Drug Safety Evaluation
Pharmaceutical Development (Band Nr. 1)
4. Auflage Januar 2023
992 Seiten, Hardcover
Wiley & Sons Ltd
ISBN:
978-1-119-75585-2
John Wiley & Sons
Weitere Versionen
Drug Safety Evluation
Comprehensive and practical guide presenting a roadmap for safety assessment as an integral part of the development of drugs and therapeutics
This fourth edition of Drug Safety Evaluation maintains the central objective of presenting an all-inclusive practical guide for those who are responsible for ensuring the safety of drugs and biologics to patients, healthcare providers, those involved in the manufacture of medicinal products, and all those who need to understand how the safety of these products is evaluated and shepherding valuable candidates to market.
Individual chapters address specific approaches to evaluation hazards, including problems that are encountered and their solutions. Also covered are the scientific and philosophical bases for evaluation of specific concerns (e.g., carcinogenicity, development toxicity, etc.) to provide both understanding and guidance for approaching the new problems that have come to face both our society and the new challenges they brought.
The many changes in regulatory requirements, pharmaceutical development, technology, and the effects of Covid on our society and science have required both extensive revision to every chapter and the addition of four new chapters.
Specific sample topics covered in Drug Safety Evaluation include:
* The drug development process and the global pharmaceutical marketplace and regulation of human pharmaceutical safety
* Sources of information for consideration in study and program design and in safety evaluation
* Electronic records, reporting and submission, screens in safety and hazard assessment, and formulations, routes, and dosage regimens
* Mechanisms and endpoints of drug toxicity, pilot toxicity testing in drug safety evaluation, and repeat dose toxicity
* Genotoxicity, QSAR tools for drug safety, toxicogenomics, nonrodent animal studies, and developmental and reproductive toxicity testing
* An appendix which provides an up to date guide to CROs for conducting studies
Drug Safety Evaluation was written specifically for the pharmaceutical and biotechnology industries, including scientists, consultants, and academics, to show a utilitarian yet scientifically valid path to the everyday challenges of safety evaluation and the problem solving that is required in drug discovery and development.
PREFACE xxv
ABOUT THE AUTHOR xxvii
Chapter 1: The Drug Development Process and the Global Pharmaceutical Marketplace
1.1 Introduction
1.2 The Marketplace
1.3 History of Modern Therapeutics
1.4 The Drug Development Process
1.5 Strategies for Development: Large vs. Small Company or the Short vs. Long Game
1.5.1 Do Only What You Must (the short game)
1.5.2 Minimize the Risk of Subsequent Failure
1.6 Safety Assessment and the Evolution of Drug Safety
1.7 The Three Stages of Drug Safety Evaluation in the General Case
Chapter 2: Regulation of Human Pharmaceutical Safety: Routes to Human Use and Market
