Drug Safety Evaluation

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.

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