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Drug Safety Evaluation

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  • Edition: 4th
  • Format: Hardcover
  • Copyright: 2023-01-12
  • Publisher: Wiley
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Supplemental Materials

What is included with this book?


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.

Author Biography

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.

Table of Contents

PREFACE              xxv


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

                       Carcinogenicity Studies

                       Chronic Toxicity

                       Developmental and Reproductive Toxicity

                2.10.2 Other International Considerations

                       European Union



                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

       Center Jurisdiction

       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

                       Intravenous Route

                6.3.3 Bolus vs. Infusion

                       Subcutaneous Route

                       Intramuscular Route

                       Intraperitoneal Route

                6.3.4 Oral Route

                       Mechanisms of Absorption

                       Factors Affecting Absorption

                       Bioavailability and Thresholds

                       Techniques of Oral Administration            

                6.3.5 Minor Routes        

                       Periocular Route

                       Rectal Administration

                       Vaginal Administration

                       Nasal Administration

                       Volume Limitations by Route

                6.3.6 Route Comparison and Contrasts 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

                       Classical LD50

                       Dose Probes

                       Up/Down Method

                       “Pyramiding” Studies

                       Limit Tests

                       Fixed-Dose Procedure

                       “Rolling” Acute Test

8.2.2 Using Range-Finding Lethality Data in Drug Development: The Minimum Lethal Dose

       Minimum Lethal Dose Protocols

8.3 Acute Systemic Toxicity Characterization

                8.3.1 Minimal Acute Toxicity Test

                       Clinical Signs

                8.3.2 Complete Acute Toxicity Testing

                       Body Weight Considerations

                       Pathology Considerations

                       Supplemented Acute Studies

                8.3.3 Acute Toxicity Testing with Nonrodent Species

                8.3.4 Factors that Can Affect Acute tests

                       Number, Size, and Sex of Dosage Groups

                8.3.5 Selection of Dosages


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

                       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

                                       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

                                       In Vitro Metabolic Activation

                                10.3.6 Bacterial Mutation Tests

                                       Reversion Test: Background

                                       Genetic Makeup of Tester Strains

                                       The Use of the Plasmid pKM101

                                       Ames Salmonella/Plate Incorporation Method

                                10.3.7 Controls

                                       Positive Controls

                                       Untreated/Vehicle Controls

                                       Evaluation of Results

                                       Preincubation tests

                                       E. Coli Tester Strains

                                       Storage and Checking of Tester Strains

                                10.3.8 Plate Incorporation Assay

                                       Protocol for Dose Ranging and Selection

                                       Eukaryotic Mutation Tests

                                10.3.9 Eukaryotic Mutation Tests

10.3.10 In Vitro Tests for the Detection of Mammalian Mutation

       Chinese Hamster Lines

       V79 System

       Preliminary Cytotoxicity Testing

       Data Analysis Chinese Hamster Ovary (CHO)/Hypoxanthine-Guanine Phosphoribosyltransferase (HGPRT) Assay Mouse Lymphoma L5178Y TK+/- Assay Selection of Dose Levels Main Mutation Assay In Vivo Genotoxicity Tests for the Assessment of Primary DNA Lesions The Comet Assay Principle of Method Status of Mammalian Mutation Tests

                                10.3.11 In Vivo Mammalian Mutation Tests

                                       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

                                       Metaphase Analysis


                                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

                       Oral Rat LD50

                11.3.5 Carcinogenicity

11.4 Genotoxicity

                11.4.1 QSAR for Mutagenicity




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

                                       Multiple Computer-Automated Structural Evaluation

                                       Toxicity Prediction by Computer-Assisted Technology

                                11.5.5 VEGA

                                       Global AD Index Similar Molecules with Known Experimental Value Accuracy of Prediction for Similar Molecules Concordance for Similar Molecules Atom-Centered Fragments Similarity Check 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




