BIOLOGICS AND BIOSIMILARS WORLD MARKETS - … · 5.9 Patent Expiry for Biologic Drugs 86 ... 5.15.28 Global Market for Actemra 138 ... Biologics and Biosimilars World Markets August

TriMark Publications

August 2013 Volume: TMRBIOL13-0801

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Biologics and Biosimilars World Markets August 2013

© 2013 TriMark Publications, LLC. All rights reserved. 1 www.trimarkpublications.com

TABLE OF CONTENTS 1. Overview 18 1.1 Statement of this Report 18 1.2 About this Report 18 1.3 Scope of the Report 19 1.4 Objectives 20 1.5 Methodology 20 1.6 Executive Summary 21 2. Pharmaceutical Industry: An Overview 23 2.1 Global R&D Spending by Pharma and Biotech Companies 23 2.1.1 Top 20 Companies in R&D Spending 24 2.1.2 Top 20 Most Valuable Pharmaceutical R&D projects 24 2.1.3 Most Valuable R&D Projects Ranked by Net Present Value 25 2.2 FDA New Drug Approvals 26 2.2.1 Top Ten NMEs 27 2.3 Impact of Patent Expirations 27 2.4 Immunity of Pharmaceutical Growth against Drop in GDP Growth 28 2.5 Minimal Annual Growth Rates of Pharmaceuticals in Developed Markets 29 2.6 Falling Operating Profit Rate for Big Pharma 30 2.7 Top Ten Global Pharmaceutical Firms 30 2.6 Top Ten Pharmaceuticals by Sales Revenue 32 2.7 Worldwide Prescription and OTC Sales by Therapy Area in 2018 33 2.8 Top Companies in Oncology Sales 34 2.8.1 Top Five Oncology Products 35 2.9 Top Companies in Anti-Diabetes Market 36 2.9.1 Top Five Anti-Diabetes Products 36 2.10 Top Ten Companies in Anti-Rheumatics Market 37 2.10.1 Top Ten Anti-Rheumatics Products 37 2.11 Top Ten Vaccine Companies and Global Sales 38 2.11.1 Top Five Vaccine Products 38 2.12 Top Ten Anti-Viral Companies 39 2.12.1 Top Five Anti-Viral Products 39 2.13 Top 50 Global Pharmaceutical Brands in 2018 40 2.14 M&A Transactions in 2012 41 2.15 Global Pharmaceutical Market 42 2.15.1 Global Pharmaceutical Sales by Region 43 2.15.2 North American Pharmaceutical Market 44 2.15.2.1 U.S. Prescription Drug Sales by Company 45 2.15.2.2 Top 50 Pharmaceutical Products in the U.S. 46 2.15.2.3 Top 50 Products in the U.S. in 2018 48 2.15.3 Pharmaceutical Market in Europe 49 2.15.3.1 European Prescription Drug Sales by Company 50 2.15.4 Pharmaceutical Market in Asia/Pacific 52 2.15.4.1 Prescription Drug Sales in Japan by Company 53 2.15.5 Pharmaceutical Market in Latin America 54 2.15.6 Pharmaceutical Market in Africa 55 2.15.7 Pharmaceutical Market in the Middle East 56 2.16 Regional Prescription Drug Sales in the U.S., Europe and Japan 57 2.17 Global Prescription Drug Sales 58 3. Brand Name Pharmaceuticals: A Brief Overview 59 3.1 Birth Pangs and Life Span of Branded Drugs 59 3.2 Major Patent Expiries of Branded Drugs 60 3.3 Global Market for Branded Drugs 61 3.4 Increasing R&D Pipeline 62 3.4.1 The 2012 R&D Pipeline by Phase 63



3.4.2 Top Companies by Pipeline Size 64 3.4.3 Total Number of Companies with Active R&D 65 3.4.4 Global Distribution of Companies Active in Pharma R&D 66 3.4.5 Top Therapy Areas in R&D 67 3.4.5.1 Top 25 Individual Diseases in the R&D Pipeline 68 3.4.6 Top 20 Mechanism of Action in R&D Pipeline 69 3.4.7 Top 25 Drug Protein Targets 70 4. Generic Drugs: A Brief Overview 72 4.1 Bioequivalence of Generics 72 4.2 Global Market for Generics 73 4.3 Operating Profit Rate for Generic Companies 74 4.4 Outsourced Manufacture of Generics 75 4.5 Generic Utilization in International Markets 76 4.6 Global Generic Sales by Company 77 5. Biologics 79 5.1 Regulations for Biologics 79 5.2 Complexity of Biologics 80 5.3 Concentration of Global Biopharmaceutical Manufacturing 80 5.4 Number of Biologics Available in the Global Market 82 5.5 Share of Biologics by Country/Region 82 5.6 Rate of Growth for Biologics by Region 83 5.6.1 Growth Rates of APIs and Biologics Compared 84 5.7 Manufacturing Capacity of Biologics 85 5.8 Biologics Market by Segment 85 5.9 Patent Expiry for Biologic Drugs 86 5.9.1 India’s Opportunity from Biologic Patent Expirations 87 5.10 Major Players in Biologics 88 5.11 Biopharmaceutical Outsourcing 89 5.12 Top 20 Biologics by Sales 90 5.12.1 Roche’s Biologics Arsenal 91 5.12.2 Johnson & Johnson’s Biologics Arsenal 92 5.12.3 Lonza in Biologics 92 5.13 The Best Selling Biologics by Class 92 5.14 Biologic Drugs: Market Trends in the Past Seven Years 93 5.14.1 Global Market for Biologics 94 5.15 Global and U.S. Sales of Blockbuster Biologics 95 5.15.1 Global Market for Humira 95 5.15.1.1 Humira (Adalimumab) Pen’s Market by Geography 95 5.15.1.2 U.S. Sales of Humira 96 5.15.1.3 The Leader among Biologics 97 5.15.2 Global Market for Remicade 97 5.15.2.1 Remicade’s Market by Geography 98 5.15.2.2 U.S. Sales of Remicade 99 5.15.3 Global Market for Enbrel 100 5.15.3.1 Enbrel’s Market by Geography 100 5.15.3.2 U.S. Sales of Enbrel 101 5.15.4 Global Market for Simponi 102 5.15.5 Global Market for Tysabri 103 5.15.5.1 U.S. Market for Tysabri 104 5.15.6 Global Market for Lantus 104 5.15.6.1 Lantus’ Market by Geography 105 5.15.6.2 U.S. Market for Lantus 106 5.15.7 Global Market for NovoRapid 106 5.15.7.1 Market for NovoLog/NovoRapid by Geography 107 5.15.7.2 U.S. Market for NovoRapid 108 5.15.8 Global Market for Victoza 108



5.15.9 Global Market for Levemir 110 5.15.9.1 U.S. Market for Levemir 111 5.15.10 Global Market for Humalog 111 5.15.10.1 Market for Humalog by Geography 113 5.15.11 Global Market for Neulasta 113 5.15.11.1 Neulasta’s Market by Geography 114 5.15.11.2 U.S. Market for Neulasta 115 5.15.12 Global Market for Privigen 115 5.15.13 Global Market for Perjeta 116 5.15.14 Global Market for Xgeva/Prolia 117 5.15.15 Global Market for Soliris 119 5.15.15.1 U.S. Market for Soliris 120 5.15.16 Global Market for Botox 120 5.15.17 Global Market for Lucentis 122 5.15.17.1 U.S. Market for Lucentis 123 5.15.18 Global Market for Eylea 123 5.15.19 Global Market for Avastin 125 5.15.19.1 U.S. Market for Avastin 126 5.15.20 Global Market for Rituxan 126 5.15.20.1 Rituxan’s Market by Geography 127 5.15.20.2 U.S. Market for Rituxan 128 5.15.21 Global Market for Revlimid 128 5.15.22 Global Market for Herceptin 130 5.15.22.1 Herceptin’s Market by Geography 130 5.15.22.2 U.S. Market for Herceptin 131 5.15.23 Global Market for Prevnar 13 132 5.15.23.1 U.S. Market for Prevnar 13 133 5.15.24 Global Market for Gardasil 133 5.15.25 Global Market for Fluzone/Varigrip 135 5.15.26 Global Market for Varivax 135 5.15.27 Global Market for Stelara 137 5.15.27.1 U.S. Market for Stelara 138 5.15.28 Global Market for Actemra 138 5.15.29 Global Market for Gammagard Liquid 139 5.16 The U.S. Biotech Landscape 141 5.16.1 Top U.S. Biotech Companies 141 5.16.1.1 Amgen 141 5.16.1.2 Gilead Sciences 142 5.16.1.3 Biogen Idec, Inc. 143 5.16.1.4 Celgene Corporation 144 5.16.1.5 Genzyme (Sanofi) 144 5.16.1.6 Life Technologies Corporation 145 5.16.1.7 Cephalon, Inc/Teva Pharmaceutical Industries Ltd. 145 5.16.1.8 Alexion Pharmaceuticals, Inc. 145 5.16.1.9 Cubist Pharmaceuticals, Inc. 145 5.16.1.10 United Therapeutics Corporation 146 5.16.2 Overall Performance of the U.S. Biotech Companies 146 5.16.3 R&D Spending by Biotech Companies in the U.S. 146 5.16.4 U.S. Market for Biologic Drugs 147 5.16.5 The Leading Biologic Drug Classes in Terms of U.S. Sales 148 5.16.5.1 Top Selling Biologic Drugs in the U.S. 149 5.16.5.2 U.S. Sales of Biologics by Manufacturer 150 5.16.6 U.S. Sales of mAbs 151 5.16.7 U.S. Sales of Recombinant Hormones 152 5.16.8 U.S. Sales of Blood Cell Growth Factors 153 5.16.9 U.S. Market for Cytokines 154 5.16.10 U.S. Sales of Blood Factors 155 5.16.11 U.S. Sales of Therapeutic Enzymes 156



