- ISBN: 9781119755852 | 1119755859
- Cover: Hardcover
- Copyright: 1/12/2023
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.
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.
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
13.12 Summary
Chapter 14: Nonrodent Animal Studies
14.1 Introduction
14.2 Comparison Between Rodent and Nonrodent Experimental Design
14.2.1 Number of Animals
14.3 Differences in Study Activities
14.3.1 Blood Collection
14.3.2 Dosing
14.3.3 Handling of Animals
14.3.4 Behavioral Evaluation
14.4 Nonrodent Models (Species Selection)
14.5 Dog
14.5.1 Environmental and Dietary Requirements
14.5.2 Common Study Protocols
14.5.3 General Study Activities
14.5.3.1 Dosing Techniques
14.5.3.2 Clinical Observations and Physical Examinations
14.5.3.3 Feed consumption
14.5.3.4 Electrocardiograms
14.5.3.5 Blood and Urine Collection
14.5.4 Advantages and Disadvantages
14.6 The Ferret
14.6.1 Environmental and Dietary Requirements
14.6.2 Study Protocols
14.6.3 General Study Activities
14.6.3.1 Dosing techniques
14.6.3.2 Clinical Observations and Physical Examinations
14.6.3.3 Feed consumption
14.6.3.4 Electrocardiograms
14.6.3.5 Blood and Urine Collection
14.6.4 Advantages and Disadvantages
14.7 The Pig
14.7.1 Background
14.7.7.7 Restraint and Dosing
14.7.2 Clinical Laboratory
14.7.3 Xenobiotic Metabolism
14.7.4 Dermal Toxicity
14.7.5 Cardiovascular Toxicity
14.7.6 Advantages and Disadvantages
14.8 The Rabbit
14.8.1 Husbandry
14.8.1.1 Facilities
14.8.1.2 Feed and Water
14.8.1.3 Handling and Restraint
14.8.2 Dosing techniques
14.8.3 Collection Techniques
14.8.4 Study Designs
14.9 Nonhuman Primates
14.9.1 Environmental and Dietary Requirements
14.9.2 Common Study Protocols
14.9.3 General Study Activities
14.9.3.1 Common Dosing Techniques
14.9.3.2 Clinical Observations and Examinations
14.9.3.3 Feed Consumption
14.9.3.4 ECGs and Cardiovascular Measurements
14.9.3.5 Blood and Urine Collections
14.9.4 Advantages and Disadvantages
14.10 Issues in Animal Model Selection
14.11 Statistics in Large Animal Studies
14.11.1 Reasons for Small Sample Sizes in Large Animal Toxicology
14.11.2 Cross-Sectional or Longitudinal Analysis?
14.11.3 Repeated Measures: Advantages
14.11.4 Repeated Measures: Disadvantages
14.11.5 Common Practices in Large Animal Toxicology
14.11.6 Univariate (Repeated Measures) Techniques: Advantages
14.11.7 Univariate (Repeated Measures) Techniques: Disadvantages
14.11.8 Multivariate Techniques: Advantages
14.11.9 Multivariate Techniques: Disadvantages
14.11.10 Some other design factors to be considered in analysis
14.11.11 Covariates: Advantages
14.11.12 Covariates: Disadvantages
14.11.13 Missing Values
14.12 Read-across for Data Integration
14.13 Summary
Chapter 15: Developmental and Reproductive Toxicity Testing
15.1 Introduction
15.2 ICH Study Designs
15.2.1 Male and Female Fertility and Early Embryonic Development to Implantation
15.2.2 Embryo-fetal Development
15.2.3 Adverse Effects
15.2.4 Pre- and Postnatal Development
15.2.5 Single-Study and two-Study Designs for Rodents
15.2.6 Preliminary Studies
15.2.7 Potential Male Mediated Developmental Effects
15.2.8 Toxicokinetics
15.2.9 Timing of Studies
15.3 Methodological Issues
15.3.1 Control of Bias
15.3.2 Diet
15.3.3 Clinical Pathology
15.3.4 Gravid Uterine Weights
15.3.5 Implant Counts and Determination of Pregnancy
15.3.6 Fetal Examinations
15.3.6.1 Examination of External Genitalia
15.3.6.2 Visceral Fetal Examinations
15.3.6.3 Skeletal Fetal Examination