                       Nitrogen Mustards


                       Heavy Metals


13.5 Immunostimulation

                                13.5.1 Hypersensitivity (or Allergenicity)

                                       Type I Hypersensitivity

                                       Type II Hypersensitivity

                                       Type III Hypersensitivity

                                       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

                       Organ and Body Weights

13.7.2 Humoral (Innate) Immune Response and Possible Entry Points for Immunotoxic Actions


       Clinical Chemistry


       Antibody Plaque-Forming Cell (PFC) Assay

       B-Cell Lymphoproliferation Response

                13.7.3 Cell-Mediated Immunity

                       T-Cell Lymphoproliferation Response

                       Mixed Lymphocyte Response (MLR) Assay

                       Cytotoxic T Lymphocyte (CTL)-Mediated Assay

                       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

                       Host-Resistance Assays

13.9 T-Cell-Dependent Antibody Response (TDAR)

                13.9.1 Treatment

                13.9.2 Hypersensitivity

                       Type I Hypersensitivity

                       Types II and III Hypersensitivity

                       Type IV Hypersensitivity

                       Modified Buehler

                       Guinea Pig Maximization Test

                13.9.3 Local Lymph Node Assay (LLNA)

                13.9.4 Photosensitization

                       Harber and Shalita Method

                       Armstrong Method

13.10 Approaches to Compound Evaluation

                13.10.1 Use of In Vivo Tests

                       Species Selection

                       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

                       Dosing Techniques

                       Clinical Observations and Physical Examinations

                       Feed consumption


                       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

                       Dosing techniques Clinical Observations and Physical Examinations

                       Feed consumption


                       Blood and Urine Collection

                14.6.4 Advantages and Disadvantages

                14.7 The Pig

                14.7.1 Background

                       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


       Feed and Water

       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

                       Common Dosing Techniques

                       Clinical Observations and Examinations

                       Feed Consumption

                       ECGs and Cardiovascular Measurements

                       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

       Examination of External Genitalia

       Visceral Fetal Examinations

       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

                                       Interval Selection for Occult (Internal Organ) Tumors

                                       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


                                       Blood Compatibility

                                                18.8,1.3 Sterility

                                18.8.2 Test Systems for Parenteral Irritation                        

                                       Acute Intramuscular Irritation in the Male Rabbit

                                       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

                       Apparatus and Diluents

                       Temperature Recording

                       Test Animals


                       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

                       Absorption from the Pulmonary System

                       Absorption across the Skin Parameters Controlling Absorption

                19.3.3 Distribution          

                       Protein Binding

                       Water Solubility

                       Volume of Distribution

                19.3.4 Metabolism/Biotransformation  

                       Metabolic Activation

                       Induction of P450 Metabolism and Isoenzymes

                       Species Differences

                19.3.5 Excretion



                       Expired Air

19.4 Pharmacokinetics

19.5 Laboratory Methods

                19.5.1 Analytical Methods

                       Instrumental Methods

                       Radiochemical Methods

                       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

                       Sampling Interval

19.7 Study Types

                19.7.1 Whole-Body Autoradiography

                19.7.2 Mass Balance Studies

                       In Vitro Studies

19.8 Analysis of Data

19.8.1 Use of Data from Metabolism and Pharmacokinetic Studies

       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

                       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

       Cloned Human Potassium Channels

       Cardiac Action Potential in Vitro: Purkinje Fibers

       Monophasic Action Potential in Anesthetized Guinea Pigs

       ECG by Telemetry in Conscious Dogs or Primates

       Hemodynamics and ECG in Anesthetized or Conscious Dogs or Primates

20.4.8 Relevance of hERG to QT Prolongation

       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

       DNA/Oligonucleotide Hybridization

       Hybrid Selection and Cell-Free Translation

       Expression Cloning

       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

       Mass Dose Route of Administration Frequency of Use Biological, Physical, and Effective Half-Lives

23.2.4 Performance of Nonclinical Safety Assessments

       Nonclinical Safety Assessments for Nonbiological Drug Products

       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

       Long-Term Exposure in Pediatric Subjects

       Short-Term Exposure in Pediatric Subjects

       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 Relating the Time Course of Plasma Concentrations to the Time Course of Effect

30.1.2 Safety of Clinical Trial Subjects


       Increased Frequency Reports

       Reporting Forms

       Definitions Time Frames Continuous Safety Monitoring 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

       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) Number of Subjects

30.7 Clinical Trial Safety Indicators

30.7.1 Overall Approach to Assessing Safety

       Choosing Safety Parameters

       Measuring Safety Parameters Parameters That Measure either Safety or Efficacy Appropriateness of Each Parameter for the Clinical Trial and Patient

                30.7.2 Precautions         

                       Summary of Tests

                       Choosing Laboratory Tests

                       Tests in Phase I

                       Tests in Later Phases

                       Tests in Medical Practice

                       Less Commonly Used Methods

       Identifying the Most Important Laboratory Analytes to Monitor in a Clinical Trial Uses of Specific Laboratory Tests to Discover, Confirm, and/or Exclude a Disease Hematology

30.7.3 Clinical Chemistry

       Drug Levels in Plasma

       Total Blood That May be Taken from Patients

30.7.4 Urinalysis

30.7.5 Urine Screens

       Type of Container to Be Used

       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

       Anxiety Status Inventory Back Depression Inventory Brief Psychiatric Rating Scale Carroll Rating Scale for Depression Clinical Global Impressions Clyde Mood Scale Covi Anxiety Scale Crichton Geriatric Rating Scale Depression Status Inventory Hamilton Anxiety Scale Hamilton Depression Scale Hopkins Symptom Checklist Inpatient Multidimensional Psychiatric Scale Nurses’ Observation Scale for Inpatient Evaluation Plutchik Geriatric Rating Scale Profile of Mood States Sandoz Clinical Assessment-Geriatric Self-Report Symptom Inventory Wittenborn Psychiatric Rating Scale Zung Self-Rating Anxiety Scale Zung Self-Rating Depression Scale

30.7.13 Pediatric Behavioral Rating and Diagnostic Scales Children’s Behavior Inventory Children’s Diagnostic Classification Children’s Diagnostic Scale Children’s Psychiatric Rating Scale Clinical Global Impression Conners Parent Questionnaire Conners Parent/Teacher Questionnaire Conners Teacher Questionnaire Devereux Child Behavior Rating Scale Devereux Elementary School Behavior Rating Scale

30.7.14 Psychometric and Performance Tests Bender-Gestalt Test Conceptual Clustering Memory Test Digit Symbol Substitution Test Embedded Figures Test Frostig Developmental Test of Visual Perception Goodenough–Harris Figure-Drawing Test Peabody Picture Vocabulary Test Porteus Mazes Reaction Time Vigilance Tests Wechsler Adult Intelligence Scale Wechsler Intelligence Scale for Children Wechsler Memory Scale 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 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

                                       FDA European Union 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

       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 Device Programs That CDER and CDRH Each will Administer Coordination Submissions Center Jurisdiction 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

       Primary Considerations for Toxicology Study Design

       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



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




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