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Value Creation in the Pharmaceutical Industry

The Critical Path to Innovation
1. Aufl.

von: Alexander Schuhmacher, Markus Hinder, Oliver Gassmann
97,99 €
Verlag:	Wiley-VCH
Format:	PDF
Veröffentl.:	19.01.2016
ISBN/EAN:	9783527693436
Sprache:	englisch
Anzahl Seiten:	508

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Titelbeschreibung

This practical guide for advanced students and decision-makers in the pharma and biotech industry presents key success factors in R&D along with value creators in pharmaceutical innovation. A team of editors and authors with extensive experience in academia and industry and at some of the most prestigious business schools in Europe discusses in detail the innovation process in pharma as well as common and new research and innovation strategies. In doing so, they cover collaboration and partnerships, open innovation, biopharmaceuticals, translational medicine, good manufacturing practice, regulatory affairs, and portfolio management. Each chapter covers controversial aspects of recent developments in the pharmaceutical industry, with the aim of stimulating productive debates on the most effective and efficient innovation processes. A must-have for young professionals and MBA students preparing to enter R&D in pharma or biotech as well as for students on a combined BA/biomedical and natural sciences program.

Inhaltsverzeichnis

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 Antibodies 261 12.3.4 Nonantibody Scaffolds 261 12.3.5 Bispecific Single-Chain Fragment Variables and Diabodies 263 12.3.6 Other Bispecific Antibody Formats 264 12.4 Antibody-Drug Conjugates 265 12.5 The Next Wave of Biologics 270 12.5.1 Orally Available Biologics 271 12.5.2 Biologics That Enter the Cytoplasm 271 12.5.3 Biologics That Pass the Blood–Brain Barrier 272 12.5.4 Translational Medicine as Driver of Innovation 272 Disclaimer 273 References 273 13 Vaccines: Where Inertia, Innovation, and Revolution Create Value, Simultaneously and Quietly 277 Pierre A. Morgon and Hannah Nawi 13.1 Introduction 277 13.2 TheWorld of Vaccines 278 13.2.1 What Are Vaccines? 278 13.2.2 Current Vaccines Are Mainly Prophylactic: Curative Vaccines Are Emerging 278 13.2.3 Drivers to Immunize: Individual and Collective 280 13.2.4 The Pivotal Role of Recommendations 280 13.3 The Vaccine Market: Substantial, Fast Growing, with Intense and Concentrated Competition 281 13.4 The Vaccine Industry: Domination of the Heavyweights, for Now… 282 13.4.1 Barriers to Entry: From R&D Risk to Capital Intensiveness 290 13.4.2 Five Forces Analysis: Competitive Intensiveness and Downstream Hurdles 291 13.4.2.1 Acceptability 291 13.4.2.2 Accessibility 292 13.4.2.3 Availability 293 13.4.2.4 Affordability 293 13.5 New Vaccine Developments: Strategic Trends and Why Innovation Is Needed All along the Value Chain 295 13.5.1 Where Is Innovation Needed? R&D 296 13.5.2 Where Is Innovation Needed? Manufacturing and Product Improvement 301 13.5.3 Where Is Innovation Needed? Acceptability 301 13.5.4 Where Is Innovation Needed? Accessibility, Both as a Function of Supply (Availability) and Logistics 302 13.5.5 Affordability and Sustainability 303 13.6 WhereWill Innovation Come from? Strategy and Players 304 13.6.1 Take-Home Messages 305 References 306 14 The Patient-Centric Pharma Company: Evolution, Reboot, or Revolution? 309 Pierre A. Morgon 14.1 Introduction 309 14.2 Health, Always… 310 14.3 The Mission of the Healthcare Industry 310 14.4 Megatrends Affecting the Strategic Scorecard of the Healthcare Industry 312 14.5 Focus on the Societal Trends and Their Consequences for the Management of Healthcare Innovation 314 14.6 The DNA of the Healthcare Industry: R&D and the Management of Innovation 316 14.7 Societal Expectations for Personalized Medicine 318 14.8 New Players Contributing to Information Management to Substantiate Value Propositions for NovelTherapies 319 14.9 The Role of the Key Stakeholders in Shaping a New Regulatory Framework 323 14.10 The Consequences for the Healthcare Industry in Terms of Governance and Capabilities 325 14.11 The Sustainable Path Forward for the Healthcare Industry 329 14.11.1 Take-Home Messages 331 References 332 15 The Pharmaceutical Industry is Opening Its R&D Boundaries 335 Alexander Schuhmacher and Ulrich A. K. Betz 15.1 Introduction 335 15.2 Open Innovation versus Closed Innovation 336 15.3 Business Models in an Open Innovation Framework 341 15.4 Open Innovation Processes 342 15.5 Capabilities and Attitudes Enabling Open Innovation 344 15.6 Open Innovation in the Pharmaceutical Industry 