2.1 Introduction
2.2 Brief History of US Pharmaceutical Law
2.2.1 1906: Pure Food and Drug Act
2.2.2 1938: Food, Drug, and Cosmetic Act
2.2.3 1962: Major Amendment
2.2.4 1992, 1997, 2002, 2007, 2012 and 2017: PDUFA, FDAMA, and FDARA
2.2.5 PREA: the Pediatric Research Equity Act
2.2.6 ICH: the International Conference on Harmonization
2.2.7 Electronic Recordings: Electronic Submission Impact
2.2.8 COVID-19
2.3 FDAMA Summary: Consequences and Other Regulations
2.4 Overview of US Regulations
2.4.1 Regulations: General Considerations
2.4.2 Regulations: Human Pharmaceuticals
2.4.3 Regulations: Environmental Impact
2.4.4 Regulations: Antibiotics
2.4.5 Regulations: Biologics
2.4.6 Regulations vs. Law
2.5 Organizations Regulating Drug and Device Safety in the U.S.
2.6 Process of Pharmaceutical Product Development and Approval
2.7 Testing Guidelines
2.7.1 Toxicity Testing: Traditional Pharmaceuticals
2.7.2 General or Systematic Toxicity Assessment
2.7.3 Genetic Toxicity Assessment
2.7.4 Safety Pharmacology
2.7.5 Local Tissue Tolerance
2.7.6 Reproductive and Developmental
2.7.7 Carcinogenicity
2.7.8 Toxicity Testing: Biotechnology Product
2.7.9 Special Cases
2.8 Toxicity/Safety Testing: Cellular and Gene Therapy Products
2.8.1 Cellular Therapies
2.8.2 Gene Therapies
2.8.3 Ex Vivo
2.8.4 In Vivo
2.8.5 Preclinical Safety Evaluation
2.8.6 Basic Principles for Preclinical Safety Evaluation of Cellular and Gene Therapies
2.8.7 Additional Considerations for Cellular Therapies
2.8.8 Additional Considerations for Gene Therapieces
2.9 Toxicity Testing: Special Cases
2.9.1 Oral Contraceptives
2.9.2 Life-Threatening Diseases (Compassionate Use)
2.9.3 Vaccines
2.9.4 Oncology Drugs and Imaging Agents
2.9.5 Optical Isomers
2.9.6 Special Populations: Pediatric and Geriatric Claims
2.9.7 Orphan Drugs
2.9.8 Expedited and Augmented Routes to Approval
2.9.9 Botanical Drug Products
2.9.10 Types of New Drug Applications (NDAs)
2.10 International Pharmaceutical Regulation and Registration
2.10.1 International Conference on Harmonization
2.10.1.1 Carcinogenicity Studies
2.10.1.2 Chronic Toxicity
2.10.1.3 Developmental and Reproductive Toxicity
2.10.2 Other International Considerations
2.10.2.1 European Union
2.10.2.2 Japan
2.10.2.3 China
2.10.3 Safety Pharmacology
2.11 Combination Products
2.11.1 Device Programs that CDER and CBRH each will Administer
2.11.2 Coordination
2.11.3 Submissions
2.11.3.1 Center Jurisdiction
2.11.3.2 General Criteria Affecting Drug/Device Determination
2.12 Meetings and submissions to FDA for Toxicologists
2.13 Conclusions
Chapter 3: Data Mining: Sources of Information for Consideration in Study and Program Design and in Safety Evaluation
3.1 Introduction
3.1.1 Claims
3.1.2 Time and Economies
3.1.3 Prior Knowledge
3.1.4 Miscellaneous Reference Sources
3.1.5 Search Procedure
3.1.6 Monitoring Published Literature and Other Research in Progress
3.1.7 Kinds of information
3.1.8 Toxic Release Inventory (TRI)
3.1.9 Material Safety Data Sheets (MSDS)
3.1.10 Canadian Centre for Occupational health and Safety (CCINFO)
3.1.11 Pollution and Toxicology (POLTOX)
3.1.12 MEDLINE and PubChem
3.2 PC-Based Information Products: Laser DISC
3.2.1 International Veterinary Pathology Slide Bank (IVPSB)
3.3 Conclusions
Chapter 4: Electronic Records, Reporting and Submission: eCTD and SEND
4.1 Introduction
4.2 Submission of SEND data in Module 4 of the eCTD
4.3 SEND Background
4.4 SEND Regulatory
4.5 SEND Features
4.6 SEND Study Submission Package
4.7 Determination of Studies that Need Data to be Submitted as SEND Files
4.7.1 FDA Center
4.7.2 Type of Application
4.7.3 Study Start Date
4.8 Storage of Files at the FDA
4.9 Recommended Regulatory Resources
Chapter 5: Screens in safety and hazard assessment
5.1 introduction
5.2 characteristics of screens
5.3 uses of screens
5.4 types of screens
5.4.1 Single stage
5.4.2 Sequential
5.4.3 Tier (or multistage)
5.5 Criterion: Development and Use
5.6 Analysis of Screening Data
5.7 univariate data
5.7.1 control charts