5.16.12 U.S. Sales of Recombinant Vaccines 157 5.16.13 U.S. Sales of Recombinant Anticoagulants 157 5.16.14 Costs of Commonly Used Biologicals in the U.S. 158 5.16.15 Biologics Used for Treating Rheumatoid Arthritis 159 5.16.15.1 Cost Comparison of Arthritis Biologics 160 5.17 Biologics in Europe 160 5.17.1 Uptake of Biologics in Europe by Drug Type 161 5.17.2 European Market for mAbs 162 5.18 Biologics in Hemophilia 163 5.18.1 Marker Leaders in Hemophilia 164 5.18.2 Hemophilia A 164 5.18.3 Hemophilia B 165 5.18.4 Inhibitors 166 6. Biosimilars 168 6.1 Different Names in Different Countries for Biologics 168 6.2 E.U. Approval Pathway for Biosimilars 168 6.3 Contentious Issues in Biosimilars 168 6.4 Biosimilars Opportunity 168 6.5 Challenges in Biosimilar Introduction 169 6.6 Production and Market Access of Biosimilars 169 6.7 Country Selection for Biosimilars 169 6.8 High Barriers to the Entry of Biosimilars 169 6.9 Global Competition among Biosimilars 170 6.10 Definitions and Interpretations of Biosimilar Products 171 6.10.1 Regulatory Requirements 171 6.10.1.1 World Health Organization 171 6.10.1.2 Key Principles and Basic Concept 172 6.10.2 Reference Biotherapeutic Product 172 6.10.2.1 Quality 172 6.10.2.2 Non-Clinical and Clinical Studies 172 6.10.3 E.U. 173 6.10.3.1 Key Principles and Basic Concept 173 6.10.3.2 Reference Biotherapeutic Product 174 6.10.3.3 Quality 174 6.10.3.4 Non-Clinical and Clinical Evaluation 174 6.10.3.5 Product Class-Specific Guidelines 174 6.10.4 U.S. 175 6.10.5 Canada 176 6.10.6 Japan 176 6.10.7 Korea 176 6.11 FDA Guidelines for Biosimilars 177 6.12 Market Drivers 177 6.12.1 Cost Pressures 177 6.13 Core Therapy Areas for Biosimilars 177 6.14 Competitive Landscape in Biosimilar Sector 178 6.15 Opportunities for Biosimilars in Three Geographies 179 6.15.1 Opportunities for Biosimilars in the U.S. 180 6.15.2 European Opportunities for Biosimilars 180 6.15.3 Opportunities for Biosimilars in Emerging Markets 180 6.16 Biosimilar Experience 181 6.17 Development of Biosimilars 182 6.17.1 Current and Future Trends in Biosimilar Development 182 6.18 Top Players in Biosimilars Market 183 6.18.1 Other Key Players in Biosimilars Market 185 6.19 Number of Biologics Patent Expiries Prior to 2020 186 6.19.1 Biologics Patent Expiries by Region 187 6.20 Monoclonal Antibodies: The Key Focus Area for Biosimilars Development 188



6.20.1 Biosimilar mAbs in Pipeline 188 6.20.2 Disease Indications for Biosimilar mAbs 190 6.21 Global Leaders in Biosimilars 191 6.22 Market Leading Biosimilars 191 6.23 Biosimilar Opportunities: Only for the Heartiest Biotech Firms 192 6.24 Biosimilars Pipeline by Class 193 6.25 Global Biosimilars Market 193 6.25.1 Estimated Value and Growth Rates for Biosimilars by Type 194 6.25.2 Market Leading Biosimilars in 2015 196 6.26 Regulations for Biosimilars in the U.S. 196 6.26.1 BPCIA and Guidance 197 6.26.2 Scientific Considerations 197 6.26.3 Quality Considerations 197 6.26.4 Biosimilar User Fee Act 197 6.26.5 12-Year Exclusivity Period 198 6.26.6 Biosimilars Competitive Landscape in the U.S. 199 6.26.7 Manufacturing Capabilities 199 6.26.8 Clinical Trial Experience 200 6.26.9 Market Experience 201 6.26.10 Likely Early Entrants 201 6.26.11 Recombinant Protein Competition 202 6.26.12 mAbs Competition 202 6.27 U.S. Biosimilars Market 203 6.27.1 HGH Biosimilars in the U.S. Market 204 6.27.2 Cost Benefits from Biosimilars for U.S. Healthcare 205 6.27.3 Development Pipeline and Market Evolution of Biosimilars in the U.S. 206 6.27.3.1 Target Reference Products 207 6.27.3.2 Launchable Dates for Biosimilars in the U.S. 207 6.27.3.3 Number of Biosimilar Products in the Pipeline 209 6.28 Geographic Distribution of Biosimilars Pipeline 210 6.28.1 Developers of Biosimilars 211 6.29 Future of U.S. Biosimilars Market 214 6.29.1 Future Pricing Models 214 6.29.2 Future Price Reduction and the Profit Margin 214 6.30 Biosimilars Market in Europe and Japan 215 6.30.1 The Instant Growth of Biosimilars in Europe 216 6.30.2 Biosimilar mAbs on the Horizon in Europe 217 6.30.3 Biosimilars Approved in the E.U 218 6.30.4 Utilization of G-CSF in Europe 219 6.31 Revenue Forecast for Biosimilar Insulins 220 6.32 Revenue Forecast for Biosimilar HGH 221 6.33 Revenue Forecast for Biosimilar IFN Alpha 222 6.34 Revenue Forecast for Biosimilar IFN Beta Ia222 6.35 Revenue Forecast for Biosimilar Filgrastim 223 6.36 Revenue Forecast for Biosimilar Epoetin Alpha 224 6.37 Uptake of Biosimilars in Europe 224 6.38 Biosimilars in China 225 6.38.1 Biosimilars Sales in China 226 6.39 Indian Market for Biosimilars 228 6.39.1 Domestic Biosimilar Developers in India 228 6.40 Biosimilar Pipeline of Celltrion in Korea 229 6.41 Deals in Biosimilar Space 230 6.41.1 Technologies 230 6.41.2 Manufacturing Agreements 230 6.41.3 Clinical Development 231 6.41.4 Licensing Agreements 231 6.42 Transactions in Biosimilars Industry 231 6.42.1 Biosimilars Market: Opportunities and Challenges 232



