Outlook for Predictive Safety Technologies

Chapter 1.
INTRODUCTION
  1.1. ADME/Tox: The Cornerstone of Safety Assessments 
  1.2. Areas of Potential for Improvement of Safety Pharmacology

Chapter 2.
PRECLINICAL SAFETY TESTING AND DRUG DEVELOPMENT COSTS
  2.1. Unexpected Toxicity: A Constant Source of Attrition to Pharmaceutical Productivity 
  2.2. Complex Drug Actions Cause Complex Failures 
  2.3. A Savings Scenario for a Mid-Sized Drug Developer 
  2.4. Cutting Back on Research Animal Use

Chapter 3.
ASPECTS OF DRUG SAFETY CONCERNS
  3.1. Relative Drug Safety, Not Absolute Toxicity, is the Issue 
  3.2. Toxicity vs. Side Effects 
  3.3. The Objective for Predictive Safety Testing 
  3.4. Mutagenicity and Reproductive Toxicity 
  3.5. Drug-Drug Interactions and  Metabolic Poisoning 
  3.6. High-Throughput Testing: A Challenge for Predictive Safety Assessments 
  3.7. Knockout Safety Tests with Essentially Unknown Positive Predictive Value

Chapter 4.
PREDICTIVE SAFETY TOOLS AND TECHNOLOGIES
  4.1. Toxicogenomics 
         A New Dynamic 
  4.2. High-Content Cell-Based Screening for Safety Parameters 
         HCS for General Aspects of Drug Safety 
         Rat and Human Hepatocytes 
         Cell Models for Modulation of Cardiac Function 
         In Vitro Nephrotoxicity Evaluation Using Primary Human Kidney Cells
         HCS for Assessing Hematology Toxicity 
         HCS for Genotoxicity Profiling 
         Biochips as Solid-State Biosensors for Toxicity and Mutagenicity 
  4.3. Tissue Histology and Tissue Proteomics: Creating Powerful New Tools from Old Ones 
         Pioneering Efforts in Histopathology 
         NeuroScience Associates 
         HistoRX 
         Phase I Molecular Toxicology 
  4.4. Metabolite Profiling and Metabonomics As a Tool for Toxicity Prediction
         Metabolite Profiling 
         Predicting Drug Interactions from In Vitro Metabolic Data 
         Predicting Cytochrome P450 Interactions and Inhibition 
         Pharmaco-Metabolomics 
  4.5. Animal Models 
         The Zebrafish: An Intriguing Vertebrate Model for Toxicity Testing 
         Rodents Tailored for Predictive Toxicology 
         Isogenic Rat Panels 
         Mice Under Realistic Stress Conditions
         Transgenic Animals for Carcinogenicity Testing 
         Unconventional Animal Models 
  4.6. In Silico Approaches to Toxicity and Carcinogenicity 
         The ToxML Format: A Platform for Toxicity Data Exchange 
         Structure-Based Prediction of Hepatotoxicity 
         In Silico Identification of Compounds at Risk for Inducing Cardiac Arrythmia 
         Other In Silico Toxicity Prediction Models 
         Commercial Software Packages and Services 

Chapter 5.
SAFETY SIGNALS FOR BIOTECH DRUG CANDIDATES: AN EMERGING FIELD
  5.1. Cases in Point 
  5.2. Predictive Safety Testing and Regulatory Authorities 
         The Predictive Safety Testing Consortium: A Spin-Off from the Critical Path Initiative 
         Voluntary Genomics Data Submissions: An Exercise for the Future 
         The FDA s Intramural Biomarker Program 
  5.3. The European Innovative Medicines Initiative 
  5.4. A Synopsis of Facts and Perspectives for Predictive Safety Testing Approaches 

Chapter 6.
INTERIVEWS WITH EXPERTS IN THE PREDICTIVE SAFETY TESTING FIELD
Felix W. Frueh, PhD, US Food and Drug Administration 
Joseph F. Contrera, PhD, US Food and Drug Administration 
Donald Halbert, PhD, Iconix Biosciences 
D. Lansing Taylor, PhD, Cellumen 
Michael Milburn, PhD, Metabolon 
Patricia McGrath, MBA, Phylonix 
Paul Stroobant, PhD, HistoRx
Peter-Jan van Doorn, MD, MBA, MDS Pharma Services 
Manfred Windisch, PhD, JSW Research 

APPENDIX
A WEB SURVEY OF INDUSTRY EXPERTS HANDLING OR DECIDING PREDICTIVE SAFETY TESTING 

Glossary 

Company Index with Web Addresses