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Principles of Biomedical Sciences and Industry
Principles of Biomedical Sciences and
Industry
Translating Ideas into Treatments
Edited by
Markus Hinder
Alexander Schuhmacher
Jörg Goldhahn
Dominik Hartl
Editors All books published by WILEY-VCH are carefully
produced. Nevertheless, authors, editors, and
Prof. Dr. Markus Hinder publisher do not warrant the information
Novartis Global Drug Development contained in these books, including this book,
Chief Medical Office & Patient Safety to be free of errors. Readers are advised to keep
Postfach Forum 1 in mind that statements, data, illustrations,
4002 Basel procedural details or other items may
Switzerland inadvertently be inaccurate.
Prof. Dr. Alexander Schuhmacher Library of Congress Card No.: applied for
Technische Hochschule Ingolstadt
THI Business School British Library Cataloguing-in-Publication Data
Esplanade 10 A catalogue record for this book is available
85049 Ingolstadt from the British Library.
Germany
Bibliographic information published by the
Prof. Dr. Jörg Goldhahn Deutsche Nationalbibliothek
ETH Zürich The Deutsche Nationalbibliothek lists
Institute for Translational Medicine this publication in the Deutsche
HCP H15.3 Leopold-Ruzicka-Weg 4 Nationalbibliografie; detailed bibliographic
ETH-Hönggerberg data are available on the Internet at
8093 Zürich <http://dnb.d-nb.de>.
Switzerland
© 2022 WILEY-VCH GmbH, Boschstr. 12,
Prof. Dr. Dominik Hartl 69469 Weinheim, Germany
University Hospital Tübingen
Department of Pediatrics I All rights reserved (including those of
Hoppe-Seyler-Strasse 1 translation into other languages). No part of
72076 Tübingen this book may be reproduced in any form – by
Germany photoprinting, microfilm, or any other
means – nor transmitted or translated into a
machine language without written permission
from the publishers. Registered names,
trademarks, etc. used in this book, even when
not specifically marked as such, are not to be
considered unprotected by law.
Print ISBN: 978-3-527-34571-7

ePDF ISBN: 978-3-527-82399-4
ePub ISBN: 978-3-527-82400-7
oBook ISBN: 978-3-527-82401-4
Cover Design: ADAM DESIGN, Weinheim,

Germany, based on an idea by Alexander
Schuhmacher / frontcover: iStock /@ ko_orn
Typesetting Straive, Chennai, India
v
Contents
Foreword xvii
About the Editors xix
List of Abbreviations xxi
1 Biopharmaceutical Innovation at a Glance 1

Markus Hinder, Dominik Hartl, and Alexander Schuhmacher
Summary 1
1.1 Biopharmaceutical Innovation and Drug Development, the Past and
Present 2
1.2 Why We Wrote This Book and What Readers Can Expect to Gain from
Reading It 4
References 5
2 Pharmacology and Drug Targets – The Basis of

Therapeutics 7
Lena Hartl, Martin A. Fink, and Sandra Beer-Hammer
Summary 7
2.1 Introduction 8
2.2 Pharmacodynamics 10
2.3 Receptors and Ion Channels 11
2.3.1 G-protein-Coupled Receptors (GPCRs) 11
2.3.2 Ion Channels 12
2.3.3 Enzyme-Associated Receptors 12
2.3.4 Non-receptor-Mediated Effects 14
2.4 Receptor Agonism and Antagonism 15
2.5 Implications for Drug Development 18
2.6 Pharmacokinetics 19
2.6.1 Liberation and Administration 19
2.6.2 Absorption 21
2.6.3 Distribution 21
2.6.4 Metabolism/Biotransformation 22
2.6.5 Phase I Reaction 23
2.6.5.1 Oxidation 23
vi Contents
2.6.5.2 Reduction and Hydrolysis 24

2.6.5.3 Phase II Reaction 24
2.6.5.4 Phase III Reaction 25
2.6.6 Excretion 25
2.6.6.1 Renal Elimination 25
2.6.6.2 Biliary Elimination 27
2.6.6.3 Intestinal Elimination 27
2.6.6.4 Pulmonary Elimination 27
2.7 Quantitative Pharmacokinetics 27
2.7.1 Dosing Regimen 27
2.7.2 Clearance (CL) 27
2.7.3 Exposure as Area Under the Curve 28
2.7.4 Bioavailability 28
2.7.5 Cmax , Ctrough , and Peak-to-Trough-Ratio 28
2.7.6 Volume of Distribution 29
2.7.7 Half-Life 29
2.7.8 Accumulation and Loading Dose 29
2.7.9 Induction and Maintenance Dose 30
2.8 Pharmacokinetic Models 30
2.9 Implications for Drug Development 31
2.9.1 PK/PD Modelling 31
2.9.2 Characteristics of Pharmacokinetics in Age, Disease and Others 33
2.9.3 Dose Finding/Determination of Dosing Regimens 33
2.9.4 Individualized Dosing and Therapeutic Drug Monitoring 34
2.10 Conclusions 34
References 34
3 Principles and Methods of the Pharmaceutical Drug Discovery

Process – From Idea over Target to a Development
Candidate 37
Werner Kramer
Summary 37
3.1 What is the Purpose of Drug Discovery? 38
3.2 Phases of the Drug Discovery Process 38
3.3 Target Identification 40
3.3.1 What is a Pharmaceutical Target? 40
3.3.2 Sources for Target Identification 41
3.3.2.1 An Extensive Inquiry of All Published Data on a Particular Target and Its
Pathway(s) 41
3.3.2.2 (Pharmaco)-Genetic Links to a Phenotype 41
3.3.2.3 Phenotypic Screening 41
3.3.3 Target Validation 42
3.3.3.1 Genetic Target Validation 42
3.3.3.2 Chemical Target Validation (‘Chemical Genomics’) 42
3.4 Strategies to Modulate Biological Targets 43
Contents vii
3.4.1 Preventing Formation of the Target Protein 43

3.4.2 Targeting the Ligand Binding Site of the Protein 44
3.4.3 Targeting Protein–Protein Interactions (PPI) 44
3.4.4 Masking Proteins 44
3.5 The Lead Identification Process 44
3.6 Strategies to Identify Lead Compounds 45
3.6.1 High-Throughput Screening (HTS) 45
3.6.1.1 Assay Criteria for Screening Approaches 47
3.6.1.2 Structure-Based Rational Drug Design 49
3.6.1.3 Phenotypic Screening 51
3.6.2 Chemical Libraries 52
3.6.2.1 Criteria for the Compounds in a Chemical Library 53
3.6.2.2 DNA-Encoded Chemical Libraries (DEL Libraries) 54
3.7 Drug Candidates 55
3.7.1 Lead Optimization and Candidate Selection 56
3.8 Outlook 59
References 60
4 Biomarkers: Definitions and Utility for Drug Development 63

Dominik Hartl
Summary 63
4.1 Introduction 64
4.2 Biomarker Modalities 69
4.2.1 Molecular Biomarkers 71
4.2.2 Imaging Biomarkers 72
4.2.3 Digital Biomarkers 73
4.3 Biomarkers in Drug Development 73
4.4 Biomarker Use Cases 75
4.5 Outlook 78
References 78
5 Toxicology in Drug Development – Understanding a Drug’s

Toxicity and Managing Safety and Risks 81
Elisabeth Rosner
Summary 81
5.1 Introduction to Toxicology and Definitions 82
5.2 The General Toxicological Framework 83
5.3 The Concept of the Therapeutic Index 84
5.4 The International Regulatory Framework for Safety Evaluations 85
5.4.1 The Data Package Required for First in Human (FIH) Trials 86
5.4.2 The Data Package Required for Studies Beyond FIH 87
5.4.2.1 The Data Package Required for Studies Beyond FIH for Large
(Bio)molecules and Oncology Compounds 87
5.5 Animal Species Selection 89
5.6 Basic Concepts for Non-clinical Studies to Support Clinical Trials 89
viii Contents
5.7 What Activity at Which Stage of Development? 92

5.8 Estimating the Safe Starting Dose in FIH Trials 93
5.8.1 Anti-cancer Drugs 93
5.9 Toxicological Evaluations During Late-Stage Drug Development 94
5.10 Outlook 96
References 97
6 Introduction to Chemistry Manufacturing and Controls – From

Compound and Development Candidate to Drug 99
Thomas Eichinger
Summary 99
6.1 CMC Introduction and Background 100
6.2 Some Basic Thoughts 100
6.2.1 Transition from Research to Development 100
6.2.2 Some Fundamentals About Physico-chemical Characteristics 101
6.2.3 The Biopharmaceutical Classification System (BCS) 102
6.2.4 Stability Investigations 104
6.2.5 The Physical Appearance: Morphology and Polymorphism 105
6.3 Preclinical Development and the Clinical Phase 1 from a CMC
Perspective 107
6.3.1 The Active Pharmaceutic Ingredient (API) 107
6.3.2 The Drug Product 108
6.3.3 Analytical Development 109
6.3.4 Regulatory Green Light for FIH Study 110
Perspective 110
6.4.1 The Active Pharmaceutic Ingredient (API) 111
6.4.2 The Drug Product 111
6.4.3 Analytical Development 111
Perspective 111
6.6 The Compilation and Authoring of the Submission Dossier for
Marketing Authorization 112
6.7 The NDA Submission and the Steps to Product Launch 116
References 117
7 Translational Medicine – The Bridging Discipline. Role and

Tools in the Drug Development Process 119
Markus Hinder and Dominik Hartl
Summary 119
7.1 Translational Medicine, Definitions and History 120
7.2 The Translational Gap 122
7.2.1 Failed Translation: Why It Happens and Why We Need to Avoid It 122
7.2.2 Predictivity of Models and the Translatability Gap 123
7.2.3 The Learning and Confirming Paradigm 124
Contents ix
7.3 Paths of Translation 126

7.3.1 Forward vs Reverse/Back-Translation 126
7.4 Translational Medicine in Drug Development 129
7.4.1 Bench to Bedside and Back or Forward and Backward Translation 129
7.4.1.1 Examples of Classical Forward Translation 129
7.4.1.2 Examples of Bedside to Bench or Backward Translation 130
7.5 Serendipity 132
7.5.1 Serendipity Examples: Sildenafil and the SGLT2 inhibitors 133
7.6 Conclusions 134
References 136
8 Decision-Making: What are the Key Drivers Around

Decision-Making in Drug Development? 139
Nigel McCracken
Summary 139
8.1 Background 140
8.1.1 Drug Development Process 140
8.1.2 Target Product Profile 141
8.2 Key Decision Points 142
8.3 Moving Towards ‘Go IND Enabling’ 143
8.4 Moving Towards Go/No Go First in Human (FIH) 144
8.5 Moving Towards Go/No Go Phase 2 146
8.6 Moving Towards Go Confirmatory Development 148
8.7 Concluding Remarks 150
References 150
9 Clinical Drug Development – Clinical Characterization for

Regulatory Approval 151
Werner Seiz
Summary 151
9.1 Clinical Drug Development, Definition, and Framework 152
9.2 The Different Stages of Clinical Development 153
9.3 The Basic Framework and Elements for Clinical Trials 155
9.4 The Clinical Study Protocol 156
9.5 Written Subject Information 156
9.6 Graphical Study Design and Schedule of Activities 156
9.7 Definition of Patient Population and Sample Size Calculation 160
9.8 Study Design 161
9.9 General Methods and Statistical Tools 163
9.9.1 Analysis Populations 163
9.9.2 Clinical Operations 163
9.10 Target Product Profile, Clinical Development Plan, and Other
Documents During Development 166
9.11 Changing Environment: Sensors, Digitalization, and COVID-19
Pandemic 166
x Contents
9.12 Key Studies During Clinical Development 167

9.12.1 First-In-Human Study 167
9.12.2 Mechanistic Study 169
9.12.3 Clinical Proof-of-Concept 169
9.12.4 Dose-Ranging Studies 170
9.12.5 Efficacy Studies 171
9.12.6 Specific Approaches – Adaptive Trial Designs 171
9.12.7 Oncology Trials 173
9.12.8 Basket, Umbrella, and Platform Trials 173
9.13 Advisory Boards, Steering Committees, Data and Safety Monitoring
Boards 174
9.13.1 Advisory Boards 174
9.13.2 Steering Committees 174
9.13.3 Endpoint Adjudication Committees 174
9.13.4 Data Safety and Monitoring Boards/Data Monitoring Committee 174
9.14 Summary of Information 175
References 175
10 Regulatory Affairs – Communicating with Health

Authorities 177
Hans-Juergen Fuelle and Valerie Lanctin
Summary 177
10.1 Regulatory Environment – Getting Started 178
10.2 The Role of Regulatory Affairs in Early Drug Development 180
10.3 The Common Technical Document 182
10.4 Investigational New Drug 184
10.5 Clinical Trial Application 184
10.6 Early Consultations with Health Authorities 185
10.7 Regulatory Requirements for Paediatric Diseases 186
10.8 Regulatory Pathways for Drug Development for Orphan/Rare
Diseases 187
10.9 Accelerated Pathways for Expedited Clinical Development and
Regulatory Review 188
10.10 The Role of Regulatory Affairs in Late-Stage Drug Development 190
10.11 The Role of Regulatory Affairs Before, During and After
Registration 194
10.12 Pre-submission Meetings with Health Authorities 195
10.13 Additional Submission-Enabling Regulatory Affairs Activities 196
10.14 Health Authority Review of Registration Dossiers 196
References 200
Contents xi
11 Regulatory Affairs in Device Development – How to Design

