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List of Contributors XVII Foreword XXI 1 Introduction to the Book 1 Alexander Schuhmacher, Oliver Gassmann, and Markus Hinder Reference 8 2 Global Epidemiological Developments 11 Stephan Luther and Peter Schmitz
2.1 Introduction 11
2.2 Model of Epidemiological Transition 12
2.3 Global Burden of Diseases 15
2.3.1 Trends in the Distribution of Disease Burden 16
2.4 Infectious Diseases 20
2.4.1 (Re-)emerging Infectious Diseases 23
2.4.2 Neglected Tropical Diseases 26
2.5 Noncommunicable Diseases 29
2.6 Antimicrobial Resistance 32
2.7 Dynamics 35 References 38 3 The Value of Pharmaceutical Innovation: Concepts and Assessment 45 Sam Salek and Paul Kamudoni
3.1 Introduction 45
3.2 Concepts and Definitions of Value 46
3.3 Stakeholder''s Perspectives on Value 47
3.3.1 Drug Regulatory Agencies 47
3.3.2 Health Technology Assessment 47
3.3.3 Patients 49
3.3.4 Prescribers/Clinicians 49
3.4 Recent Developments Influencing the Definition and Assessment of Value 50
3.5 Recommendations: Implications for R&D 51
3.6 Discussion 52
3.7 Conclusion 56 References 57 4 A Review of the Pharmaceutical R&D Efficiency: Costs, Timelines, and Probabilities 61 Alexander Schuhmacher, Oliver Gassmann, and Markus Hinder
4.1 Introduction 61
4.2 The Historical Perspective 62
4.3 The R&D Phase Model 63
4.4 The Low R&D Success Rates 63
4.5 The Long R&D Time Intervals 67
4.6 The High Cost of Pharmaceutical R&D 71
4.7 The Reduced R&D Efficiency 73
4.8 Can an Increase in R&D Value Compensate the Reduced R&D Efficiency? 76 References 78 5 Financing Pharmaceutical Innovation 81 Sviataslau Sivagrakau
5.1 Introduction 81
5.2 Measuring Innovation: Categories of New Drugs 84
5.3 Productivity of Pharmaceutical Industry throughout Time 86
5.4 Measuring the Cost of Developing New Medicines 87
5.5 Funding Drug Development: a Global Endeavor 91
5.6 Public and Private Funds: Complementary Finance for Drug Development 95
5.7 How Commercial Drug Development Projects Are Financed Today: Big Firms, Small Firms, andTheir Cooperation 97
5.8 Public Health Economics and Financing Pharmaceutical Innovation 99
5.9 Conclusion 101 Acknowledgment 102 References 102 6 Challenges and Options for Drug Discovery 107 Werner Kramer
6.1 Introduction 107
6.2 Paradigm Shifts of R&D Organizations 108
6.3 Productivity of Drug Discovery 109
6.4 IsThere an Innovation Gap in Biomedical Research? 111
6.4.1 To Go for First in Class or Best in Class 112
6.4.2 HowWe Define Medical Innovation? 112
6.5 Why Did Drug Candidates Fail? 113
6.5.1 Why Is the Dropout Rate So High in Early Clinical Development? 115
6.5.1.1 Drug Behavior In Vivo: Role of Transport Proteins 115
6.5.1.2 Hypes and Lack of Scientific Thoroughness 116
6.6 Implications from the "Lessons Learnt" for Future Drug Discovery Research 123
6.6.1 Organization of Drug Discovery and Development 123
6.6.2 Elucidation of the Physiological Validity of a Target for the Human Disease 125
6.6.2.1 Extensive Inquiry of (All) Published Data of a Target or Pathway 125
6.6.2.2 Integrative Knowledge Management 127
6.6.2.3 Demonstration of the Involvement of a Target in Human Disease 128
6.6.2.4 A Stringent and Comprehensive Test Sequence 132
6.6.2.5 Translational Clinical Trials 135 Acknowledgment 136 References 136 7 Translational Medicine: Enabling the Proof of Concepts 141 Gezim Lahu and John Darbyshire
7.1 Introduction 141
7.2 Translational Medicine and Its Role/Value in Early Development 143
7.3 Knowledge Generation 144
7.4 Types of Data, Experiments, and Tools Needed to Move from Basic Research to Early Clinical Development 144
7.4.1 Dose Selection 145
7.4.2 Animal Models 146
7.4.3 Fraction of NOAEL and Efficacious Dose 149
7.4.4 Allometric Scaling and PBPK 150
7.4.5 Physiologically Based Pharmacokinetic Models PBPK 151
7.4.6 Pharmacokinetic and Pharmacodynamic Modeling 151
7.5 FIM (Dose Escalation and MTD) 153
7.6 Proof of Concept (PoC) 154 Summary 156 References 157 8 Preclinical Safety and Risk Assessment 161 Paul Germann and Rob Caldwell
8.1 Introduction 161
8.2 Test Systems 161
8.2.1 In Silico Analysis 161
8.2.2 In Vitro Experiments 162
8.3 Case Study: hERG Assay 163
8.3.1 In Vivo Experiments 164
8.4 The Preclinical "Package" during the Development of an NME 165