15.3.7 Developmental Signs
15.3.8 Behavioral Tests
15.3.9 Detecting Effects on Male Reproduction
15.4 Developmental Studies in Primates
15.5 Data Interpretation
15.5.1 Use of Statistical Analyses
15.5.2 Potential Hazard Categories of Developmental Toxins
15.5.3 Associations between developmental and Maternal Toxicity
15.5.4 Assessment of Human Risk
15.6 Juvenile and Pediatric Toxicology
15.7 In Vitro Tests for Developmental Toxicity
15.8 Appraisal of Current Approaches for Determining Developmental and Reproductive Hazards.
Chapter 16: Carcinogenicity Studies
16.1 Introduction
16.1.1 History of Xenobiotic Carcinogenesis
16.2 Mechanisms and Classes of Carcinogens
16.3 Genotoxic Carcinogens
16.4 Epigenetic Carcinogens
16.5 Regulatory Requirements and timing
16.5.1 Waivers of Required Testing
16.6 Species and strain
16.7 Animal Husbandry
16.8 Dose
16.8.1 Number of Dose Levels
16.8.2 Number of Control Groups
16.8.3 Criteria for Dose Selection
16.9 Group Size
16.10 Route of Administration
16.11 Study Duration
16.12 Survival
16.13 End Points Measured
16.14 Transgenic Mouse Models
16.14.1 The Tg.AC Mouse Model
16.14.2 The Tg.rasH2 Mouse Model
16.14.3 The P53+/- Mouse Model
16.14.4 The XPA-/- Mouse Model
16.15 Interpretation of Results: Criteria for a Positive Result
16.16 Statistical Analysis
16.16.1 Exact Tests
16.16.2 Trend Tests
16.16.3 Life Table and Survival Analysis
16.16.4 Peto Analysis
16.16.4.1 Interval Selection for Occult (Internal Organ) Tumors
16.16.4.2 Logistic Regression Method for Occult (Internal organ) Tumors
16.16.5 Methods to be Avoided
16.16.6 Use of Historical Controls
16.16.7 Relevance to Human Controls
16.17 Weight-of-Evidence Factors for Consideration in a Carcinogenicity Assessment Document (CAD)
16.18 Conclusions
Chapter 17: Histopathology and Clinical Pathology in Nonclinical Pharmaceutical Safety Assessment '
17.1 Introduction
17.1.1 Pathological Techniques
17.1.2 Organ Weights
17.2 Clinical Pathology
17.2.1 Clinical Chemistry
17.2.2 Target Organ Toxicity Biomarkers
17.2.3 Integrated Analysis of Available Data
Chapter 18: Irritation and Local Tissue Tolerance in Pharmaceutical Safety Assessment
18.1 Introduction
18.2 Factors Affecting Irritation Responses and Test Outcome
18.3 Primary Dermal Irritation (PDI) Test
18.4 Other Nonparenteral Route Irritation Tests
18.5 Ocular Irritation Testing
18.6 Vaginal Irritation
18.7 Acute Primary Vaginal Irritation Study in the Female Rabbit
18.7.1 Repeated-dose Vaginal Irritation in the Female Rabbit
18 .7.2 Repeated-dose Vaginal Irritation in the Ovariectomized Rats
18.8 Parenteral Irritation/Tolerance
18.8.1 Parenteral Routes
18.8.1.1 Irritation
18.8.1.2 Blood Compatibility
18.8,1.3 Sterility
18.8.2 Test Systems for Parenteral Irritation
18.8.2.1 Acute Intramuscular Irritation in the Male Rabbit
18.8.2.2 Acute Intravenous Irritation in the Male Rabbit
18.9 Problems in Testing (and Their Resolutions)
18.9.1 Alternative to In Vivo Parenteral Tests
18.10 Phototoxicity
18.10.1Theory and Mechanisms
18.10.2 Factors Influencing Phototoxicity/Photosensitization
18.10.3 Predictive Tests for Phototoxicity
18.10.4 3/t3 In Vitro Test
18.10.5 Rabbit Phototoxicity Test
18.10.6 Guinea Pig
18.10.7 Pyrogenicity
18.10.7.1 Apparatus and Diluents
18.10.7.2 Temperature Recording
18.10.7.3 Test Animals
18.10.7.4 Procedure
18.10.7.5 Test Interpretation and Continuation
18.11 Hemocompatibility
18.12 Emetic Responses
Chapter 19: Pharmacokinetics and Toxicokinetics in Drug Safety Evaluation
19.1 Introduction
19.2 Regulations