5.7.2 central tendency plots
5.7.3 multivariate data
5.7.4 the analog plot
Chapter 6: Formulations, Routes, and Dosage Regimens
6.1 Introduction
6.2 Mechanisms
6.2.1 Local Effects
6.2.2 Absorption and Distribution
6.2.3 Metabolism
6.3 Common Routes
6.3.1 Dermal Route
6.3.2 Parenteral Route
6.3.2.1 Intravenous Route
6.3.3 Bolus vs. Infusion
6.3.3.1 Subcutaneous Route
6.3.3.2 Intramuscular Route
6.3.3.3 Intraperitoneal Route
6.3.4 Oral Route
6.3.4.1 Mechanisms of Absorption
6.3.4.2 Factors Affecting Absorption
6.3.4.3 Bioavailability and Thresholds
6.3.4.4 Techniques of Oral Administration
6.3.5 Minor Routes
6.3.5.1 Periocular Route
6.3.5.2 Rectal Administration
6.3.5.3 Vaginal Administration
6.3.5.4 Nasal Administration
6.3.5.5 Volume Limitations by Route
6.3.6 Route Comparison and Contrasts
6.3.6.1 Vehicles that Can Mask the Effects of Active Ingredients
6.4 Formulation of Test Materials
6.4.1 Preformulation
6.4.2 Dermal Formulations
6.4.3 Interactions between Skin, Vehicle and Test Chemical
6.4.4 Oral Formulations
6.4.5 Parenteral Formulations
6.5 Dosing Calculations
6.6 Calculating Material Requirements
6.7 Excipients
6.7.1 Regulation of Excipients
Chapter 7: Mechanisms and Endpoints of Drug Toxicity
7.1 Manifestations
7.2 Mechanisms of Toxicity
7.3 End Points Measured in General Toxicity Studies
7.3.1 Clinical Observations
7.3.2 Body Weights
7.3.3 Food and Water Consumption
7.3.4 Clinical Signs
7.3.5 Clinical Chemistry and Pathology
7.3.6 Hematology
7.3.7 Gross Necropsy and Organ Weights
7.3.8 Histopathology
7.3.9 Ophthalmology
7.3.10 Cardiovascular Function
7.3.11 Neurotoxicology
7.3.12 Immunotoxicology
7.3.13 Imaging and Telemetry
7.4 Complications
Chapter 8: Pilot Toxicity Testing in Drug Safety Evaluation: MTD and DRF
8.1 Introduction
8.2 Range-Finding Studies
8.2.1 Lethality Testing
8.2.1.1 Classical LD50
8.2.1.2 Dose Probes
8.2.1.3 Up/Down Method
8.2.1.4 "Pyramiding" Studies
8.2.1.5 Limit Tests
8.2.1.6 Fixed-Dose Procedure
8.2.1.7 "Rolling" Acute Test
8.2.2 Using Range-Finding Lethality Data in Drug Development: The Minimum Lethal Dose
8.2.2.1 Minimum Lethal Dose Protocols
8.3 Acute Systemic Toxicity Characterization
8.3.1 Minimal Acute Toxicity Test
8.3.1.1 Clinical Signs
8.3.2 Complete Acute Toxicity Testing
8.3.2.1 Body Weight Considerations
8.3.2.2 Pathology Considerations
8.3.2.3 Supplemented Acute Studies
8.3.3 Acute Toxicity Testing with Nonrodent Species
8.3.4 Factors that Can Affect Acute tests
8.3.4.1 Number, Size, and Sex of Dosage Groups
8.3.5 Selection of Dosages
8.3.5.1 Timing
8.4 Screens
8.4.1 General Toxicity Screens
8.4.2 Specific Toxicity Screens
8.5 Pilot and DRF Studies
Chapter 9: Repeat Dose Toxicity Studies
9.1 Objectives
9.2 Regulatory Considerations
9.2.1 Good Laboratory Practices
9.2.2 Animal Welfare Act
9.2.3 Regulatory Requirements for Study Design
9.3 Study Design and Conduct
9.3.1 Animals
9.3.2 Routes and Setting Doses
9.3.3 Parameters to Measure
9.3.3.1 Pharmacokinetics and Metabolism
9.3.4 Study Designs
9.4 Study Interpretation and Reporting
9.5 Read Across for Program Wide Evaluation
Chapter 10: Genotoxicity
10.1 ICH Test Profile
10.2 DNA Structure
10.2.1 Transcription
10.2.2 Translation
10.2.3 Gene Regulation
10.2.4 DNA Repair
10.2.4.1 Excision Repair
10.2.5 Error-Prone Repair
10.2.6 Mismatch Repair
10.2.7 The Adaptive Repair Pathway
10.2.8 Plasmids
10.2.9 Plasmids and DNA Repair
10.2.10 Nature of Point Mutations
10.2.11 Suppressor Mutations
10.2.12 Adduct Formation
10.2.13 Mutations Due to Insertion Sequences
10.2.14 The Link Between Mutation and Cancer
10.2.15 Genotoxic vs. Nongenotoxic Mechanisms of Carcinogenesis
10.2.16 Genetic Damage and Heritable Defects
10.2.17 Reproductive Effects
10.3 Cytogenetics
10.3.1 Cytogenetic Damage and its Consequences
10.3.2 Individual Chromosomal Damage
10.3.3 Chromosome Set Damage
10.3.4 Test Systems
10.3.5 In Vitro Test Systems
10.3.5.1 In Vitro Metabolic Activation
10.3.6 Bacterial Mutation Tests
10.3.6.1 Reversion Test: Background
