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Cover -- Title Page -- Copyright Page -- Acknowledgment -- Contents -- Preface -- About the Authors -- 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 Versus Small Company or The Short Versus 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 -- References -- 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: International Conference on Harmonization -- 2.2.7 Electronic Recordings: Electronic Submissions 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 Versus Law -- 2.5 Organizations Regulating Drug And Device Safety In The United States -- 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 Products -- 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 Therapies -- 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 (Once you have an IND) -- 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 Council for Harmonization -- 2.10.2 Other International Considerations -- 2.10.3 Safety Pharmacology -- 2.11 Combination Products -- 2.11.1 Device Programs That Are CDER and CBRH Each Will Administer -- 2.11.2 Coordination -- 2.11.3 Submissions -- 2.12 Meetings And Submissions To Fda Toxicologists -- 2.13 Conclusion -- References -- Further Reading -- 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 -- 3.2 Pc-Based Information Products: Laser Disc -- 3.2.1 International Veterinary Pathology Slide Bank (IVPSB) -- 3.3 Conclusion -- References -- Further Reading -- 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 -- References -- 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 -- References -- 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 Routes -- 6.3.3 Bolus versus Infusion -- 6.3.4 Oral Route -- 6.3.5 Minor Routes -- 6.3.6 Route Comparisons and Contrasts -- 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 -- References -- Chapter 7 Mechanisms And End Points 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 -- References -- Chapter 8 Pilot Toxicity Testing In Drug Safety Evaluation: MTD and DRF -- 8.1 Introduction -- 8.2 RangeFinding Studies -- 8.2.1 Lethality Testing -- 8.2.2 Using Range-Finding Lethality Data in Drug Development: The Minimum Lethal Dose -- 8.3 Acute Systemic Toxicity Characterization -- 8.3.1 Minimal Acute Toxicity Test -- 8.3.2 Complete Acute Toxicity Testing -- 8.3.3 Acute Toxicity Testing with Non -- 8.3.4 Factors that Can Affect Acute Tests -- 8.3.5 Selection of Dosages -- 8.4 Screens -- 8.4.1 General Toxicity Screens -- 8.4.2 Specific Toxicity Screening -- 8.5 Pilot And DRF Studies -- References -- Chapter 9 RepeatDose 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 -- 9.3.4 Study Designs -- 9.4 Study Interpretation and Reporting -- 9.5 Read Across For Program Wide Evaluation -- References -- 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.
10.2.5 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 Versus 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 -- 10.3.6 Bacterial Mutation Tests -- 10.3.7 Controls -- 10.3.8 Plate Incorporation Assay -- 10.3.9 Eukaryotic Mutation Tests -- 10.3.10 In vitro Tests for the Detection of Mammalian Mutation -- 10.3.11 in vivo Mammalian Mutation Tests -- 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 -- 10.5.2 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 -- References -- 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.
11.3.5 Carcinogenicity.
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Drug safety evaluation / / Shayne Cox Gad, Dexter W. Sullivan
