Rick Ng, PhD, MBA, has worked for more than 25 years in senior management positions in the private sector pharmaceutical industry. He is currently providing consulting services to the pharmaceutical industry and training for graduates, postgraduates, and pharmaceutical professionals at the National University of Singapore and the University of New South Wales, Australia.

Preface xv

1 Introduction 1

1.1 Aim of this Book 1

1.2 An Overview of the Drug Discovery to Approval Process 2

1.3 The Pharmaceutical Industry 6

1.4 Economics of Drug Discovery and Development 11

1.5 Trends in Drug Discovery and Development 13

1.6 Case Study #1.1 15

1.7 Case Study #1.2 17

1.8 Summary of Important Points 20

1.9 Review Questions 20

1.10 Brief Answers and Explanations 21

1.11 Further Reading 22

2 Drug Discovery: Targets and Receptors 23

2.1 Drug Discovery Processes 23

2.2 Medical Needs 24

2.3 Target Identification 26content

2.4 Target Validation 33

2.5 Drug Interactions with Targets or Receptors 36

2.6 Enzymes 40

2.7 Receptors and Signal Transduction 42

2.8 Assay Development 52

2.9 Case Study #2.1 52

2.10 Case Study #2.2 53

2.11 Summary of Important Points 57

2.12 Review Questions 57

2.13 Brief Answers and Explanations 58

2.14 Further Reading 58

3 Drug Discovery: Small Molecule Drugs 61

3.1 Introduction 61

3.2 Irrational Approach 62

3.3 Rational Approach 67

3.4 Antisense Approach 85

3.5 RNA Interference Approach 88

3.6 Chiral Drugs 91

3.7 Closing Remarks 92

3.8 Case Study #3.1 94

3.9 Case Study #3.2 96

3.10 Summary of Important Points 98

3.11 Review Questions 99

3.12 Brief Answers and Explanations 99

3.13 Further Reading 100

4 Drug Discovery: Large Molecule Drugs 103

4.1 Introduction 103

4.2 Vaccines 105

4.3 Antibodies 117

4.4 Cytokines 128

4.5 Hormones 134

4.6 Gene Therapy 137

4.7 Stem Cells and Cell Therapy 139

4.8 Case Study #4.1 141

4.9 Case Study #4.2 144

4.10 Summary of Important Points 146

4.11 Review Questions 147

4.12 Brief Answers and Explanations 148

4.13 Further Reading 148

5 Drug Development and Preclinical Studies 151

5.1 Introduction 151

5.2 Pharmacodynamics 154

5.3 Pharmacokinetics 158

5.4 Toxicology 168

5.5 Animal Tests, In Vitro Assays, and In Silico Methods 172

5.6 Formulations and Delivery Systems 175

5.7 Nanotechnology 183

5.8 Case Study #5.1 184

5.9 Case Study #5.2 185

5.10 Summary of Important Points 187

5.11 Review Questions 188

5.12 Brief Answers and Explanations 188

5.13 Further Reading 189

6 Clinical Trials 191

6.1 Definition of Clinical Trial 191

6.2 Ethical Considerations 192

6.3 Clinical Trials 195

6.4 Regulatory Requirements for Clinical Trials 204

6.5 Clinical Data Management 215

6.6 Role of Regulatory Authorities 218

6.7 Gene Therapy Clinical Trial 218

6.8 Adaptive Clinical Trial 220

6.9 Meta-Analysis 221

6.10 Case Study #6.1 222

6.11 Case Study #6.2 226

6.12 Summary of Important Points 227

6.13 Review Questions 228

6.14 Brief Answers and Explanations 228

6.15 Further Reading 229

7 Regulatory Authorities 231

7.1 Role of Regulatory Authorities 231

7.2 US Food and Drug Administration 233

7.3 European Medicines Agency 236

7.4 Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) 238

7.5 China Food and Drug Administration 240

7.6 India’s Central Drugs Standard Control Organization 240

7.7 Australia’s Therapeutic Goods Administration 241

7.8 Canada’s Health Canada 243

7.9 Other Regulatory Authorities 243

7.10 Authorities other than Drug Regulatory Agencies 243