Medical Devices Capable to Enter the Market 203
Dietmar Schaffarczyk
Summary 203
11.1 Introduction 204
11.2 Product Commercialization 206
11.3 Ten Things to Know and Consider When Developing a Device 208
11.4 Obtaining Qualified Input from Interested Parties 212
11.5 Planning and Executing All Important Development Milestones 216
11.6 Design and Development Verification: Did I MAKE the Product
Right? 218
11.7 Design and Development Validation: Did I MAKE the Right
Product? 219
References 222
12 Market Entry and Reimbursement: Making Drugs Available for

Patients After Drug Approval 225
Ahmad Bechara and Rola Haroun
Summary 225
12.2 Healthcare Challenges 226
12.3 What Does Market Access Mean? 227
12.4 Market Access Gatekeepers 228
12.5 Drug Purchasing 228
12.6 Payers and Value Assessment 229
12.7 Health Economics as a Decision Tool for Market Access 231
12.7.1 What Is Health Economics? 232
12.7.2 What Is the Aim of a HTA? 232
12.7.3 HTA Process 233
12.8 Setting the Right Price 234
12.8.1 Pricing Policy 234
12.8.2 Therapeutic Reference Pricing (Internal) 234
12.8.3 International/External Reference Pricing 235
12.8.4 Value-Based Pricing 235
12.8.5 Overview of the Pricing and Reimbursement Process in Key European
Markets 236
12.9 How Does the Pharma Industry Prepare for Market Entries? 237
12.10 Early Patient Access 240
12.11 Managed Entry Agreements 240
12.12 Market Access Trends 242
xii Contents
12.12.1 USA and Canada 242

12.12.2 Europe 242
12.13 Future Market Access Challenges 243
References 243
13 Pricing in Germany – Key Learnings for Optimizing Price

Potential After the Introduction of AMNOG 247
Jacqueline Jones
Summary 247
13.2 Structure of the Pricing and Reimbursement Process in Germany 249
13.3 Analysis of Effects of the AMNOG Process on Drug Prices in
Germany 251
13.4 Learnings from AMNOG to Ensure Success in the German Market 253
13.5 Study Design 254
13.6 Dossier Preparation 254
13.7 Pre-launch Strategy 254
13.8 Post-launch 255
13.9 Price Negotiation 255
13.10 Post-negotiation 255
13.11 Key Takeaways 256
Key Resources 256
References 256
14 Project, Risk, and Portfolio Management – Managing R&D

Projects Today 257
Alexander Schuhmacher and Markus Hinder
Summary 257
14.2 The Phases of the Pharma R&D Process 259
14.3 Projects and Project Management 263
14.4 Project Life Cycle and Project Phases 270
14.5 Risk Management 272
14.6 Portfolio Management 274
References 279
15 Intellectual Property – How to Protect Innovation in the

Biopharmaceutical Industry 281
Charles E. Jeffries and Karen D. Larbig
Summary 281
15.1 Introduction to Intellectual Property Rights 282
15.2 Patent Rights 284
15.2.1 What is a Patent? 284
15.2.2 Patentability Criteria 285
15.2.3 Why and How to Apply for a Patent? 286
Contents xiii
15.2.4 Patenting Procedure 287

15.2.4.1 From Invention Harvesting to Patent Filing 287
15.2.4.2 Patent Prosecution and Grant Procedure 288
15.2.5 Value and Use of Patent Rights 291
15.3 The ‘Freedom to Operate’ Principle 292
15.4 Intellectual Property Protection in the Biopharmaceutical Industry 294
15.4.1 Patent Protection for a Pharmaceutical Drug Product 296
15.4.2 Life Cycle Management 298
15.4.3 Patent Term Extensions 298
15.4.4 Regulatory Data Protection 299
15.4.5 Loss of Exclusivity 299
15.4.6 FTO Issues in the Biopharmaceutical Industry 300
15.4.7 Role of an In-house Intellectual Property Department 301
15.5 Conclusion 302
Key Resources 302
16 Patents in the Biomedical Sciences and Industry – The Case of

the Swiss Life Science Company Prionics 305
Martin A. Bader and Oliver Gassmann
Summary 305
16.1 Patents in the Biomedical Sciences and Industry 306
16.2 The Swiss Life Science Company Prionics 309
16.3 Success Factors and Failures 312
16.4 Consequences and Insights 313
Key Resources 314
References 314
17 Pharmaceutical Business Development and

Licensing – Overview of a Cross-Functional and Multifaceted
Role and Its Key Elements in Biopharmaceutical Industry 317
Monika Schuessler
Summary 317
17.2 Types of Collaborations 318
17.3 Licensing Agreements 319
17.4 Commercial or Distribution Partnerships 320
17.5 Research Collaborations 321
17.6 Other Types of Agreements 321
17.7 Tech Transfer Agreements 322
17.8 Structured Approach – How to Start a Transaction? 322
17.9 Evaluation Process 324
17.10 Due Diligence 327
17.11 Letter of Intent and Term Sheet 329
17.12 Negotiation and Contract Closure 330
17.13 Alliance Management 331
xiv Contents
17.14 Conclusions 332

References 332
18 The Entrepreneur’s Guide Through the Galaxy of Biotech

Funding 333
Mathias Schmidt
Summary 333
18.2 Seed Funding – from a Research Concept to Validation of a Business
Idea 335
18.3 Getting Serious – Series A 336
18.3.1 Valuation 338
18.3.2 Building the Team 338
18.3.3 Alternatives to Venture Financing 338
18.4 Getting more Serious – Series B 339
18.5 Venture Debt as an Alternative to a Series B 341
18.6 Getting most Serious – Series C 341
18.7 Exit Options 342
18.8 Closing Remarks 343
Reference 343
19 Medical Technologies – Key Learning from Two Case

Studies 345
Günter Lorenz and Andreas Schüle
19.1 Case Study 1 – Medical Grade Plastics (MPG) 345
19.1.1 Consistency of Formulation 347
19.1.2 Security of Supply 348
19.1.3 Appendix – ISO 10993 349
19.2 Case Study 2 – Vitrectomy Using Fast Pneumatic-Driven Cutter
Systems 350
19.3 Innovative Valve Technology 352
19.4 Integration Technology 353
20 Laboratory Diagnostics – Tools for Clinical Decision-Making

and Clinical Trial Endpoints 357
Bhuwnesh Agrawal
Summary 357
20.1 Definition of Diagnostics, Why Diagnostics, Importance of Diagnostics,
Sample Types 358
20.2 The Diagnostics Industry – Key Figures and Key Players 361
20.3 Brief History of Diagnostics 362
20.4 Elements of the Laboratory Workflow (Pre-analytics, Analytics, and
Post-analytics) 362
20.5 Various Types of Diagnostic Tests in the Laboratory 363
20.5.1 Clinical Chemistry 363
Contents xv
20.5.2 Immunology 364

20.5.3 Haematology and Coagulation 364
20.5.4 Microbiology 365
20.5.5 Molecular Diagnostics 365
20.5.6 Histopathology 366
20.6 Place of Diagnostics in the Clinical Workflow 366
20.7 Quality Management 367
20.7.1 Commercial Tests 367
20.7.2 Laboratory-Developed Tests (LDTs) 367
20.7.3 Test Performance Characteristics 369
20.8 Regulatory Approval of Diagnostics 370
20.9 The Diagnostics R&D Process – Stage Gate and Agile Development
Processes 373
20.9.1 The Stage-Gate Process 373
20.9.2 The Agile Development Process 373
20.10 The Future of Diagnostics – Key Technologies and Trends, Personalized
Diagnostics 375
20.10.1 Automation 375
20.10.2 Molecular Testing 375
20.10.3 Personalized/Precision Medicine 375
20.10.4 Point of Care Testing 375
20.10.5 Digitization and Artificial Intelligence 376
20.11 Conclusions 376
References 376
21 Vaccination: Towards an Improved Influenza Vaccine 377

Pierre A. Morgon
Summary 377
21.1 Influenza – A Deadly Disease with a Long History 378
21.2 The Annual Challenge 383
21.3 Mechanisms of the Immune Response 384
21.4 Antigen Content 385
21.5 Although Influenza Vaccine Formulation Evolves to Reflect the
Circulating Strains, Innovation is Rare 386
21.6 Medical Rationale for Intradermal Administration (ID) 386
21.7 Search for Greater Acceptability 387
21.8 Acceptability of the New Device 389
21.9 Acceptability in Real Life 391
21.10 Outlook and Trends 393
References 394
Index 397
xvii
Foreword
This book with many critically important chapters is addressing key topics in
biopharmaceutical research & development and innovation. It aims at explaining
new modalities to diagnose, prevent, and treat human diseases. It also provides
real examples (case-in-points) of prototypes of innovative approaches that are
tested in biological systems of increasing size, complexity, and relevance where
the early phase spans from individual receptors over cell, organ systems to first
therapeutic exploration in small and well-defined patient populations. It debates
the latest know-how and the common commitment to the vision of a revitalized and
impactful biopharmaceutical development as well as other characters such as reg-
ulatory and health technology agencies instrumental to completing the journey of
medicines development, i.e. delivering to the respective patient population. This is a
recognition of the current environment where patient advocacy groups demanding
equitable access to affordable, quality products in reasonable timeframes.
The editors’ vision of recognizing the science of decision-making or ‘decision
science’ as an important process in medicines development is commendable. This
is often neglected in books addressing the process of medicines development. The
quality decision-making process as an integral part of medicines development has
a much higher chance of leading to quality outcomes. It can be argued that a poor
quality or bad decision-making process could lead to a good outcome; however,
this could only happen by chance. For example, applying quality decision-making
process by incorporating validated methodologies for benefit-risk assessment into
guidance for regulatory review. Such approaches are all twenty first century best
practices, which will have the outcomes of improved predictability, accountability,
consistency, and transparency of a public health focused, science-based medicines
development.
The book’s editors are active or former pharmaceutical executives who have
been lecturing biopharmaceutical innovation, pharmacology, and pharmaceutical
medicine over decades and who have brought together 27 experts in medicines
development to write the 21 chapters addressing development of biopharmaceuti-
cals/pharmaceuticals from molecule to market place. The chapters have focused
on the evaluation of many aspects of pre-clinical and clinical development very
helpful to students in biopharmaceutical sciences, pharmaceutical medicine, and
life science management. These chapters also provide insights that can be of benefit
xviii Foreword
to not only those engaged in biomedical postgraduate studies but also to those
early career researchers involved in medicines development. Undoubtedly, this
comprehensive body of work will improve scientific, regulatory, and reimbursement
processes and more efficiently facilitate access to quality versions of needed medical
products.
It is my hope that this book and the research it contains will provide significant
insight into pre-clinical and clinical development of biopharmaceuticals as well
as fostering innovation and quality decision-making practices applied to key
milestones of medicines development. I believe the roadmap provided in this book
could be considered as a blueprint for other health technology innovations, whether
a new active substance or an incremental innovation.
Professor Sam Salek, PhD, RPh, FFPM, GFMD, FRPS, FESCP, MCMS
Professor of Pharmacoepidemiology
Head – Public Health and Patient Safety Research Group
School of Life and Medical Sciences
University of Hertfordshire, UK
Visiting Professor – Estate of Hessen, Germany

Vice-President, PharmaTrain Federation
xix
About the Editors
Prof. Dr. Markus Hinder studied medicine at the

Universities of Heidelberg, Paris, and Zürich and
obtained a doctoral degree in pharmacology from
Heidelberg University. After graduation, he trained
in clinical pharmacology, cardiology, and emergency
medicine and underwent postgraduate training in
clinical trial methodology and statistics at the Uni-
versities of Basel and Brussels. Markus joined the
pharmaceutical industry more than 20 years ago and
held senior leadership positions in clinical pharma-
cology, translational medicine, clinical development,
medical affairs, drug safety and project management.
He has been lecturing pharmacology and pharma-
Photo: Markus Hinder.
ceutical R&D since 2004. In 2010, he was appointed
professor at Cardiff University/Hochschule Fresenius. He serves as a reviewer for
several journals and as an associate editor for the Journal of Translational Medicine.
Prof. Dr. Alexander Schuhmacher graduated in

biology from the University of Konstanz (Germany),
in pharmaceutical medicine at the University of
Witten/Herdecke (Germany) and did a Ph.D. in
molecular biology at the University of Konstanz; he
is also a graduate of the Executive MBA program at
the University of St. Gallen (Switzerland). Alexander
holds a full professorship in Life Science Manage-
ment at the THI Business School (Germany). His
research focus is on biopharmaceutical innovation
management with a specialization on R&D effi-
ciency, artificial intelligence, and open innovation.
Prior to that, Alexander worked 9 years as professor
at Reutlingen University (Germany) and 14 years
Photo: Alexander
in various senior R&D leadership positions in the
Schuhmacher.
pharmaceutical industry.
xx About the Editors
Prof. Dr. Jörg Goldhahn received his M.D. in 1997

from the Friedrich-Schiller University in Jena, Ger-
many, finished a postgraduate course (MAS) in Med-
ical Physics and Biomechanics at the ETH Zürich in
2000, received the postdoctoral lecture qualification
(Habilitation) in 2008, and became a faculty member
of the department for health sciences and technol-
ogy (D-HEST) as adjunct professor 2014. He worked
as a translational medicine expert at the Novartis
Institutes for Biomedical Research (NIBR) in Basel
in addition to more than 15 years in clinical research.
He is currently the head of the Institute for Transla-
Photo: Jörg Goldhahn. tional Medicine and medical director of the bachelor
in medicine at ETH in Zurich, Switzerland.
Prof. Dr. Dominik Hartl studied Medicine at the

Universities of Regensburg, Munich, and Melbourne
and obtained his doctoral degree in Immunology
from Munich/LMU University. He is board certified
in Pediatrics and Infectious Diseases and worked as
Physician Scientist/Post-Doc Scholar at Yale Univer-
sity. He joined the pharmaceutical industry more
than seven years ago and gained extensive experi-
ence in his positions in Drug Discovery, Transla-
tional Medicine, Biomarkers, Clinical Development
and Precision Medicine/Personalized Healthcare in
Biotech and Big Pharma. In addition to working in
Photo: Dominik Hartl. the pharmaceutical industry, Dominik is a Professor
for Pediatric Immunology/Infectious Diseases at the
University of Tübingen.
xxi
List of Abbreviations
More than
Abbreviations Meaning one meaning
AAALAC Association for Assessment and Accreditation of

