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Drug Safety Evaluation, 3rd Edition

ISBN: 978-1-119-09741-9
918 pages
December 2016
Drug Safety Evaluation, 3rd Edition (111909741X) cover image

Description

This practical guide presents a road map for safety assessment as an integral part of the development of new drugs and therapeutics.
  • Helps readers solve scientific, technical, and regulatory issues in preclinical safety assessment and early clinical drug development
  • Explains scientific and philosophical bases for evaluation of specific concerns – including local tissue tolerance, target organ toxicity and carcinogenicity, developmental toxicity, immunogenicity, and immunotoxicity
  • Covers the development of new small and large molecules, generics, 505(b)(2) route NDAs, and biosimilars
  • Revises material to reflect new drug products (small synthetic, large proteins and cells, and tissues), harmonized global and national regulations, and new technologies for safety evaluation
  • Adds almost 20% new and thoroughly updates existing content from the last edition
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Table of Contents

PREFACE xxv

ABOUT THE AUTHOR xxvii

1 The Drug Development Process and the Global Pharmaceutical Marketplace 1

1.1 Introduction 1

1.2 The Marketplace 1

1.3 History of Modern Therapeutics 4

1.4 The Drug Development Process 6

1.5 Strategies for Development: Large Versus Small Company or the Short Versus Long Game 7

1.6 Safety Assessment and the Evolution of Drug Safety 11

1.7 The Three Stages of Drug Safety Evaluation in the General Case 11

References 12

2 Regulation of Human Pharmaceutical Safety: Routes to Human Use and Market 13

2.1 Introduction 13

2.2 Brief History of US Pharmaceutical Law 13

2.3 FDAMA Summary: Consequences and Other Regulations 19

2.4 Overview of US Regulations 21

2.5 Organizations Regulating Drug and Device Safety in the United States 24

2.6 Process of Pharmaceutical Product Development and Approval 25

2.8 Toxicity/Safety Testing: Cellular and Gene Therapy Products 33

2.9 Toxicity Testing: Special Cases 35

2.10 International Pharmaceutical Regulation and Registration 41

2.11 Combination Products 50

2.12 Conclusions 55

References 55

Further Reading 57

3 Data Mining: Sources of Information for Consideration in Study and Program Design and in Safety Evaluation 59

3.1 Introduction 59

3.2 PC‐Based Information Products: Laser DISC 65

3.3 Conclusions 65

References 65

4 Screens in Safety and Hazard Assessment 67

4.1 Introduction 67

4.2 Characteristics of Screens 68

4.3 Uses of Screens 70

4.4 Types of Screens 71

4.5 Criterion: Development and Use 71

4.6 Analysis of Screening Data 73

4.7 Univariate Data 73

References 76

5 Formulations, Routes, and Dosage Regimens 79

5.1 Mechanisms 81

5.2 Common Routes 83

5.3 Formulation of Test Materials 96

5.4 Dosing Calculations 105

5.5 Calculating Material Requirements 105

5.6 Excipients 106

References 111

6 Nonclinical Manifestations, Mechanisms, and End Points of Drug Toxicity 115

6.1 Manifestations 115

6.2 Mechanisms of Toxicity 116

6.3 End Points Measured in General Toxicity Studies 116

6.4 Complications 126

References 126

7 Pilot Toxicity Testing in Drug Safety Evaluation: MTD and DRF 129

7.1 Introduction 129

7.2 Range‐Finding Studies 130

7.3 Acute Systemic Toxicity Characterization 138

7.4 Screens 150

7.5 PILOT and DRF Studies 154

References 156

8 Repeat‐Dose Toxicity Studies 159

8.1 Objectives 159

8.2 Regulatory Considerations 161

8.3 Study Design and Conduct 162

8.4 Study Interpretation and Reporting 165

References 166

9 Genotoxicity 169

9.1 ICH Test Profile 169

9.2 DNA Structure 169

9.3 Cytogenetics 176

9.4 In Vitro Cytogenetic Assays 193

9.5 In Vivo Cytogenetic Assays 196

9.6 Sister Chromatid Exchange Assays 197

References 199

10 QSAR Tools for Drug Safety 209

10.1 Structure–Activity Relationships 209

