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Drug Discovery and Development - E-Book

Drug Discovery and Development - E-Book

Raymond G Hill

(2012)

Additional Information

Book Details

Abstract

The modern pharmacopeia has enormous power to alleviate disease, and owes its existence almost entirely to the work of the pharmaceutical industry. This book provides an introduction to the way the industry goes about the discovery and development of new drugs. The first part gives a brief historical account from its origins in the mediaeval apothecaries’ trade, and discusses the changing understanding of what we mean by disease, and what therapy aims to achieve, as well as summarising case histories of the discovery and development of some important drugs. The second part focuses on the science and technology involved in the discovery process: the stages by which a promising new chemical entity is identified, from the starting point of a medical need and an idea for addressing it. A chapter on biopharmaceuticals, whose discovery and development tend to follow routes somewhat different from synthetic compounds, is included here, as well as accounts of patent issues that arise in the discovery phase, and a chapter on research management in this environment. The third section of the book deals with drug development: the work that has to be undertaken to turn the drug candidate that emerges from the discovery process into a product on the market.

  • The definitive introduction to how a pharmaceutical company goes about its business of discovering and developing drugs.

    The second edition has a new editor: Professor Raymond Hill ● non-executive director of Addex Pharmaceuticals, Covagen and of Orexo AB ● Visiting Industrial Professor of Pharmacology in the University of Bristol ● Visiting Professor in the School of Medical and Health Sciences at the University of Surrey ● Visiting Professor in Physiology and Pharmacology at the University of Strathclyde ● President and Chair of the Council of the British Pharmacological Society ● member of the Nuffield Council on Bioethics and the Advisory Council on Misuse of Drugs.

    New to this edition:

    • Completely rewritten chapter on The Role of Medicinal Chemistry in the Drug Discovery Process.
    • New topic - DMPK Optimization Strategy in drug discovery.
    • New chapter on Scaffolds: Small globular proteins as antibody substitutes.
    • Totally updated chapters on Intellectual Property and Marketing
    • 50 new illustrations in full colour

    Features

    • Accessible, general guide to pharmaceutical research and development.
    • Examines the interfaces between cost and social benefit, quality control and mass production, regulatory bodies, patent management, and all interdisciplinary intersections essential to effective drug development.
    • Written by a strong team of scientists with long experience in the pharmaceutical industry.
    • Solid overview of all the steps from lab bench to market in an easy-to-understand way which will be accessible to non-specialists.

    From customer reviews of the previous edition:

    ‘… it will have everything you need to know on this module. Deeply referenced and, thus, deeply reliable.

    • Highly Commended in the medicine category of the BMA 2006 medical book competition
    • Winner of the Royal Society of Medicine Library Prize for Medical Book of the Year

