Design and Implementation of Biosimilar Development Programs NY Pharma Forum 31 st January 2012 Dr. Nigel Rulewski Vice President, Global Strategic Drug Development Quintiles
Unprecedented Interest in Biosimilars Established multinational bio-pharmaceutical companies Generic companies Biotech – small independent and large conglomerate backed Local, regional and global Downsizing for almost every major pharmaceutical company Patent expiration of Major failures in major blockbuster late stage drug products development Reduced availability Products withdrawn of venture funding from the market 2
Generic Companies and Pharmemerging Players are Penetrating Markets Country Marketed Biosimilars* Companies GH, Heparin Sandoz, Momenta, Merck (Bioventures Division), Pfizer, Lilly, J&J, Protalix, US Biotherapeutics, Momenta Pharma, Hospira, Itero, Phage Biotech GH, EPO, G-CSF, IFN alpha2B, EPO Sandoz, Teva, Biopartners, Medice Arzneimittel Pütter , CT Arzneimittel, EU Ratiopharm , AstraZeneca, GSK, Novo Nordisk, Sanofi Aventis GH, G-CSF, GM-CSF, IL-2, Zenotech Sandoz, Daiichi Sankyo (Ranbaxy), Japan GH, EPO, G-CSF, Peg-GSF, IFNa, insulin, teriparatide, mAbs, Bharat Biotech International, Dr. Reddy's Laboratories, Shantha Biotechnics India Regen-D (rhEGF), Indikina, se (streptokinase), Glargine, Lispro, Ltd, Wockhardt, Biocon , Intas Biopharmaceuticals, Lupin, Reliance Life Aspart, EPO, G-CSF, Streptokinase Sciences GH, EPO, G-CSF, PEG-GSF, IFNa, IL-2, IL-11, insulin Beijing Tri-Prime Genetic SinoBiomed Inc., Shanghai Sunway Biotech, 3SBio Inc., Shenzhen Kexing Biotech, Amoytop Biotech Co. Ltd., CP GuoJian China Pharmaceutical, GeneScience Pharmaceuticals Recombinant human erythropoietin, Recombinant human interferon Probiomed, SICOR Biotech UAB Mexico alfa-2b, Recombinant human interferon alfa-2a, Filgramosim rHu G- CSF Vaccines (Recombinant hepatitis B surface antigen, Attenuated Instituto Butantan, FK Biotecnologic, Bio-Manguinhos, Novo Nordisk virus, Autologous whole cell) Brazil Therapeutics (Recombinant human insulin, Recombinant erythropoietin- α, Monoclonal antibodies) HGH, IFN alpha2B, G-CSF Teva Israel Rh-insulin, rhGH Biopartners Switzerland Canada hGH Cangene Germany EPO-zeta Stada S. Africa EPO Bioclones Epogen, hGH, EPO, EGFR, GCSF, IFN alpha2A, follitropin LG Lifescience, Daewoong, Dong-A S. Korea *GH and Heparin approved in US under FFD&C Act via 505(b)(2) pathway
Global Regulatory Guidelines for Biosimilars The EMA set precedent guidance for biosimilar approvals for certain product classes in 2006, and recently followed up with draft guidance for monoclonal antibodies. The WHO, in order to encourage regulatory harmonization across markets, also finalized guidance in 2010. Many countries are now forming their own guidance, referencing either the EMA or WHO. Snapshot as of January 2011 Europe Pathway in place 2005 Russia USA Guidance in development Canada Draft guidance issued 2010 Canada Europe Australia Using the EU Approach 2006 USA Japan China Japan Final guidance issued 2009 India Final recommendations issued WHO (2010) Brazil Final guidance issued 2010 India Draft guidance issued 2011 Brazil No specific pathway for China Australia biosimilars No specific pathway for Russia biosimilars Some countries are beginning to implement guidance following EMA or WHO (e.g. Malaysia, Taiwan, Korea); ROW many others do not have the healthcare infrastructure to support complex biologics
Status of Guidelines Country Inception Approval Pathway Argentina Sept 09 Biologic and biosimilar approval guidance Malaysia Jul 09 Guidance for Registration of Biosimilars in Malaysia Mexico Jun 09 Article 222 of the General Health Law Saudi Dec 10 Guidelines on Biosimilars Version 1.1 Arabia Singapore Apr 10 Guidance on Medicinal Product registration in Singapore South Sept 10 Guidelines on Evaluation of Biosimilar Products Korea Taiwan Nov 08 Market Approval of Biosimilar Products Turkey Aug 08 Instruction Manual on Biosimilar Medical Products 5
Recent Changes to Guidelines – US user fees will be set at the same level as innovative fee. – US user fees may vary between $770,000 -$1.54m. – US Biologic exclusivity requirements may be reduced from 10 to 7 years. – EMA issued concept paper of reform of biosimilar guidelines to incorporate all they have learnt over last six years. – EMA and FDA plan to collaborate of biosimilar development requirements and approvals . 6