10.2 SAR Modeling Methods 210

10.3 Applications in Toxicology 212

10.4 Genotoxicity 215

10.5 Comparison of Available Models/Applications 216

References 222

11 Immunotoxicology in Drug Development 225

11.1 Introduction 225

11.2 Overview of the Immune System 227

11.3 Immunotoxic Effects 229

11.4 Immunosuppression 231

11.5 Immunostimulation 235

11.6 Regulatory Positions 240

11.7 Evaluation of the Immune System 245

11.8 Nonspecific Immunity Function Assay 251

11.9 T‐Cell‐Dependent Antibody Response (TDAR) 253

11.10 Approaches to Compound Evaluation 259

11.11 Problems and Future Directions 263

References 264

12 Nonrodent Animal Studies 269

12.1 Introduction 269

12.2 Comparison Between Rodent and Nonrodent Experimental Design 269

12.3 Differences in Study Activities 270

12.4 Nonrodent Models 270

12.5 Dog 270

12.6 The Ferret 273

12.7 The Pig 275

12.8 Nonhuman Primates 279

12.9 Statistics in Large Animal Studies 283

12.10 Summary 288

References 288

13 Developmental and Reproductive Toxicity Testing 291

13.1 Introduction 291

13.2 ICH Study Designs 293

13.3 Methodological Issues 298

13.4 Developmental Studies in Primates 303

13.5 Data Interpretation 304

13.6 Juvenile and Pediatric Toxicology 310

13.7 In Vitro Tests for Developmental Toxicity 312

13.8 Appraisal of Current Approaches for Determining Developmental and Reproductive Hazards 316

References 317

14 Carcinogenicity Studies 321

14.1 Introduction 321

14.2 Mechanisms and Classes of Carcinogens 322

14.3 Genotoxic Carcinogens 322

14.4 Epigenetic Carcinogens 325

14.5 Regulatory Requirements and Timing 328

14.6 Species and Strain 328

14.7 Animal Husbandry 330

14.8 Dose Selection 330

14.9 Group Size 331

14.10 Route of Administration 332

14.11 Study Duration 332

14.12 Survival 332

14.13 End Points Measured 333

14.14 Transgenic Mouse Models 335

14.15 Interpretation of Results: Criteria for a Positive Result 338

14.16 Statistical Analysis 338

14.17 Weight‐of‐Evidence Factors for Consideration in a Carcinogenicity Assessment Document (CAD) 344

14.18 Conclusions 345

References 345

15 Histopathology in Nonclinical Pharmaceutical Safety Assessment 351

15.1 Introduction 351

15.2 Clinical Pathology 355

References 356

16 Irritation and Local Tissue Tolerance in Pharmaceutical Safety Assessment 359

16.1 Introduction 359

16.2 Factors Affecting Irritation Responses and Test Outcome 359

16.3 Primary Dermal Irritation (PDI) Test 360

16.4 Other Nonparenteral Route Irritation Tests 362

16.5 Ocular Irritation Testing 362

16.6 Vaginal Irritation 364

16.7 Acute Primary Vaginal Irritation Study in the Female Rabbit 365

16.8 Parenteral Irritation/Tolerance 367

16.9 Problems in Testing (and Their Resolutions) 370

16.10 Phototoxicity 371

16.11 Hemocompatibility 377

References 378

17 Pharmacokinetics and Toxicokinetics in Drug Safety Evaluation 381

17.1 Introduction 381

17.2 Regulations 382

17.3 Principles 382

17.4 Pharmacokinetics 395

17.5 Laboratory Methods 395

17.6 Sampling Methods and Intervals 397

17.7 Study Types 400

17.8 Analysis of Data 402

17.9 Physiologically Based Pharmacokinetic (PBPK) Modeling 404

17.10 Points to Consider 405

17.11 Biologically Derived Materials 406

17.12 Points to Consider 410

References 410

18 Safety Pharmacology 413

18.1 Regulatory Requirements 414

18.2 Study Designs and Principles 415

18.3 Organ System‐Specific Tests 416

18.4 Cardiovascular 416

18.5 Central Nervous System 419

18.6 Respiratory/Pulmonary System 422

18.7 Secondary Organ System 427

18.8 Renal Function Tests 428

18.9 Summary 428

References 428

19 Special Concerns for the Preclinical Evaluation of Biotechnology Products 433

19.1 Regulation 436

19.2 Preclinical Safety Assessment 437

19.3 Recombinant DNA Technology 439

19.4 Immunogenicity/Allergenicity 440

19.5 Monoclonal Antibody Technology 441

19.6 Bioprocess Technology 446

19.7 Gene Therapy Products 446

19.8 Vaccines 449