6.42.2 Recent Transactions in Biosimilars Industry 233 6.43 Top Ten Biosimilar Drugs to Watch 234 6.43.1 Aranesp (Darbepoetin Alfa) 234 6.43.2 Enbrel (Etanercept) 235 6.43.3 Epogen/Procrit/Eprex/Erypo (Epoetin Alfa) 235 6.43.4 Genotropin (Somatropin) 236 6.43.5 Herceptin (Trastuzumab) 236 6.43.6 Humira (Adalimumab) 236 6.43.7 Neulasta (Pegfilgrastim) 237 6.43.8 Neupogen (Filgrastim) 237 6.43.9 Remicade (Infliximab) 238 6.43.10 Rituxan/MabThera (Rituximab) 238 7. Company Profiles 240 7.1 3Bio, Inc. 240 7.1.1 EPIAO 240 7.1.2 TPIAO 240 7.1.3 INTEFEN 241 7.1.4 INLEUSIN 241 7.1.5 IV Iron Sucrose 242 7.2 Abbott Laboratories 242 7.3 AbbVie, Inc. 243 7.3.1 Products 244 7.4 Actelion Ltd. 244 7.5 Amgen, Inc. 245 7.5.1 Neulasta (Filgrastim) 245 7.5.2 Enbrel (Etanercept) 245 7.5.3 Aranesp (Darbepoetin Alfa) 245 7.5.4 Epogen (Epoetin Alfa) 245 7.5.5 Sensipar/Mimpara (Cinacalcet) 245 7.5.6 Vectibix (Panitumumab) 246 7.5.7 Nplate (Romiplostim) 246 7.5.8 Prolia/Xgeva (Denosumab) 246 7.6 Amoytop Biotech Co., Ltd 246 7.6.1 Molgramostim (rhGM-CSF) 246 7.6.2 Filgrastim (rh G-CSF) 247 7.6.3 Oprelvekin (rhIL-11) 247 7.7 Anhui Anke Biotechnology (Group) Co., Ltd. 247 7.7.1 Anterferon Alpha 2b Injection 248 7.7.2 Ansomone 248 7.7.3 Anterferon Alpha 2b Cream 248 7.7.4 Anterferon alpha 2b Eyedrop 248 7.8 Apotex, Inc. 248 7.9 Astellas Pharma, Inc. 249 7.10 AstraZeneca 250 7.10.1 AstraZeneca’s R&D Portfolio 250 7.10.2 Patent Expiries of AstraZeneca’s Products 251 7.11 Bayer AG 251 7.12 Beijing Four Rings Biopharmaceuticals 252 7.12.1 Products 252 7.13 Bharat Serums and Vaccines Limited 252 7.14 Biocon Ltd. 253 7.15 Biogen Idec, Inc. 255 7.16 Bioton SA 256 7.17 Boehringer Ingelheim Pharmaceuticals, Inc. 257 7.18 Bristol-Myers Squibb, Co. 258 7.19 Celgene Corporation 259 7.20 Celltrion, Inc. 259



7.20.1 Technology Overview 259 7.20.2 Biosimilars Development 259 7.20.3 Contract Manufacturing 259 7.21 Cipla Ltd. 260 7.21.1 Cipla’s Prescription Product Category 260 7.22 Dr. Reddy’s Laboratories Ltd. 261 7.23 Elan Corporation, PLC 262 7.23.1 Tysabri 262 7.24 Eli Lilly & Co. 263 7.25 Gideon Richter 263 7.26 Gilead Sciences, Inc. 264 7.27 GlaxoSmithKline PLC 265 7.28 Hospira, Inc. 267 7.29 Intas Pharmaceuticals Limited 268 7.30 Johnson & Johnson 268 7.31 Merck & Co., Inc. 269 7.32 Mylan, Inc. 270 7.32.1 Mylan’s Generics 271 7.32.2 Mylan’s Active Pharmaceutical Ingredients 271 7.32.3 Mylan’s Specialty 271 7.32.4 Mylan’s Anti-Retroviral Franchise 271 7.33 Novartis AG 271 7.34 Pfizer, Inc. 273 7.35 Roche Holdings AG 274 7.36 Sandoz International GmbH 276 7.37 Sanofi 276 7.38 Stada Arzneimittel Aktiengesellschaft 278 7.39 Teva Pharmaceutical Industries Limited 279 7.40 Watson Pharmaceuticals, Inc. 280 APPENDIX Appendix 1: Biologic Medicines by Development Phase 281 Appendix 2: Declining Medicine Use in the U.S. 305 Appendix 2.1: Changes in Utilization 305 Appendix 2.2: Healthcare Costs and Spending on Medicines 306 Appendix 2.3: Total Spending on Medicines 309 Appendix 2.4: Transformations in Disease Treatment 319 Appendix 2.5: Key Breakthrough Therapies Approved in 2012 322 Appendix 2.5.1: Cystic Fibrosis: Ivacaftor (Kalydeco) 322 Appendix 2.5.2: Rheumatoid Arthritis: Tofacitinib (Xeljanz) 323 Appendix 2.5.3: Basal-Cell Carcinoma: Vismodegib (Erivedge) 323 Appendix 2.5.4: Irritable Bowel Syndrome with Constipation: Linaclotide (Linzess) 323 Appendix 2.5.5: HIV: Emtricitabine and Tenofovir Disoproxil Fumarate (Truvada) 323 Appendix 2.5.6: Combination of Elvitegravir, Cobicistat, Emtricitabine and Tenofovir Disoproxil Fumarate 323 Appendix 2.6: Spending in Major Therapies 323 Appendix 2.6.1: Oncology Spending ($25.9 Billion) by Area, 2012 324 Appendix 2.6.1.1: U.S. Market for Oncology Drugs 325 Appendix 2.6.1.2: U.S. Market for Rituxan 326 Appendix 2.6.1.3: U.S. Market for Avastin 327 Appendix 2.7: Mental Health Spending by Area 327 Appendix 2.7.1: U.S. Market for Mental Health Drugs 328 Appendix 2.7.2: U.S. Market for Cymbalta 329 Appendix 2.7.3: U.S. Market for Abilify 330 Appendix 2.8: Respiratory Spending by Area 331 Appendix 2.8.1: U.S. Market for Respiratory Drugs 332 Appendix 2.8.2: U.S. Market for Advair 333



Appendix 2.8.3: U.S. Market for Singulair 334 Appendix 2.8.4: U.S. Market for Spiriva 335 Appendix 2.9: Antidiabetes Spending by Area 335 Appendix 2.9.1: U.S. Market for Antidiabetics 336 Appendix 2.9.2: U.S. Market for Januvia 337 Appendix 2.9.3: U.S. Market for Lantus 338 Appendix 2.9.4: U.S. Market for Lantus SoloSTAR 339 Appendix 2.10: Pain Spending by Area 341 Appendix 2.10.1: U.S. Market for Pain Management Drugs 341 Appendix 2.11: U.S. Market for Medicines Used in Nervous System Disorders 342 Appendix 2.11.1: U.S. Market for Oxycontin 343 Appendix 2.11.2: U.S. Market for Lyrica 343 Appendix 2.11.3: U.S. Market for Copaxone 344 Appendix 2.12: U.S. Market for Lipid Regulators 345 Appendix 2.12.1: U.S. Market for Crestor 346 Appendix 2.13: U.S. Market for Autoimmune Drugs 346 Appendix 2.13.1: U.S. Market for Humira 347 Appendix 2.13.2: U.S. Market for Enbrel 348 Appendix 2.13.3: U.S. Market for Remicade 349 Appendix 2.14: U.S. Market for Medicines Used for Multiple Sclerosis 350 Appendix 2.15: U.S. Market for Antiulcerants 351 Appendix 2.15.1: U.S. Market for Nexium 352 Appendix 2.16: U.S. Market for Neulasta 352 Appendix 2.17: U.S. Market for Epogen 353 Appendix 2.18: U.S. Market for Platelet Aggregation Inhibitors 354 Appendix 2.18.1: U.S. Market for Plavix 355 Appendix 2.19: U.S. Market for HIV Antivirals 355 Appendix 2.19.1: U.S. Market for Atripla 356 Appendix 2.19.2: U.S. Market for Truvada 357 Appendix 2.20: U.S. Market for Antibacterials 358 Appendix 2.21: U.S. Market for Antihypertensives 359 Appendix 2.21.1: U.S. Market for Diovan 359 Appendix 2.22: U.S. Market for ADHD 360 Appendix 2.23: U.S. Market for Vaccines (Pure, Comb and Others) 361 Appendix 2.24: U.S. Market for Systemic Hormonal Contraceptives 362 Appendix 2.25: Number of Treated Patients in Selected Therapies in the U.S. 363 Appendix 2.26: Top Therapeutic Classes of Drugs Prescribed in the U.S. 363 Appendix 2.27: Top Medicines Prescribed in the U.S. 365 Appendix 3: Pharma Deals in 2012 367 Appendix 4: Pharma Outsourcing in Asia 370 Appendix 4.1: Cluster One: Pharma Revenue Constraints 370 Appendix 4.2: Cluster Two: Asia Growth Forces 370 Appendix 4.3: Cluster Three: East/West Convergence/Divergence Trends 371 Appendix 4.4: Cluster Four: Technological/Business Model Forces 372 Appendix 4.5: Implications of the Four Clusters for Asia Outsourcing 372 Appendix 4.5.1: Rapid Expansion of Clinical Trials in Asia 373 Appendix 4.5.2: Manufacturing Scales 373 Appendix 4.5.3: Risk and Opportunity Overview 373 Appendix 4.5.4: Cost Ranking of Asian Territories 374 Appendix 4.5.5: Market Opportunity Ranking 375 Appendix 4.6: Outsourcing Hot Spots in Asia 376 Appendix 4.6.1: China 376 Appendix 4.6.2: India 378 Appendix 4.6.3: Singapore 379 Appendix 5: The Changing Payment Landscape for the U.S. Pharmaceutical Industry 381 Appendix 5.1: The Impetus for Defining Value 381 Appendix 5.1.1: Force I 381 Appendix 5.1.2: Force II 382