Table of Contents

Section Title Page Action Price
Front cover cover
Drug Discovery and Development i
Copyright page iv
Foreword v
Preface to 2nd Edition vii
Preface to 1st edition viii
Contributors x
Table of Contents xiii
1 Introduction and background 1
1 The development of the pharmaceutical industry 3
Antecedents and origins 3
Therapeutics in the 19th century 4
An industry begins to emerge 4
Developments in biomedicine 4
Developments in chemistry 5
The apothecaries’ trade 6
The industry enters the 20th century 7
Chemistry-driven drug discovery 7
Synthetic chemistry 7
Natural product chemistry 8
Target-directed drug discovery 8
The sulfonamide story 9
Hitchings and Elion and the antimetabolite principle 12
James Black and receptor-targeted drugs 12
Accidental clinical discoveries 13
The regulatory process 13
Concluding remarks 14
References 18
2 The nature of disease and the purpose of therapy 19
Introduction 19
Concepts of disease 19
What is health? 20
What is disease? 20
Deviation from normality does not define disease 20
Phenomenology and aetiology are important factors – the naturalistic view 21
Harm and disvalue – the normative view 21
The aims of therapeutics 21
Components of disvalue 21
Therapeutic intervention is not restricted to treatment or prevention of disease 22
Conclusions 23
Function and dysfunction: the biological perspective 24
Levels of biological organization 24
Therapeutic targets 25
The relationship between drug targets and therapeutic targets 26
Therapeutic interventions 26
Measuring therapeutic outcome 27
Effect, efficacy, effectiveness and benefit 27
Pharmacoepidemiology and pharmacoeconomics 27
Summary 30
References 30
3 Therapeutic modalities 33
Introduction 33
Conventional therapeutic drugs 34
Biopharmaceuticals 34
Gene therapy 37
Cell-based therapies 38
Tissue and organ transplantation 39
Summary 39
References 40
2 Drug discovery 41
4 The drug discovery process: 43
Introduction 43
Some case histories 46
Paclitaxel (Taxol) 47
Flecainide (Tambocor) 48
Omeprazole (Losec) 48
Imatinib (Gleevec/Glivec) 49
Trastuzumab (Herceptin) 50
Comments and conclusions 50
The stages of drug discovery 50
Trends in drug discovery 52
Project planning 54
Research in the pharmaceutical industry 55
References 56
5 Choosing the project 57
Introduction 57
Making the decision 57
Strategic issues 57
Unmet medical need 57
Market considerations 58
Company strategy and franchise 59
Legislation, government policy, reimbursement and pricing 59
Scientific and technical issues 60
The scientific and technological basis 60
Competition 60
Development and regulatory hurdles 60
The patent situation 61
Operational issues 61
A final word 62
6 Choosing the target 63
Introduction: the scope for new drug targets 63
How many drug targets are there? 63
The nature of existing drug targets 65
Conventional strategies for finding new drug targets 65
New strategies for identifying drug targets 67
Trawling the genome 67
Disease genes 68
Disease-modifying genes 69
Gene expression profiling 69
Gene knockout screening 70
’Druggable’ genes 72
Target validation 72
Pharmacological approaches 72
Genetic approaches 73
Antisense oligonucleotides 73
RNA interference (RNAi) 73
Transgenic animals 73
Summary and conclusions 74
References 74
7 The role of information, bioinformatics and genomics 77
The pharmaceutical industry as an information industry 77
Innovation depends on information from multiple sources 77
Bioinformatics 78
Bioinformatics as data mining and inference 79
General principles for data mining 79
Pattern discovery 80
Predictive analysis 81
Association analysis 81
Genomics 82
The genome and its offspring ‘-omes’ 82
A few genome details 83
Genome variability and individual differences 85
The epigenome 85
The transcriptome 85
In defence of the genome 87
Genomic information in drug discovery and development 88
Understanding human disease intrinsic mechanisms 89
Understanding the biology of infectious agents 89
Identifying potential drug targets 89
Validating drug targets 89
Assay development for selected drug targets 89
Phase 0 clinical studies – understanding from compounds in low concentration 89
Phase I clinical studies – pharmacokinetics and safety 90
Phase II and III clinical studies – efficacy and safety 90
Genomic information and drug regulatory authorities 90
Critical Path Initiative and the EMEA’s equivalent programme 91
Voluntary exploratory data submissions and guidance documents 91
Conclusion 91
References 93
8 High-throughput screening 95
Introduction: a historical and future perspective 95
Lead discovery and high-throughput screening 97
Assay development and validation 99
Biochemical and cell-based assays 100
Assay readout and detection 102
Ligand binding assays 102
Fluorescence technologies 103