Laboratory Animal Care
ACE Angiotensin-converting enzyme
ADH Autosomal dominant hypercholesterolaemia
ADME Absorption, distribution, metabolism and
excretion
ADMET Absorption, distribution, metabolism, excretion,
toxicity
AEMPS Spanish Agency for Drugs and Medical Products
AI Artificial intelligence
AIDS Acquired immunodeficiency syndrome
AIFA Italian Medicines Agency
AIS Arztinformationssystem
AMNOG Arzneimittelmarkt Neuordnungsgesetz
AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid (receptor)
AP Angina pectoris
API Active pharmaceutical ingredient
AR Assessment report
ASMF Active substance master file
ASMR Amélioration du Service Médical Rendu
ATC Anatomical therapeutic chemical
ATMP Advanced therapy medicinal product
ATP Adenosine triphosphate
AUC Area under the curve
BA Bioavailability
BBB Blood-brain barrier
xxii List of Abbreviations
More than
BCS Biopharmaceutical classification system

BEST Biomarker, endpoints and other tools
BLA Biologics license application
BMP Bone morphogenetic protein
BNP Brain natriuretic peptide
BPCA Best Pharmaceuticals for Children Act
BQP Biomarker qualification program
BSE Bovine spongiform encephalopathy
CA Competent authority
CAP College of American Pathologists
CAPA Corrective and preventive action
CAR-T Chimeric antigen receptor T-cell (therapy)
CAS Chemical abstract service (registration number)
CAT Committee for advanced therapies
CBA Cost–benefit analysis
CBER Center for Biologics Evaluation and Research
CD4 Cluster of differentiation 4 (cell)
CDA Confidentiality agreement
CDER Center for Drug Evaluation and Research
CDP Clinical development plan
CDRH Center for Devices and Radiological Health
CE Conformité Européenne
CEA Cost-effectiveness analysis
CED Coverage with evidence development
CEO Chief executive officer
CEREP Inhibitory activity and selectivity of compounds on
the PDE superfamily
CETP Cholesteryl-ester-transfer-protein
cGMP Cyclic guanosine monophosphate
CJD Creutzfeldt–Jakob disease
CKD-EPI Chronic kidney disease epidemiology
collaboration equation
CKL Clearance
CLIA Clinical Laboratory Improvement Act
clogP Partition coefficient between n-octanol and water
CMA Critical material attributes or cost-minimization
analysis
CMC Chemistry, manufacturing, and control
CNS Central nervous system
COGs Cost of goods
COMP Committee for orphan medicinal products
List of Abbreviations xxiii
More than
CP Centralized procedure
CPP Critical process parameters
CQA Critical quality attributes
CRO Contract research organization
CRP C-reactive protein
CSE Cystathionine-γ-lyase
CSP Clinical study protocol
CT Computed tomography
CTA Clinical trial application
CTD Common technical document
CUA Cost–utility analysis
CYP Cytochrome P450
CyTOF Cytometry by time-of-flight
DCDS Development core data sheet
DD Due diligence
DDI Drug–drug interaction
DDP Drug development pathway or design and 1
development plan
DEL DNA-encoded chemical libraries
DLTs Dose-limiting toxicities
DMC Data monitoring board
DMF Drug master file
DMSO Dimethyl sulphoxide
DNA Deoxyribonucleic acid
DoH Declaration of Helsinki
DP Drug product or decentralized procedure 1
DRF Dose-range finding
DSMB Data safety monitoring board
EAC Endpoint adjudication committee
EAP Early access program
EC Ethics committee
ECG Electrocardiogram
ECHA European Chemical Agency
ED Exectile dysfunction
ED50 50% of the test objects show the expected effect
EDMF European drug master file
EFD Embryofetal development
EGF Epidermal growth factor
ELISA Enzyme-linked immunosorbent assay
EMA European Medicines Agency
EoP End-of-phase
xxiv List of Abbreviations
More than
EPC European Patent Convention

EPO European Patent Office
EQA External quality assurance
ERA Environmental risk assessment
ERK Extracellular signal-regulated kinase
ERP External reference pricing
ESTs Expressed sequence tags
eTOC Electronic table of content
EUDAMED European Database for Medical Devices
EUnetHTA European Network for Health Technology
Assessment
FACS Fluorescence-activated cell sorting
Fas FS-7-associated surface antigen
FDA (American) Food and Drug Administration
FEED Fertility and early embryonic development
FGF Fibroblast growth factor
FIBC Fully integrated Biopharmaceutical Company
FIH First in human
FIM First in men
FISH Fluorescence in situ hybridization
Flunet Flue network
FPE First pass effect
FRET Fluorescence resonance energy transfer
FTE Full-time employee
FTO Freedom to operate
GABA Gamma aminobutyric acid
G-BA Germany, Federal Joint Committee
GC Gas chromatography
GCP Good clinical practice
GDP Guanosine diphosphate or gross domestic product 1
GDPR General Data Protection Regulation
GFR Glomerular filtration rate
GHTF Global Harmonization Task Force
GI Gastrointestinal
GIRK G-protein-coupled inwardly rectifying K+ channel
GKV-SV Umbrella Organization of the Statutory Health
Insurers
GLP Good laboratory practice
GMP Good manufacturing practice
GPCR G-protein-coupled receptor
GTMP Gene therapy medicinal product
List of Abbreviations xxv
More than
GTP Guanosine triphosphate

GxP Good …practice
HA Hemagglutinin
HAV Hepatitis A virus
HbA1c Hemoglobin A1c
HCP Health care providers
HCV Hepatitis C virus
HED Human equivalent dose
hERG human ether-a-go-go-related gene (channel)
HI Hemagglutination inhibition
HIV Human immunodeficiency virus
HMG-CoA Hydroxy-methyl-glutaryl-coenzyme-A
HNSTD Highest non severely toxic dose
HPLC High-performance liquid chromatography
HR Human resources
HTA Health technology assessment
HTS High-throughput screening
HV Health volunteer
i.p. Intraperitoneal
i.v. Intravenous
IB Investigator’s brochure
IC50 Half maximal inhibitory concentration
ICANN Internet Corporation for Assigned Names and
Numbers
ICER Incremental cost-effectiveness ratio or Institute for 1
Clinical and Economic Review
ICH International Conference on Harmonization
ID Intradermal administration
IDP Integrated development plan
IFCC International Federation of Clinical Chemistry and
Laboratory Medicine
IGF Insulin-like growth factor
Il-6 Interleukin 6
IMDRF International Medical Device Regulators Forum
IMP Investigational medicinal product
IMPD Investigational medicinal product documentation
IND Investigational New Drug
INN International non-proprietary name
INTERACT INitial Targeted Engagement for Regulatory
Advice on CBER producTs
xxvi List of Abbreviations
More than
IP Intellectual property
IPI Swiss Federal Institute of Intellectual Property
IPO Initial public offering
IPR Intellectual property right(s)
IPRP International preliminary report on patentability
iPS (cell) Induced pluripotent stem cells
IQVIA Company name, formerly Quintiles and IMS
Health, Inc.
IQWiG Institut für Qualität und Wirtschaftlichkeit im
Gesundheitswesen
IRB Institutional Review Board
ISO International Organization for Standardization
ISP Indication-specific pricing
ISR Injection site reactions
ITT Intent-to-treat population
IVD In vitro diagnostics
IVDR In vitro Diagnostic Device Regulation
JAK Just another kinase (Janus kinase)
JNK c-Jun N-terminal kinases
KCNQ Potassium channel, voltage-gated, KQT-like
subfamily
Kir-channel Inwardly rectifying K+ channel
Km Michaelis constant
KOL Key opinion leader
LADME Liberation/absorption/distribution/
metabolism/elimination
LCM Life Cycle Management
LD Loading dose or lead discovery 1
LD50 Lethal dose for 50% of the animals
LDL Low-density lipoprotein
LDT Lab developed test
LO Lead optimization
LoE Loss of exclusivity
LoI Letter of intent
LRV Lower reference value
MA&P Market access and pricing team
MAA Marketing authorization application
mAb Monoclonal antibody
MABEL Minimum anticipated biological effect level
MAD Multiple ascending doses
MALDI-TOF Matrix-associated laser desorption/ionization
List of Abbreviations xxvii
More than
MAP-kinase Mitogen-activated protein kinase

MD Medical device
MDG Medical grade plastics
MDR Medical Device Regulation
MDRD Modification of diet in renal disease
MEA Managed entry agreements
MedDRA Medical Dictionary for Regulatory Activities
MHLW (Japanese) Ministry of Health, Labour, and Welfare
MIC90 Minimum inhibitory concentration
mM Millimolar
MoA Mechanism/mode of action
MRI Magnetic resonance imaging
mRNA Messenger ribonucleic acid
MRSA Methicillin-resistant Staphylococcus aureus
MTA Material transfer agreement
MTD Maximum tolerated dose
NA Neuraminidase
NADPH Nicotinamide adenine dinucleotide phosphate
NAT N-acetyltransferase
NB Notified body
NBTS Non-binding term sheet
NCA Non-compartmental analysis
NDA New drug application or non-disclosure agreement 1
NeeS Non-eCTD electronic submission format
NEP Nuclear export protein
NICE National Institute for Health and Care Excellence
NIH National Institutes of Health (US)
NMDA N-methyl-D-aspartate
NME New molecular entity
NMPA National Medical Products Administration (China)
NNT Numbers-needed-to-treat
NO Nitric oxide
NOAEL No-observed-adverse-effect level
NPV Net-present value or negative predictive values 1
NRTL Nationally Recognized Testing Laboratory
NSAID Non-steroidal anti-inflammatory drug
NTEL No toxic effect level
OAT Organic anion transporter
OBA Outcomes-based agreement
OCT Organic cation transporter
OD Orphan drug
xxviii List of Abbreviations
More than
ODA Orphan Drug Act

OECD Organisation for Economic Co-operation and
Development
OGTT Oral glucose tolerance test
OOPD Office of Orphan Products Development
OSHA Occupational Safety and Health Administration’s
PAH Pulmonary arterial hypertension
PAI Pre-approval inspection
PAS Patient access scheme
PBB Polybrominated biphenyls
PBDE Polybrominated diphenyl ether
PBM Pharmacy Benefit Manager
PBPK Physiologically based PK
PC Paris convention
PCR Polymerase chain reaction
PCSK9 Proprotein convertase subtilisin/kexin type 9
PCT Patent Cooperation Treaty
PD Pharmacodynamics
PDCO Paediatric Committee
PDE5 Phosphodiesterase type 5
PDGF Platelet-derived growth factor
PE Polyethylene
PET Positron-emission tomography
Ph. Eur. EU Pharmacopeia
PI Principal investigator
PIP Paediatric investigation plan
PK Pharmacokinetics
pKa pKa is the negative log of the acid dissociation
constant
PKPD Pharmacokinetic––Pharmacodynamic
PMDA Pharmaceuticals and Medical Devices Agency
PMI Project Management Institute
PoC Proof of concept (study)
PoCT Point of care testing
PoM Proof-of-mechanism
PopPK Population PK
PoS Probability of success
PP Per-protocol
PPB Plasma protein binding
PPI Protein–protein interaction
PPND Peri- and postnatal development
List of Abbreviations xxix
More than
PPQ Process performance qualification

PPV Positive predictive value
PREA Pediatric Research Equity Act
PRIME (EMA’s) Priority medicines
PRN Pro re nata
PRO Patient-reported outcomes
PSP Paediatric study plan
PSUR Periodic safety update reports
PTE Patent term extensions
PTRS Probability of technical and regulatory success
QALY Quality-adjusted life year
QbD Quality by design
QDM Quantitative decision making
QED quod erat demonstrandum
QIV Quadrivalent influenza vaccine
QMS Quality management system
QSE Quality, safety efficacy (requirements)
QSP Quantitative systems pharmacology
QTPP Quality target product profile
R&D Research and development
RA Regulatory affairs
RAPS Regulatory Affairs Professionals Society
RDP Regulatory data protection
REACH Registration, evaluation, authorization, and
restriction of chemicals
RIP Receptor-interacting protein
RMAT Regenerative medicine advanced therapy
RMS Reporting member state
RNA Ribonucleic acid
rNPV Risk adjusted net present value
ROC Receiver-operating characteristics (curve)
RohS Restriction of certain hazardous substances
ROI Return of investment
RP2D Recommended phase 2 dose
RUO Research use only
RWE Real-world evidence
s.c. Subcutaneous
SAD Single ascending doses
SAR Structure–activity relationship
SBDD Structure-based drug design
SC Steering committee
xxx List of Abbreviations
More than
scRNAseq Single-cell RNA sequencing

SCTMP Somatic cell therapy medicinal product
SE Substantially equivalent
SGLT Sodium-glucose linked transporter
siRNA Small interfering RNA
SISH Silver in situ hybridization
SLC Solute carrier
SME Small- and medium-sized enterprises
SmPC Summary of product characteristics
SNP Single-nucleotide polymorphism
SoC Standard of care
SOP Standard operating procedure
SP Safety population
SPA Special Protocol Assessment
SPC Supplemental protection certificate
SPECT Single-photon emission computed tomography
STAT Signal transducers and activators of transcription
STD10 Severely toxic dose in 10% of the rodent
STDI Sexually transmitted infectious diseases
STI Sexually transmitted infection
SVHC Substances of very high concern
T2D Type 2 diabetes
TEP Tissue-engineered product
TET2 Tet methylcytosine dioxygenase 2
TGA Therapeutic Goods Administration (Austria)
TGF Transforming growth factor
TI Therapeutic index or target identification 1
TIV Trivalent influenza vaccine
TM Translational medicine
TMP Target marketing profile
TNF Tumor necrosis factor
TOP Target out-licensing profile
TPP Target product profile
TRADD TNF (tumor necrosis factor) R1 (receptor type
1)-associated death domain
TRAF TNF receptor-associated factor
TRF Time-resolved fluorescence
TRP Therapeutic reference pricing
TRV Target reference value
TS Term sheet
TV Target validation
List of Abbreviations xxxi
More than
UGE Urinary glucose excretion