Appendix 5.1.3: Force III 383 Appendix 5.1.4: Force IV 384 Appendix 5.1.5: Force V 385 Appendix 5.2: The New Arbiters of Value 386 Appendix 5.2.1: Prescribers Looking for Value 386 Appendix 5.2.2: More Investment in Comparative Effectiveness Research 387 Appendix 5.2.3: Unleashing of Imprisoned Value 387 Appendix 5.2.4: Role of Companion Diagnostics 388 Appendix 5.2.5: Outcomes-Dependent Contracts 389 Appendix 5.2.6: Data-Sharing Agreements 391 Appendix 5.2.7: Patient-Reported Outcomes 392 Appendix 5.2.8: Evidence Needed to Secure Formulary Slots 393 Appendix 6: Medical Cost Trend in the U.S., 2013 394 Appendix 6.1: The Components of Medical Cost 394 Appendix 6.2: Leading Factors in Setting Insurance Premiums 395 Appendix 6.3: Factors Affecting 2013 Trend 395 Appendix 6.3.1: Medical Supply and Equipment Cost 395 Appendix 6.3.2: Newer Delivery Methods for Primary Care 396 Appendix 6.4: Uptick in Utilization and Expensive Advances 397 Appendix 6.4.1: Economic Utilization and Economic Growth 397 Appendix 6.4.2: Medical Advances Driving Growth 397 Appendix 6.4.3: The “New Normal” 399 Appendix 6.4.4: Current Practices by Employers 400 Appendix 6.4.4.1: Things to be considered by Employers 400 Appendix 6.5: Current Practices by Providers 401 Appendix 6.5.1: Things to be considered by Providers 401 Appendix 6.6: Current Practices by Health Insurers 401 Appendix 6.6.1: Things to be considered by Health Insurers 401 Appendix 6.7: Current Practices by Pharmaceutical and Life Sciences 402 Appendix 6.7.1: Things to be considered by Pharmaceutical and Life Sciences 402 Appendix 7: Naming of Drug Molecules and Pharmaceutical Brands 403 Appendix 7.1: Names of a Drug 403 Appendix 7.1.1: Chemical Name 403 Appendix 7.1.2: Generic Name 403 Appendix 7.2: Brand Name 404 Appendix 7.2.1: Criteria for Brand Names 405 Appendix 7.3: Stories behind Some Blockbuster Molecules 406 INDEX OF FIGURES Figure 2.1: Global R&D Spending by Pharma and Biotech Companies, 2005-2018 23 Figure 2.2: Worldwide Sales at Risk by Patent Expiration, 2004-2018 28 Figure 2.3: Immunity of Pharmaceutical Growth against Drop in GDP Growth 29 Figure 2.4: Falling Operating Profit Rate for Big Pharma 30 Figure 2.5: Global Pharmaceutical Market, 2012-2019 43 Figure 2.6: Global Pharmaceutical Sales by Region 43 Figure 2.7: North American Pharmaceutical Market, 2012-2019 44 Figure 2.8: European Pharmaceutical Market, 2012-2019 50 Figure 2.9: Pharmaceutical Market in Asia/Pacific, 2012-2019 52 Figure 2.10: Pharmaceutical Market in Latin America, 2012-2019 55 Figure 2.11: Pharmaceutical Market in Africa, 2012-2019 56 Figure 2.12: Pharmaceutical Market in the Middle East, 2012-2019 57 Figure 2.13: Worldwide Total Prescription Drug Sales, 2004-2018 58 Figure 3.1: The Long-Drawn R&D Process for Branded Drugs 60 Figure 3.2: Global Market for Branded Drugs, 2012-2019 62 Figure 3.3: R&D pipeline, 2001-2012 63 Figure 3.4: R&D Pipeline by Phase, 2007-2012 64



Figure 3.5: Total Number of Companies with Active R&D, 2000-2012 66 Figure 3.6: Global Distribution of Companies Active in Pharma R&D, 2012 67 Figure 4.1: Differences between Originals and Copies (Branded/Generics & Biologics/Biosimilars) 72 Figure 4.2: Global Market for Generics, 2012-2019 74 Figure 4.3: Operating Profit Rate for Top Six Generic Companies, 2006-2012 75 Figure 4.4: Outsourced Manufacturing of Generics by Region/Country 76 Figure 4.5: Generic Drug Use in International Markets 77 Figure 5.1: The Biologic Drug Development Process 79 Figure 5.2: Comparison of Small Molecule Drugs and Biologics 80 Figure 5.3: Concentration of Global Biopharmaceutical Manufacturing as of 2013 81 Figure 5.4: Share of Biologics Sales by Country/Region 83 Figure 5.5: Rate of Growth for Biologics by Region 84 Figure 5.6: Growth Rates (CAGR) of APIs and Biologics Compared 84 Figure 5.7: Global Installed Biopharmaceutical Manufacturing Capacity by Top Ten Companies 85 Figure 5.8: Biologics Market by Segment 86 Figure 5.9: Top Biologics Losing Patent Protection and Market Exclusivity Prior to 2018 87 Figure 5.10: Global Value and Number of Biologic Drugs Losing Patent Protection, 2010-2015 88 Figure 5.11: Top Ten Biopharmaceuticals Manufacturing Companies 88 Figure 5.12: Outsourcing Trends in Biological Production across All Cell-Based Platforms 89 Figure 5.13: The Largest Selling Biologics by Class, 2012 92 Figure 5.14: Global Biologic Drugs Market Trends, 2006-2012 93 Figure 5.15: Global Market for Biologics, 2010-2020 94 Figure 5.16: Global Market for Humira, 2012-2019 95 Figure 5.17: Humira Pen’s Market by Geography 96 Figure 5.18: U.S. Market for Humira, 2012-2019 96 Figure 5.19: Global Market for Remicade, 2012-2019 98 Figure 5.20: Remicade’s Market by Geography 99 Figure 5.21: U.S. Market for Remicade, 2012-2019 99 Figure 5.22: Global Market for Enbrel, 2012-2019 100 Figure 5.23: Enbrel’s Market by Geography 101 Figure 5.24: U.S. Market for Enbrel, 2012-2019 101 Figure 5.25: Global Market for Simponi, 2012-2019 102 Figure 5.26: Global Market for Tysabri, 2012-2019 103 Figure 5.27: U.S. Market for Tysabri, 2012-2019 104 Figure 5.28: Global Market for Lantus, 2012-2019 105 Figure 5.29: Lantus’ Market Share by Geography 105 Figure 5.30: U.S. Market for Lantus, 2012-2019 106 Figure 5.31: Global Market for NovoRapid, 2012-2019 107 Figure 5.32: Market for NovoLog/NovoRapid by Geography 107 Figure 5.33: U.S. Market for NovoRapid, 2012-2019 108 Figure 5.34: Global Market for Victoza, 2012-2019 109 Figure 5.35: U.S. Market for Victoza, 2012-2019 109 Figure 5.36: Global Market for Levemir, 2012-2019 110 Figure 5.37: U.S. Market for Levemir, 2012-2019 111 Figure 5.38: Global Market for Humalog, 2012-2019 112 Figure 5.39: U.S. Market for Humalog, 2012-2019 112 Figure 5.40: Humalog’s Market by Geography 113 Figure 5.41: Global Market for Neulasta, 2012-2019 114 Figure 5.42: Neulasta’s Market Share by Geography 114 Figure 5.43: U.S. Market for Neulasta, 2012-2019 115 Figure 5.44: Global Market for Privigen, 2012-2019 116 Figure 5.45: Global Market for Perjeta, 2012-2019 117 Figure 5.46: Global Market for Xgeva/Prolia, 2012-2019 118 Figure 5.47: U.S. Market for Xgeva/Prolia, 2012-2019 118 Figure 5.48: Global Market for Soliris, 2012-2019 119 Figure 5.49: U.S. Market for Soliris, 2012-2019 120 Figure 5.50: Global Market for Botox, 2012-2019 121 Figure 5.51: U.S. Market for Botox, 2012-2019 121