345 15.6.1 The More Traditional Elements of Open Innovation 345 15.6.1.1 Target Scouting 345 15.6.1.2 Research Collaborations 346 15.6.1.3 Drug Licensing 346 15.6.1.4 Outsourcing 348 15.6.1.5 Joint Ventures 349 15.6.2 The Newer Concepts of Open Innovation 349 15.6.2.1 New Frontier Science 350 15.6.2.2 Drug Discovery Alliances 350 15.6.2.3 Private–Public Partnerships 351 15.6.2.4 Innovation Incubator 351 15.6.2.5 Virtual R&D 352 15.6.2.6 Crowdsourcing 353 15.6.2.7 Open Source Innovation 355 15.6.2.8 Innovation Camps 355 15.6.2.9 Fluctuating Open Teams 356 15.7 New Business Models in View of the Potential of Open Innovation 356 15.7.1 General Trends in the Pharmaceutical Industry 356 15.8 Outlook 358 References 359 16 Out-Licensing in Pharmaceutical Research and Development 363 Oliver Gassmann, Carol A. Krech, Martin A. Bader, and Gerrit Reepmeyer 16.1 Introduction 363 16.2 Performance-Based R&D Collaborations on the Rise 364 16.3 The Impact of Collaborations on the Value Chain 365 16.4 Generating Value from Pipeline Assets by Out-Licensing 367 16.5 Pharmaceutical Companies’ Resistance toward Out-Licensing 372 16.6 Managing Out-Licensing at Novartis: A Case Study 372 16.6.1 Out-Licensing as a 10-Step Process 373 16.6.2 Out-Licensing Contract Design 375 16.6.3 Structure of the Out-Licensing Collaboration with Speedel 375 16.7 Future Directions and Trends 377 References 378 17 Trends and Innovations in Pharmaceutical R&D Outsourcing 383 Antal K. Hajos 17.1 Introduction 383 17.2 Drivers to the Use of Outsourcing 383 17.2.1 Overview on the CRO Market 383 17.2.2 Core versus Noncore Activities 387 17.3 Genesis of Outsourcing in the Twentieth Century: From Commodity to Contribution 388 17.3.1 Outsourcing Portfolio and the Move to Full-Service Provision 388 17.3.2 Globalization and the Emerging Market Hype 389 17.3.3 Procurement Takes over the Outsourcing Function 391 17.4 Current and Future Trends in Outsourcing: From Contribution to Innovation 392 17.4.1 How Has Outsourcing Itself Innovated and What Are the Future Trends? 392 17.4.2 How Does andWill Outsourcing Contribute to Innovation? 394 17.5 Discussion and Conclusion 395 References 398 18 New Innovation Models in Pharmaceutical R&D 401 Alexander Schuhmacher, Oliver Gassmann, and Markus Hinder 18.1 Introduction 401 18.2 Some AttemptsThatWere Recommended in the Past 402 18.3 The Increasing Pipeline Size 403 18.4 The Reduction of R&D Investments 404 18.5 The Opening of the R&D Processes 407 18.6 The Challenge with the Return on Investment 411 18.7 Changing the R&D Processes Is Not Enough 412 18.8 What Is the Best R&D Model? 413 References 414 19 The Influence of Leadership Paradigms and Styles on Pharmaceutical Innovation 416 Aubyn Howard 19.1 Introduction 417 19.2 What Is Your Concept or Model of Good Leadership? 419 19.3 Approaches to Leadership Modeling and Profiling 420 19.3.1 Personality Types 421 19.3.2 Behavioral Preferences 421 19.3.3 Developmental Stages 421 19.3.4 Competency Frameworks 421 19.4 The Developmental Approach to Leadership Paradigms and Styles 422 19.5 Inner and Outer Leadership 424 19.6 Dynamics of How Leadership Paradigms Evolve 425 19.6.1 Magic–Animistic 426 19.6.2 Impulsive–Egocentric 427 19.6.3 Conformist–Absolutist 428 19.6.4 Achievement–Multiplistic 429 19.6.5 Pluralistic–Relativistic 430 19.6.6 Evolutionary–Systemic 432 19.7 Leadership at Different Levels within Pharma 433 19.8 Optimizing Innovation in Different Organizational Models and Cultures 437 19.9 How DoWe Support the Development of Evolutionary Leaders? 439 19.10 What Does It Mean to Operate from the Evolutionary Paradigm? 440 19.11 Leadership and Personal Mastery 441 19.12 Building an Evolutionary Bridge to Release Innovation 442 19.13 Conclusions 445 References 446 20 The Role of Modern Portfolio Management in Pharma Innovation 449 Joachim M. Greuel and Axel Wiest 20.1 Introduction 449 20.2 Challenges in R&D and the Origin of Pharmaceutical Portfolio Management 450 20.3 Goals and Metrics of Portfolio Management 451 20.4 Portfolio Management as Enabler of Innovation 456 20.5 Modern Portfolio Management Integrates In-House R&D, Business Development, and M&A 457 References 458 21 Patent Management Throughout the Innovation Life Cycle 461 Martin A. Bader and Oliver Gassmann 21.1 Introduction 461 21.2 The Changing Role of Patents: From Legal to Strategic 462 21.3 The Patent Life Cycle Management Model 467 21.3.1 Exploration 468 21.3.2 Generation 469 21.3.3 Protection 469 21.3.4 Optimization 470 21.3.5 Decline 470 21.4 Example: Managing IP Rights at Bayer 471 21.5 Concluding Remarks 472 References 473 Index 475