19.9 Special Challenges 452

19.10 Planning a Safety Evaluation Program 454

19.11 Challenges: Biosimilars 458

References 459

20 Safety Assessment of Inhalant Drugs and Dermal Route Drugs 461

20.1 Inhaled Therapeutics 461

20.2 The Pulmonary System 461

20.3 Penetration and Absorption of Inhaled Gases and Vapors 462

20.4 Deposition of Inhaled Aerosols 463

20.5 Absorption and Clearance of Inhaled Aerosols 464

20.6 Pharmacokinetics and Pharmacodynamics of Inhaled Aerosols 464

20.7 Methods for Safety Assessment of Inhaled Therapeutics 465

20.8 Parameters of Toxicity Evaluation 467

20.9 Inhalation Exposure Techniques 470

20.10 The Utility of Toxicity Data 473

20.11 Formulation and Potential Mucosal Damage 473

20.12 Therapeutic Drug Delivery by the Dermal Route 474

References 476

21 Special Case Products: Imaging Agents 483

21.1 Introduction 483

21.2 Imaging Agents 483

References 487

22 Special Case Products: Drugs for Treatment of Cancer 489

22.1 Introduction 489

References 493

23 Pediatric Product Safety Assessment (2006 Guidance, Including Juvenile Toxicology) 495

23.1 Introduction 495

23.2 Issues to Consider Regarding Juvenile Animal Studies 498

23.3 General Considerations in Designing Toxicity Studies in Juvenile Animals 499

23.4 Study Designs and Considerations 500

References 501

24 Use of Imaging, Imaging Agents, and Radiopharmaceuticals in Nonclinical Toxicology 503

24.1 Introduction 503

24.2 X‐ray 505

24.3 Positron Emission Tomography (PET) 505

24.4 Single‐photon Emission Computed Tomography (SPECT) 505

24.5 Computed Tomography (CT) 506

24.6 Magnetic Resonance Imaging (MRI) 506

24.7 Optical Imaging 507

24.8 Ultrasound 508

24.9 Nanoparticle Contrast Agents 509

24.10 Radiopharmaceuticals 509

24.11 Applications of Preclinical Imaging in Laboratory Animals 509

24.12 Nonclinical Safety Assessment for Imaging Agents 515

24.13 Radiopharmaceuticals 517

24.14 Nonclinical Late Radiation Toxicity Studies 519

24.15 Study Design 519

References 520

25 Occupational Toxicology in the Pharmaceutical Industry 523

25.1 Introduction 523

25.2 Occupational Toxicology versus Drug Safety Evaluation 523

25.3 Regulatory Pressures in the United States and the European Community 525

25.4 Organizational Structure 526

25.5 Activities 527

25.6 Conclusion 534

References 534

26 Strategy and Phasing for Nonclinical Drug Safety Evaluation in the Discovery and Development of Pharmaceuticals 537

26.1 Introduction 537

26.2 Regulatory Requirements 539

26.3 Essential Elements of Project Management 542

26.4 Screens: Their Use and Interpretation in Safety Assessment 544

26.5 Strategy and Phasing 546

26.6 Critical Considerations 550

26.7 Special Cases in Safety Assessment 551

26.8 Summary 551

References 551

27 The Application of In Vitro Techniques in Drug Safety Assessment 553

27.1 Introduction 553

27.2 In Vitro Testing in Pharmaceutical Safety Assessment 555

27.3 Defining Testing Objective 558

27.4 Test Systems: Characteristics, Development, and Selection 558

27.5 In Vitro Models 559

27.6 Lethality 560

27.7 In Silico Methods 572

27.8 The Final Frontier and Barrier: Regulatory Acceptance 573

27.9 Summary 573

References 575

Further Reading 581

28 Evaluation of Human Tolerance and Safety in Clinical Trials: Phase I and Beyond 583

28.1 The Pharmaceutical Clinical Development Process and Safety 583

28.1.1 Pharmacokinetics 589

28.1.2 Safety of Clinical Trial Subjects 591

28.2 Limitations on/of Clinical Trials 598

28.3 The Clinical Trial Process 598

28.4 Institutional Review Boards (IRBS)/Ethics Committees in the Clinical Trial Process 602

28.5 Drug Formulations and Excipients 604

28.6 Phase I Designs 605

28.7 Clinical Trial Safety Indicators 609

28.8 Assessment of Unwanted Drug Effects 621

References 626

29 Postmarketing Safety Evaluation : Monitoring, Assessing, and Reporting of Adverse Drug Responses (ADRs) 629