19.3 Principles
19.3.1 Preliminary Work
19.3.2 Absorption
19.3.2.1 Absorption from the Pulmonary System
19.3.2.2 Absorption across the Skin
19.3.2.3 Parameters Controlling Absorption
19.3.3 Distribution
19.3.3.1 Protein Binding
19.3.3.2 Water Solubility
19.3.3.3 Volume of Distribution
19.3.4 Metabolism/Biotransformation
19.3.4.1 Metabolic Activation
19.3.4.2 Induction of P450 Metabolism and Isoenzymes
19.3.4.3 Species Differences
19.3.5 Excretion
19.3.5.1 Urine
19.3.5.2 Feces
19.3.5.3 Expired Air
19.4 Pharmacokinetics
19.5 Laboratory Methods
19.5.1 Analytical Methods
19.5.1.1 Instrumental Methods
19.5.1.2 Radiochemical Methods
19.5.1.3 Immunoassay Methods
19.6 Sampling Methods and Intervals
19.6.1 Blood
19.6.2 Excreta
19.6.3 Bile
19.6.4 Expired Air
19.6.5 Milk
19.6.5.1 Sampling Interval
19.7 Study Types
19.7.1 Whole-Body Autoradiography
19.7.2 Mass Balance Studies
19.7.2.1 In Vitro Studies
19.8 Analysis of Data
19.8.1 Use of Data from Metabolism and Pharmacokinetic Studies
19.8.1.2 Design of Toxicity Studies
19.9 Noncompartmental Analysis
19.10 Physiologically Based Pharmacokinetic (PBPK) Modeling
19.11 Biologically Derived Materials
19.11.1 Immunoassay Methods
19.11.1.1 Metabolism and Elimination
19.12 Points to Consider
Chapter 20: Safety Pharmacology
20.1 Regulatory Requirements
20.2 Study Designs and Principles
20.3 Organ System-Specific Tests
20.3.1 General Considerations in Selection and Design of Safety Pharmacology Studies
20.3.2 Studies on Metabolites, Isomers, and Finished Products
20.4 Cardiovascular
20.4.1 Hemodynamics, ECG, and Respiration in Anesthetized Dogs or Primates
20.4.2 Cardiac Conduction Studies
20.4.3 Conscious Dog, Primate, or Minipig Telemetry Studies
20.4.4 Six-Lead ECG Measurement in the Conscious Dog and Minipig
20.4.5 Systems for Recording Cardiac Action Potentials
20.4.6 Special Case (and Concern): QT Prolongation
20.4.7 Some Specific Techniques which can be Employed
20.4.7.1 Cloned Human Potassium Channels
20.4.7.2 Cardiac Action Potential in Vitro: Purkinje Fibers
20.4.7.3 Monophasic Action Potential in Anesthetized Guinea Pigs
20.4.7.4 ECG by Telemetry in Conscious Dogs or Primates
20.4.7.5 Hemodynamics and ECG in Anesthetized or Conscious Dogs or Primates
20.4.8 Relevance of hERG to QT Prolongation
20.4.8.1 Expression and Recording Systems
20.5 Central Nervous System
20.5.1 Isolated Tissue Assays
20.5.2 Electrophysiology Methods
20.5.3 CNS Function: Electroencephalography
20.5.4 Neurochemical and Biochemical Assays
20.6 Respiratory/Pulmonary System
20.6.1 Design of Respiratory Function Safety Studies
20.6.2 Capnography
20.7 Secondary Organ System
20.7.1 Gastric Emptying Rate and Gastric pH Changes: A New Model
20.8 Renal Function Tests
20.9 Summary
Chapter 21: Special Concerns for the Preclinical Evaluation of Biotechnology Products
21.1 Regulation
21.2 Preclinical Safety Assessment
21.3 Recombinant DNA Technology
21.3.1 General Safety Issues
21.3.2 Specific Toxicological Concerns
21.4 Immunogenicity/Allergenicity
21.5 Monoclonal Antibody Therapeutics
21.5.1 Toxicological Concerns with Monoclonal Antibodies
21.6 Bioprocess Technology
21.7 Gene Therapy Products
21.7.1 Vectors
21.7.2 Studies to Support the First Dose in Man
21.7.3 Distribution of the Gene and Gene Product
21.7.4 Studies to Support Multiple Doses in Humans
21.7.5 Unnecessary Studies
21.7.6 Ex Vivo Procedures
21.7.7 Change of Gene or Vector
21.7.8 Change of Route
21.7.9 Insertional Mutagenesis
21.8 Vaccines
21.8.1 Approaches to Vaccination
