Unexpected toxicity is the single greatest cause of pipeline attrition. Despite the fact that a typical preclinical safety program will consume about 1,300 rats and 90 dogs, there is no guarantee that the compound will not present safety problems serious enough to warrant termination. Outlook for Predictive Safety Technologies, a new CHA Advances report, surveys the latest developments in discovery-stage and preclinical predictive safety assessment tools—from in silico methods for lead selection and optimization to high-content cell-based screens, toxicogenomics, tissue proteomics, and advanced animal models. It provides the information and analysis you need to get the best return—in terms of confidence, cost-benefit, and ease of maintenance and use—on your preclinical safety technology investments.
Specifically, the report delivers:
A comparative assessment of the leading predictive safety technologies, with an emphasis on performance, specific applications in non-clinical testing, and total cost of ownership
Estimates of potential savings in research costs and animal use—including a case study scenario of cost savings for a mid-sized biopharma company
Adoption rates by industry—which technologies are attracting resources, and why?
A “virtual roundtable” where 10 leading safety experts in industry and FDA provide their extended views on key scientific and business issues around predictive safety technologies
A quantitative survey (n=46) of the views, practices, and plans of ADME/Tox researchers in industry and academia presented in easy-to-scan charts
Expert insight into critical issues such as safety challenges presented by large molecule drugs, the implications of FDA’s Exploratory IND Guideline, and timelines to reduced FDA emphasis on animal safety studies
The Relative Predictive Value of Early-Stage Safety Assessment Methods
Nearly half of the respondents to our survey used some sort of predictive safety technology. Other noteworthy trends revealed in our research:
Large companies were more likely to use equipment-intense safety solutions that are easily scalable to the degree of throughput required in large library-based drug development.
The vast majority of respondents believed that early-stage predictive safety testing would result in significant savings, but were skeptical that it would result in reduced animal use.
The pharmaceutical industry is responding to the challenge of moving safety assessments upstream to the discovery and early preclinical stages. However, to fully embrace predictive safety testing in drug development, the industry must understand the “total cost of ownership,” a term that encompasses all the costs involved in acquiring, implementing, maintaining, and using such procedures.
Outlook for Predictive Safety Technologies is designed to help managers understand the range of technologies available, their pros and cons, and to decide on the one best suited to their organization.
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Additional InformationAbout the Author
Hermann A.M. Mucke, PhD, spent 17 years in academia and industry before he founded H.M. Pharma Consultancy in 2000 to become an independent pharmaceutical consultant, analyst, and science author. His last industry position was Vice President R&D in a European pharmaceutical company that he helped to take public on the Frankfurt Stock Exchange in 1999. Since then, Dr. Mucke, who holds a PhD in biochemistry from the University of Vienna (Austria), became a consultant and advisory board member for several European and US pharmaceutical companies and a regular reviewer of drugs and patents for Thomson Current Drugs and Ashley Publications. He has served as an outside expert author for CHA since 2004.
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
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