Figure 5.52: Global Market for Lucentis, 2012-2019 122 Figure 5.53: U.S. Market for Lucentis, 2012-2019 123 Figure 5.54: Global Market for Eylea, 2012-2019 124 Figure 5.55: U.S. Market for Eylea, 2012-2019 124 Figure 5.56: Global Market for Avastin, 2012-2019 125 Figure 5.57: U.S. Market for Avastin, 2012-2019 126 Figure 5.58: Global Market for Rituxan, 2012-2019 127 Figure 5.59: Rituxan’s Market Share by Geography 127 Figure 5.60: U.S. Market for Rituxan, 2012-2019 128 Figure 5.61: Global Market for Revlimid, 2012-2019 129 Figure 5.62: U.S. Market for Revlimid, 2012-2019 129 Figure 5.63: Global Market for Herceptin, 2012-2019 130 Figure 5.64: Herceptin’s Market Share by Geography 131 Figure 5.65: U.S. Market for Herceptin, 2012-2019 131 Figure 5.67: Global Market for Prevnar 13, 2012-2019 132 Figure 5.68: U.S. Market for Prevnar 13, 2012-2019 133 Figure 5.69: Global Market for Gardasil, 2012-2019 134 Figure 5.70: U.S. Market for Gardasil, 2012-2019 134 Figure 5.71: Global Market for Fluzone/Varigrip, 2012-2019 135 Figure 5.72: Global Market for Varivax, 2012-2019 136 Figure 5.73: U.S. Market for Varivax, 2012-2019 136 Figure 5.74: Global Market for Stelara, 2012-2019 137 Figure 5.75: U.S. Market for Stelara, 2012-2019 138 Figure 5.76: Global Market for Actemra, 2012-2019 139 Figure 5.77: Global Market for Gammagard Liquid, 2012-2019 140 Figure 5.78: U.S. Market for Gammagard Liquid, 2012-2019 140 Figure 5.79: U.S. Market for Biologic Drugs, 2007-2012 148 Figure 5.80: The Leading Biologic Drug Classes in Terms of U.S. Sales 149 Figure 5.81: Top Selling Biologic Drugs in the U.S. 150 Figure 5.82: U.S. Sales of Biologics by Manufacturer 151 Figure 5.83: U.S. Sales of mAbs 152 Figure 5.84: U.S. Sales of Recombinant Hormones 152 Figure: 5.85: U.S. Sales of Blood Cell Growth Factors 154 Figure 5.86: U.S. Sales of Cytokines 155 Figure 5.87: U.S. sales of Blood Factors 156 Figure 5.89: U.S. Sales of Therapeutic Enzymes 156 Figure 5.90: U.S. Sales of Recombinant Vaccines 157 Figure 5.91: U.S. Sales of Recombinant Anticoagulants 158 Figure 5.92: Market for Biologics in Europe, 2012-2019 161 Figure 5.93: Uptake of Biologics in Europe by Drug Type 162 Figure 5.94: European Market for mAbs 163 Figure 5.95: Hemophilia Market Share by Company, 2016 164 Figure 6.1: Core Therapy Areas for Biosimilars 178 Figure 6.2: Biosimilars’ Market by Geography/Country 179 Figure 6.3: Top Players in Biosimilars Market 184 Figure 6.4: Number of Biologics per Indication to Go Off Patent prior to 2020 187 Figure 6.5: Patent Expiration of leading mAbs 188 Figure 6.6: Biosimilar mAbs in Pipeline 189 Figure 6.7: Disease Indications for Biosimilar mAbs Currently in Clinical Trials 190 Figure 6.8: Global Leaders in Biosimilars, 2012 191 Figure 6.9: Projected Biosimilars Market Split ($10 Billions) in 2015 192 Figure 6.10: The Exploding Global Biosimilars Market, 2012-2020 194 Figure 6.11: Estimated Value and Growth Rates for Biosimilars by Type, 2015 195 Figure 6.12: Global Spending (%) for Biosimilars by Drug Type ($2.5 Billion), 2015 196 Figure 6.13: Biosimilars Market in the U.S., 2011-2019 204 Figure 6.14: HGH Biosimilars in the U.S. Market, June 2009-September 2012 205 Figure 6.15: Projected U.S. Spend on 11 Specific Biologics, 2012-2024 206 Figure 6.16: Biosimilar Launchable Dates in the U.S., 2012-2022 208



Figure 6.17: Cumulative Worldwide Sales of Reference Products, 2012-2022 209 Figure 6.18: Geographic Distribution of Biosimilar Companies as of 2013 211 Figure 6.19: Number of Products by Country as of 2013 212 Figure 6.20: Biosimilars/Biobetters Companies by Size Range (Revenue $ Billions) Worldwide, 2013 213 Figure 6.21: Biosimilars Approved in the E.U., 2012 215 Figure 6.22: Biosimilars Market in Europe and Japan, 2012-2019 216 Figure 6.23: Annual European Sales of Filgrastim Products, 2010-2012 217 Figure 6.24: Number of Scientific Advice from EMA by Biosimilars Firms 218 Figure 6.25: Biosimilars Penetration Rate (%) in Daily G-CSF Class Market, 2012 220 Figure 6.26: Revenue Forecast for Biosimilar Insulin Glargine in Major Seven Markets, 2009-2020 221 Figure 6.27: Revenue Forecast for Biosimilar HGH in the Major Seven Markets, 2009-2020 221 Figure 6.29: Revenue Forecast for Biosimilar IFN Beta Ia in the Major Seven Markets, 2009-2020 223 Figure 6.30: Revenue Forecast for Biosimilar Filgrastim in the Major Seven Markets, 2009-2020 223 Figure 6.31: Revenue Forecast for Biosimilar Epoetin Alpha in the Major Seven Markets, 2009-2020 224 Figure 6.32: Biosimilars Uptake Rates in Europe’s Top Five Countries, 2012 225 Figure 6.33: Market for Biosimilars in China, 2012-2019 227 Figure 6.34: Biosimilar Market in India, 2008-2012 228 Figure A.2.1: Percent Change in Hospital Admissions and Office Visits, 2012 306 Figure A.2.2: Percent Population, Prescriptions and Per Capita Change in Prescriptions by Age 307 Figure A.2.3: Therapy Areas for Largest Positive and Negative Contribution to Growth 307 Figure A.2.4: U.S. National Respiratory Illness Estimates, 2010-2013 308 Figure A.2.5: Per Capita Spending Growth, 2002-2017 309 Figure A.2.6: Percent of Health Plan Members Ranked by Healthcare Spending 310 Figure A.2.7: Percent of Health Plan Members Healthcare Spending 311 Figure A.2.8: Components of Change in Total Spending ($ Billion), 2011-2012 312 Figure A.2.9: Protected Brand Price Spending Growth, 2008-2012 313 Figure A.2.10: New Brand Spending ($ Billions) 314 Figure A.2.11: Percent Share of Prescriptions, 2003-2012 314 Figure A.2.12: Comparison of Medicine Spending by Segment, 2012 315 Figure A.2.13: Significant Increase in Consumer-Driven Health Plans Enrollment, 2008-2012 315 Figure A.2.14: Average Patient Out-of-Pocket Costs by Plan Type, 2008-2012 316 Figure A.2.15: Average Annual Out-of-Pocket Costs for Deductibles, Co-Pay and Co-Insurance Spend 317 Figure A.2.16: Percent of Retail Dispensed Prescriptions by Out-of-Pocket Costs, 2012 318 Figure A.2.17: Percent of Retail Dispensed Prescriptions by Out-of-Pocket Costs 318 Figure A.2.18: New Molecular Entities Launched in the U.S., 2003-2012 319 Figure A.2.19: New Oncology NME Launches in the U.S., 2003-2012 320 Figure A.2.20: Spending in Leading Therapy Areas 324 Figure A.2.21: Oncology Spending by Area 325 Figure A.2.22: U.S. Market for Oncologics, 2008-2012 326 Figure A.2.23: U.S. Market for Rituxan, 2008-2012 326 Figure A.2.24: U.S. Market for Avastin, 2008-2012 327 Figure A.2.25: Mental Health Spending by Area, 2012 328 Figure A.2.26: U.S. Market for Mental Health Medicines, 2008-2012 329 Figure A.2.27: U.S. Market for Cymbalta, 2008-2012 330 Figure A.2.28: U.S. Market for Abilify, 2008-2012 331 Figure A.2.29: Respiratory Spending by Area, 2012 332 Figure A.2.30: U.S. Market for Respiratory Agents, 2008-2012 333 Figure A.2.31: U.S. Market for Advair Diskus, 2008-2012 334 Figure A.2.32: U.S. Market for Singulair, 2008-2012 334 Figure A.2.33: Spiriva HandiHaler, 2008-2012 335 Figure A.2.34: Antidiabetes Spending by Area, 2008-2012 336 Figure A.2.35: U.S. Market for Antidiabetics, 2008-2012 337 Figure A.2.36: U.S. Market for Januvia, 2008-2012 338 Figure A.2.37: U.S. Market for Lantus, 2008-2012 339 Figure A.2.38: U.S. Market for Lantus SoloSTAR, 2008-2012 340 Figure A.2.39: Pain Spending by Area, 2008-2012 340 Figure A.2.40: Pain Spending by Area, 2008-2012 341 Figure A.2.41: U.S. Market for Pain Management Drugs, 2008-2012 342