10.3.6.2 Genetic Makeup of Tester Strains
10.3.6.3 The Use of the Plasmid pKM101
10.3.6.4 Ames Salmonella/Plate Incorporation Method
10.3.7 Controls
10.3.7.1 Positive Controls
10.3.7.2 Untreated/Vehicle Controls
10.3.7.3 Evaluation of Results
10.3.7.4 Preincubation tests
10.3.7.5 E. Coli Tester Strains
10.3.7.6 Storage and Checking of Tester Strains
10.3.8 Plate Incorporation Assay
10.3.8.1 Protocol for Dose Ranging and Selection
10.3.8.2 Eukaryotic Mutation Tests
10.3.9 Eukaryotic Mutation Tests
10.3.10 In Vitro Tests for the Detection of Mammalian Mutation
10.3.10.1 Chinese Hamster Lines
10.3.10.2 V79 System
10.3.10.3 Preliminary Cytotoxicity Testing
10.3.10.4 Data Analysis
10.3.10.5 Chinese Hamster Ovary (CHO)/Hypoxanthine-Guanine Phosphoribosyltransferase (HGPRT) Assay
10.3.10.6 Mouse Lymphoma L5178Y TK+/- Assay
10.3.10.7 Selection of Dose Levels
10.3.10.8 Main Mutation Assay
10.3.10.9 In Vivo Genotoxicity Tests for the Assessment of Primary DNA Lesions
10.3.10.10 The Comet Assay
10.3.10.11 Principle of Method
10.3.10.12 Status of Mammalian Mutation Tests
10.3.11 In Vivo Mammalian Mutation Tests
10.3.11.1 The Mouse Specific Locus Test
10.4 In Vitro Cytogenetic Assays
10.4.1 Cell Types
10.4.2 Chinese Hamster Cell Lines
10.4.3 Human Peripheral Blood Lymphocytes
10.4.4 Positive and Negative Controls
10.4.5 Treatment of Cells
10.4.6 Scoring Procedures
10.4.7 Data Recording
10.4.8 Presentation of Results
10.5 In Vivo Cytogenetic Assays
10.5.1 Somatic Cell Assays
10.5.1.1 Metaphase Analysis
10.5.1.2 Micronuclei
10.5.2 Germ Cell Assays
10.5.3 Heritable Chromosome Assays
10.5.4 Germ Cell Cytogenetic Assays
10.6 Sister Chromatid Exchange Assays
10.6.1 Relevance of SCE in Terms of Genotoxicity
10.6.2 Experimental Design
10.7 How to Deal with Positive Test Results
Chapter 11: QSAR Tools for Drug Safety
11.1 Structure- Activity Relationships
11.1.1 Basic Assumptions
11.1.2 Molecular Parameters of Interest
11.2 SAR Modeling Methods
11.3 Applications in Toxicology
11.3.1 Metabolism
11.3.2 Reproductive
11.3.3 Eye Irritation
11.3.4 Lethality
11.3.4.1 Oral Rat LD50
11.3.5 Carcinogenicity
11.4 Genotoxicity
11.4.1 QSAR for Mutagenicity
11.4.1.1 Sensitization
11.4.1.2 Hepatotoxicity
11.4.1.3 Cardiotoxicity
11.5 Comparison of Available Models/Applications
11.5.1 QSAR of Metabolism
11.5.2 Meteor
11.5.3 Derek
11.5.4 Leadscope
11.5.4.1 Multiple Computer-Automated Structural Evaluation
11.5.4.2 Toxicity Prediction by Computer-Assisted Technology
11.5.5 VEGA
11.5.5.1 Global AD Index
11.5.5.2 Similar Molecules with Known Experimental Value
11.5.5.3 Accuracy of Prediction for Similar Molecules
11.5.5.4 Concordance for Similar Molecules
11.5.5.5 Atom-Centered Fragments Similarity Check
11.5.5.6 Model Descriptors Range Check
11.5.6 Derek vs. Leadscope
11.6 Near Neighbor Surrogates and their Use
Chapter 12: Toxicogenomics
12.1 Introduction
12.2 Uses of Toxicogenomics
Chapter 13: Immunotoxicology in Drug Development
13.1 Introduction
13.2 Overview of the Immune System
13.3 Immunotoxic Effects
13.4 Immunosuppression
13.4.1 Immunosuppressive Drugs
13.4.1.1 Antimetabolites
13.4.1.2 Glucocorticosteroids
13.4.1.3 Cyclosporine
13.4.1.4 Nitrogen Mustards
13.4.1.5 Estrogens
13.4.1.6 Heavy Metals
13.4.1.7 Antibiotics
13.5 Immunostimulation
13.5.1 Hypersensitivity (or Allergenicity)
13.5.1.1 Type I Hypersensitivity
13.5.1.2 Type II Hypersensitivity
13.5.1.3 Type III Hypersensitivity
13.5.1.4 Type IV Delayed-Type Hypersensitivity (DTH)
13.5.2 Photosensitization
13.5.3 Autoimmunity
13.6 Regulatory Positions
13.6.1 CDER Guidance for Investigational New Drugs
13.7 Evaluation of the Immune System
13.7.1 Immunopathologic Assessments
13.7.1.1 Organ and Body Weights
13.7.2 Humoral (Innate) Immune Response and Possible Entry Points for Immunotoxic Actions
13.7.2.1 Hematology
13.7.2.2 Clinical Chemistry
13.7.2.3 Histopathology
13.7.2.4 Antibody Plaque-Forming Cell (PFC) Assay
13.7.2.5 B-Cell Lymphoproliferation Response
13.7.3 Cell-Mediated Immunity
13.7.3.1 T-Cell Lymphoproliferation Response