7.11 International Conference on Harmonization 244

7.12 World Health Organization 245

7.13 Pharmaceutical Inspection Cooperation Scheme 246

7.14 Case Study # 7.1 246

7.15 Case Study # 7.2 249

7.16 Summary of Important Points 250

7.17 Review Questions 251

7.18 Brief Answers and Explanations 251

7.19 Further Reading 252

8 Regulatory Applications 253

8.1 Introduction 253

8.2 United States 254

8.3 European Union 272

8.4 Japan 280

8.5 China 282

8.6 India 287

8.7 Australia 287

8.8 Canada 287

8.9 Case Study #8.1 290

8.10 Case Study #8.2 292

8.11 Summary of Important Points 294

8.12 Review Questions 299

8.13 Brief Answers and Explanations 299

8.14 Further Reading 300

9 Good Manufacturing Practice: Regulatory Requirements 301

9.1 Introduction 301

9.2 United States 302

9.3 Europe 308

9.4 International Conference on Harmonization (ICH) 309

9.5 Pharmaceutical Inspection Cooperation Scheme (PIC/S) 311

9.6 Selected Core Elements of GMP 312

9.7 Selected GMP Systems 335

9.8 New cGMP Initiatives 350

9.9 Case Study #9.1 352

9.10 Case Study #9.2 358

9.11 Summary of Important Points 362

9.12 Review Questions 363

9.13 Brief Answers and Explanations 363

9.14 Further Reading 364

10 Good Manufacturing Practice: Drug Manufacturing 367

10.1 Introduction 367

10.2 GMP Manufacturing 371

10.3 GMP Inspection 372

10.4 Manufacture of Small Molecule APIs (Chemical Synthesis Methods) 379

10.5 Manufacture of Large Molecule APIs (Recombinant DNA Methods) 385

10.6 Finished Dosage Forms 394

10.7 Product Quality Review 398

10.8 Manufacturing Variations 399

10.9 Case Study #10.1 400

10.10 Case Study #10.2 404

10.11 Summary of Important Points 407

10.12 Review Questions 408

10.13 Brief Answers and Explanations 408

10.14 Further Reading 408

11 Future Perspectives 411

11.1 Past Advances and Future Challenges 411

11.2 Small Molecule Pharmaceutical Drugs 412

11.3 Large Molecule Biopharmaceutical Drugs 414

11.4 Traditional Medicine 414

11.5 Personalized Medicine 419

11.6 Gene Therapy 420

11.7 Cloning and Stem Cells 420

11.8 Old Age Diseases and Aging 423

11.9 Lifestyle Drugs 423

11.10 Performance-Enhancing Drugs 428

11.11 Chemical and Biological Terrorism 428

11.12 Transgenic Animals and Plants 432

11.13 Antibiotics Drug Resistance 433

11.14 Regulatory Issues 435

11.15 Intellectual Property Rights and Marketing Exclusivities 437

11.16 Bioethics 440

11.17 Concluding Remarks 442

11.18 Case Study #11.1 445

11.19 Case Study #11.2 447

11.20 Further Reading 449

Appendix 1 History of Drug Discovery and Development 451

A1.1 Early History of Medicine 451

A1.2 Drug Discovery and Development in the Middle Ages 453

A1.3 Foundation of Current Drug Discovery and Development 454

A1.4 Beginnings of Modern Pharmaceutical Industry 454

A1.5 Evolution of Drug Products 455

A1.6 Further Reading 456

Appendix 2 Cells, Nucleic Acids, Genes, and Proteins 457

A2.1 Cells 457

A2.2 Nucleic Acids 460

A2.3 Genes and Proteins 462

A2.4 Further Reading 468

Appendix 3 Selected Drugs and Their Mechanisms Of Action 469

Appendix 4 A DHFR Plasmid Vector 481

Appendix 5 Vaccine Production Methods 483

Appendix 6 Vaccines Approved By FDA 485

Appendix 7 Pharmacology/Toxicology Review Format 489

Appendix 8 Examples of General Biomarkers 495

Appendix 9 Toxicity Grading 499

Appendix 10 Health Systems in Selected Countries 505

Acronyms 509

Glossary 515

Index 519

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