UGT UDP-glucuronosyltransferase
UPOV Convention of the International Union for the
Protection of New Varieties of Plants
US PI US packaging insert
USP United States Pharmacopeia or unique selling 1
point (context dependent)
USPTO United States Patent and Trademark Office
UV Ultra violet (radiation)
VBP Value-based pricing
VDI Association of German Engineers
VEGF Vascular endothelial growth factor
VFA Verband der forschenden Pharma-Unternehmen
VHP Voluntary harmonization process
VN Virus neutralization
VoC Voice of customer
WBS Work breakdown structure
WIPO World Intellectual Property Organization
WoCBP Women of childbearing potential
WR Written request
1
Biopharmaceutical Innovation at a Glance

Markus Hinder 1 , Dominik Hartl 2 , and Alexander Schuhmacher 3
1
Novartis, Global Drug Development, Chief Medical Office & Patient Safety, Forum 1, CH-4002, Basel,
Switzerland
2
Eberhard Karls Universität Tübingen, Universitätsklinik für Kinder- und Jugendmedizin, Department of
Pediatrics I, Hoppe-Seyler-Straße 1, 72076, Tübingen, Germany
3
Technische Hochschule Ingolstadt, THI Business School, Esplanade 10, D-85049, Ingolstadt, Germany
Summary
Biopharmaceutical Research & Development (R&D) aims at finding new modalities

to diagnose, prevent, and treat human diseases. Prototypes of innovative approaches
are tested in biological systems of increasing size, complexity, and relevance. The
early phase spans from individual receptors over cell, organ systems to first therapeu-
tic exploration in small and well-defined patient populations. This exploratory phase
ends once clinical proof of concept (PoC) is established. Subsequently, large clinical
programs are undertaken to confirm the efficacy and (if applicable) superiority of
the new approach by means of long clinical programs. Health authorities around the
world play a key role in this process. During the clinical test phase, together with the
biopharmaceutical companies, they surveil and ensure the scientifically sound and
safe conduct of clinical trials. In a second step, health authorities review the entire
data set that has been generated during both the exploratory and the confirmatory
phases. If, based on these data, they come to conclude that the benefits conferred
to the patients outweigh the risks, authorization to market the drug in the respec-
tive country is conferred. In order to get reimbursed, approved new drugs need to
undergo an economic review process. There the decision is made if the new drug
confers enough clinical benefits to justify its price. The drug approval process and
the economic evaluation/reimbursement process are two distinct processes carried
out by different institutions.
Although R&D leverages a number of academic disciplines like epidemiology,
genetics, biology, chemistry, bioinformatics, pharmacology, toxicology, pharmacy,
and medicine, it is not primarily an academic discipline and cannot be studied in one
program at a university. It is difficult to find coherent overarching information on
Principles of Biomedical Sciences and Industry: Translating Ideas into Treatments, First Edition.
Edited by Markus Hinder, Alexander Schuhmacher, Jörg Goldhahn, and Dominik Hartl.
© 2022 WILEY-VCH GmbH. Published 2022 by WILEY-VCH GmbH.
2 1 Biopharmaceutical Innovation at a Glance
concepts generally applicable to the industry beyond individual company processes.

Thus, this book attempts to bridge this gap and provide an overview and concepts
and reliable details which apply across the industry and are valuable for everyone
working in or with the biopharmaceutical industry.
Tools
● Pharmacology
● Pharmacokinetics
● Toxicology
● Clinical studies
● Project and portfolio management
● IP management
Regulatory framework
● National and regional drug approval regulations
● International Conference on Harmonization (ICH)
● Declaration of Helsinki (DoH)
Risks
● Strategic risks, such as enormous R&D investments
● External risks, such as drug approval regulations
● Internal risks, such as degree of predictivity of early trials for late-stage development
Success factors
● Understanding molecular mechanisms
● Disease understanding
● Biomarkers
1.1 Biopharmaceutical Innovation and Drug

Development, the Past and Present
‘Définissez les termes, vous dis-je, ou jamais nous ne nous entendrons’.

Voltaire (François-Marie Arouet 1694–1778)
If you wish to converse with me, define your terms.
To alleviate or even cure human disease has always been an area of paramount
interest and activity of mankind. Documentation from around the globe (e.g. Middle
East, India, China, America) indicates that since ancient times people observed and
collected information about techniques to treat human disease. The oldest available
documents are approximately 4000 years old and date from approximately 2000
1.1 Biopharmaceutical Innovation and Drug Development, the Past and Present 3
B.C. (papyrus Ebers (1500 BC) and papyrus Kahun (1800 BC)). From ancient times
up to the Middle Ages, the key source to finding ways to treat human disease were
trial and observation and in many cases folk memory to preserve useful knowledge.
Thus, the first treatments were rather found by chance than actively discovered.
Pharmacology as a scientific discipline, which deals with the discovery and char-
acterization of xenobiotics to treat diseases, is a relatively young discipline and had
to wait until physics, chemistry, and biology had established themselves as sciences
and laid the foundations for a scientific understanding of human health and disease.
Until the 1950s, classical (forward) pharmacology dominated the scientific
approach to find new medicines. During this time, most of the discoveries focused
mainly on medications providing symptomatic amelioration or relief as opposed to
changing long-term prognosis of patients suffering from a disease or treatment of
risk factors (Drews 2000).
Drug approval in the early days was often restricted to small series of clinical tests
demonstrating that the desired effects were detectable. Systematic testing in broad
populations of interest and a systematic approach to investigating a drug’s preclinical
and clinical safety only became a prerequisite on both sides of the Atlantic after two
drug disasters became public (1930 Sulfanilamide and 1960 Thalidomide) (Paine
2017; Silverman 2002). Subsequently, more and more processes and standards
which were related to drug discovery and more importantly drug approval became
standardized and regulated – thus today’s notion of a highly regulated industry.
In 1990, the Japanese Ministry of Health, Labour and Welfare (MHLW), the
American Food and Drug Administration (FDA), and the European Medicines
Evaluation Agency (EMEA, today EMA) agreed on common procedures and
standards that apply to the investigation approval of new drugs in all three countries
and regions. These standards are laid down in the documents of the ‘International
Council for Harmonisation of Technical Requirements for Pharmaceuticals for
Human Use’, often just called ICH (ICH, n.d.). From the 1990s on, some researchers
started to discuss a ‘productivity crisis’ in the biopharmaceutical industry. Since
these times, productivity, determined as the number of new drugs approved, and
efficiency, determined as the ratio of investments needed by the number of new
drugs approved, are figures that are constantly watched by decision makers inside
and outside of the biopharmaceutical industry. Recent analyses indicate that
discovering and bringing a new drug to the market need investments in the range
of US$ 5–10 billion (Schuhmacher et al. 2016).
The more drugs became available to treat a specific condition and the more
drugs were used as chronic or preventive treatments, the more long-term clinical
safety became a focus area. Altered benefit/risk assessments in this context led to
marketing withdrawals for numerous approved drugs from nearly all therapeutic
areas. Prominent examples include some fluoroquinolone antibiotics, some per-
oxisome proliferator-activated receptor agonists, cyclooxygenase 2 inhibitors and
anti-histaminics and ant-psychotics, just to name a few. Based on these experiences,
health authorities started to require prior to approval of a new medicine an active
risk exclusion approach. In other words, the long accepted ‘no difference approach’
to demonstrate clinical safety was abandoned by an active process able to rule out
a certain degree of hazard (Brass et al. 2006).
The core responsibility of a pharmaceutical company towards society is to discover
and develop solutions which help patients to lead a better and longer life. In order
to generate the necessary cash flow which can be invested in R&D, many companies
have focused in the past on the so-called blockbuster model, i.e. on products with
worldwide sales in excess of US$ 1 billion/year. Traditionally, these were products
at relatively low daily dosage cost in highly prevalent diseases and thus large world-
wide populations. Triggered by an improved mechanistic understanding of diseases
and genetics enhancing the identification of new drug targets, the biopharmaceuti-
cal sector has developed in recent years more and more medicines to treat so-called
orphan diseases which by definition affect less than 1 in 2000 people (Trusheim et al.
2007). By today, orphan drugs represent around one-eighth of worldwide prescrip-
tion drug sales indicating the importance of this new market segment (Waters and
Urquhart 2019).
With more and more competitive drugs entering the market and the availability of
a plethora of therapeutic options in the highly prevalent diseases, the question arises,
how to best invest scarce healthcare resources. As a reaction, payors around the globe
have at different pace and to different extent started to ask the ‘value for money’
question. This has led to a situation, where a new drug today needs to conform or
exceed the quality, safety efficacy (QSE) requirements set forth by health authorities
to gain marketing authorization on the one hand. On the other hand, these new
medicinal products need to demonstrate their cost-effectiveness before they can be
reimbursed by national health insurers and other payors.
1.2 Why We Wrote This Book and What Readers Can

Expect to Gain from Reading It
Biopharmaceutical sciences and pharmaceutical innovation belong to the highly
innovative, cost-intense, high tech endeavours which can provide important
progress to both the individual and the society.
Finding and developing a new medicine is a complex undertaking which requires
many diverse scientific disciplines with different scientific languages and ways of
thinking to collaborate effectively and efficiently towards a common goal over many
years.
The editors of this book realized through own experience as academicians and
as associates in the biopharmaceutical industry, as well as university lecturers that
becoming a drug hunter or developer is a year-long, often unstructured process and
that biopharmaceutical innovation and the art and science of drug development are
not yet established as an academic university discipline. Universities are home to
excellent disciplines wh are an essential part of the pharmaceutical value chain. As
academic institutions, their scope is broader and contributions to pharmaceutical
innovation often are a more peripheral aspect of their overall work. Equally
important, the integrating, connective band between the multiple critical academic
References 5
disciplines is frequently not established. Accordingly, it is challenging to gather

coherent overarching information on concepts generally applicable to the industry
beyond individual company processes.
This book aims to provide a comprehensive and coherent insight into pharmaceu-
tical R&D and related functions, such as business development and market entry.
In general, biopharmaceutical R&D relies on external innovation and on qualified
academics transitioning from basic and clinical research into pharmaceutical indus-
try. Drug discovery and development in biopharmaceutical companies, however,
usually is an internally focused process and easily perceived by industry outsiders as
a ‘black-box’ without insights into strategies and operations, making it difficult for
academics to consider and prepare for a career in R&D in pharmaceutical industry.
Based on feedback from industry-internal and academic-external colleagues and
stakeholders, we identified the clear unmet need to map out the different phases
and frameworks of drug discovery, drug development, business development, and
market access within the pharmaceutical industry. Pharmaceutical R&D makes
intensive use of a broad number of academic disciplines, including epidemiol-
ogy, genetics, biology, chemistry, biochemistry, bioinformatics, pharmacology,
toxicology, pharmacy, veterinary medicine, and medicine.
This book covers all relevant disciplines along the pharmaceutical value chain,
introduces key success-critical concepts to find, select, and develop new drugs,
as well as introduces the reader into basic concepts and the technical jargon
of integrated drug developers. All book authors are recognized experts in their
respective areas. They know the ins and outs of their disciplines from a theoretical
perspective, they all know from own practical work which parts of the theory are
critically important and wrote their respective chapters with the reader and future
application of knowledge in mind. The chapters include comprehensive referencing
for readers who want to get down to the primary sources and in many cases contain
practical examples and illustrations.
The editors believe that this book can bridge and close the existing knowledge gap
and therefore provides a comprehensive overview on different components, phases,
and frameworks of biopharmaceutical R&D, with broad relevance across pharma-
ceutical industries and valuable for a broad readership working either in, together
with or interested in joining the biopharmaceutical industry.
References
No author (1550 BC). Papyrus Ebers. University library Leipzig https://papyrusebers.de/

en/ (accessed 3 October 2020).
No author (1800 BC). Papyrus Lahun. University College London library https://www
.ucl.ac.uk/museums-static/digitalegypt/med/birthpapyrus.html (accessed 3 October
2020).
Brass, E.P., Lewis, R.J., Lipicky, R. et al. (2006). Risk assessment in drug development
for symptomatic indications: a framework for the prospective exclusion of
unacceptable cardiovascular risk. Clin. Pharmacol. Ther. 79 (3): 165–172.
Drews, J. (2000). Drug discovery: a historical perspective. Science 287 (5460): 1960–1964.
ICH (n.d.). International Council for Harmonisation of Technical Requirements for
Pharmaceuticals for Human Use (ICH). https://www.ich.org/ (accessed 3 October
2020).
Paine, M.F. (2017). Therapeutic disasters that hastened safety testing of new drugs. Clin.
Pharmacol. Ther. 101 (4): 430–434.
Schuhmacher, A., Gassmann, O., and Hinder, M. (2016). Changing R&D models in
research-based pharmaceutical companies. J. Transl. Med. 14 (1): 105.
Silverman, W.A. (2002). The schizophrenic career of a “monster drug”. Pediatrics 110
(2 Pt 1): 404–406.
Trusheim, M.R., Berndt, E.R., and Douglas, F.L. (2007). Stratified medicine: strategic
and economic implications of combining drugs and clinical biomarkers. Nat. Rev.
Drug Discovery 6: 287–293.
Waters, R. and Urquhart, L. (2019). Evaluate Pharma. World Preview, Outlook to 2024.
https://www.evaluate.com/thought-leadership/pharma/evaluatepharma-world-
preview-2019-outlook-2024 (accessed 27 September 2020).
7
Pharmacology and Drug Targets – The Basis of Therapeutics