13.7.3.2 Mixed Lymphocyte Response (MLR) Assay
13.7.3.3 Cytotoxic T Lymphocyte (CTL)-Mediated Assay
13.7.3.4 Delayed-Type Hypersensitivity (DTH) Response
13.8 Nonspecific Immunity Function Assay
13.8.1 Natural Killer Cell Assays
13.8.2 Macrophage Function
13.8.3 Mast Cell/Basophil Function
13.8.3.1 Host-Resistance Assays
13.9 T-Cell-Dependent Antibody Response (TDAR)
13.9.1 Treatment
13.9.2 Hypersensitivity
13.9.2.1 Type I Hypersensitivity
13.9.2.2 Types II and III Hypersensitivity
13.9.2.3 Type IV Hypersensitivity
13.9.2.4 Modified Buehler
13.9.2.5 Guinea Pig Maximization Test
13.9.3 Local Lymph Node Assay (LLNA)
13.9.4 Photosensitization
13.9.4.1 Harber and Shalita Method
13.9.4.2 Armstrong Method
13.10 Approaches to Compound Evaluation
13.10.1 Use of In Vivo Tests
13.10.1.1 Species Selection
13.10.1.2 Route and Treatment Regimen
13.10.2 Use of In Vitro Tests
13.10.3 Assessment of Immunotoxicity and Immunogenicity/Allergenicity of Biotechnology-Derived Drugs
13.10.4 Suggested Approaches to Evaluation of Results
13.11 Problems and Future Directions
13.11.1 Data Interpretation
13.11.2 Appropriate Animal Models
13.11.3 Indirect Immunotoxic Effects
13.11.4 Hypersensitivity Tests
13.11.5 Anaphylaxis Tests
13.11.6 Autoimmunity
13.11.7 Functional Reserve Capacity
13.11.8 Significance of Minor Perturbations
13.11.9 Biotechnology Products and antigenicity
ABOUT THE AUTHOR xxvii
Chapter 1: The Drug Development Process and the Global Pharmaceutical Marketplace
1.1 Introduction
1.2 The Marketplace
1.3 History of Modern Therapeutics
1.4 The Drug Development Process
1.5 Strategies for Development: Large vs. Small Company or the Short vs. Long Game
1.5.1 Do Only What You Must (the short game)
1.5.2 Minimize the Risk of Subsequent Failure
1.6 Safety Assessment and the Evolution of Drug Safety
1.7 The Three Stages of Drug Safety Evaluation in the General Case
Chapter 2: Regulation of Human Pharmaceutical Safety: Routes to Human Use and Market
2.1 Introduction
2.2 Brief History of US Pharmaceutical Law
2.2.1 1906: Pure Food and Drug Act
2.2.2 1938: Food, Drug, and Cosmetic Act
2.2.3 1962: Major Amendment
2.2.4 1992, 1997, 2002, 2007, 2012 and 2017: PDUFA, FDAMA, and FDARA
2.2.5 PREA: the Pediatric Research Equity Act
2.2.6 ICH: the International Conference on Harmonization
2.2.7 Electronic Recordings: Electronic Submission Impact
2.2.8 COVID-19
2.3 FDAMA Summary: Consequences and Other Regulations
2.4 Overview of US Regulations
2.4.1 Regulations: General Considerations
2.4.2 Regulations: Human Pharmaceuticals
2.4.3 Regulations: Environmental Impact
2.4.4 Regulations: Antibiotics
2.4.5 Regulations: Biologics
2.4.6 Regulations vs. Law
2.5 Organizations Regulating Drug and Device Safety in the U.S.
2.6 Process of Pharmaceutical Product Development and Approval
2.7 Testing Guidelines
2.7.1 Toxicity Testing: Traditional Pharmaceuticals
2.7.2 General or Systematic Toxicity Assessment
2.7.3 Genetic Toxicity Assessment
2.7.4 Safety Pharmacology
2.7.5 Local Tissue Tolerance
2.7.6 Reproductive and Developmental
2.7.7 Carcinogenicity
2.7.8 Toxicity Testing: Biotechnology Product
2.7.9 Special Cases
2.8 Toxicity/Safety Testing: Cellular and Gene Therapy Products
2.8.1 Cellular Therapies
2.8.2 Gene Therapies
2.8.3 Ex Vivo
2.8.4 In Vivo
2.8.5 Preclinical Safety Evaluation
2.8.6 Basic Principles for Preclinical Safety Evaluation of Cellular and Gene Therapies
2.8.7 Additional Considerations for Cellular Therapies
2.8.8 Additional Considerations for Gene Therapieces
2.9 Toxicity Testing: Special Cases
2.9.1 Oral Contraceptives
2.9.2 Life-Threatening Diseases (Compassionate Use)
2.9.3 Vaccines
2.9.4 Oncology Drugs and Imaging Agents
2.9.5 Optical Isomers
2.9.6 Special Populations: Pediatric and Geriatric Claims
2.9.7 Orphan Drugs
2.9.8 Expedited and Augmented Routes to Approval
2.9.9 Botanical Drug Products
2.9.10 Types of New Drug Applications (NDAs)
2.10 International Pharmaceutical Regulation and Registration
