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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Drug Safety Evaluation

9781119755852

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