Autorenportrait

Prof. Dr. Alexander Schuhmacher is a professor for R&D management, Vice Dean of the Faculty of Applied Chemistry and Senator at Reutlingen University. And he is Director for R&D performance metrics and business model innovation at Bioscience Valuation. Before joining the academic world, he worked 14 years in the pharmaceutical industry in various functions in R&D, such as in R&D portfolio management and strategic planning. He studied biology at the University of Constance (Germany), Pharmaceutical Medicine at Witten-Herdecke University (Germany) and he is also a graduate of the Executive MBA program at the University of St. Gallen (Switzerland). Prof. Dr. Markus Hinder studied medicine at the Universities of Heidelberg, Paris and Zurich and obtained a doctoral degree in pharmacology from Heidelberg University. After graduation he trained in clinical pharmacology, cardiology and emergency medicine. Before joining Novartis he held leadership positions in clinical pharmacology, translational medicine, clinical development, medical affairs and project management. Markus is a professor at Cardiff University/ Hochschule Fresenius, reviewer for several journals and associate editor for the Journal of Translational Medicine. Prof. Dr. Oliver Gassmann is a Professor for technology and innovation management at St. Gallen University, where he chairs the Institute of Technology Management. His teaching activities include several executive MBA programs. He has written or edited 18 books and published more than 300 journal articles on technology and innovation management. Until 2002 he headed the R&D department of Schindler. The main focus of his research lies in open innovation and global innovation processes. He is the 1998 recipient of the RADMA Prize and in 2009 was elected among the top 50 researchers by IAMOT, the International Association for Management of Technology.