Over View of EU Guidelines Biosimilars must demonstrate close similarity/comparability to the innovator/originator reference product in respect of: CMC nonclinical and clinical (efficacy & safety) Biosimilars must be comparable to the original molecule and the development strategy should be defined on a case by case basis as agreed by regulators. Clinical development in stepwise fashion though pk/pd and clinical equivalence. 7
EMA Approval Requirements for Biosimilars vs Biologics The EMA guidance provides a legal framework, general requirements and guidelines to ensure quality, safety, and efficacy of approved biosimilar products since 2005 Reference Biologic Biosimilar CMC Quality Studies -- Pharmacokinetics Pharmacodynamics in vitro & in vivo Non-Clinical Studies • Single & Repeat dose toxicity • Repeat dose toxicity • Safety pharmacology • Local tolerance testing Toxicology • Reproduction toxicology • Immunogenicity • Mutagenicity • Carcinogenicity • Immunogenicity Pharmacokinetics Pharmacodynamics Clinical Studies Clinical Efficacy • Each indication • Comparative, in single indication Clinical Tolerability • Each indication • Comparative, in single indication Source: www.ema.europa.edu 8
Overview of a Biosimilar Clinical Development Program Simple Overview – Stepwise approach through Phase I and Phase III. – Phase I pharmacokinetic comparison of Biosimilar to innovator product, to establish single dose and steady state pharmacokinetics. – Phase III comparison of Biosimilar to innovator product to clinical endpoint. – Phase I and III may be combined in one continuous study. 9
Choice of Reference Product – All guidelines state comparator product must be the product marketed in territory in question. – EU and US markets are often supplied by different manufacturing sites for a particular product. – Even when all product is made in one plant –final filling for EU and US markets may be conducted at different sites and into different containers. – Does this mean a world wide biosimilar program has two comparator products, one from the EU and another from the USA. – EU regulators are being very firm on need to conduct comparator trial with local product. – How is this being dealt with in practice? 10
Overview of a Biosimilar Clinical Development Program – Pharmacokinetic comparison of Biosimilar to innovator product –single doses in healthy volunteers or patients. – These studies are three way comparisons---Biosimilar vis US sourced innovator vis EU sourced innovator. – Pharmacokinetic equivalence requires comparison at steady state-this may also require a three arm study. – Multiple dose pharmacokinetic studies are conducted as standalone or as part of the large Phase III comparison with Innovator product in a combined Phase I/III Study. 11
Overview of a Biosimilar Clinical Development Program – EMA have remained firm on need to use EU marketed innovator product. – FDA have shown signs of accepting EU product as active comparator once pharmacokinetic equivalence has been shown between EU and US innovator products. 12
Overview of a Biosimilar Clinical Development Program Reference Indication Phase III Efficacy comparison Phase I three way comparison EU innovator Biosimilar US innovator EU innovator product? Biosimilar This may all be conducted within one continuous study or as two separate standalone studies Additional Major Indication Phase I comparison to steady state Biosimilar EU innovator product 13
Choice of Reference Indication – EU Guidelines suggest choice of reference indication should be based on which is the most sensitive indication. – If mechanism of action can be shown or is believed to be the same in other indications, extrapolation /assumption of efficacy in those indications is possible. – Even if efficacy is extrapolated to other indications, pharmacokinetic data may be needed in additional major indications. – Will EMA and FDA agree on when efficacy can be extrapolated to other indications?? 14
Best Selling Drugs of 2009 15 Source: Evaluate Pharma, PWC Biotech Reinvented.
Choice of Reference Indication and Extrapolation RA Cancer Juv Psoriatic Ank Plaque Crohn’s Arthritis Arthritis Spon Psoriasis Disease /UC Rituximab X NHL/CLL Enbrel X X X X X Remicade X X X X X Humira X X X X X X • Clearly RA is the largest indication for all four products. • RA is also the most sensitive indication, possibly with the exception of plaque psoriasis with Remicade, psoriatic arthritis with Humira- viable reference indications? • Can you extrapolate Rituximab efficacy in RA to Oncology indications? • Can you extrapolate Remicade and Humira efficacy in RA to Crohn’s or UC? 16
Recommend
More recommend