Figure A.2.42: U.S. Market for Medicines Used in Nervous System Disorders, 2008-2012342 Figure A.2.43: U.S. Market for Oxycontin, 2008-2012 343 Figure A.2.44: U.S. Market for Lyrica, 2008-2012 344 Figure A.2.45: U.S. Market for Copaxone, 2008-2012 345 Figure A.2.46: U.S. Market for Lipid Regulators, 2008-2012 345 Figure A.2.47: U.S. Market for Crestor, 2008-2012 346 Figure A.2.48: U.S. Market for Autoimmune Drugs, 2008-2012 347 Figure A.2.49: U.S. Market for Humira, 2008-2012 348 Figure A.2.50: U.S. Market for Enbrel, 2008-2012 349 Figure A.2.51: U.S. Market for Remicade, 2008-2012 350 Figure A.2.52: U.S. Market for Medicines Used for Multiple Sclerosis, 2008-2012 351 Figure A.2.53: U.S. Market for Antiulcerants, 2008-2012 351 Figure A.2.54: U.S. Market for Nexium, 2008-2012 352 Figure A.2.55: U.S. Market for Neulasta, 2008-2012 353 Figure A.2.56: U.S. Market for Epogen, 2008-2012 354 Figure A.2.57: U.S. Market for Platelet Aggregation Inhibitors, 2008-2012 354 Figure A.2.58: U.S. Market for Plavix, 2008-2012 355 Figure A.2.59: U.S. Market for HIV Antivirals, 2008-2012 356 Figure A.2.60: U.S. Market for Atripla, 2008-2012 357 Figure A.2.61: U.S. Market for Truvada, 2008-2012 358 Figure A.2.62: U.S. Market for Antibacterials, 2008-2012 358 Figure A.2.63: U.S. Market for Antihypertensives, Plain & Combo, 2008-2012 359 Figure A.2.64: U.S. Market for Diovan, 2008-2012 360 Figure A.2.65: U.S. Market for ADHD, 2008-2012 361 Figure A.2.66: U.S. Market for Vaccines (Pure, Comb and Others), 2008-2012 362 Figure A.2.67: U.S. Market for Systemic Hormonal Contraceptives, 2008-2012 362 Figure A.2.68: Treated Patients in Selected Therapies in the U.S., 2012 363 Figure A.4.1: Ranking of Asian Territories across All Factors 374 Figure A.4.2: Cost Ranking of Asian Territories 375 Figure A.4.3: Market Opportunity Ranking of Asian Territories 376 Figure A.5.1: Steady Increase of Biologics as a Share of Total FDA Approval 382 Figure A.5.2: Proportion of Health Insurers with Plans for Implementing Novel Contracting Models 383 Figure A.5.3: Insurer Expectations of Evidence from Manufacturer for Formulary Placement 384 Figure A.5.4: Data on Total U.S. Prescription Drug Spending 385 Figure A.5.5: Need for Aligned Efforts of Providers, Payers and Patients for Better Patient Outcomes 388 Figure A.5.6: Number of Companion Diagnostics Partnerships with Pharma 389 Figure A.5.7: Payer’s Perceived Barriers to Novel Contracting Practices 390 Figure A.5.8: Current and Future State of Data Conversions and Analysis 392 Figure A.5.9: Sources of Influence for Formulary Coverage and Decision Making 393 Figure A.6.1: Medical Cost Trend, 2010-2013 394 Figure A.6.2: Private Health Insurance Benefits by Spending Category 395 Figure A.6.3: Percent of U.S. Patients Seeking Treatment in Retail Clinics 396 Figure A.6.4: Surgical Cosmetic Procedures in the U.S. 397 Figure A.6.5: Increase in High-Cost Insurance Claims 398 Figure A.6.6: Percentage of Individuals with Employer-Sponsored Coverage in a High-Deductible Plan with a Savings Option 399 Figure A.6.7: Percentage of Consumers Delaying Care Because of Cost 399 INDEX OF TABLES Table 2.1: R&D Spending by Top 20 Companies, 2012-2018 24 Table 2.2: Top 20 Most Valuable Pharmaceutical R&D projects, 2018 25 Table 2.3: Most Valuable R&D Projects (Ranked by NPV), May 2012 and Current 26 Table 2.4: FDA Approval Count (NMEs & Biologics) vs. Fifth Year after Launch U.S. Product Sales 26 Table 2.5: Top Ten NMEs of 2012 Ranked by U.S. Consensus Sales in 2017 27 Table 2.6: Increasing Demand for Pharmaceuticals in Emerging Markets 29 Table 2.7: Top Ten Global Pharmaceutical Firms, 2011-2012 32 Table 2.8: Top Ten Pharmaceuticals by Sales in 2012 33



Table 2.9: Worldwide Prescription and OTC Sales by Therapy Area in 2018 34 Table 2.10: Top Ten Companies in Global Oncology Sales, 2012-2018 35 Table 2.11: Top Five Oncology Product Sales, 2018 36 Table 2.12: Top Ten Companies and Global Antidiabetic Sales, 2012-2018 36 Table 2.13: Top Five Anti-Diabetic Products, 2018 37 Table 2.14: Top Ten Companies and Global Anti-Rheumatic Sales, 2012-2018 37 Table 2.15: Top Five Anti-Rheumatic Products, 2012-2018 38 Table 2.16: Top Ten Companies and Total Global Vaccine Sales, 2012-2018 38 Table 2.17: Top Five Vaccine Products, 2018 39 Table 2.18: Top Ten Companies and Total Global Anti-Viral Sales, 2012-2018 39 Table 2.19: Top Five Anti-Viral Products, 2018 40 Table 2.20: Top 50 Global Pharmaceutical Brands in 2018 40 Table 2.21: M&A Transactions in 2012 42 Table 2.22: U.S. Prescription Drug Sales by Top 20 Companies, 2010-2012 46 Table 2.23: Top 50 Pharmaceutical Products in the U.S., 2012 47 Table 2.24: Top 50 Pharmaceutical Brands in the U.S. in 2018 48 Table 2.25: Prescription Drug Sales in Europe by Top 20 Companies, 2010-2012 51 Table 2.26: Prescription Drug Sales in Japan by the Top 20 Companies, 2010-2012 54 Table 2.27: Regional Prescription Drug Sales in the U.S., Europe and Japan (Top 20 Companies), 2012 57 Table 3.1: Patent Expiries by Country and Year, 2011-2015 61 Table 3.2: Top 25 Companies by R&D Pipeline Size, 2012 65 Table 3.3: Top 25 Therapeutic Categories in R&D, 2011-2012 68 Table 3.4: Top 25 Individual Diseases in the R&D Pipeline, 2012 69 Table 3.5: Top 20 Mechanism of Action in 2012 R&D Pipeline 70 Table 3.6: Top 25 Drug Protein Targets in 2012 R&D Pipeline 71 Table 4.1: Top 20 Companies in Global Generics Sales, 2012 78 Table 5.1: Number of Biologics Available in the Global Market 82 Table 5.2: Global Sales of Top 12 Biologics ($67 Billion), 2012 91 Table 5.3: Patent Protection for Roche’s Biologics 91 Table 5.4: Humira’s Revenues, Growth Rate and Market Share, 2010-2015 97 Table 5.6: Humira’s Revenues, Growth Rate and Market Share, 2016-2022 97 Table 5.7: Top U.S. Biotech Companies Ranked by Revenue, 2011-2012 141 Table 5.8: Sales if Neulasta/Neupogen, 2010-2012 142 Table 5.9: U.S. Biotechnology at a Glance, 2011-2012 146 Table 5.10: R&D Investment by the Top Ten Biotech Companies in the U.S., 2010-2012 147 Table 5.11: Cost of Commonly Used Biologics in the U.S. 158 Table 5.12: Biologics Used for Treating Rheumatoid Arthritis 159 Table 5.13: Biologics and Their Mode of Administration for Arthritis Patients 160 Table 5.14: Cost Comparison of Arthritis Biologics 160 Table 5.15: Total Hemophilia Market, 2011-2016 164 Table 5.16: Hemophilia A (Factor VIII) and von Willebrand Disease, Sales from Marketed Products and Late-Stage Pipeline, 2012-2016 165 Table 5.17: Hemophilia B, Marketed Products and Late Stage Pipeline, 2012-2016 166 Table 5.18: The Inhibitor Market: Products and Pipeline 167 Table 6.1: Definitions of Biosimilar Products 171 Table 6.2: Biosimilar Pipeline in the U.S. 182 Table 6.3: Other Key Players in Biosimilars Space 186 Table 6.4: Patent Expiration for Major Biologics 187 Table 6.5: Development Status of mAbs Biosimilars 190 Table 6.6: Generic Companies Active in Biosimilar Space 193 Table 6.7: Biosimilars Pipeline by Class, 2012 193 Table 6.8: Market Exclusivity Period for Specific Biologics in the U.S. 199 Table 6.9: Selected Biosimilars and Biobetters Currently in Development as of 2013 210 Table 6.10: Companies with the Largest Biosimilar Portfolios as of 2013 213 Table 6.11: Biosimilars Approved by the E.U. 219 Table 6.12: Native mAbs Developers in China 227 Table 6.13: Domestic Biosimilar Developers in India 229 Table 6.14: Celltrion’s Biosimilar Pipeline 229