21.8.2 Genetic Engineering and Vaccine Development
21.8.2.1 DNA/Oligonucleotide Hybridization
21.8.2.2 Hybrid Selection and Cell-Free Translation
21.8.2.3 Expression Cloning
21.8.2.4 Expression of Potential Vaccine Antigens
21.9 Special Challenges
21.9.1 Purity and Homology
21.9.2 Immunogenicity
21.10 Planning a Safety Evaluation Program
21.10.1 The Producing System
21.10.2 The Process
21.10.3 The Product
21.10.4 Biology of Bioengineered Products
21.10.5 Animal Models
21.10.6 Study Design
21.10.7 Frequency and Route of Administration
21.10.8 Duration
21.10.9 Special Toxicity Testing
21.10.10 Program Design Considerations
21.11 Challenges: Biosimilars
Chapter 22: Safety Assessment of Inhalant Drugs and Dermal Route Drugs
22.1 Inhaled Therapeutics
22.2 The Pulmonary System
22.3 Penetration and Absorption of Inhaled Gases and Vapors
22.4 Deposition of Inhaled Aerosols
22.5 Absorption and Clearance of Inhaled Aerosols
22.6 Pharmacokinetics and Pharmacodynamics of Inhaled Aerosols
22.7 Methods for Safety Assessment of Inhaled Therapeutics
22.8 Parameters of Toxicity Evaluation
22.8.1 The Inhaled “Dose”
22.8.2 The Dose–Response Relationship
22.8.3 Exposure Concentration versus Response
22.8.4 Product of Concentration and Duration (Ct) versus Responses
22.8.5 Units for Exposure Concentration
22.9 Inhalation Exposure Techniques
22.10 The Utility of Toxicity Data
22.11 Formulation and Potential Mucosal Damage
22.11.1 Methods to Assess Irritancy and Damage
22.12 Therapeutic Drug Delivery by the Dermal Route
Chapter 23: Special Case Products: Imaging Agents
23.1 Introduction
23.2 Imaging Agents
23.2.1 Contrast Agents
23.2.2 Diagnostic Radiopharmaceuticals
23.2.3 Medical Imaging Agent Characteristics Relevant to Safety
23.2.3.1 Mass Dose
23.2.3.2 Route of Administration
23.2.3.3 Frequency of Use
23.2.3.4 Biological, Physical, and Effective Half-Lives
23.2.4 Performance of Nonclinical Safety Assessments
23.2.4.1 Nonclinical Safety Assessments for Nonbiological Drug Products
23.2.4.2 Diagnostic Radiopharmaceuticals (Nonbiological Products)
Chapter 24: Special Case Products: Drugs for Treatment of Cancer
24.1 Introduction
24.1.1 Animal Models
24.1.2 Statistical Analysis of Study Results
24.2 How Oncology is Different
24.3 Dose Conversions: Perspective
24.3.1 The Use of the mg/m2 Dose Unit
24.3.2 Calculations of Drug Dosages for Treatment
24.3.3 Conversion of mg/kg BW Doses to Units of mg/m2
24.4 Dose Setting in Oncology and non-infectious Imminently Fatal Diseases: STD10 and HNSTD
24.4.1 Determination of first in human dose levels based on pivotal toxicology study data
Chapter 25: Pediatric Product Safety Assessment (2006 Guidance, Including Juvenile Toxicology)
25.1 Introduction
25.1.1 Scope of Nonclinical Safety Evaluation
25.1.2 Timing of Juvenile Animal Studies in Relation to Clinical Testing
25.1.2.1 Long-Term Exposure in Pediatric Subjects
25.1.2.2 Short-Term Exposure in Pediatric Subjects
25.1.2.3 Insufficient Clinical Data to Support Initiation of Pediatric Studies
25.2 Issues to Consider Regarding Juvenile Animal Studies
25.2.1 Developmental Stage of Intended Population
25.2.2 Evaluating Data to Determine When Juvenile Animal Studies Should Be Used
25.2.3 Considering Developmental Windows When Determining Duration of Clinical Use
25.2.4 Timing of Exposure
25.2.5 Selection of Study Models
25.3 General Considerations in Designing Toxicity Studies in Juvenile Animals
25.4 Study Designs and Considerations
Chapter 26: Use of Imaging, Imaging Agents, and Radiopharmaceuticals in Nonclinical Toxicology
