Considerations James S. Cohen, Esq. McDermott Will & Emery DIA Webinar April 10, 2012.
EPAA Annual conference November Regulatory acceptance of alternative approaches for pharmaceuticals Jean-Marc Vidal Safety & Efficacy of Human Medicines.
Promoting patient-centred healthcare around the world Regulation of Biosimilars Jo Harkness.
Biosimilars Where Are We Now? Where Are We Going? Sheldon Bradshaw January 24, 2008.
1 Bolar Provisions in Europe Robert Watson Chartered Patent Attorney European Patent Attorney AIPLA, February 2006.
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, October, 2010 Regulatory principles reflected in practice of WHO PQP Milan Smid,
Anthony C. Tridico, Ph.D. AIPLA BIOTECHNOLOGY COMMITTEE Pinning Down a Moving Target: Patenting Biotech in Uncertain Times.
Ivowen Ltd1 Ivowen Limited Preparation and Submission of a Traditional Herbal Medicinal Product Application.
1 6 th European Patients Rights Day The EMA Geriatric Medicines Strategy and the empowered aging patient Francesca Cerreta EMA (European Medicines Agency)
NICE and biosimilars 4 March 2015 Paul Chrisp Programme Director, NICE Medicines and Prescribing Centre.
1 SAFETY IMPLICATIONS FOR BIOTECH PRODUCTS Peter Feldschreiber & Leigh-Ann Mulcahy Four New Square.
Clinical Trials of Traditional Herbal Medicines In India Y.K.Gupta Professor & Head, Department of Pharmacology, All India Institute of Medical Sciences,
Data protection and extension of patent rights TRIPS requirements & TRIPS-plus provisions Carlos Correa.
Pharma.be The Initiative to Promote Clinical Trials in Belgium Key Performance Indicators: Impact on Clinical Research of European Legislation Square –
The ICH E5 Question and Answer Document Status and Content Robert T. O’Neill, Ph.D. Director, Office of Biostatistics, CDER, FDA Presented at the 4th Kitasato-Harvard.
Final Canadian Guidelines for “Biosimilars” Subsequent Entry Biologics (SEBs) DIA RA SIAC RD/RI Working Groups 11-May-2010 Stephen Sherman.
Therapeutic or preventive medicine derived from living cells using recombinant DNA technology Conventional pharmaceuticals are generally small molecules.
1. Within a few years, more than half of newly approved medicines will be biopharmaceuticals. To ensure safety and efficacy, the FDA created a daunting.
Regulatory Framework Leigh Shaw, Director.
Introduction to Biosimilars Biologicals Marketing Authorization Directorate Central Administration for Pharmaceutical Affairs
Authorisation of medicinal products: selected challenges Rocío Salvador Roldán Pharmaceuticals Unit/DG SANCO This presentation only reflects the views.
Summary: Biological Therapeutics for Rare Plasma Protein Disorders Workshop July 21, 2005 Mark Weinstein, Ph.D. Office of Blood Research and Review CBER,
Biotech Inventions in Latin America Argentina Ignacio Sánchez Echagüe Marval, O’Farrell & Mairal.
Federal agency for medicines and health products EC REGULATION 1901/2006 ON MEDICINAL PRODUCTS FOR PAEDIATRIC USE AND HOMEOPATHIC MEDICINAL PRODUCTS Marie-Anne.
Subsequent Entry Biologics (SEBs) – Canada Presentation to AIPLA Biotechnology Committee January 25, 2012 Daphne C. Lainson
Copyright 2010, Morgan, Lewis & Bockius LLP Healthcare Reform--New Path for Biosimilars Kathleen M. Sanzo, Esq. Washington, DC May.
THE UK EXPERIENCE RELATED TO ESCITALOPRAM seeking clarity in the EU interest IS THE UK’S REFERRAL TO CHMP UNDER ARTICLE 31 OF DIRECTIVE 2001/83 LEGITIMATE?
Registration in Europe Current situation and future outlook Thomas K ü rner, M.D. Nippon Boehringer Ingelheim Co., Ltd.
1 The European Paediatric Initiative Agnès Saint Raymond, MD Scientific Advice and Orphan Drugs The European Medicines Evaluation Agency.
Follow-On Biologics: The New Regulatory Frontier [?] Michael S. Labson August 23, 2007.
DMF Procedures and Communication between API, FP Manufacturers and Regulatory Authorities Jean-Louis ROBERT National Health Laboratory L – 1011 LUXEMBOURG.
Biosimilars in Canada: A Perspective from Innovative Industry Karen A. Burke, Ph.D. Director, Regulatory Affairs and Safety Amgen Canada Montreal Forum.
SAFETY CONCERNS OF BIOSIMILARS IN TURKEY Serra Vildan Akgül¹, Sevcan Gül Akgün¹, Gülden Z. Omurtag¹, Semra Şardaş¹ ¹ Department of Pharmaceutical Toxicology,
Pharmacovigilance forum Risk Management Plans (RMP) - a TGA update Dr Jane Cook Branch Head Post-market Surveillance Branch Monitoring and Compliance Division,
European Patients’ Academy on Therapeutic Innovation Marketing authorisation.
BEIJING BRUSSELS CHICAGO DALLAS FRANKFURT GENEVA HONG KONG LONDON LOS ANGELES NEW YORK PALO ALTO SAN FRANCISCO SHANGHAI SINGAPORE SYDNEY TOKYO WASHINGTON,
Our PatientsOur PeopleOur BusinessOur Community © 2008 Endo Pharmaceuticals. All Rights Reserved. Biosimilars 2009 Update Pending Legislation Review Pam.
Compassionate use programs and the European regulatory system Filip Josephson M.D., Ph.D. Clinical Assessor.
Tanzania, August, 2006 Dr. Barbara Sterzik, BfArM, Bonn 1 Guidelines and Tools available TRS 937 and BTIF (Bioequivalence Trial Information Form)
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