Fluorescence intensity 103
Fluorescence resonance energy transfer (FRET) 103
Time resolved fluorescence (TRF) 103
Fluorescence polarization (FP) 104
Fluorescence correlation methods 104
AlphaScreen™ Technology 105
Cell-based assays 105
Readouts for cell-based assays 105
Fluorometric assays 106
Reporter gene assays 106
Yeast complementation assay 107
High throughput electrophysiology assays 107
Label free detection platforms 108
High content screening 108
Biophysical methods in high-throughput screening 108
Assay formats – miniaturization 109
Robotics in HTS 109
Data analysis and management 111
Screening libraries and compound logistics 112
Compound logistics 112
Profiling 113
References 114
9 The role of medicinal chemistry in the drug discovery process 119
Introduction 119
Target selection and validation 120
Lead identification/generation 123
Lead optimization 125
Addressing attrition 129
Summary 131
References 131
10 Metabolism and pharmacokinetic optimization strategies in drug discovery 135
Introduction 135
Optimization of DMPK properties 135
Absorption and oral bioavailability 136
Introduction 136
Tactics 136
Cautions 138
Avoidance of PK based drug–drug interactions 139
Introduction 139
Tactics 140
Competitive (reversible) CYP inhibition 140
Mechanism-based/time-dependent CYP inhibition 140
Uptake and efflux transporter inhibition 140
Determination of clearance mechanism and CYP phenotyping 141
CYP induction mediated risk for DDI 142
Prediction of DDI risk 142
Cautions 143
Central nervous system uptake 143
Introduction 143
Tactics 143
Cautions 145
Clearance optimization 145
3 Drug development 201
14 Drug development: 203
Introduction 203
The nature of drug development 203
Components of drug development 204
The interface between discovery and development 207
Decision points 207
The need for improvement 208
References 209
15 Assessing drug safety 211
Introduction 211
Types of adverse drug effect 212
Safety pharmacology 213
Tests for QT interval prolongation 215
Exploratory (dose range-finding) toxicology studies 215
Genotoxicity 216
Selection and interpretation of tests 218
Chronic toxicology studies 218
Experimental design 219
Evaluation of toxic effects 219
Biopharmaceuticals 220
Special tests 220
Carcinogenicity testing 220
Reproductive/developmental toxicology studies 221
Other studies 222
Toxicokinetics 222
Toxicity measures 223
Variability in responses 223
Conclusions and future trends 223
References 224
16 Pharmaceutical development 227
Introduction 227
Preformulation studies 227
Solubility and dissolution rate 228
Stability 228
Particle size and morphology 228
Routes of administration and dosage forms 229
Formulation 230
Principles of drug delivery systems 231
Polymers and surfactants 231
Micelles 232
Liposomes 233
Nanontechnology more then nanoparticles 234
Modified-release drug formulations 235
Delivery and formulation of biopharmaceuticals 235
Drug delivery to the central nervous system 236
Summary 237
References 238
17 Clinical development: 239
Introduction 239
Clinical development phases 240
Phase I – Clinical pharmacology 240
First in man, single ascending dose, pharmacokinetics and safety 242
Objectives 242
Subjects 242
Design 242
Outcome measures 243
Multiple ascending repeat-dose studies 244
Design 244
Outcome measures 244
Pharmacodynamic studies 245
Drug–drug interaction studies 245
Absolute bioavailability and bioequivalence of new formulations 245
Absorption distribution metabolism excretion (ADME) in man (radiolabelled studies) 246
Other safety pharmacology studies 246
Special populations 246
Phase IIa – Exploratory efficacy 247
Objectives 247
Design consideration for first in class compounds – large pharma vs small pharma 247
Design 247
Patients to be studied 248
Outcome measures 249
Phase IIb to III dose range finding and confirmatory efficacy studies 249
Objectives 249
Design 249
Patients and study setting 250
Outcome measures 250
Phase IIIb and IV studies 251
Bridging studies 251
Patient recruitment in efficacy studies 251
Clinical trials in children 252
Regulatory and ethical environment 252
Ethical procedures 253
Clinical trial operations and quality assurance 253
Issues of confidentiality and disclosure 254
Seamless drug development with adaptive clinical trial design: the future of clinical development? 254
Conclusions 256
References 257
18 Clinical imaging in drug development 259
Introduction 259
Imaging methods 259
Positron emission tomography (PET) 259
Magnetic resonance imaging (MRI) 260
Functional magnetic resonance imaging (fMRI) 260
Human target validation 261
Biodistribution 262
Target interaction 264
Pharmacodynamics 266
Patient stratification and personalized medicine 268
Towards personalized medicine 269
Imaging as a surrogate marker 270