26.1 Introduction
26.1.1 Multimodality Imaging Techniques
26.1.2 Dynamic Molecular Imaging Techniques
26.2 X‐ray
26.2.1 Angiography
26.3 Positron Emission Tomography (PET)
26.4 Single‐photon Emission Computed Tomography (SPECT)
26.5 Computed Tomography (CT)
26.6 Magnetic Resonance Imaging (MRI)
26.7 Optical Imaging
26.8 Ultrasound
26.8.1 Echocardiography
26.9 Nanoparticle Contrast Agent
26.10 Radiopharmaceuticals
26.11 Applications of Preclinical Imaging in Laboratory Animals
26.11.1 Molecular Imaging as an ADME Platform in Drug Screen
26.11.2 Preclinical Imaging in Oncology
26.11.3 Preclinical Imaging of CNS Disease
26.11.4 Preclinical Imaging of Autoimmune Disease
26.11.5 Imaging Animal Model of Infectious Disease
26.11.6 Preclinical Imaging of Cardiac Disease
26.12 Nonclinical Safety Assessment for Imaging Agents
26.13 Radiopharmaceuticals
26.14 Nonclinical Late Radiation Toxicity Studies
26.14.1 Study Goals
26.15 Study Design
26.15.1 Good Laboratory Practices
26.15.2 Species Selection
26.15.3 Timing of Study
26.15.4 General Study Design
26.15.5 Dose Levels
26.15.6 Clinical Pathology
26.15.7 Necropsy and Histopathology
Chapter 27: Occupational Toxicology in the Pharmaceutical Industry
27.1 Introduction
27.2 Occupational Toxicology versus Drug Safety Evaluation
27.3 Regulatory Pressures in the United States and the European Community
27.4 Organizational Structure
27.5 Activities
27.5.1 Data Evaluation and Dissemination
27.5.2 Data Development
27.5.3 Occupational Exposure Limits (OELs)
27.5.4 Hazard Assessment
27.5.5 Employee Training
27.6 Conclusion
Chapter 28: Strategy and Phasing for Nonclinical Drug Safety Evaluation in the Discovery and Development of Pharmaceuticals
28.1 Introduction
28.2 Regulatory Requirements
28.3 Essential Elements of Project Management
28.4 Screens: Their Use and Interpretation in Safety Assessment
28.4.1 Characteristics of Screens
28.5 Strategy and Phasing
28.6 Critical Considerations
28.7 Special Cases in Safety Assessment
28.8 Potential Market Withdrawal Issues
28.9 Summary
Chapter 29: The Application of In Vitro Techniques in Drug Safety Assessment
29.1 Introduction
29.2 In Vitro Testing in Pharmaceutical Safety Assessment
29.3 Defining Testing Objective
29.3.1 Objectives behind Data Generation and Utilization
29.4 Test Systems: Characteristics, Development, and Selection
29.5 In Vitro Models
29.6 Local Tissue Tolerance
29.6.1 Ocular Irritation
29.6.2 Dermal Irritation
29.6.3 Irritation of Parenterally Administered Pharmaceuticals
29.6.4 Sensitization and Photosensitization
29.6.5 Phototoxicity and Photosensitization
29.6.6 Pyrogenicity
29.6.7 Developmental Toxicity
29.6.8 Target Organ Toxicity Models
29.7 In Silico Methods
29.8 The Final Frontier and Barrier: Regulatory Acceptance
29.9 Summary
Chapter 30: Evaluation of Human Tolerance and Safety in Clinical Trials: Phase I and Beyond
30.1 The Pharmaceutical Clinical Development Process and Safety
30.1.1 Pharmacokinetics
30.1.1.1 Relating the Time Course of Plasma Concentrations to the Time Course of Effect
30.1.2 Safety of Clinical Trial Subjects
30.1.2.1 Regulations
30.1.2.2 Increased Frequency Reports
30.1.2.3 Reporting Forms
30.1.2.4 Definitions
30.1.2.5 Time Frames
30.1.2.6 Continuous Safety Monitoring
30.1.2.7 Sponsor Pharmacovigilance
30.2 Limitations on/of Clinical Trials
30.3 The Clinical Trial Process
30.3.1 Development of an Application Unrelated to Original Approved Use
30.3.1.1 Special Considerations