Table 6.15: Summary of Publicly Announced Biosimilar Product Transactions Through 2012 233 Table 7.1: Selected Generics from Apotex 249 Table 7.2: AstraZeneca’s Development Projects 251 Table 7.3: Patent Expiries of AstraZeneca’s Key Marketed Products 251 Table 7.4: Plasma Derivatives from Bharat Serums and Vaccines Limited 253 Table 7.5: Biogen Idec’s Product Pipeline 256 Table 7.6: Bristol’s Key Products 258 Table 7.7: Reddy’s Product List 262 Table 7.8: New Products Launched by Richter in Hungary 263 Table 7.9: New Products Launched by Richter in Central and Eastern Europe 264 Table 7.10: GSK’s Prescription Medicines 265 Table 7.11: Key Products from Intas 268 Table 7.12: Merck’s Key Pharmaceutical Products 269 Table 7.13: Pfizer’s Major Biopharmaceutical Products 273 Table A.1.1: Biologic Medicines by Development Phase, 2013 281 Table A.2.1: List of NMEs Launched in 2012 321 Table A.2.2: Other NMEs Launched in 2012 322 Table A.2.3: Top Therapeutic Classes by Prescriptions, 2008-2012 364 Table A.2.4: Top Medicines by Prescriptions in the U.S., 2008-2012 365 Table A.3.1: Pharmaceutical Deals in 2012 367



1. Overview 1.1 Statement of Report The pharmaceutical and biopharmaceutical industries continue to be energetic, lucrative and growing segments, regardless of the slow ongoing recovery from worldwide economic problems. There are more than 10,000 therapeutics in R&D, both drugs (chemical substance pharmaceuticals) and biopharmaceuticals (biotechnology-derived pharmaceuticals), with 41,000 ongoing clinical trials. Among these, approximately 40% or more than 4,000 to 5,000 candidate products in R&D are biopharmaceuticals. This is a significant increase from as short as five years ago and indicates a basic shift in the pharmaceutical industry from small molecule drugs to biopharmaceuticals for new, innovative and profitable products. This TriMark report is mainly focused on the development and market potentials of biopharmaceuticals (biologics) and biosimilar drugs. Biopharmaceuticals are being developed by an ever-increasing number of companies, including Big Pharma and even generic drug companies, with many of these focused on developing biosimilars. As biopharmaceuticals are becoming important part of the pharmaceutical industry, several new firms are entering the field and existing manufacturers are expanding their bioprocessing capacity. While focused on cost-saving efforts, these biopharmaceutical firms are outsourcing many support and even critical tasks. The recent global economic downturn has done very little damage to the biopharmaceutical industry and there are now clear signs of real growth. Companies have started spending more in R&D and also are increasing their bioprocessing capacity. The global market for biopharmaceuticals is now nearly $145 billion; growing at about 15% annually, definitely a very healthy rate. Launching of new products continue to support global market growth. The global market for recombinant protein therapeutics has exceeded the $100 billion/year landmark. The impressive high growth rate in biopharmaceutical markets will continue to bring in investment in the industry, including at the expense of traditional small molecule drug developers. Larger companies are now paying attention to in-house manufacturing capacity instead of outsourcing their R&D and other tasks. Biopharmaceutical firms in many emerging economies that are serving their domestic, regional or lesser-regulated international markets are witnessing rapid growth. Despite the fact that majority of drugs (mostly generics) are now being manufactured in China and India, no Asian country yet manufactures biopharmaceutical products marketed in the U.S. or the European Union (E.U.). South Korea is another country that has the potential to become one of the manufacturing centers of biopharmaceuticals. Nowadays, Ireland has become the choice for large companies to build their biopharmaceutical manufacturing facilities. 1.2 About this Report This study first describes the existing and projected markets for pharmaceuticals in general, encompassing regional and country-wise trends. The data provided give an insight into the market potential of pharmaceutical drugs in general and also the sales revenues generated by specific drugs used in different therapeutic areas. Drugs losing patent protection from 2011 to 2015 are listed their volume of business in the past few years also have been shown. The predominance of generic drugs in the emerging markets is well documented with the support of graphs and tables. The report illustrates how the generics are gaining a foothold in the under-penetrated markets such as Japan and Western Europe with the assistance of government regulations and incentives. The report mainly discusses about the emergence of biologics and biosimilars and their potential role in shaping the future of global healthcare industry. The main objectives of the analysis in this report are:

• To analyze the changing dynamics of the pharmaceutical market. • To look into the ever increasing public healthcare expenditure that drives the growth of pharmaceutical

market. • To assess the potential global market for pharmaceutical drugs and the current market in different

geographical regions. • To identify the drugs losing patent protection until 2015 by country.



• To estimate the loss of big pharmaceutical firms due to patent expiries. • To evaluate the decline in market share for branded drugs by geography. • To study the global and regional markets for generics. • To analyze the utilization rates for generics in various countries. • To identify the top ten generic markets in the world. • To assess the savings from generics use in the U.S. • To identify the therapeutic areas that lead in generics savings. • To identify the top 30 generic launches from 2012 to 2017. • To estimate the global market for biologics. • To identify the largest selling biologics. • To analyze the large number of clinical trials involving biologics. • To identify the leading manufacturing firms in biologics. • To estimate the uptake of biologics by region/country in 2012. • To find the number of biosimilars approved in the E.U. • To estimate the global and regional markets for biosimilars. • To identify the centers of fast-growing biosimilars markets.

By purchasing this study, the reader will gain:

• An understanding of the regulatory pathways for branded pharmaceuticals and the biologics. • An understanding of how the generics and biosimilars have successfully eroded the strong and unassailable

positions enjoyed by the branded and biologics. • An insight into the number of patent expiries in the domain of branded and biologics drugs and the

consequent wave of opportunities for generics and biosimilars in the next ten years. • An understanding of how the pharmaceutical firms are changing their business strategies by shifting their

focus from developed markets to the emerging markets in order to retain their share in pharmaceutical business.

• An insight into the vast number of biologics in clinical trials and their applications in various clinical needs. Key questions answered in this review are:

• Does the pharmaceutical industry possess the required level of immunity to withstand the onslaught of economic vagaries around the globe?

• What are the growth rates for the pharmaceutical market in North America, Japan, Western Europe, Latin America, Eastern Europe and Asia/Africa regions?

• What are the comparative growth rates for branded and generic drugs? • What is the average price difference between branded and generic drugs in the U.S. and European markets? • What is the projected market value for branded, generic, biologic and biosimilar drugs from 2012 to 2019

in different geographic regions and countries? • Which are the leading manufacturing companies of branded, generic, biologic and biosimilar drugs, what

share do they have in the global and regional markets? • Which are the leading MNC companies operating in the two largest emerging markets; China and India?

1.3 Scope of the Report This analysis mainly dwells on the global and regional markets for branded, generic, biologic and biosimilar drugs to emphasize generic and biosimilars are gaining market shares from branded and biologic drugs. The report discusses in detail how the patent expirations of a large number of branded and biologic drugs are paving the way for the ascendancy of generics and biosimilars in the global pharmaceutical landscape. The report does not discuss the profiles of all the participating firms in the pharmaceutical industry, but focuses only on the leading manufacturing firms which control the market globally with a larger share in the market. The reader can consult other TriMark Publication reports on the TriMark website to gain insight into other pharmaceutical sub-segments.