29.1 Causes of Safety Withdrawals 637

29.2 Regulatory Requirements 638

29.3 Management of ADR and ADE Data 641

29.4 Causality Assessment 647

29.5 Courses of Corrective Action 647

29.6 Legal Consequences of Safety Withdrawal 648

References 651

30 Statistics in Pharmaceutical Safety Assessment 653

30.1 Introduction 653

30.2 Experimental Design 659

30.3 Data Recording 664

30.4 Generalized Methodology Selection 665

30.5 Statistical Analysis: General Considerations 665

30.6 Hypothesis Testing of Categorical and Ranked Data 679

30.7 Hypothesis Testing: Univariate Parametric Tests 684

30.8 Methods for the Reduction of Dimensionality 694

30.9 Meta‐Analysis 701

30.10 Bayesian Inference 702

30.11 Data Analysis Applications in Safety Assessment Studies 704

References 708

31 Combination Products: Drugs and Devices 711

31.1 Combination Products 711

References 720

32 Qualification of Impurities, Degradants, Residual Solvents, Metals, and Leachables in Pharmaceuticals 721

32.1 Impurities 721

32.2 Residual Solvents 726

32.3 Extractables and Leachables 727

32.4 Residual Metals and Elements 728

References 730

33 Tissue, Cell, and Gene Therapy 731

33.1 Safety Assessment of Cell Therapy (CT) Products 732

33.2 Nonclinical Safety Assessment of Gene Therapy Products (GTPS) 738

33.3 Definitions 741

References 742

Appendix A: Selected Regulatory and Toxicological Acronyms 743

Appendix B: Definition of Terms and Lexicon of “Clinical” Observations in Nonclinical (Animal) Studies 745

Appendix C: Notable Regulatory Internet Addresses 749

Appendix D: Glossary of Terms Used in the Clinical Evaluation of Therapeutic Agents 755

Appendix E: Common Vehicles for the Nonclinical Evaluation of Therapeutic Agents 759

Appendix F: Global Directory of Contract Pharmaceutical Toxicology Labs 857

INDEX 879

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Author Information

Shayne Cox Gad, BS, PhD, DABT,  has more than 39 years of experience in regulatory toxicology, drug and device development, statistics, and risk assessment. He is Principal of Gad Consulting Services, a firm with eight employees and more than 500 clients worldwide in the pharmaceutical and medical  device industries. He is Past President of the American College of Toxicology (ACT), the Roundtable of Toxicology Consultants, and three of the Society of Toxicology’s specialty sections. Dr. Gad received the 2008 ACT Lifetime Contribution Award and has authored or edited 47 books (10 with Wley) and more than 350 chapters, articles, and abstracts. Has preparated 110 INDs and 8 NDAs and teaches 3-5 professional education courses a year.
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Reviews

"The stated goal of the third edition of Drug Safety Evaluation is to present an all-inclusive practical guide of how the safety of human drugs and biologics are evaluated. One just needs to peruse the table of contents to see that this book provides a comprehensive overview of human drug development as it applies to safety. The content encompasses the regulatory process for small molecules and biologics, and includes detailed descriptions of the toxicological tests that can be conducted and how the results are evaluated"... "Although the content is clearly meant for human pharma, this book will be useful to those involved in safety evaluations for veterinary drug development. The in-depth explanations of how data are evaluated from toxicity studies conducted for human drug development can be applied to animal drug development. The chapter on statistics in pharmaceutical safety assessment is particularly useful, with assumptions and limitations provided for each of the common statistical tests"...... "This comprehensive book on drug safety evaluation is a welcomed addition to my reference library" (Reviewed by Lesley C. Rausch-Derra, DVM, MS, Scout Bio Inc, Kansas City, Mo 15th June 2017)
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