Lena Hartl 1 , Martin A. Fink 2 , and Sandra Beer-Hammer 3
1
University of Tübingen, Department of Pediatrics, Hoppe-Seyler-Strasse 1, 72072, Tübingen, Germany
2
Novartis Pharma AG, Novartis Campus, CH-4056, Basel, Switzerland
3
University of Tübingen, Institute for Experimental and Clinical Pharmacology and Toxicology, Department
of Pharmacology and Experimental Therapy, Hoppe-Seyler-Strasse 1, 72072, Tübingen, Germany
Summary
This chapter covers (i) basics of pharmacology such as dosage forms, routes of
administration, delivery to the target site, (ii) pharmacodynamics (PD), and (iii)
pharmacokinetics (PK) and provides (iv) examples of its use in drug discovery
and development. In particular, basic principles of drug–target receptor inter-
actions, agonistic and antagonistic mechanisms of action (MoA), liberation/
absorption/distribution/metabolism/elimination (LADME) phases of PK, dosage
forms, PK/PD modelling, drug–drug interactions (DDIs), drug transporters, aspects
of clinical pharmacology, therapeutic window/index calculations, and illustrative
examples of how these tools are utilized in drug discovery and development are
provided.
Tools
● In vitro systems
● In vivo systems
● Genetics
● Screening
● Modelling
Regulatory framework
● ICH
(Continued)
Principles of Biomedical Sciences and Industry: Translating Ideas into Treatments, First Edition.
Edited by Markus Hinder, Alexander Schuhmacher, Jörg Goldhahn, and Dominik Hartl.
© 2022 WILEY-VCH GmbH. Published 2022 by WILEY-VCH GmbH.
8 2 Pharmacology and Drug Targets – The Basis of Therapeutics
(Continued)
Risks
● Limited understanding of pathophysiology
● Target validation/reproducibility
● Lack of appropriate models
Success factors
● Translating pre-clinical compounds into drugs for patients
2.1 Introduction
After human health was believed to be determined solely by God and fate for long
times, the theory of humourism (also known as the four humours) developed
in antiquity under the influence of important Greek savants as Hippocrates and
Galen dominated Western medicine until modern times. In his works, Galen wrote
numerous texts on the composition and manufacture of medicines and gave his
name to the Galenic formulation of medicines. In the sixteenth century, the famous
savant Paracelsus also included chemical substances in drug therapy. Under his
influence, the pharmacy laboratory also gained more importance. During the course
of the industrialization in the nineteenth century, pharmaceutical industry evolved
from pharmacies specialized on the manufacturing of pharmaceuticals and the
tar and paint industry. At that time, the prevailing teaching of humoral pathology
was replaced by the research of the physician Rudolf Virchow and based on it the
so-called cellular pathology and formed the fundament for science-based medicine.
Pharmacology (greek for ‘pharmacon’: drug and ‘-logos’: doctrine/knowledge of)
explores interactions between compounds and organism and describes it in a quan-
titative and qualitative manner (Tozer and Rowland 2016; Simmons 2011). The term
pharmacon describes the active element of a drug and is non-judgemental; e.g. it
contains no statement if the substance is harmful (poison) or healing (drug).
The interaction between drug and organism can be classified in three phases:
1. Pharmaceutical phase
The pharmaceutical phase includes administration and drug release. This is
decisively determined by the type of administration (e.g. oral, intravenous
(iv), intramuscular, subcutaneous, inhalative, epicutaneous, sublingual, and
rectal) and the galenics (composition and manufacture of drugs). Together with
so-called adjuvants, the drug becomes a dosage form. Galenics can be used, for
example, to influence the duration of action, the concentration of the active
substance in the blood and sometimes even the site of action.
2. Pharmacokinetics (PK)
Pharmacokinetics deals with the concentrations of a drug in the body and is
affected by all processes to which a drug is exposed to in the body. Pharma-
cokinetics includes absorption, distribution, metabolism and excretion of a
compound (ADME).
2.1 Introduction 9
3. Pharmacodynamics (PD)
Pharmacodynamics describes the effect of the drug on the organism. Here, bind-
ing to a target (e.g. receptors, ion channels, enzymes, and bacterial metabolism)
and the resulting biological effect play a major role. The pharmacological effect
of a substance can be divided into desirable and undesirable effects (side effects).
Pharmacodynamics: Effect of the Drug on the Organism. The pharmacological

effect of a substance can be divided into desirable (potency) and undesirable
effects (side effects).
Pharmacokinetics: Effect of the Organism on the Drug. Concentrations of a
drug in the body, affected by all processes to which a drug is exposed to, includ-
ing absorption, distribution, metabolism, and excretion of a compound (ADME).
The pharmacology differs between individuals – for instance higher weight

subjects often show lower concentrations. Diseases may need different concen-
tration levels for efficacy but might also influence the pharmaceutical phase and
the PK. There are many factors that influence the interaction between drug and
organism (Figure 2.1) – and all these aspects influence the dose and regimen (i.e.
frequency) that provide an optimal benefit–risk relationship for the individual
patient.
Studying the pharmacology of a compound during drug development is essential
to learn about the influencing factors on the pharmacokinetics and pharmacody-
namics and, if necessary, provide information in the drug label on adjusting the dose
or regimen accordingly (Rosenbaum 2016).
In this chapter, we describe general concepts mainly related to small molecules
(low molecular weight compounds) and monoclonal antibodies. Of note, there exist
newer therapeutic approaches, like cell and gene therapies (e.g. CAR-T therapies or
Drug/
Disease
formulation
Demographics Co-medication
Individual
dose/
regimen
Efficacy
Safety (risk)
(benefit)
Figure 2.1 Factors influencing the interaction between a drug and an organism. Source:
Book editors based on Hartl, Fink, and Beer-Hammer.
adeno-associated virus vector therapies) which can show different dynamics over
time and are not covered here even though the basic concepts of pharmacology
still hold.
2.2 Pharmacodynamics
Pharmacodynamics is the science of biochemical and physiological drug effects on

animal or human organisms as well as microorganisms and parasites.
Pharmacodynamics:
● Type of action (profile and quality)
● Mechanisms of action (MoA)
● Place of action
● Potency
● Efficacy
Specific substances interact with defined endogenous target molecules that are
structurally proteins such as receptors, transporters, and enzymes, DNA, RNA, or
lipids. They already act in low dosages or concentrations, and their effect depends on
the chemical structure and thus on the shape, size, and stereochemical arrangement
of the molecule. The specific effect also means that a drug affects as selectively as
possible on the target structures.
Two main classes of molecules used as therapeutics:

a) Small molecules
● low molecular weight compounds
● chemically produced
● defined by exact chemical structure
● usually oral drugs
b) Large molecules/biomolecules
● recombinant proteins or monoclonal antibodies
● produced in genetically modified cells
● usually intravenous (IV) or subcutaneously (SC) administered drugs
Small molecules are mostly less specific in their action than biomolecules or mon-
oclonal antibodies; they can bind to receptors other than the target (off-target bind-
ing) which can result in unwanted side effects (off-target toxicity, which is compound
specific). Strong inhibition of a pathway by on-target binding can also induce adverse
effects (on-target toxicity, which is target-specific), for instance, immunosuppressive
drugs often lead to higher infection risks. At the molecular pharmacological level,
specificity implies that the drug binds to its target with sufficient affinity and has the
ability to enhance or inhibit its function as a result of this binding.
Unspecific substances are characterized by the fact that they do not react specif-
ically with endogenous compounds and that they do not change their effect if the
chemical modification is not too profound.
Most pharmacological effects can be attributed to a few MoA:
● Interaction with membrane receptors (stimulation or inhibition)
● Opening or blockade of voltage-dependent or ligand-controlled ion channels
● Regulation of gene transcription by binding to intracellular receptors
● Influence of transmembrane or intracellular transporters
● Inhibition or activation of enzymes
2.3 Receptors and Ion Channels
Pharmacological receptors are characterized as intracellular or membrane receptors,

which upon binding of an endogenous or exogenous ligand to a specific binding site
elicit direct or indirect effects (E). With this definition, the basic equation is ligand
(L)–receptor (R) interaction: L + R ↔ [LR] →→ E. Thus, a (pharmacological) recep-
tor has a dual role: (i) signal recognition through interaction with the ligand and
formation of the ligand–receptor complex and (ii) direct or indirect triggering of an
effect. Receptors can be found intracellularly or bound to membranes. Intracellu-
lar receptors, which act as transcription factors, include the receptors of (i) steroid
hormones, (ii) retinoids, and (iii) thyroid hormones. The membrane receptors can be
divided into (i) G-protein-coupled receptors (GPCRs), (ii) ion channels (voltage- and
ligand-controlled), and (iii) receptor protein kinases (enzyme-associated receptors).
2.3.1 G-protein-Coupled Receptors (GPCRs)

With 800 genes, GPCRs are not only the largest group within the family of mem-
brane receptors in the human genome, but also the group with the highest diversity.
Various extracellular stimuli induce intracellular signalling cascades via the intra-
cellularly coupled Guanine-nucleotide-binding proteins (G-protein). This receptor
group includes numerous neurotransmitter receptors that are particularly important
for drug therapy, such as adenosine-, adrenergic, ATP- (P2Y-), dopamine-, GABAB -,
metabotropic glutamate-, histamine-, muscarinergic, opioid- and serotonin (except
5-HT3 ) receptors. In GPCRs, signal transmission takes place via the G-protein.
Activation of GPCRs by an agonist results in dissociation of the heterotrimeric G
protein into the Gα- and Gβγ-subunit after exchange of GDP bound to the α-subunit
for guanosine triphosphate (GTP). According to the various functions of GPCRs,
there is a multitude of different G proteins, e.g. cyclase stimulating (Gs proteins),
cyclase inhibiting (Gi proteins) or phospholipase C-activating G proteins (Gq
proteins).
2.3.2 Ion Channels

Ion channels are in third place after the GPCRs and protein kinases and play impor-
tant roles in a variety of biological processes, e.g. formation of action potentials, car-
diac, skeletal and smooth muscle constrictions, epithelial transport, T-cell activation
or insulin secretion. Ion channels are integrated in the cell membrane and consist
of several subunits. These subunits form a channel pore that is opened or closed by
conformational changes. Due to their selective permeability for distinct ions, they
are named sodium-, potassium-, calcium-, and chloride channel. The inflow and
outflow of the respective ions is controlled by the concentration gradient between
extracellular and intracellular space and by the membrane potential. The extent of
the ion flow depends on the number of open channels, the duration of opening and
the permeability of the corresponding ions of the so-called conductivity. There are
two kinds of receptors distinguished:
● Ligand-controlled ion channels or ionotropic receptors: (e.g. ATP- (P2X-),
GABAA -, glutamate- (NMDA- and AMPA-), glycine-, 5-HT3 - and nicotine recep-
tors, and K+ (ATP-sensitive, Ca2+ /calmodulin-activated, Gi -protein-regulated
‘GIRK’), where opening and closing of the channel is controlled by extracellular
binding of a ligand. For example, binding of acetylcholine or nicotine to the
α-subunit of the nicotinic receptor leads to the opening of the channel, thus
releasing an action potential through the influx of sodium ions.
● Voltage-controlled channels: (e.g. Na+ -, Ca2+ - [L-type, N-type, T-type, P/Q-type]
and K+ - [Kγ, hERG-, KCNQ-, Kir-] channels) that are opened or closed by mem-
brane depolarization or hyperpolarization. For example, the influx of Na+ ions
into a myocardial cell allows rapid membrane depolarization, which is necessary
to open L-type Ca2+ channels. The incoming calcium ions now lead to Ca2+ release
from the endoplasmic reticulum and allow the initiation of the contraction of car-
diomyocytes. K+ channels, which are also activated by depolarization, repolarize
the cell membrane and allow previously inactivated Na+ - and Ca2+ channels to
revert to the activatable state by conformational change and thus be available
again for subsequent excitation.
2.3.3 Enzyme-Associated Receptors