8.5 Factors Influencing the Preclinical Data Set 166
8.5.1 Timing and Costs 167
8.5.2 Intended Clinical Application Route 167
8.5.3 Treatment Duration and Treatment Frequency 167
8.5.4 Clinical Indication 167
8.5.5 Ongoing Changes of the Regulatory Landscape 168
8.5.6 New Drug Formats 168
8.6 Translation into Humans:The "TherapeuticWindow" 169
8.7 Influence of Intended Therapeutic Use on the Risk Assessment (RA) 169
8.8 Deep Dive Case Study: Safety Assessment of Biological Drug Formats 170
8.9 NBE Case Study 1 175
8.10 NBE Case Study 2 175
8.11 Carcinogenicity Risk Assessment for Marketed Drugs 176
8.12 Treatment Duration 178
8.13 Conclusion - the "Art" of Preclinical Safety: Summarizing the Concept of Hazard Identification and Description, Risk Assessment, and Risk Management 179 Acknowledgment 179 Disclosures 180 References 180 9 Developing Commercial Solutions for Therapeutic Proteins 183 Galina Hesse
9.1 Introduction 183
9.2 Developing Commercial Solutions for Therapeutic Proteins 184
9.2.1 Defining a Target Product Profile 184
9.2.2 Developing Formulations for Therapeutic Proteins 186
9.2.3 Testing Formulations for Therapeutic Proteins 188
9.2.4 Development of Primary Containers 188
9.2.5 Development of Application Systems 190
9.3 Quality by Design 192
9.4 Examples for Innovations in Manufacture of Sterile Pharmaceutical Products 194
9.5 Summary 197 List of FDA/ICH Guidances Referenced 198 Disclaimer 199 References 199 10 The Evolution of Clinical Development: From Technical Success to Clinical Value Creation 203 Markus Hinder and Alexander Schuhmacher
10.1 Introduction 203
10.2 CD: Changes and Challenges 204
10.2.1 Clinical Endpoints: From Symptom-Oriented Endpoints to Hard and Predefined Endpoints 204
10.2.2 Determination and Quantification of Risks 205
10.2.3 Assessment of Medical Progress in Context of Available Therapeutic Options 206
10.2.3.1 EbM 206
10.2.3.2 Health Economics, Pharmacoeconomics, and the Fourth Hurdle 207
10.2.3.3 Results of These Changes and Challenges 208
10.3 Technical Success and Clinical Value Creation in CD in the Future 208
10.3.1 Established and Novel Approaches to Determine the Dose-Exposure-Response Relationship 210
10.3.2 Comparators 212
10.3.3 Patient Stratification to Increase Treatment Response and Benefit and Reduce Risk 212
10.3.4 New Operational Tools to Succeed in Trials with Increased Complexity, Special Populations, or Large Size 213
10.3.5 Collaboration and Outsourcing as Tools toWork in Networks 214
10.3.6 Collaboration across Sectors and Industries to Boost the NextWave of Innovation 215 Disclaimer 218 References 218 11 Translational Development 225 Nigel McCracken
11.1 Introduction 225
11.1.1 Legacy 226
11.2 Translational Development 227
11.2.1 TP 228
11.2.2 Translational Toolkit 229
11.3 Dose Optimization 230
11.3.1 Physicochemical Properties 231
11.3.2 Target Affinity and Selectivity 231
11.3.3 Clearance 231
11.3.4 Prediction of Human Dose 232
11.4 Pharmacogenomics 233
11.4.1 Patient Segmentation 233
11.4.2 Disease Segmentation 234
11.4.3 Utility 237
11.5 Biomarker Development 238
11.5.1 Biomarker Activities 239
11.5.2 Assessing the Opportunity 239
11.6 Systems Pharmacology 240
11.7 Rational Drug Development 241
11.8 Concluding Remarks 242 References 242 12 Forty Years of Innovation in Biopharmaceuticals - Will the Next 40 Years Be as Revolutionary? 245 Mathias Schmidt, Sanjay Patel, Petter Veiby, Qiang Liu, and Michael Buckley
12.1 Introduction 245
12.1.1 The Value Proposition of Biologics 246
12.1.1.1 The Patient Perspective 246
12.1.1.2 The Pharmaceutical Industry''s Perspective 248
12.1.2 Biosimilars: A Blessing or aThreat to Innovation? 250
12.1.3 Further Innovation in Biologics - Incremental or Revolutionary? 252
12.2 The Evolution of Biologics Manufacturing 252
12.2.1 Introduction 252
12.2.2 CHO Cells: The Industry Workhorse 253
12.2.3 Protein Production Strategies 253
12.2.4 The Impact of Increasing Titers on Manufacturing Facilities 255
12.2.5 Protein Purification Platforms 256
12.2.6 Conclusion: WhatWill the Next 40 Years of Innovation Bring? 258
12.3 The Evolution of Alternative Scaffolds 259
12.3.1 Novel Small Protein Scaffolds 260
12.3.2 Single-Chain Fragment Variables and Diabodies 260
12.3.3 Single-Domain Ant