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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.
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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 |