This group of receptors belong (i) receptors with tyrosine kinase activity, (ii) recep-
tors with associated tyrosine kinases, (iii) receptors with guanylyl cyclase-activity,
(iv) receptor serine/threonine kinases as well as (v) tumour necrosis factor (TNF)
receptors, which mediate apoptosis.
Tyrosine kinase receptors are characterized to have a ligand binding site
extracellularly and a domain with the property of a tyrosine kinase on the cytosolic
protein part and thus exert both the function of a receptor and that of an enzyme.
Mitogen-activated protein kinases (MAP kinases) are involved in further signal
transduction. Since they regulate a variety of cellular activities such as gene
expression, mitosis, differentiation, and apoptosis/necrosis, they are of great
importance for the whole organism. Notably, their proliferative effect is critical for
signal transduction of most oncogenes. MAP kinases are divided into four groups:
extracellular signal-regulated kinases (ERK), c-Jun N-terminal kinases (JNK), p38
kinases, and as a special ERK form ERK5. The signalling cascade of ERK is mainly
stimulated by growth factors, JNK and p38 kinases are active in the presence of
stress stimuli such as cytokine release, UV radiation, heat or osmotic shock. ERK5,
on the other hand, is activated by both growth factors and stress stimuli. Receptors
with tyrosine kinase activity include the receptors of insulin, insulin-like growth
factor (IGF-1), as well as various other growth factors (e.g. vascular endothelial
cell factor [VEGF], epidermal growth factor [EGF], fibroblast growth factor [FGF],
and platelet-derived growth factor [PDGF]). Insulin and IGF-1 each consist of two
α- and β-subunits, which are linked by disulphide bridges. The other growth factors,
however, are monomeric proteins that dimerize only after ligand binding. The
dimerization leads to autophosphorylation of tyrosine residues in the cytosolic part
of the receptor. This generates docking sites for signalling proteins that bind to the
phosphorylated residues of the receptor. In this way, receptor tyrosine kinases are
coupled to the Ras signalling cascade, which controls cell growth and proliferation.
Receptors with associated tyrosine kinases, like the growth factor receptors,
are monomeric membrane proteins with a transmembraneous region, which in turn
dimerize after ligand binding, but the receptor group does not possess its own tyro-
sine kinase domain. This group of receptors includes numerous cytokine receptors
as well as growth hormone, prolactin, and erythropoietin receptors. Upon activa-
tion and dimerization, just another kinase (JAK) proteins dock and phosphorylate
tyrosine residues of the receptor. As a result, signal transducers and activators of
transcription (STAT) proteins associate with the phosphorylated receptor domains.
The associated STAT proteins are then also phosphorylated by JAK kinases. Finally,
the phosphorylated STAT proteins dimerize, are translocated into the nucleus and
activate transcription of specific genes.
Receptors with guanylyl cyclase activity (membrane-bound guanylyl cyclase)
in particular comprise the receptors for natriuretic peptides and the intestinal hor-
mone guanylin. These monomeric transmembrane proteins, like the receptors with
tyrosine kinase activity, have an extracellular binding site for the activating ligand
and an intracellular enzyme domain. When a ligand binds to receptors with guanylyl
cyclase activity, their guanylyl cyclase domain is activated. As a consequence, GTP is
formed into cyclic guanosine monophosphate (cGMP) which, as second messenger,
triggers further reactions, e.g. the relaxation of smooth muscle cells or the secretion
of chloride in the intestinal lumen.
Receptor serine/threonine kinases include the receptors of transforming
growth factor-β (TGF-β), of which two types, TGF-β-R-I and TGF-β-R-II, exist. Also,
the cytokine bone morphogenetic protein 2 (BMP2) unfolds its action by means
of such a receptor type. TGF-β is a local cytokine which acts via TGF-β receptors
and is associated with healing processes but also fibrosis of tissue, e.g. diabetic
nephropathy, renal and pulmonary fibrosis, as well as cardiac remodelling after
myocardial infarction. Angiotensin converting enzyme (ACE) inhibitors reduce the
release of TGF-β. The transduction mechanism of TGF-β receptors is the following:
initially, TGF-β binds to TGF-β-R-II and then forms a heterodimer together with
TGF-β-R-I. In the next step, a transphosphorylation of TGF-R-II to TGF-R-I occurs,

which triggers the actual signal transduction. The activated receptor complex
then triggers gene expression via so-called Smad proteins, which migrate into the
nucleus in an active form.
TNF receptors, also called death receptors, include 29 different receptor subtypes.
They are integrated into the membrane of most cells. Important representatives
are the TNF receptor 1 and FAS. The binding of TNF to its receptor results in
homotrimerization and recruitment of an adapter protein (e.g. TRADD, TRAF,
and RIP) to the so-called ‘death domains’ of the three subunits. The nature of the
associated adapter protein determines which signalling pathways (e.g. apoptosis
and inflammation) are induced by the stimulation of the TNF receptor. In the case
of programmed cell death, apoptosis, the resulting complex activates the caspase
cascade, which leads to inactivation of enzymes and degradation of structural
proteins as well as fragmentation of genomic DNA.
2.3.4 Non-receptor-Mediated Effects

Beside of receptor-mediated effects, there are also drug effects mediated by trans-
porters or enzymes. The transport of small organic molecules or ions through
the cell membrane often occurs with the help of transport molecules when the
molecules to be transferred are too polar to overcome the membrane alone. In
addition to the transporters for neurotransmitters in terminal nerve endings
(neurotransmitter-specific transporters, e.g. for norepinephrine, serotonin, or
GABA), which serve to resume the secreted transmitter in the presynaptic neuron,
and the transporters for electrolytes (e.g. Na+ /K+ /2Cl− – and Na+ /Cl− – symporter),
which predominantly occur in epithelia with secretory function (among others
in renal tubules, bronchial epithelium, and intestinal mucosa), there are also
transporters for glucose and amino acids.
In particular, the transporters for neurotransmitters and electrolytes represent
targets for important drugs such as antidepressants, diuretics, cardiac glycosides,
and proton pump inhibitors. Antidepressants inhibit the active (re-)transport of
norepinephrine and/or serotonin. Diuretics are to be characterized as selective elec-
trolyte transport inhibitors: Furosemide-type loop diuretics block the Na+ /K+ /2Cl+
and thiazides the Na+ /Cl− symporter. Cardiac glycosides inhibit the outward trans-
port of sodium ions from the intracellular space into the extracellular space as well
as the inward transport (extracellular/intracellular) of potassium ions by blocking
the sodium–potassium pump (Na+ /K+ ATPase). The proton pump inhibitors used
as antiulcer drugs suppress the production of hydrochloric acid in the stomach by
inhibiting the proton potassium pump (H+ /K+ ATPase).
Numerous effects of drugs are due to the inhibition or (less common) of the
activation of enzymes. Similar to the pharmacon receptor interaction, it first
comes to the formation of a drug–enzyme complex and thereby, depending on
the nature of the drug, to enzyme inhibition or enzyme activation. At constant
enzyme concentration, the reaction rate depends on the substrate concentration.
The more the substrate there is, the more the enzymes can be occupied and cause
the reaction.
2.4 Receptor Agonism and Antagonism 15
Substrate saturation: From a certain substrate concentration, all enzymes are

present in enzyme–substrate complexes, and thus the maximum velocity V max
for this amount of enzyme is reached.
Substrate excess: If more substrate molecules are present than can be bound by the
enzymes, the reaction rate is no longer increased.
The substrate concentration K m , which is half of the maximum reaction rate, is

called Michaelis constant (K m ). It is a measure of the affinity of an enzyme for its
substrate, i.e. the smaller the K m , the higher the enzyme–substrate affinity, because
the less substrate it takes to occupy half of all binding sites of the enzymes. The value
of the maximum velocity (V max ) depends on the enzyme concentration. The more
the enzymes are present, the more the enzyme–substrate complexes can be formed,
which is why a higher maximum speed can be achieved. Also, the half-maximal
velocity is larger and is still reached at the substrate concentration K m (the affinity
is independent of the enzyme concentration).
Drug-induced enzyme inhibition may be competitive or non-competitive.
Competitive inhibition occurs when the drug reversibly competes with the sub-
strate for its binding site. In non-competitive inhibition, the drug reacts irreversibly
with the active site or suppresses the formation of the substrate–enzyme complex
following reaction and not the binding of the substrate to the enzyme. Impor-
tant examples of enzyme blocking drugs are the monoamine oxidase inhibitors,
non-steroidal anti-inflammatory drugs (NSAID) as inhibitors of cyclooxygenase,
anticoagulants as xanthine oxidase inhibitors, indirect parasympathicomimetics as
choline esterase blocker, hydroxy-methyl-glutaryl-coenzyme-A reductase inhibitors
(HMG-CoA reductase inhibitors, CSE inhibitors, and statins), phosphodiesterase
inhibitors, ACE inhibitors, and tyrosine kinase inhibitors. Many anti-infective
agents also exert their effect by selective enzyme inhibition in microorganisms,
e.g. penicillins and other beta-lactam antibiotics by inhibiting transpeptidases,
gyrase inhibitors by interacting with DNA gyrase, azole antifungals by blocking
lanosterol dimethylase or antiviral HIV by interacting with viral polymerases or
proteases.
Enzyme activation is usually effected by second messengers such as cAMP,
cGMP, or Ca2+ . Nitrates catalyse the soluble guanylyl cyclase via nitric oxide (NO).
The effect of some coagulation factors on blood clotting is based on the fact that
they convert inactive into active proteases. Fibrinolytic convert plasminogen to
plasmin, also a protease.
2.4 Receptor Agonism and Antagonism
As physiological ligands drugs can interact as exogenous ligands with the receptor.
The prerequisite for this is a drug (D)–receptor (R) complex. This is dependent on the
affinity of the drug to the receptor. The higher the affinity, the higher the tendency
that the drug forms a complex with the receptor. Hereby, the receptor can exist in
two conformations, in an inactive (R) and in an active (R*) state. Both conformations
are in dynamic equilibrium, which in the absence of an endogenous or exogenous

ligand is usually shifted to the inactive side. Receptors, which are active even without
a ligand, are called constitutively active receptors.
Agonist: Substances that both bind to and stimulate the receptor

Inverse agonists: Substances which bind to a constitutively active receptor,
shift their equilibrium to the inactive state and reduce the proportion of consti-
tutively active receptors even more than at basal levels.
Antagonist: Substances which reduce or completely abolish a receptor-
mediated effect
Substances that both bind to and stimulate the receptor are agonists (Figure 2.2).
Substances which reduce or completely abolish a receptor-mediated effect are
antagonists.
Substances which bind to a constitutively active receptor shift their equilibrium to
the inactive state and reduce the proportion of constitutively active receptors even
more than at basal levels are called inverse agonists.
Agonists possess affinity as well as intrinsic activity. The intrinsic activity is
usually indicated as relative intrinsic activity α. This is proportional to the quotient
of the effect EA triggered by the agonist and the maximum possible effect Em in the
biological system. The maximum relative intrinsic activity is evident as α = EA /Em .
Agonists with an intrinsic activity of 1 are named as full agonists. Agonists with
an intrinsic activity >0 and <1 are named partial agonists. Partial agonists are
Signal
+ Agonist Effect
Receptor transduction
Agonist
Competitive No signal
+ No effect
antagonist transduction
Receptor
Figure 2.2 Illustration of drug–receptor intercations leading to activation or inhibition of

signal transduction and an effect. Source: Book editors based on Hartl, Fink, and
Beer-Hammer.
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154. Mors dicitur ultimum supplicium. Death is said to be
the extreme penalty.
Death is the utmost limit of all things. Capital punishment is now
only inflicted in cases of high treason and murder.
155. Multi multa, nemo omnia novit. Many have known

many things; no one has known everything.
So long, at least, as the law is ever changing, this must remain true.
156. Mutatis mutandis. Making such changes or alterations as

the sense requires.
157. Nam silent leges inter arma. Laws are silent in time of
war.
It is to be noticed that during those periods of our history in which
wars, civil or foreign, were most prevalent, very little was
accomplished in the way of legislature. Domestic legislation is always
a sure index of a peaceful administration.
158. Necessitas non habet legem. Necessity has no law.

(See next Max.)
159. Necessitas vincit legem. Necessity defeats the law.

(See last Max. and No. 230.)
160. Nemo contra factum suum venire potest. No one can

go against his own deed.
This maxim illustrates the doctrine of estoppel, of which there are
three kinds. (1) By matter of record; (2) by deed; (3) by matter in
pais. No person can, after execution, dispute his own solemn deed,
which is conclusive against him and those claiming under him, even
as to facts recited therein. (See Chitty on Contracts, 16th ed. p. 5.)
161. Nemo dat quod non habet. No one can give what he has
not.
No one can, other than by sale in market overt, confer upon
another a better title than he himself has. A great exception to this
principle occurs in the case of “negotiable securities,” which by
custom are transferable like cash by delivery. (See Miller v. Race, 1
Sm. L. C. p. 463.) A thief can confer no title to stolen goods. (See
Maxs. Nos. 166 and 232.)
162. Nemo de domo suâ extrahi potest. No man can be

dragged out of his own house.
(See Max. No. 62.)
163. Nemo debet bis punari, pro uno delicto. No one should
be twice punished for the same offence.
(See next Max.)
* 164. Nemo debet bis vexari pro unâ et eâdem causâ. No

one ought to be tried twice (twice put to trouble) for one and the
same cause.
It is a well-established principle of Criminal Law, that where a
man is indicted for an offence and acquitted, he cannot afterwards be
again indicted for the same offence, if he might have been convicted
at the onset by proof of the facts contained in the second indictment.
(See last Max.)
* 165. Nemo est haeres viventis. No man is heir of a living

person.
There may be either an heir apparent, as the eldest son, or an heir
presumptive, as an only daughter. The question of actual heirship
arises only on the death of the owner. No inheritance can vest, and
no one can be a complete heir until the ancestor is dead. (See Max.
No. 59.)
* 166. Nemo plus juris in alium transferre potest quam
ipse habet. No one can confer a better right to another than he
has himself.
(But see Miller v. Race, 1 Sm. L. C. 11th ed. p. 463, and Max. No.
161.)
167. Nemo potest esse agens et patiens. No one can be alike

an active and a passive party.
* 168. Nemo potest mutare consilium suum in alterius
injuriam. No one can change his purpose (or advice) to the
injury of another.
It will be noticed that Acts of Legislation are generally prospective
and not retrospective in their application. The doctrine of estoppel
also illustrates the meaning intended to be conveyed.
169. Nemo praesumitur malus. No one is presumed to be bad.