Imaging in the real world – challenges to implementation 270
Summary 272
Acknowledgments 272
References 272
19 Intellectual property in drug discovery and development 275
What is a patent? 275
The patent specification 276
Bibliographic details 276
Description 276
Claims 276
What can be patented? 276
Pharmaceutical inventions 276
Requirements for patentability 277
Novelty 277
Novelty in the USA 277
Inventive step (non-obviousness) 277
Industrial applicability (utility) 278
Patent issues in drug discovery 278
The state of the art 278
Patent documents as state of the art 278
Evaluation by the scientist 279
Evaluation by the patent professional 279
Sources of information 279
Results of the evaluation – NCEs 279
Patenting of research tools 280
Obtaining patent protection for a development compound 280
Filing a patent application 280
When to file 280
Where to file 280
The foreign filing decision 281
Abandonment 281
Refiling 281
Home-country patenting 281
Foreign filing 281
Procedures on foreign filing 282
National filings 282
Regional patent offices 282
Patent cooperation treaty (PCT) 282
Selection of countries 282
Maintenance of patents 282
Extension of patent term 282
Enforcement of patent rights 283
Other forms of intellectual property 283
Further reading 284
Useful websites 284
Patent offices 284
Professional organizations 284
Lists of links 284
20 Regulatory affairs 285
Introduction 285
Brief history of pharmaceutical regulation 285
International harmonization 286
Roles and responsibilities of regulatory authority and company 287
The role of the regulatory affairs department 287
The drug development process 288
Quality assessment (chemistry and pharmaceutical development) 289
Safety assessment (pharmacology and toxicology) 289
Primary pharmacology 289
General pharmacology 289
Pharmacokinetics: absorption, distribution, metabolism and excretion (ADME) 290
Toxicology 290
Single and repeated-dose studies 290
Genotoxicity 290
Carcinogenicity 290
Reproductive and developmental toxicity 291
Local tolerance and other toxicity studies 291
Efficacy assessment (studies in man) 291
Human pharmacology 291
Therapeutic exploratory studies 292
Studies in special populations: elderly, children, ethnic differences 292
Clinical trials in children 293
Ethnic differences 293
Therapeutic confirmatory studies 293
Clinical safety profile 293
Regulatory aspects of novel types of therapy 294
Biopharmaceuticals 294
Quality considerations 294
Safety considerations 295
Efficacy considerations 295
Regulatory procedural considerations 295
Personalized therapies 295
Orphan drugs 296
Environmental considerations 296
Regulatory procedures 296
Clinical trials 296
Europe 296
USA 297
Japan 297
Application for marketing authorization 297
Europe 297
USA 299
Japan 299
The common technical document 299
Administrative rules 300
Patent protection and data exclusivity 300
Supplementary protection certificate 300
Data exclusivity 300
Pricing of pharmaceutical products – ‘the fourth hurdle’ 300
References 301
Website references 301
List of abbreviations 301
21 The role of pharmaceutical marketing 303
Introduction 303
History of pharmaceutical marketing 303
Product life cycle 305
Product development phase 305
Introduction phase 305
Growth phase 305
Maturity phase 306
Decline phase 306
Pharmaceutical product life cycle (Figure 21.3) 306
Traditional Pharmaceutical marketing 307
Clinical studies 307
Identifying the market 307
The product 308
Features, attributes, benefits, limitations (FABL) 308
Assessing the competition 308
e-Marketing 310
CME 310
Key opinion leaders 310
Pricing 310
Freedom of pricing 310
Regulated pricing 311
Health technology assessment (HTA) 311
New product launch 312
Registration 312
Manufacturing and distribution 312
Resource allocation 312
Launch meeting 312
Media launch 312
Target audience 312
The influence of innovators and early adopters on group prescribing 313
Patients driving launch success 313
The first 6 months 313
Decline in prescriber decision-making power 314
Implementing the market plan 314
Changing environment – changing marketing 314
The key stakeholder 315
Values of the stakeholders 315
Innovation 315
R&D present and future 316
Products of the future 316
The future of marketing 316
The new way of marketing 316
References 317
4 Facts and figures 319
22 Drug discovery and development: 321
Spending 321
How much does it cost to develop a drug? 324
Sales revenues 325
Profitability 325
Pattern of sales 326
Blockbuster drugs 326
Timelines 327
Pipelines and attrition rates 329
Biotechnology-derived medicines 331
Recent introductions 331
Predicting the future? 332
References 333
Index 335
A 335
B 336
C 336
D 337
E 338
F 339
G 339
H 339
I 340
J 340
K 340
L 340
M 341
N 341
O 341
P 342
Q 343
R 343
S 344
T 344
U 345
V 345
W 345
X 345
Y 345
Z 345