John Wiley & Sons Drug Safety Evaluation Cover Drug Safety Evluation Comprehensive and practical guide presenting a roadmap for safety assessment .. Product #: 978-1-119-75585-2 Regular price: $266.36 $266.36 Auf Lager

Drug Safety Evaluation

Gad, Shayne Cox / Sullivan, Dexter W.

Pharmaceutical Development (Band Nr. 1)


4. Auflage Januar 2023
992 Seiten, Hardcover
Wiley & Sons Ltd

ISBN: 978-1-119-75585-2
John Wiley & Sons

Jetzt kaufen

Preis: 285,00 €

Preis inkl. MwSt, zzgl. Versand

Weitere Versionen


Drug Safety Evluation

Comprehensive and practical guide presenting a roadmap for safety assessment as an integral part of the development of drugs and therapeutics

This fourth edition of Drug Safety Evaluation maintains the central objective of presenting an all-inclusive practical guide for those who are responsible for ensuring the safety of drugs and biologics to patients, healthcare providers, those involved in the manufacture of medicinal products, and all those who need to understand how the safety of these products is evaluated and shepherding valuable candidates to market.

Individual chapters address specific approaches to evaluation hazards, including problems that are encountered and their solutions. Also covered are the scientific and philosophical bases for evaluation of specific concerns (e.g., carcinogenicity, development toxicity, etc.) to provide both understanding and guidance for approaching the new problems that have come to face both our society and the new challenges they brought.

The many changes in regulatory requirements, pharmaceutical development, technology, and the effects of Covid on our society and science have required both extensive revision to every chapter and the addition of four new chapters.

Specific sample topics covered in Drug Safety Evaluation include:
* The drug development process and the global pharmaceutical marketplace and regulation of human pharmaceutical safety
* Sources of information for consideration in study and program design and in safety evaluation
* Electronic records, reporting and submission, screens in safety and hazard assessment, and formulations, routes, and dosage regimens
* Mechanisms and endpoints of drug toxicity, pilot toxicity testing in drug safety evaluation, and repeat dose toxicity
* Genotoxicity, QSAR tools for drug safety, toxicogenomics, nonrodent animal studies, and developmental and reproductive toxicity testing
* An appendix which provides an up to date guide to CROs for conducting studies

Drug Safety Evaluation was written specifically for the pharmaceutical and biotechnology industries, including scientists, consultants, and academics, to show a utilitarian yet scientifically valid path to the everyday challenges of safety evaluation and the problem solving that is required in drug discovery and development.



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 Japan 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 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 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 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 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 Oral Rat LD50

11.3.5 Carcinogenicity

11.4 Genotoxicity

11.4.1 QSAR for Mutagenicity Sensitization Hepatotoxicity 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 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 Antimetabolites Glucocorticosteroids Cyclosporine Nitrogen Mustards Estrogens Heavy Metals Antibiotics

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 Hematology Clinical Chemistry Histopathology 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
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.

S. C. Gad, IBS, Raleigh, North Carolina