2.10.1 International Conference on Harmonization
2.10.1.1 Carcinogenicity Studies
2.10.1.2 Chronic Toxicity
2.10.1.3 Developmental and Reproductive Toxicity
2.10.2 Other International Considerations
2.10.2.1 European Union
2.10.2.2 Japan
2.10.2.3 China
2.10.3 Safety Pharmacology
2.11 Combination Products
2.11.1 Device Programs that CDER and CBRH each will Administer
2.11.2 Coordination
2.11.3 Submissions
2.11.3.1 Center Jurisdiction
2.11.3.2 General Criteria Affecting Drug/Device Determination
2.12 Meetings and submissions to FDA for Toxicologists
2.13 Conclusions
Chapter 3: Data Mining: Sources of Information for Consideration in Study and Program Design and in Safety Evaluation
3.1 Introduction
3.1.1 Claims
3.1.2 Time and Economies
3.1.3 Prior Knowledge
3.1.4 Miscellaneous Reference Sources
3.1.5 Search Procedure
3.1.6 Monitoring Published Literature and Other Research in Progress
3.1.7 Kinds of information
3.1.8 Toxic Release Inventory (TRI)
3.1.9 Material Safety Data Sheets (MSDS)
3.1.10 Canadian Centre for Occupational health and Safety (CCINFO)
3.1.11 Pollution and Toxicology (POLTOX)
3.1.12 MEDLINE and PubChem
3.2 PC-Based Information Products: Laser DISC
3.2.1 International Veterinary Pathology Slide Bank (IVPSB)
3.3 Conclusions
Chapter 4: Electronic Records, Reporting and Submission: eCTD and SEND
4.1 Introduction
4.2 Submission of SEND data in Module 4 of the eCTD
4.3 SEND Background
4.4 SEND Regulatory
4.5 SEND Features
4.6 SEND Study Submission Package
4.7 Determination of Studies that Need Data to be Submitted as SEND Files
4.7.1 FDA Center
4.7.2 Type of Application
4.7.3 Study Start Date
4.8 Storage of Files at the FDA
4.9 Recommended Regulatory Resources
Chapter 5: Screens in safety and hazard assessment
5.1 introduction
5.2 characteristics of screens
5.3 uses of screens
5.4 types of screens
5.4.1 Single stage
5.4.2 Sequential
5.4.3 Tier (or multistage)
5.5 Criterion: Development and Use
5.6 Analysis of Screening Data
5.7 univariate data
5.7.1 control charts
5.7.2 central tendency plots
5.7.3 multivariate data
5.7.4 the analog plot
Chapter 6: Formulations, Routes, and Dosage Regimens
6.1 Introduction
6.2 Mechanisms
6.2.1 Local Effects
6.2.2 Absorption and Distribution
6.2.3 Metabolism
6.3 Common Routes
6.3.1 Dermal Route
6.3.2 Parenteral Route
6.3.2.1 Intravenous Route
6.3.3 Bolus vs. Infusion
6.3.3.1 Subcutaneous Route
6.3.3.2 Intramuscular Route
6.3.3.3 Intraperitoneal Route
6.3.4 Oral Route
6.3.4.1 Mechanisms of Absorption
6.3.4.2 Factors Affecting Absorption
6.3.4.3 Bioavailability and Thresholds
6.3.4.4 Techniques of Oral Administration
6.3.5 Minor Routes
6.3.5.1 Periocular Route
6.3.5.2 Rectal Administration
6.3.5.3 Vaginal Administration
6.3.5.4 Nasal Administration
6.3.5.5 Volume Limitations by Route
6.3.6 Route Comparison and Contrasts
6.3.6.1 Vehicles that Can Mask the Effects of Active Ingredients
6.4 Formulation of Test Materials
6.4.1 Preformulation
6.4.2 Dermal Formulations
6.4.3 Interactions between Skin, Vehicle and Test Chemical
6.4.4 Oral Formulations
6.4.5 Parenteral Formulations
6.5 Dosing Calculations
6.6 Calculating Material Requirements
6.7 Excipients
6.7.1 Regulation of Excipients
Chapter 7: Mechanisms and Endpoints of Drug Toxicity
7.1 Manifestations
7.2 Mechanisms of Toxicity
7.3 End Points Measured in General Toxicity Studies
7.3.1 Clinical Observations
7.3.2 Body Weights
7.3.3 Food and Water Consumption
7.3.4 Clinical Signs
7.3.5 Clinical Chemistry and Pathology
7.3.6 Hematology
7.3.7 Gross Necropsy and Organ Weights
7.3.8 Histopathology
7.3.9 Ophthalmology
7.3.10 Cardiovascular Function
7.3.11 Neurotoxicology
7.3.12 Immunotoxicology
7.3.13 Imaging and Telemetry
7.4 Complications
Chapter 8: Pilot Toxicity Testing in Drug Safety Evaluation: MTD and DRF
8.1 Introduction
8.2 Range-Finding Studies
8.2.1 Lethality Testing
8.2.1.1 Classical LD50
8.2.1.2 Dose Probes
8.2.1.3 Up/Down Method
8.2.1.4 "Pyramiding" Studies
8.2.1.5 Limit Tests
8.2.1.6 Fixed-Dose Procedure
8.2.1.7 "Rolling" Acute Test
