Managing Toxicology for the Future: Improving Predictive Power Through Integrated Technologies (2nd Edition)
Drug and Market Development Publishing
August 1, 2006 226 Pages - SKU: DSMD1331785
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During the last three years mergers, the drive to integrate ADME/Tox screening throughout the drug development process is now impacting the issue of late stage candidate attrition. This organizational shift is highlighted in D&MD’s new market analysis report—Managing Toxicology for the Future: Improving Predictive Power Through Integrated Technologies, 2nd Edition. The strategy of moving ADME/Tox-based decision making forward into early compound discovery has been embraced and the report examines the impact this re-structuring is having on Phase II and Phase III drug failures.
This report focuses on the new technologies being employed in toxicology and how they integrate with the discovery and preclinical stages of drug development. Emphasis is placed on the fact that none of the new approaches, including toxicogenomics, toxicoproteomics, in vitro assays or predictive toxicology databases and computational methods, will emerge as a stand-alone solution to drug safety assessment. Each will instead find its place as a component of a larger system of R&D, providing complementary information and supporting conventional methods of animal testing. The state of current and emerging technologies are presented in Chapter 2, along with an assessment of their impact and future role in preclinical research. Chapter 3 analyzes business strategies of companies offering technology platforms in toxicology, pharmaceutical company strategies for technology adoption and outsourcing, the regulatory environment, the business case for pre-competitive development of predictive toxicology, and the impact of pharmacogenomics on drug safety. Chapter 4 examines the impact of adverse drug effects through a case study, and how unanticipated toxicity has resulted in numerous product withdrawals, liability and the reversal of corporate fortunes. Finally, Chapter 5 presents profiles of the top innovative companies and service providers in predictive toxicology and a summary of recent collaborative activity.
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- Chapter 1: Introduction: Industry Environment
- Focus of the Report
- The Pharmaceutical Industry: A Historical Perspective
- The Problem—The Increase in & Costs
- Industrialization of Drug Discovery
- The Trend Toward Pulling Risk Upstream
- The Three Bottlenecks of Pharmaceutical &
- Competitive Advantages of Early Safety Screening
- Adverse Drug Reactions and Drug-Drug Interactions
- References
- Chapter 2: Technology Strategies
- Traditional Animal Studies
- Preclinical Safety Testing—An Overview
- Categories of Preclinical Animal Toxicity Testing
- Preclinical Safety Testing for Biopharmaceuticals
- Limitations of Preclinical Animal Testing
- Phase I-IV Clinical Studies
- Clinical Development.(Phase I-III Clinical Trials)
- Post-Marketing Studies.(Phase IV Studies)
- The Product Quality Control Problem in Drug Development
- Improving Animal Studies
- Telemetry Sensors
- Liquid Chromatography and Mass Spectrometry
- Non-mammalian Animal Models
- Transgenic Animal Models
- Imaging Technologies
- The “Omic” Triad
- Toxicogenomics
- Reference Databases in Toxicogenomics
- Toxicogenomics and Traditional Pathology
- Maximizing the Benefit of Toxicogenomic Studies
- Toxicoproteomics
- Key Technologies for Toxicoproteomics
- Toxicoproteomic Applications
- Maximizing the Benefit of Toxicoproteomics
- Metabonomics
- Key Technologies for Metabonomics
- Maximizing the Benefit of Metabonomics
- Predictive Toxicology
- The Need for In Vitro and In Silico Models
- In Vitro Toxicity Assays