1.4 Objectives Between 2009 and 2015, the pharmaceutical industry is facing the largest and most unexpected loss of revenue in history. During this period, about 18 of the top 20 blockbuster drugs are losing patent protection, causing losses for almost all the big pharmaceutical firms. This period provides unlimited opportunities for the generics to flood the market and garner a larger share in almost all the geographical segments of the market. Lipitor, Plavix, Singulair, Seroquel, Actos, Lexapro and Zyprexa lost the patent protection in 2011 and 2012 and other drugs will be losing the protection between 2013 and 2019. Biologics are medicines of large complex molecules manufactured through cell culture recombinant DNA technology and comprise recombinant insulin, growth hormone and monoclonal antibodies for treating conditions such as cancer and autoimmunity. The manufacture, testing and quality control of biologics is an expensive process, and therefore they represent some of the most expensive pharmaceutical products. However, they represented 16% of global pharmaceutical spending, with sales value reaching about $158 billion in 2012. Just as generics are to branded drugs, biosimilars are to biologics and adoption of biosimilars can effectively bring down the healthcare expenditure significantly. Currently, the biosimilars market is relatively small focused only on a small number of diseases; but the market has been predicted to grow substantially particularly in the U.S. and the developing economies such as Brazil and South Korea. The U.S. is an important market representing about 60% of the potential market that biosimilars firms need to tap into in the coming years. Faced with patent expiries, the pharmaceutical industry, generics and biotech firms are turning, for future revenues, to biosimilars. Thus, this report discusses in detail, the various strategies adopted by the pharmaceutical manufacturing firms to retain their market shares, expand their sphere of influence in different market segments and excel in their performance. 1.5 Methodology The author of this report is a retired college professor with more than three decades of experience in teaching, biochemistry, biochemical pharmacology, biotechnology, genetics and cell biology. He also has six years of experience in editing healthcare related market research reports. Company-specific information is obtained mainly from industry trade publications, academic journals, news and research articles, press releases and corporate websites, as well as annual reports for publicly-held firms. Additionally, sources of information include non-governmental organizations (NGOs), such as the World Health Organization (WHO), and governmental entities like the U.S. Department of Health and Human Services (HHS), and U.S. federal agencies such as the National Cancer Institute (NCI), the National Institutes of Health (NIH), the Food and Drug Administration (FDA), the American Cancer Society (ACS) and the Centers for Disease Control and Prevention (CDC). Where possible and practicable, the most recent data available have been used. Some of the most valuable data were sourced from the most recently published report “World Preview 2013, Outlook to 2018,” by EvaluatePharma in June 2013. These data offer insight into the 2012 sales of different classes of drugs including the top-selling biologics. Data on monoclonal antibodies (mAb) were sourced from articles from Antibody Society. Some statistical information was taken from Biotechnology Associates’ databases and from TriMark’s private data stores. The information in this study was obtained from sources that we believe to be reliable, but we do not guarantee the accuracy, adequacy or completeness of any information or omission, or the results obtained by the use of such information. Key information from the business literature was used as a basis to conduct dialogue with and obtain expert opinion from market professionals regarding commercial potential and market sizes. Senior managers from major company players were interviewed for part of the information in this report. Primary Sources TriMark collects information from hundreds of Database Tables and many comprehensive multi-client research projects, as well as Sector Snapshots that we publish annually. We extract relevant data and analytics from TriMark’s research as part of this data collection.



Secondary Sources TriMark uses research publications, journals, magazines, newspapers, newsletters, industry reports, investment research reports, trade and industry association reports, government-affiliated trade releases and other published information as part of its secondary research materials. The information is then analyzed and translated by the Industry Research Group into a TriMark study. The Editorial Group reviews the complete package with product and market forecasts, critical industry trends, threats and opportunities, competitive strategies and market share determinations. TriMark Publication’s Report, Research and Data Acquisition Structure The general sequence of research and analysis activity prior to the publication of every report in TriMark Publications includes the following items:

• Completing an extensive secondary research effort on an important market sector, including gathering all relevant information from corporate reporting, publicly-available data and proprietary databases.

• Formulating a study outline with the assigned writer, including important items, as follows:

• Market and product segment grouping, and evaluating their relative significance. • Key competitors’ evaluations, including their relative positions in the business and other relevant facts

to prioritize diligence levels and assist in designing a primary research strategy. • End-user research to evaluate analytical significance in market estimation. • Supply chain research and analysis to identify any factors affecting the market. • New technology platforms and cutting-edge applications.

• Identifying the key technology and market trends that drive or affect these markets.

• Assessing the regional significance for each product and market segment for proper emphasis of further

regional/national primary and secondary research.

• Completing a confirmatory primary research assessment of the report’s findings with the assistance of expert panel partners from the industry being analyzed.

1.6 Executive Summary The biopharmaceutical market keeps on expanding. There are now over 10,000 therapeutic candidates in R&D and about 40% of them are biopharmaceuticals. There is a visible trend of a shift towards biopharmaceuticals, with the large traditionally small molecule drug-oriented Big Pharma firms shifting their focus on biopharmaceuticals. For these firms, biopharmaceuticals offer higher sales and profits per sale. The global biopharmaceutical market is now about $145 billion per year. The biopharmaceutical market continues to increase globally, with a CAGR of about 15% to 18%, making biopharmaceuticals a fairly recession-proof, growing and profitable industry. Biotech drugs are anticipated to grow two to three times faster than the pharmaceutical market as a whole. Industry experts have estimated that there will be $50 billion in patent expiries of biologic drugs by 2015, and 90% of today’s biotech drugs will be off-patent by 2020. Sensing the market potential of biologics the larger global companies have declared programs to produce innovative drugs, biosimilars or follow-on biologics in all the major classes. Totally, 174 biologic drugs are available in the global market and among them 63 are proteins, 51 are antibodies and 160 are vaccines. Protein-based drugs are a fast growing class on the pharmaceutical market, with thousands of candidates in development. Five of the top ten prescription drugs in 2012 were biologics. AbbVie’s Humira (monoclonal antibody $8.1 billion), Amgen’s Enbrel (monoclonal antibody $7.3 billion), Johnson & Johnson/ Merck’s Remicade (monoclonal antibody $7.1 billion), Sanofi-Aventis’ Lantus (long-acting basal insulin $6.2 billion), and IDEC’s MabThera (chimeric monoclonal antibody $5.9 billion) took the first four places in the global prescription drugs market.



The global demand for recombinant proteins now exceeds $100 billion, and the industry reached this milestone two years ago in 2011. The market for recombinant monoclonal antibodies alone now stands at about $45 billion and this represents approximately 40% of the recombinant protein market and 31% of total biopharmaceuticals market. The antibodies are usually very specific in their action, do not cause severe side effects and therefore well-received in the market. As many new monoclonal antibodies have reached the final stage of clinical trials that will be available for expanded indications. The earliest approved monoclonal antibody was muromonab-CD3 in 1986. Yet, the monoclonal antibodies became financially viable only after the approval of rituximab, palivizumab, infliximab and trastuzumab in the late 1990s. Technologies in genetic engineering enabled the synthesis of these highly successful biologic products. Global market for monoclonal antibodies was about $50 billion in 2012 and it is predicted to grow at a CAGR of 8% through 2016. These biologics are mostly used in cancer therapies and the leading players in this sector are Roche, Abbott, Johnson & Johnson and Merck. Biosimilars have also increased in number and gained importance. Presently, the markets for approved biosimilars in Europe remain relatively small, only about $300 million for a dozen products, generally no more than 10% of the market for the established reference product. The utilization and market penetration of biosimilars has been slowly increasing, as E.U. member and other countries have started implementing their own cost-controls and recommendations for biosimilars use, and as these countries’ health care systems adopt these products. Howsoever, unlike Europe, utilization and market penetration by biosimilars in the U.S. is likely to be more rapid, upon approval, with private sector insurers expected to rapidly adopt and require use of biosimilars wherever possible. Therefore, it is reasonable to predict that biosimilars will have a global market of several billion dollars over the next few years. Many more companies are entering the biosimilars industry and all these firms are most likely to bring in many other new products. Thus, biosimilars will only be fracturing the markets for successful biopharmaceuticals coming off-patent. As of April 2012, there were more than 435 biopharmaceutical drugs cleared in the U.S. and European markets, including 166 recombinant proteins and 43 monoclonal antibodies. There were 283 biologics cleared in both the U.S. and Europe, including 117 recombinant proteins and 33 monoclonal antibodies. There are a minimum of 50 biologic drug candidates with FDA applications either pending or expected within coming months. The U.S. accounts for approximately half of global biopharmaceutical sales. Thus, U.S. sales of biologic drugs have been estimated to be in the range of $70 to $75 billion annually. The U.S. economy and health care system can afford to support adoption of new biopharmaceuticals. The same is not true for other major market countries, where cost-conscious centralized government control of pharmaceutical markets, e.g., U.K., can lead to reluctance to adopt certain biologics which are quite expensive. Growth in most of the rest of the world seems to be propelled more by overall economic improvement, including the development of a middle class, and other broad economic and social trends supporting improved health care in these countries. The most important class of biopharmaceuticals showing the fastest growth in market revenue is recombinant monoclonal antibodies. Monoclonal antibodies have become well-entrenched in the marketplace, having proven to be effective therapeutics candidates since the mid-1990s. Quite a large number of mAb products are blockbusters, with many of these used for cancer treatment.

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