8.2.2 Using Range-Finding Lethality Data in Drug Development: The Minimum Lethal Dose
8.2.2.1 Minimum Lethal Dose Protocols
8.3 Acute Systemic Toxicity Characterization
8.3.1 Minimal Acute Toxicity Test
8.3.1.1 Clinical Signs
8.3.2 Complete Acute Toxicity Testing
8.3.2.1 Body Weight Considerations
8.3.2.2 Pathology Considerations
8.3.2.3 Supplemented Acute Studies
8.3.3 Acute Toxicity Testing with Nonrodent Species
8.3.4 Factors that Can Affect Acute tests
8.3.4.1 Number, Size, and Sex of Dosage Groups
8.3.5 Selection of Dosages
8.3.5.1 Timing
8.4 Screens
8.4.1 General Toxicity Screens
8.4.2 Specific Toxicity Screens
8.5 Pilot and DRF Studies
Chapter 9: Repeat Dose Toxicity Studies
9.1 Objectives
9.2 Regulatory Considerations
9.2.1 Good Laboratory Practices
9.2.2 Animal Welfare Act
9.2.3 Regulatory Requirements for Study Design
9.3 Study Design and Conduct
9.3.1 Animals
9.3.2 Routes and Setting Doses
9.3.3 Parameters to Measure
9.3.3.1 Pharmacokinetics and Metabolism
9.3.4 Study Designs
9.4 Study Interpretation and Reporting
9.5 Read Across for Program Wide Evaluation
Chapter 10: Genotoxicity
10.1 ICH Test Profile
10.2 DNA Structure
10.2.1 Transcription
10.2.2 Translation
10.2.3 Gene Regulation
10.2.4 DNA Repair
10.2.4.1 Excision Repair
10.2.5 Error-Prone Repair
10.2.6 Mismatch Repair
10.2.7 The Adaptive Repair Pathway
10.2.8 Plasmids
10.2.9 Plasmids and DNA Repair
10.2.10 Nature of Point Mutations
10.2.11 Suppressor Mutations
10.2.12 Adduct Formation
10.2.13 Mutations Due to Insertion Sequences
10.2.14 The Link Between Mutation and Cancer
10.2.15 Genotoxic vs. Nongenotoxic Mechanisms of Carcinogenesis
10.2.16 Genetic Damage and Heritable Defects
10.2.17 Reproductive Effects
10.3 Cytogenetics
10.3.1 Cytogenetic Damage and its Consequences
10.3.2 Individual Chromosomal Damage
10.3.3 Chromosome Set Damage
10.3.4 Test Systems
10.3.5 In Vitro Test Systems
10.3.5.1 In Vitro Metabolic Activation
10.3.6 Bacterial Mutation Tests
10.3.6.1 Reversion Test: Background
10.3.6.2 Genetic Makeup of Tester Strains
10.3.6.3 The Use of the Plasmid pKM101
10.3.6.4 Ames Salmonella/Plate Incorporation Method
10.3.7 Controls
10.3.7.1 Positive Controls
10.3.7.2 Untreated/Vehicle Controls
10.3.7.3 Evaluation of Results
10.3.7.4 Preincubation tests
10.3.7.5 E. Coli Tester Strains
10.3.7.6 Storage and Checking of Tester Strains
10.3.8 Plate Incorporation Assay
10.3.8.1 Protocol for Dose Ranging and Selection
10.3.8.2 Eukaryotic Mutation Tests
10.3.9 Eukaryotic Mutation Tests
10.3.10 In Vitro Tests for the Detection of Mammalian Mutation
10.3.10.1 Chinese Hamster Lines
10.3.10.2 V79 System
10.3.10.3 Preliminary Cytotoxicity Testing
10.3.10.4 Data Analysis
10.3.10.5 Chinese Hamster Ovary (CHO)/Hypoxanthine-Guanine Phosphoribosyltransferase (HGPRT) Assay
10.3.10.6 Mouse Lymphoma L5178Y TK+/- Assay
10.3.10.7 Selection of Dose Levels
10.3.10.8 Main Mutation Assay
10.3.10.9 In Vivo Genotoxicity Tests for the Assessment of Primary DNA Lesions
10.3.10.10 The Comet Assay
10.3.10.11 Principle of Method
10.3.10.12 Status of Mammalian Mutation Tests
10.3.11 In Vivo Mammalian Mutation Tests
10.3.11.1 The Mouse Specific Locus Test
10.4 In Vitro Cytogenetic Assays
10.4.1 Cell Types
10.4.2 Chinese Hamster Cell Lines
10.4.3 Human Peripheral Blood Lymphocytes
10.4.4 Positive and Negative Controls
10.4.5 Treatment of Cells
10.4.6 Scoring Procedures
10.4.7 Data Recording
10.4.8 Presentation of Results
10.5 In Vivo Cytogenetic Assays
10.5.1 Somatic Cell Assays
10.5.1.1 Metaphase Analysis
10.5.1.2 Micronuclei
10.5.2 Germ Cell Assays
10.5.3 Heritable Chromosome Assays
10.5.4 Germ Cell Cytogenetic Assays
10.6 Sister Chromatid Exchange Assays
10.6.1 Relevance of SCE in Terms of Genotoxicity
10.6.2 Experimental Design
10.7 How to Deal with Positive Test Results
Chapter 11: QSAR Tools for Drug Safety
11.1 Structure- Activity Relationships
11.1.1 Basic Assumptions
11.1.2 Molecular Parameters of Interest
11.2 SAR Modeling Methods
11.3 Applications in Toxicology
11.3.1 Metabolism
11.3.2 Reproductive