30.4 Institutional Review Boards (IRBS)/Ethics Committees in the Clinical Trial Process
30.4.1 Legal Authority and Responsibilities for IRBs and ECs
30.4.2 Duties of IRBs
30.4.3 Informed Consent
30.5 Drug Formulations and Excipients
30.5.1 Route of Administration
30.6 Phase I Designs
30.6.1 First Administration: Single Dose Escalating (SDE)
30.6.2 First Administration in Humans: Multiple Dose Escalating (MDE)
30.6.2.1 Number of Subjects
30.7 Clinical Trial Safety Indicators
30.7.1 Overall Approach to Assessing Safety
30.7.1.1 Choosing Safety Parameters
30.7.1.2 Measuring Safety Parameters
30.7.1.3 Parameters That Measure either Safety or Efficacy
30.7.1.4 Appropriateness of Each Parameter for the Clinical Trial and Patient
30.7.2 Precautions
30.7.2.1 Summary of Tests
30.7.2.2 Choosing Laboratory Tests
30.7.2.3 Tests in Phase I
30.7.2.4 Tests in Later Phases
30.7.2.5 Tests in Medical Practice
30.7.2.6 Less Commonly Used Methods
30.7.2.7 Identifying the Most Important Laboratory Analytes to Monitor in a Clinical Trial
30.7.2.8 Uses of Specific Laboratory Tests to Discover, Confirm, and/or Exclude a Disease
30.7.2.9 Hematology
30.7.3 Clinical Chemistry
30.7.3.1 Drug Levels in Plasma
30.7.3.2 Total Blood That May be Taken from Patients
30.7.4 Urinalysis
30.7.5 Urine Screens
30.7.5.1 Type of Container to Be Used
30.7.5.2 Use of International System Units
30.7.6 Identifying New Diagnostic Laboratory Tests
30.7.7 Ophthalmological Examination
30.7.8 Dermatological Examinations
30.7.9 Cardiovascular Safety
30.7.10 Deaths in Clinical Trials
30.7.11 Behavioral Rating Scales, Performance, Personality, and Disability Tests
30.7.12 Adult Behavioral Rating Scales
30.7.12.1 Anxiety Status Inventory
30.7.12.2 Back Depression Inventory
30.7.12.3 Brief Psychiatric Rating Scale
30.7.12.4 Carroll Rating Scale for Depression
30.7.12.5 Clinical Global Impressions
30.7.12.6 Clyde Mood Scale
30.7.12.7 Covi Anxiety Scale
30.7.12.8 Crichton Geriatric Rating Scale
30.7.12.9 Depression Status Inventory
30.7.12.10 Hamilton Anxiety Scale
30.7.12.11 Hamilton Depression Scale
30.7.12.12 Hopkins Symptom Checklist
30.7.12.13 Inpatient Multidimensional Psychiatric Scale
30.7.12.14 Nurses’ Observation Scale for Inpatient Evaluation
30.7.12.15 Plutchik Geriatric Rating Scale
30.7.12.16 Profile of Mood States
30.7.12.17 Sandoz Clinical Assessment-Geriatric
30.7.12.18 Self-Report Symptom Inventory
30.7.12.19 Wittenborn Psychiatric Rating Scale
30.7.12.20 Zung Self-Rating Anxiety Scale
30.7.12.21 Zung Self-Rating Depression Scale
30.7.13 Pediatric Behavioral Rating and Diagnostic Scales
30.7.13.1 Children’s Behavior Inventory
30.7.13.2 Children’s Diagnostic Classification
30.7.13.3 Children’s Diagnostic Scale
30.7.13.4 Children’s Psychiatric Rating Scale
30.7.13.5 Clinical Global Impression
30.7.13.6 Conners Parent Questionnaire
30.7.13.7 Conners Parent/Teacher Questionnaire
30.7.13.8 Conners Teacher Questionnaire
30.7.13.9 Devereux Child Behavior Rating Scale
30.7.13.10 Devereux Elementary School Behavior Rating Scale
30.7.14 Psychometric and Performance Tests
30.7.14.1 Bender-Gestalt Test
30.7.14.2 Conceptual Clustering Memory Test
30.7.14.3 Digit Symbol Substitution Test
30.7.14.4 Embedded Figures Test
30.7.14.5 Frostig Developmental Test of Visual Perception
30.7.14.6 Goodenough–Harris Figure-Drawing Test
30.7.14.7 Peabody Picture Vocabulary Test
30.7.14.8 Porteus Mazes
30.7.14.9 Reaction Time
30.7.14.10 Vigilance Tests
30.7.14.11 Wechsler Adult Intelligence Scale