(See Max. No. 145.)
* 170. Nemo tenetur ad impossibile. No one is bound to an

impossibility.
If a man contracts to do anything which is physically impossible,
such contract is not binding on him; but where the contract is to do a
thing which, though possible at the time, subsequently becomes
impossible, it is otherwise; also if the impossibility is one personal
only to the contractor. (See Max. No. 139.)
171. Nemo tenetur seipsum prodere. No one is bound to

betray himself; i.e., cannot be compelled to criminate himself.
A well recognised rule of evidence in all cases. (See Max. No. 3.)
172. Nihil tam conveniens est naturali aequitati, quam

unumquodque dissolvi eo ligamine quo legatum est.
Nothing is so consonant to natural equity, as that a thing may
be dissolved by the same means which made it binding.
173. Non accipi debent verba in demonstrationem falsam
quae competunt in limitationem veram. Words which
admit of a true meaning ought not to be received in a false
sense, or one inconsistent with the facts.
Thus, where there is a subject-matter which answers in every
particular to a description contained in a will or deed, no part of the
description can be rejected so as to make it include more.
174. Non est regula quin fallat. There is no rule but it may
fail; exception proves the rule.
(See Max. No. 83)
175. Non quod dictum est, sed quod factum est,

inspicitur. Regard is to be had, not to what is said, but to what
is done.
Where a lessor gives a receipt for money tendered to him as rent,
this is in point of law a receipt for rent, and a waiver of any forfeiture
which may have been previously incurred; although the lessor,
before the tender, and on taking the rent, expressed his intention to
accept the money only as compensation for the use of the land.
(Croft v. Lumley, 5 E. & B. 648.)
176. Non videntur qui errant consentire. Those who make a

mistake are not considered to consent.
Mistake is of two kinds, either of fact or of law, the former, as a
rule, will be relieved against “Ignorantia facti excusat,” provided
there had been no acquiescence; but with regard to the latter the
Court will only grant relief in exceptional cases, “Ignorantia legis
neminem excusat.” (See Lansdowne v. Lansdowne, 2 Jacob &
Walker, 205.) Ignorance of foreign law is deemed ignorance of fact.
(See generally hereon Snell’s Eq. 16th ed. p. 396, and Max. No. 110.)
177. Noscitur a sociis. It may be known or explained from its
associates; i.e., the meaning may often be gathered from the
context (“si non cognoscitur ex se”).
This refers to the construction of words and clauses in contracts
and written instructions. (See Chitty on Contracts, 16th ed. p. 102,
and Max. No. 78.)
178. Nudum pactum. A naked agreement; i.e., a bare promise;

a contract not supported by necessary consideration.
179. Nullum scutaglum ponatur in regno nostro, nisi per
communes consilium regni nostris. No scutage can be
imposed in our realm, save by the common council of the
kingdom.
All imperial taxes are fixed and settled by the House of Commons,
in which House all “money Bills” originate.
* 180. Nullum tempus aut locus occurrit Regi. No time or

place affects the king.
Lapse of time will not generally bar the right of the Crown.
181. Nullus clericus nisi causidicus. A clerk (in holy orders)

was ever a pleader.
In early times the clergy monopolised all learning, and out of their
ranks all judges were formally appointed, all the inferior legal offices
being also filled by the lower clergy: hence their name of clerks. From
the year 1373–1530 A.D. no lawyer filled the office of Lord Chancellor,
the post being all along occupied by the clergy. “Les juges sont sages
personnes et autentiques, sicomme, les archevesques, evesques, les
chanoines, &c.”
* 182. Nullus commodum capere potest de injuria sua

propriâ. No one can obtain an advantage by his own wrong.
The examples of this maxim are numerous in every branch of the
law. (See Twyne’s Case, 1 Sm. L. C. 11th ed. p. 1, and Maxs. Nos. 80
and 82.)
183. Nullus simile est idem, nisi quotuor pedibus currit.

No like is exactly identical unless it runs on all fours.
184. Obiter dictum. Said by the way; i.e., in passing.
The “obiter dicta” of learned judges are frequently quoted,
although the same do not directly relate to the actual facts upon
which judgment is being delivered, consequently they are not so
important.
185. Odiosa et inhonesta non sunt praesumunda in lege.

Odious and dishonest things are not to be presumed in law.
186. Officium nemini debet esse damnosum. A duty should
be injurious to no one.
No one should sustain any loss by reason of doing his duty. Thus,
Justices of the Peace and County Court bailiffs should not personally
suffer loss on account of their having, in the performance of their
duty, to do things which are sometimes distasteful alike to
themselves and others.
* 187. Omne majus continet in se minus. The greater

contains the less.
A tender by a debtor to his creditor of an amount in excess of that
owing is perfectly good for what is actually due. (See Chitty on
Contracts, 16th ed. p. 326.)
188. Omne quod solo inaedificatur solo cedit. Everything

built on the soil belongs to the soil.
The grant of certain land will pass to the grantee all buildings and
erections thereon, even though such erections be not specifically
mentioned. (See Steph. Comm. I. p. 313, and Maxs. Nos. 46 and
224.)
* 189. Omne testamentum morte consummatum est, et

voluntas testatoris est ambulatoria usque ad mortem.
Every testament is perfected by death, and the will of a testator
is “ambulatory” (revocable) even unto death.
A will is of no effect and does not operate until the death of the
testator, until which time it may be revoked or altered by him at his
pleasure. It speaks from the date of death, and not that of its
execution.
A will may be defined as follows:—Voluntatis nostrae justa
sententia de eo quod quis post mortem suam fieri velet. (See Max.
No. 261.)
190. Omnia praesumuntur contra spoliatorem. Every

presumption is made against a wrongdoer.
See the third point of decision in Armory v. Delamirie, 1 Sm. L. C.
11th ed. p. 356, where it was decided that if a person withhold
evidence in his possession, every presumption shall be adopted to his
disadvantage, that is, such evidence shall be taken as adverse to his
interest.
* 191. Omnia praesumuntur rite et solenniter esse acta,

donec probetur in contrarium. All things are presumed to
have been rightly and properly performed, until the contrary is
proved.
Where there is a proper attestation clause to a will which appears
on the face of it to be duly executed, the Court assumes that the Wills
Act has been complied with, even although the witnesses may forget
the circumstances. (See Vinnicombe v. Butler, 34 L. J. (P. & M.) 18.)
192. Omnis coactio a legato abesse debet. Every suit against

an ambassador should fail.
It has now been decided that an ambassador is entitled to absolute
exemption from suits in the Courts of the country to which he is sent.
(See The Magdalene Steam Navigation Co. v. Martin, 2 El. & El. 94,
28 L. J. Q. B. 310.)
193. Omnis innovatio plus novitate perturbat quam

utilitate prodest. Every innovation occasions more harm by
its novelty than benefit by its utility.
The principle here laid down applies rather to the immediate, than
to the ultimate and permanent effects. (See Ashby v. White, 1 Smith,
L. C. 11th ed. p. 240, and Chitty on Contracts, 16th ed. p. 900.)
* 194. Omnis ratihabitio retrotrahitur et mandato priori

aequiparatur. Every ratification has a retrospective effect and
is equivalent to a previous authority or contract.
Where a person acts as agent for another, and professes (without
authority) to contract for him, a subsequent assent by the principal is
equivalent to a previous authority. (See Chitty on Contracts, 16th ed.
pp. 21 and 279, also Maxs. Nos. 55 and 208.)
195. Omnium contributione sarciatur quod per omnibus

datum est. That which is given for all should be contributed by
all.
This maxim is the essence of the law as to general average, under
which, where goods have been thrown overboard for the safety of a
ship, that being the only alternative, contribution to the loss is made
proportionately by the owners of the ship and all who have goods on
board. (See Steph. Comm. II. Cap. V. Sec. X.)
* 196. Once a mortgage always a mortgage. Where a

document is once satisfactorily established as a mortgage, a
mortgage it always will remain.
This was not formerly so at Common Law, but now, since the
Judicature Act, 1873, the rule of equity prevails. (See Snell’s Eq. 16th
ed. p. 238, and Max. No. 74.)
197. Optimus legis interpres est consuetudo. Custom is the

best interpreter of law.
(See also Maxs. Nos. 37 and 153.)
198. Pacta privata juri publico derogare non possunt.

Private contracts cannot repeal the public right—i.e., cannot
adversely affect a public right.
* 199. Partus sequitur ventrem. The offspring follows the
womb.
This maxim illustrates the doctrine of property arising from
accession, and is grounded on the right of occupancy. It has been
held in the case of all tame and domestic animals, that the offspring
belong to the owner of the mother, although in the case of human
beings it is otherwise, except as to bastards. (See Steph. Comm. II. p.
21.)
200. Patria potestas in pietate debet, non in atrocitate,

consistere. A father’s power ought to be based on affection
and not on cruelty.
Parents’ power over their children is derived from their duty
towards them, being given them, partly to enable them the more
effectually to perform their duty, and partly as a recompense for their
trouble in its discharge. (See Steph. Comm. II. Cap. III., also the
recent Acts for the Prevention of Cruelty to Children.)
201. Pendente lite nihil innovetur. Whilst a lawsuit is

pending nothing must be altered.
This principle or effect is limited to the rights of parties in that
particular suit.
202. Pluris est occulatus testis usus quam auriti decem.
One eye-witness is worth more than ten hearsay.
Hearsay or second-hand evidence is generally inadmissible except
in certain cases, such as questions of custom or pedigree.
203. Possessio fratris (de feodo simplici) facit sororem

esse haeredem. Possession by the brother of an estate in fee
simple constitutes the sister heiress.
Applicable to the old law of inheritance, under which the half-
blood were totally excluded from the succession, land descending to
a sister of the whole blood of the person last seised, rather than to a
brother of the half-blood. Now, however, by 3 & 4 Will. IV. c. 106, the
half-blood are admitted. (See Steph. Comm. I. p. 274, also Maxs.
Nos. 96 and 97.)
204. Potior est conditio possidentis. The condition of one in

possession is the more preferable.
The old English adage, “Possession is nine-tenths of the law,” now
very qualified in its truth and application, probably had its origin in
this maxim. (See Max. No. 118.)
205. Praestat cautela quam medela. Caution is better than

cure.
206. Principia probant non probantur. It is not necessary to
prove first principles—i.e., maxims (see Preface).
207. Quaelibet concessio fortissime contra donatorem
interpretanda est. Every grant is to be interpreted most
strongly against the donor.
(See Max. No. 272.)
* 208. Quando aliquid mandatur, mandatur et omne per

quod pervenitur ad illud. When anything is ordered to be
done, everything by which it is to be accomplished is also
impliedly authorised.
One of the rules affecting the law of principal and agent, is that the
latter’s authority includes all medium powers “per quod pervenitur
ad illud.”
209. Quando jus domini regis et subditi concurrunt jus

regis praeferri debet. When the right of the king and that of a
subject arise simultaneously the former takes precedence.
* 210. Quando lex aliquid alicui concedit, concedere
videtur et id sine quo res ipsa esse non potest. When the
law gives a man anything it gives him that also without which
the thing itself cannot exist.
Under the following circumstances a way of necessity is implied—
e.g., if A. grant to B. a piece of land surrounded on all sides by other
land of A.’s B. will (in case there be no right of way to his land) have a
right of way over A.’s surrounding land for such time as the necessity
exists. The application of this maxim is very limited, and it refers
more especially to contracts under seal. (See Chitty on Contracts,
16th ed. p. 115, and Max. No. 42.)
* 211. Quando res non valet ut ago, valeat quantum valere

potest. When anything does not operate in the way one
intends, let it operate as far as it can.
In the case of Roe v. Tranmarr, 2 Sm. L. C. p. 506, a deed
purporting to be a release which could not operate as such because it
attempted to convey a freehold “in futuro,” was held valid under the
circumstances as a covenant to stand seised (see Max. No. 26). A
lease in writing but not under seal, is not absolutely void, but held
good in equity as an agreement for a lease. (See Maxs. Nos. 271, 273,
and 275.)
212. Qui ex damnato coitu nascuntur inter liberos non

computantur. Those born from an unlawful intercourse are
not to be deemed among the lawful children.
Bastards are incapable under our law of being heirs, and are held
to be “nullius filii.” By the civil law they could inherit being
legitimated by the lawful marriage of their fathers and mothers.
* 213. Qui facit per alium facit per se. He who acts through
another acts through himself.
A contract made by an agent is looked upon in law as the contract
of the principal, so agents need not be “sui juris,” and infants,
married women, and others are competent to act as such. The agent
must, however, act within the scope of his authority. In Scott v.
Shepherd, 2 Black. 892, an action was held to lie against the person
who originally threw a squib which, after being knocked about by
other persons in self-defence, ultimately hit and put out the
plaintiff’s eye. (See Chitty on Contracts, 16th ed. pp. 262–7, and Max.
No. 240.)
214. Qui haeret in litera haeret in cortice. He who considers

only the mere wording of a document goes but skin deep into its
meaning.
(See Maxs. Nos. 26, 78, 177, and 273.)
215. Qui minimum probat nihil probat. He proves nothing

who proves too much.
216. Qui non improbat, approbat. He who does not blame,
approves.
(See next Max.)
* 217. Qui non prohibet id quod prohibere potest,

assentire videtur. He who does not forbid what he is able to
prevent, appears to assent.
So one who enables another to commit a fraud is answerable. A
person who has a title to property offered for sale at an auction, and,
knowing his title, stands by and encourages the sale or does not
forbid it, will be bound by the sale, for “Qui non obstat quod obstare
potest, facere videtur.” Teasdale v. Teasdale, Sel. Ch. Cas. 59. (See
Snell’s Eq. 16th ed. cap. 3, and also Maxs. Nos. 35, 98, 216, and 222.)
218. Qui parcit nocentibus, innocentes punit. He who

