Discovery to IND Filing, 2nd Edition

Table of Contents

CHAPTER 1: INTRODUCTION

• The Process

CHAPTER 2: DRUG DISCOVERY

• Introduction
• Biology of the Disease
• Selecting a Drug Target
• Target Types
  • DNA
  • RNA
  • Protein
• How Many Targets?
• The Druggable Genome
• Implications for Drug Discovery

CHAPTER 3: DRUG TARGET IDENTIFICATION AND VALIDATION

• Introduction
• The Human Genome Project
  • The Major Findings
  • Implications for Drug Discovery
  • The Promise of Genomics
  • Genomics and Drug Discovery
  • Unresolved Issues
• Target Identification
• Role of Functional Genomics
  • Knockouts
  • Antisense
  • RNA Interference
  • Transgenics
  • Limitations of Gene-modified Animal Models
  • DNA Microarrays
• Bioinformatics Techniques
• Identification of Drug targets: Tools and Techniques
  • Molecular Biology Techniques
  • DNA-Related Techniques
  • RNA-Related Techniques
  • Protein Related Techniques
    • Proteomics
• Drug Target Validation
• DTV Techniques

CHAPTER 4: SCREENING THE DRUG TARGET

• Discovery Screens
• Small Molecule Screening Libraries
  • Combinatorial Chemistry
  • HTS Assay
  • HTS Phenotypic Outcomes
  • The Impact of HTS

CHAPTER 5: DEVELOPING LEADS FROM HITS

• The Importance of Druggability
  • Predicting Druggability
  • Artificial Intelligence Screening
• Lead Discovery
• Lead Optimization
• What is an Optimized Lead Molecule
• Why Preclinical Candidates are Discontinued: Starting Points for Lead Optimization
  • Pharmacology and Toxicology
  • Scalability of Synthesis
• Regulatory Issues in Lead Optimization
  • Strategy Precedes Paperwork
  • The Implicit "Acknowledged Disorder" Criterion
  • Optimizing Lead Compounds with a Regulatory View to Synthesis
  • The "Strategy of the Backups"
• Lead Optimization and Development

CHAPTER 6: DRUG DEVELOPMENT PROCESS: FROM LEAD TO IND FILING

• Preclinical Development
• Post-Discovery Process
  • Chemistry and Synthesis of Drug Molecules
• Drug Development Phase
  • Pharmacology or In Vitro and Animal Model Efficacy
    • Route of Administration
    • Defining the Appropriate Dose
  • Defining the Right Animal Models
    • In vivo Dosage
• Drug Developability Stage
  • Preliminary Formulation Evaluation
  • Toxicity
  • Drug Metabolism
  • Formulation Development
  • Bioanalytical Chemistry Method Validation
  • IND-Directed Toxicology Studies
  • Pharmacokinetics and Drug Metabolism
  • Mechanism of Action Studies
• Other Required IND Application Studies
  • Manufacturing Program
  • Quality Control Process
  • Clinical
  • Pharmacokinetics and Drug Metabolism
  • Mechanism of Action

Phase 1: Safety and Tolerance Study

Phase 2: Efficacy Studies

Phase 3: Definitive Safety and Efficacy Studies

Phase 4: Studies

Filing an IND Application

CHAPTER 7: SUMMARY AND CONCLUSIONS

• Recent Trends

CHAPTER 8: ADDITIONAL READING

CHAPTER 9: APPENDICES

• Appendix 1: Stepwise Guide to Antibody Development for Therapeutics
• Appendix 2: Stepwise Guide to Small Molecule Development for Therapeutics

TABLE OF EXHIBITS

• Exhibit 1.1 Drug Discovery and Development in Pharma Industry
• Exhibit 1.2 Summary of Drug Discovery and Development Process
• Exhibit 2.1 Business Aspects Driving Drug Discovery and Development
• Exhibit 2.2 Evolution of Therapeutic Drug Discovery from Disease Analysis
• Exhibit 2.3 Identification of Drug Target for Gleevac
• Exhibit 2.4 Classification of Drug Targets Based upon Marketed Small Molecules
• Exhibit 2.5 Classification of Drug Targets Based on Cellular Localization
• Exhibit 2.6 The Biochemical Classes of Therapeutic Drug Targets
• Exhibit 2.7 Number of Potential Drug Targets
• Exhibit 3.1 What Sequencing the Human Genome Does Not Reveal
• Exhibit 3.2 The Drug Discovery Process
• Exhibit 3.3 Applying Bioinformatics for Drug Discovery and Development
• Exhibit 3.4 Techniques for Identification of Potential Drug Targets
• Exhibit 3.5 Therapeutic Targets and Targeting Molecules, Advantages and Disadvantages
• Exhibit 3.6 Kinase Targeting Therapeutic Molecules
• Exhibit 4.1 Methods of Measuring the Affinity of Small Molecules for Proteins
• Exhibit 5.1 Developing Lead Molecules from Hit Molecules
• Exhibit 5.2 Factors Relevant in Lead Optimization
• Exhibit 5.3 Attrition in Drug Development by Cause, from Discovery to Launch
• Exhibit 5.4 Strategies for Lead Optimization of Therapeutic Molecules
• Exhibit 6.1 Flowchart Showing Paths from Discovery to IND
• Exhibit 6.2 Flow Chart Showing Post IND Filing Drug Activities at FDA
• Exhibit 7.1 Flow Chart Showing Major Steps in the Drug Discovery and Development Process
• Exhibit 7.2 Research and Development Expenses, Total NDA and NDA for NME Submissions, 1993-2004