30.7.14.12 Wechsler Intelligence Scale for Children
30.7.14.13 Wechsler Memory Scale
30.7.14.14 Wide Range Achievement Test
30.7.15 Personality Tests
30.8 Assessment of Unwanted Drug Effects
30.8.1 Separation of Adverse Reactions from Placebo Reactions
30.8.1.1 Base-Case Causality of Single-Event Adverse Drug Reactions
30.9 Recent Changes in Safety Related Requirements for Initial Clinical Trials
Chapter 31: Postmarketing Safety Evaluation: Monitoring, Assessing, and Reporting of Adverse Drug Responses (ADRs)
31.1 Causes of Safety Withdrawals
31.2 Regulatory Requirements
31.2.1 The 15‐Day Report versus the US Periodic Report
31.3 Management of ADR and ADE Data
31.3.1 Sources of Data
31.3.2 Clinical Trials,
31.3.3 Post-marketing Surveillance Studies
31.3.4 Spontaneous Reports
31.3.5 Literature
31.3.6 Searching for ADRs in the Literature
31.3.7 Information Required for Reports
31.3.8 Adverse Drug Reaction Forms and Form Design
31.3.9 Computerization of Drug Safety Data: Data Collection and Input
31.3.10 Medical and Drug Terminology
31.3.11 Dictionaries
31.3.12 Medical Term Coding Dictionaries
31.3.13 Medical Dictionary for Regulatory Activities
31.3.13.1 FDA
31.3.13.2 European Union
31.3.13.3 Japan
31.3.14 Periodic Reports
31.4 Causality Assessment
31.4.1 Aims of Causality Assessment
31.5 Courses of Corrective Action
31.6 Legal Consequences of Safety Withdrawal
31.6.1 FDA Tools for Risk Management
31.6.1.1 The Regulatory Pyramid
31.6.2 Tier 1: Mandatory Studies
31.6.3 Tier 2: Labeling and Assessment
31.6.4 Tier 3: Enhanced Communication
31.6.5 Tier 4: Safe Use Restriction Defined by Provider
31.6.6 Tier 5: Safe Use Restriction Defined by Patient
Chapter 32: Statistics in Pharmaceutical Safety Assessment
32.1 Introduction
32.1.1 Bias and Chance
32.1.2 Hypothesis Testing and Probability (p) Values
32.1.3 Multiple Comparisons
32.1.4 Estimating the Size of the Effect
32.1.5 Functions of Statistics
32.1.6 Descriptive Statistics
32.2 Experimental Design
32.2.1 Choice of Species and Strain
32.2.2 Sampling
32.2.3 Dose Levels
32.2.4 Number of Animals
32.2.5 Duration of the Study
32.2.6 Stratification
32.2.7 Randomization
32.2.8 Adequacy of Control Group
32.3 Data Recording
32.4 Generalized Methodology Selection
32.5 Statistical Analysis: General Considerations
32.5.1 Variables to Be Analyzed
32.5.2 Combination of Observations (Such as Pathological Conditions)
32.5.3 Taking Severity into Account
32.5.4 Using Simple Methods Which Avoid Complex Assumptions
32.5.5 Using All the Data
32.5.6 Combining, Pooling, and Stratification
32.5.7 Trend Analysis, Low‐Dose Extrapolation, and NOEL Estimation
32.5.8 Need for Age Adjustment
32.5.9 Need to Take Context of Observation into Account
32.5.10 Experimental and Observational Units
32.5.11 Missing Data
32.5.12 Use of Historical Control Data
32.5.13 Methods for Data Examination and Preparation
32.5.14 Scattergram
32.5.15 Bartlett’s Test for Homogeneity of Variance
32.5.16 Statistical Goodness‐of‐Fit Tests
32.5.17 Randomization
32.5.18 Transformations
32.5.19 Exploratory Data Analysis
32.6 Hypothesis Testing of Categorical and Ranked Data
32.6.1 Fisher’s Exact Test
32.6.2 2 × 2 Chi‐Square
32.6.3 R × C Chi‐Square
32.6.4 Wilcoxon Rank‐Sum Test
32.6.5 Distribution‐Free Multiple Comparison
32.6.6 Mann–Whitney U Test
32.6.7 Kruskal–Wallis Nonparametric ANOVA
32.6.8 Log‐Rank Test
32.7 Hypothesis Testing: Univariate Parametric Tests
32.7.1 Student’s t‐Test (Unpaired t‐Test)
32.7.2 Cochran t‐Test
32.7.3 F‐Test
32.7.4 Analysis of Variance (ANOVA)