11.3.3 Eye Irritation
11.3.4 Lethality
11.3.4.1 Oral Rat LD50
11.3.5 Carcinogenicity
11.4 Genotoxicity
11.4.1 QSAR for Mutagenicity
11.4.1.1 Sensitization
11.4.1.2 Hepatotoxicity
11.4.1.3 Cardiotoxicity
11.5 Comparison of Available Models/Applications
11.5.1 QSAR of Metabolism
11.5.2 Meteor
11.5.3 Derek
11.5.4 Leadscope
11.5.4.1 Multiple Computer-Automated Structural Evaluation
11.5.4.2 Toxicity Prediction by Computer-Assisted Technology
11.5.5 VEGA
11.5.5.1 Global AD Index
11.5.5.2 Similar Molecules with Known Experimental Value
11.5.5.3 Accuracy of Prediction for Similar Molecules
11.5.5.4 Concordance for Similar Molecules
11.5.5.5 Atom-Centered Fragments Similarity Check
11.5.5.6 Model Descriptors Range Check
11.5.6 Derek vs. Leadscope
11.6 Near Neighbor Surrogates and their Use
Chapter 12: Toxicogenomics
12.1 Introduction
12.2 Uses of Toxicogenomics
Chapter 13: Immunotoxicology in Drug Development
13.1 Introduction
13.2 Overview of the Immune System
13.3 Immunotoxic Effects
13.4 Immunosuppression
13.4.1 Immunosuppressive Drugs
13.4.1.1 Antimetabolites
13.4.1.2 Glucocorticosteroids
13.4.1.3 Cyclosporine
13.4.1.4 Nitrogen Mustards
13.4.1.5 Estrogens
13.4.1.6 Heavy Metals
13.4.1.7 Antibiotics
13.5 Immunostimulation
13.5.1 Hypersensitivity (or Allergenicity)
13.5.1.1 Type I Hypersensitivity
13.5.1.2 Type II Hypersensitivity
13.5.1.3 Type III Hypersensitivity
13.5.1.4 Type IV Delayed-Type Hypersensitivity (DTH)
13.5.2 Photosensitization
13.5.3 Autoimmunity
13.6 Regulatory Positions
13.6.1 CDER Guidance for Investigational New Drugs
13.7 Evaluation of the Immune System
13.7.1 Immunopathologic Assessments
13.7.1.1 Organ and Body Weights
13.7.2 Humoral (Innate) Immune Response and Possible Entry Points for Immunotoxic Actions
13.7.2.1 Hematology
13.7.2.2 Clinical Chemistry
13.7.2.3 Histopathology
13.7.2.4 Antibody Plaque-Forming Cell (PFC) Assay
13.7.2.5 B-Cell Lymphoproliferation Response
13.7.3 Cell-Mediated Immunity
13.7.3.1 T-Cell Lymphoproliferation Response
13.7.3.2 Mixed Lymphocyte Response (MLR) Assay
13.7.3.3 Cytotoxic T Lymphocyte (CTL)-Mediated Assay
13.7.3.4 Delayed-Type Hypersensitivity (DTH) Response
13.8 Nonspecific Immunity Function Assay
13.8.1 Natural Killer Cell Assays
13.8.2 Macrophage Function
13.8.3 Mast Cell/Basophil Function
13.8.3.1 Host-Resistance Assays
13.9 T-Cell-Dependent Antibody Response (TDAR)
13.9.1 Treatment
13.9.2 Hypersensitivity
13.9.2.1 Type I Hypersensitivity
13.9.2.2 Types II and III Hypersensitivity
13.9.2.3 Type IV Hypersensitivity
13.9.2.4 Modified Buehler
13.9.2.5 Guinea Pig Maximization Test
13.9.3 Local Lymph Node Assay (LLNA)
13.9.4 Photosensitization
13.9.4.1 Harber and Shalita Method
13.9.4.2 Armstrong Method
13.10 Approaches to Compound Evaluation
13.10.1 Use of In Vivo Tests
13.10.1.1 Species Selection
13.10.1.2 Route and Treatment Regimen
13.10.2 Use of In Vitro Tests
13.10.3 Assessment of Immunotoxicity and Immunogenicity/Allergenicity of Biotechnology-Derived Drugs
13.10.4 Suggested Approaches to Evaluation of Results
13.11 Problems and Future Directions
13.11.1 Data Interpretation
13.11.2 Appropriate Animal Models
13.11.3 Indirect Immunotoxic Effects
13.11.4 Hypersensitivity Tests
13.11.5 Anaphylaxis Tests
13.11.6 Autoimmunity
13.11.7 Functional Reserve Capacity
13.11.8 Significance of Minor Perturbations
13.11.9 Biotechnology Products and antigenicity
Shayne Cox Gad, PhD, DABT is the Principal of Gad Consulting Services. He has more than 47 years of experience as a toxicologist, statistical consultant, manager, and consultant on research and development in the chemical, consumer product, contract testing, biotechnology, medical device, and pharmaceutical industries. He has successfully file 138 INDs and authored and edited 52 books, as well as numerous papers, presentations, and other publications.
Dexter W. Sullivan, Jr., MS, DABT is Senior Toxicologist at Gad Consulting Services.
Dexter W. Sullivan, Jr., MS, DABT is Senior Toxicologist at Gad Consulting Services.