spares the guilty, punishes the innocent.
219. Qui peccat ebrius, luat sobrius. Let him who sins when
drunk, be punished when sober.
An intoxicated person can derive no privilege from a madness thus
voluntarily contracted. On an indictment for murder, however,
intoxication may be taken into consideration, to show that the act
was not premeditated, and if there has been some contrivance or
inducement to allure the party into drink, or any unfair advantage
taken of his intoxication, the Court will sometimes relieve. (But see
Chitty on Contracts, 16th ed. pp. 161–162.)
* 220. Qui prior est tempore potior est jure. He who is first
in point of time is preferred in law.
(See Brace v. Duchess of Marlborough, 2 P. Wms. 49 1, and Marsh
v. Lee, 2 Wh. and Tud. L. C. Eq. 8th ed. p. 118.) Subject to the
provisions of the Conveyancing and Law of Property Act, 1881, a
mortgagee may recover in ejectment without giving notice to quit
against a tenant who claims under a lease from the mortgagor,
granted after the mortgage without the privity of the mortgagee. The
rule stated in this maxim applies as between finders of “treasure
trove,” derelicts, and such like. (See also Keech v. Hall, 1 Sm. L. C.
11th ed. p. 511.) Where several persons have interests in the same
property, and equal equities in every point except time, as in the case
of a third mortgagee who had no notice of a second mortgage when
making his advance, here both mortgagees have equal equities, but
the second mortgagee, being first in point of time, has the prior right.
In this instance, however, the third mortgagee could avail himself of
the advantages of tacking. (See Max. No. 288, and Snell, 16th ed. pp.
10, 262–3.)
* 221. Qui sentit commodum sentire debet et onus. He who
receives the advantage ought also to suffer the burden.
Equity always acted on this principle when enforcing contribution
between co-sureties. (Dering v. Earl of Winchilsea, 2 Wh. and Tud.
L. C. Eq. 8th ed. 539, and Waugh v. Carver, 2 Hen. Blackstone, 235;
Cox v. Hickman, 1 Sm. L. C. 414.)
222. Qui tacet sentire videtur. He who is silent appears to

consent.
(See Maxs. Nos. 35, 216, 217.)
223. Qui vult decipi, decipiatur. Let him be deceived who

wishes to be deceived.
A person who has been guilty of such gross negligence as to court
deception will obtain no relief from the Court. (See Maxs. Nos. 47
and 61.)
* 224. Quicquid plantatur solo solo cedit. Whatever is

planted in (or affixed to the soil) belongs to the soil.
This principle is stringently adhered to as between the heir-at-law
and the executor of a deceased person, and as between mortgagors
and mortgagees; but it has been very considerably relaxed in its
application to fixtures as between landlord and tenant. (See Chitty on
Contracts, 16th ed. p. 415, and Maxs. Nos. 46 and 188.)
* 225. Quicquid solvitur, solvitur secundum modum

solventis, quicquid recipitur, recipitur secundum
modum recipientis. Whatever money is paid, is paid
according to the direction of the payer, whatever money
received, is received according to that of the recipient.
A debtor has, at the time of payment, the first right to direct the
same to be appropriated in liquidation of whatever debt due to his
creditor he chooses. If the debtor omit to do this, the creditor has the
next right of appropriation to what debt he chooses. If neither party
makes appropriation, the law makes it—generally to the earlier debt.
(See Rule in Clayton’s Case and Snell’s Eq. 16th ed. pp. 470–1.)
226. Quisque suâ acte perito est credendum. Every one

experienced in his own calling is to be believed.
(See Max. No. 43.)
* 227. Quod ab initio non valet, in tractu temporis non

convalescit. That which was void from its commencement,
does not improve by lapse of time.
Where any contract amounts to a constructive fraud, on account of
its being opposed to some positive law, or public policy, it is void and
incapable of ratification—it is different, however, when the contract
is voidable only.
228. Quod fieri non debuit factum valet. That which ought
not to be done, is yet valid (sometimes) when done.
Money paid in pursuance of an illegal contract which has been
performed cannot, as a rule, be recovered back. (See also Max. No.
93.)
229. Quod naturalis ratio inter homines constituit

vocatur jus gentium. That which by natural reason prevails
among men is called the law of nations.
International law is not grounded upon the caprice of any
particular nation, but depends entirely upon mutual compacts and
treaties between the various States. The construction also of such
compacts is governed by the law of nations, being the only one to
which all communities are equally amenable. Civil Law, as
distinguished from International Law, is thus defined: “Jus civili, est
quod quisque sibi populus constituit.”
230. Quod necessitas cogit, excusat. That which necessity
compels, she excuses.
A person is not held criminally responsible for actions which he is
forced to commit under threats of death or grievous bodily harm,
continuing during the whole time of the commission of such acts.
This non-liability, however, does not extend to cases where the death
of an innocent person results. (See Reg. v. M‘Growther, 18 St. Tr.
394, and Maxs. Nos. 158 and 159.)
231. Quod nullius est, est domini regis. What is the property
of no one, belongs to the king.
Land will go to the Crown on the decease of the last owner or
person actually seised intestate, and without heirs. So also do waifs
(bona vacantia), and unclaimed wreckage. (See Wills Act.)
232. Quod per me non possum, nec per alium. That which
one cannot himself do, he cannot do by another.
No one can delegate a power which he himself does not possess.
(See Max. No. 161.)
233. Quod populus postremum jussit, id jus ratum esto.

That which a people has last ordained shall be the established
law.
(See Steph. Comm. I. p. 43, and Max. No. 137.)
* 234. Quod turpi ex causâ promissum est, non valet. An

immoral (illegal or base) consideration will not support a
promise (i.e., a contract).
So also one founded on an impossible or purely moral
consideration.
(See Chitty on Contracts, 16th ed. p. 4, and Maxs. Nos. 80 and 82.)
* 235. Quoties in verbis nulla est ambiguitas, ibi nulla
expositio contra verba fienda est. When there is no
ambiguity in the language of an instrument, no interpretation is
to be made contrary to the words.
It is a rule that parol evidence contrary to the express written
language itself is excluded, and the instrument itself is the only
criterion of the intention of the parties. Parol evidence may be
admissible to explain, but not to contradict or override, the express
written contents of an instrument.
(See Chitty on Contracts, 16th ed. p. 116.)
236. Quoties idem sermo duas sententias exprimit ea

potissimum accipiatur, quae rei gerendae aptior est.
When the same expression carries two meanings, that shall be
preferred which is the more fitted to elucidate the subject-
matter.
This is one of the numerous rules for the construction of legal
documents. (See Max. No. 26.)
237. Res ipse loquitur. The thing speaks for itself (without
proof).
Frequently quoted in actions for damages for negligence. (See
Max. No. 69, and Chitty on Contracts, 16th ed. pp. 523–723.)
238. Res inter alios acta alteri nocere non debet. A thing
done between two persons ought not to injure another.
(See Duchess of Kingston’s Case, 2 Sm. L. C. 731.)
239. Res judicata pro veritate accipiatur. A point judicially

decided is taken to be correct.
This is conclusive so far as Courts of inferior jurisdiction are
concerned, until the judgment is reversed.
* 240. Respondeat superior. Let the principal answer.
One authorising an unlawful act to be done by his servant, is
himself answerable. The maxim does not apply as against the Crown.
See also Max. No. 213. Also “Qui per alium facit per seipsum facere
videtur.” Also the case of Thompson v. Davenport, 2 Sm. L. C. p. 379.
Where at the time of sale the vendor is aware that there is a
principal, but does not know who he is and debits the agent, he may
nevertheless resort to the principal when known.
241. Rex debet esse sub lege, quia lex facit regem. The king
ought to be subservient to the law, for the law makes the king.
This is so in our realm at the present time, although many of our
earlier Sovereigns appeared to think otherwise, and acted
accordingly.
242. Rex in suo regno non habet parum. In his own

kingdom the king has no equal.
243. Rex nunquam moritur. The king never dies.
The person only is changed, but the Sovereign always exists—i.e.,
the Crown never falls vacant.
244. Rex peccare non potest. The king can do no wrong.

245. Salus populi est suprema lex. The public safety
(welfare) is the supreme law.
The prosperity of its people, and the proper maintenance of order
and security, as also the diffusion of domestic and social happiness,
should be the first and main object of every government.
246. Scientia utrinque par pares contrahentes facit. Equal

knowledge on both sides makes the position of the contracting
parties the same.
In an insurance policy there are many things relating to the
subject-matter thereof as to which the insured can be innocently
silent—for instance, he need not mention any facts within the
insurer’s own knowledge; for an insurer cannot insist that a policy is
void because the insurer did not inform him that which he already
knew.
247. Scire debes cum quo contrabis. One should know with
whom he contracts.
This is self-evident, so that a person may know whom to sue and
look to for damages in case of a breach of the contract.
248. Scribere est agere. To write is the same thing as to act.

A deed in writing is, at the present time, sufficient to effect the
transfer of property, without any actual livery of seisin.
* 249. Seisina (non jus) facit stipitem. Seisin (not the law)
makes the root of descent.
This was formerly a most important maxim, but the doctrine is
exploded by the Inheritance Act, 3 & 4 Will. IV. c. 106, which enacts
that “Descent shall in all cases be traced from the last purchaser,
whether he may or may not have actually obtained possession.” The
purchaser is defined by the Act as being the last person who had a
right to the land who cannot be proved to have acquired the land by
descent, or by certain means which render the land part of, or
descendible in the same manner as other land acquired by descent
(e.g., escheat, partition, or enclosure). Under the old law no one
could be such an ancestor as to have descent traced from him, unless
he had been in actual possession of the land, or in receipt of the rents
and profits prior to his death.
250. Semper in dubiis benigniora praeferenda. In doubtful

matters the more liberal (constructions) are to be preferred.
(See Max. No. 26.)
251. Semper in obscuris quod minimum est sequimur. In
obscure (constructions) the law follows that which is least
obscure.
(Williams v. Crosling, 3 C. B. 962, and Max. No. 26.)
252. Semper praesumitur pro negante. Presumption is ever

in favour of the negative.
The “onus probandi” lies on the plaintiff (see Maxs. Nos. 24 and
69). It is also to be remembered that every one is presumed in law to
be innocent until the contrary is proved.
253. Si plura sint debita, vel plus legatum fuerit, ad quae

catalla defuncti non sufficiant, fiat ubique defalcatio,
excepto regis privilegio. If the debts or legacies of a deceased
are greater than the assets will satisfy, the same shall abate
rateably, the privilege of the Crown excepted.
If the assets of a deceased person are insufficient to pay the debts
and the legacies bequeathed by his will, all the general legacies abate
rateably. A specific legacy, as of a piece of plate, is not liable to
abatement, until the fund applicable for general legacies is
exhausted; but, on the other hand, it is liable to ademption—i.e., it
may have been otherwise disposed of by the testator in his lifetime.
Debts in every case form a first charge on the estate. (See Steph.
Comm. II. p. 300.)
* 254. Sic utere tuo ut alienum non laedas. So enjoy your

own rights as not to injure those of another.
Where the natural course of a stream is over the surface of lands
belonging to different proprietors, no proprietor above can diminish
the quantity or injure the quality of the water which descends; nor
can a proprietor below throw back the water without licences from
the proprietors above. Aedificare in tuo proprio solo non licet quod
alteri noceat.

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Principles of Biomedical Sciences and

Industry Markus Hinder

(eBook PDF) Principles of Biomedical Ethics 8th Edition

Vibrational Spectroscopy Applications in Biomedical,

The Biomedical Sciences In Society: An

Biomedical Defense Principles to Counter DNA Deep

Käse für Dummies Markus Bornholdt

Forensic Face Matching Markus Bindemann

Ambient Ionization Mass Spectrometry in Life Sciences:

X-Ray Fluorescence in Biological Sciences: Principles,

Translating Ideas into Treatments

Print ISBN: 978-3-527-34571-7

Cover Design: ADAM DESIGN, Weinheim,

1 Biopharmaceutical Innovation at a Glance 1

2 Pharmacology and Drug Targets – The Basis of

2.6.5.2 Reduction and Hydrolysis 24

3 Principles and Methods of the Pharmaceutical Drug Discovery

3.4.1 Preventing Formation of the Target Protein 43

4 Biomarkers: Deﬁnitions and Utility for Drug Development 63

5 Toxicology in Drug Development – Understanding a Drug’s

5.7 What Activity at Which Stage of Development? 92

6 Introduction to Chemistry Manufacturing and Controls – From

7 Translational Medicine – The Bridging Discipline. Role and

7.3 Paths of Translation 126

8 Decision-Making: What are the Key Drivers Around

9 Clinical Drug Development – Clinical Characterization for

9.12 Key Studies During Clinical Development 167

10 Regulatory Affairs – Communicating with Health

11 Regulatory Affairs in Device Development – How to Design

12 Market Entry and Reimbursement: Making Drugs Available for

12.12.1 USA and Canada 242

13 Pricing in Germany – Key Learnings for Optimizing Price

14 Project, Risk, and Portfolio Management – Managing R&D

15 Intellectual Property – How to Protect Innovation in the

15.2.4 Patenting Procedure 287

16 Patents in the Biomedical Sciences and Industry – The Case of

17 Pharmaceutical Business Development and

17.14 Conclusions 332

18 The Entrepreneur’s Guide Through the Galaxy of Biotech

19 Medical Technologies – Key Learning from Two Case

20 Laboratory Diagnostics – Tools for Clinical Decision-Making

20.5.2 Immunology 364

21 Vaccination: Towards an Improved Inﬂuenza Vaccine 377

Visiting Professor – Estate of Hessen, Germany

About the Editors

Prof. Dr. Markus Hinder studied medicine at the

Prof. Dr. Alexander Schuhmacher graduated in

Prof. Dr. Jörg Goldhahn received his M.D. in 1997

Prof. Dr. Dominik Hartl studied Medicine at the

AAALAC Association for Assessment and Accreditation of

BCS Biopharmaceutical classification system

EPC European Patent Convention

GTP Guanosine triphosphate

MAP-kinase Mitogen-activated protein kinase

ODA Orphan Drug Act

PPQ Process performance qualification

scRNAseq Single-cell RNA sequencing

UGE Urinary glucose excretion

Biopharmaceutical Innovation at a Glance

Biopharmaceutical Research & Development (R&D) aims at finding new modalities

concepts generally applicable to the industry beyond individual company processes.

1.1 Biopharmaceutical Innovation and Drug

‘Déﬁnissez les termes, vous dis-je, ou jamais nous ne nous entendrons’.