32.7.5 Post Hoc Tests
32.7.6 Duncan’s Multiple Range Test
32.7.7 Groups with Equal Number of Data (N1 = N2)
32.7.8 Groups with Unequal Number of Data (N1 ≠ N2)
32.7.9 Scheffe’s Multiple Comparisons
32.7.10 Dunnett’s t‐Test
32.7.11 Williams’ t‐Test
32.7.12 Analysis of Covariance
32.7.13 Modeling
32.7.14 Linear Regression
32.7.15 Probit/Log Transforms and Regression
32.7.16 Nonlinear Regression
32.7.17 Correlation Coefficient
32.7.18 Kendall’s Coefficient of Rank Correlation
32.7.19 Trend Analysis
32.8 Methods for the Reduction of Dimensionality
32.8.1 Classification
32.8.2 Statistical Graphics
32.8.3 Multidimensional and Nonmetric Scaling
32.8.4 Cluster Analysis
32.8.5 Fourier or Time Analysis
32.8.6 Life Tables
32.9 Meta‐Analysis
32.9.1 Selection of the Studies to Be Analyzed
32.9.2 Pooled (Quantitative) Analysis
32.9.3 Methodological (Qualitative) Analysis
32.10 Bayesian Inference
32.10.1 Bayes’ Theorem and Evaluation of Safety Assessment Studies
32.10.2 Bayes’ Theorem and Individual Animal Evaluation
32.11 Data Analysis Applications in Safety Assessment Studies
32.11.1 Body and Organ Weights
32.11.2 Clinical Chemistry
32.11.3 Hematology
32.11.4 Histopathological Lesion Incidence,
32.11.5 Carcinogenesis
Chapter 33: Combination Products: Drugs and Devices
33.1 Combination Products
33.1.1 Historical Background
33.1.2 Future Trends
33.1.2.1 Device Programs That CDER and CDRH Each will Administer
33.1.2.2 Coordination
33.1.2.3 Submissions
33.1.2.4 Center Jurisdiction
33.1.2.5 General Criteria Affecting Drug/Device Determination
Chapter 34: Qualification of Impurities, Degradants, Residual Solvents, Metals, and Leachables in Pharmaceuticals
32.1 Impurities
32.2 Residual Solvents
32.3 Extractables and Leachables
32.4 Residual Metals and Elements
Chapter 35: Tissue, Cell, and Gene Therapy
35.1 Safety Assessment of Cell Therapy (CT) Products
35.1.1 Recommendations for General Preclinical Program Design
35.1.2 Model Species Selection
35.1.3 Selection of Animal Models of Disease/Injury
35.1.4 Information Describing Limitations of Potential Animal Model(s)
35.1.5 Information Supporting the Choice of Animal Model(s)
35.1.6 Proof‐of‐Concept (POC) Studies
35.1.7 Toxicology Studies
35.1.7.1 Primary Considerations for Toxicology Study Design
35.1.7.2 Secondary Considerations for Toxicology Study Design
35.1.8 Product Delivery Considerations
35.1.9 Study Designs
35.1.10 CT Products with Implantable Scaffolds
35.2 Nonclinical Safety Assessment of Gene Therapy Products (GTPS)
35.2.1 CBER
35.2.2 NIH
35.2.3 Study Designs
35.2.4 Ex Vivo Genetically Modified Cells
35.2.5 Biodistribution Considerations
35.3 Definitions
Chapter 36: Adverse Outcome Pathways in Drug Safety Assessment and Drug Development
36.1 Introduction
36.2 Initial Steps
36.3 Test Article – Confirming Identity and Stability
36.4 Formulation
36.5 Test Species – Animal Models
35.6 Dose Level Selection and Dosing Errors
36.7 Poor Planning
36.8 Pay Attention to the Regulatory Clock and Changes in Requirements and Guidelines
36.9 Most Advances in Safety Assessment Are Small
Appendices
A: Selected Regulatory and Toxicological Acronyms
B: Definition of Terms and Lexicon of Observations in Nonclinical (Animal) Studies
C: Notable Regulatory Internet Addresses
D: Glossary of Terms Used in the Clinical Evaluation of Therapeutic Agents
E: Common Vehicles for the Non-Clinical Evaluation of Therapeutic Agents
F: Global Directory of Contract Toxicology Labs
INDEX 879
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