- In Vitro Drug-Metabolism Assays
- Genotyping Assays for Drug-Metabolizing Enzymes
- In Silico Approaches: Computational Models and Databases
- Current In Silico Models for Toxicity
- Current In Silico Models for ADME Properties
- Role of Drug Delivery in Toxicology
- References
- Chapter 3: Business Strategies
- Platform Technology Companies
- Animal Model Companies
- ADME/Tox Assay Technology Companies
- Toxicogenomics & Toxicoproteomics Companies
- In Silico Predictive Toxicology Companies
- Other Platform Technology Companies
- The Absorption and Elimination of Platform Technology Companies
- Internal Efforts—A Shift in Focus towards ADME/Tox
- Pulling Risk Upstream
- Public and Regulatory Pressures
- References
- Chapter 4: A Case Study of Toxicity Impact—Product Withdrawals
- Introduction
- Adverse Drug Reactions
- Impact of ADRs and Drug Product Withdrawals
- Medical Need vs. Risk
- Factors Influencing Increased Incidence of Drug Product Withdrawals
- FDA Reform
- Overall Risk Management Framework
- Market Withdrawals and Clinical Trial Flaws
- Other Factors Leading to the Recent Increase in Drug Withdrawals
- The Case Study—Baycol (Avastatin)
- Baycol Overview
- Baycol ADRs
- Ramifications of Baycol ADRs and Market Withdrawal
- Bayer’s Reaction to the Baycol ADR
- Conclusions from the Baycol Case Study
- Industry Response to ADR’s and Drug Withdrawals
- Estimates of Preventable ADR’s
- Collaborative Drug Therapy Management
- Clinical Trial Design,.Pharmacogenomics and Toxicity Biomarkers
- References
- Chapter 5: Company Profiles
- TABLE OF EXHIBITS
- Exhibit 1.1 Increasing & Costs per Drug
- Exhibit 1.2 Increasing Development Times
- Exhibit 1.3 Analysis of Failed Projects.(2003 to Present)
- Exhibit 1.4 A Rapid Increase in Throughput and Data
- Exhibit 1.5 Compound Attrition During Development
- Exhibit 1.6 The Trend Towards Parallel & Processes
- Exhibit 1.7 Changes in the Pharmaceutical Organization
- Exhibit 1.8 Pulling Risk Upstream: Failing Drugs Early
- Exhibit 1.9 Distribution of Small Molecule Drug Candidates Currently in Development
- Exhibit 1.10 Pharmaceutical & Process
- Exhibit 1.11 Comparison of Duration Between Traditional and Novel Toxicity Assays
- Exhibit 2.1 Predictive Power of Animal Toxicity Testing
- Exhibit 2.2 Probability to Detect a Rare Adverse Drug Reaction
- Exhibit 2.3 Cost of the Quality Control Problem in Drug Development
- Exhibit 2.4 Concurrent vs. Serial Product Quality Control at Boeing
- Exhibit 2.5 Concurrent Product Quality Control in Pharmaceutical &
- Exhibit 2.6 Telemetry Sensors for Animal Testing
- Exhibit 2.7 Summary of Non-Mammalian Animal Model Vendors
- Exhibit 2.8 Animal Imaging
- Exhibit 2.9 Toxicogenomics by DNA Microarrays
- Exhibit 2.10 Toxicogenomic Reference Databases to Classify Novel Compound Toxicity
- Exhibit 2.11 Toxicoproteomics by 2D PAGE Plus Mass Spectrometry
- Exhibit 2.12 Toxicoproteomics by Isotope-coded Affinity Tags.(ICAT)
- Exhibit 2.13 Toxicoproteomics by Protein Microarrays
- Exhibit 2.14 Comparison of Proteomic Technologies
- Exhibit 2.15 NMR-based Metabonomic Analysis of Liver and Kidney Toxicity
- Exhibit 2.16 Time Course of Toxicological Effects
- Exhibit 2.17 ADME/Tox During Lead Optimization: Moving from a Serial to a Parallel Approach
- Exhibit 2.18 Breakout of HCS/HCA Assays by Biological Pathways and Phenotypes. that are Interrogated
- Exhibit 2.19 Forecast Growth of the Screening Space—Broken Out by Primary Screening, Secondary Screening.(includes HCS/HCA and ADME/Tox)
- Exhibit 2.20 Interspecies Differences in Bioavailability of Indinavir
- Exhibit 2.21 Predictability of Human Toxicity Based on Animal Studies
- Exhibit 2.22 Uses of Liver-based In Vitro Systems During Preclinical Drug Screening
- Exhibit 2.23 CYP450 Enzymes: Liver Expression Levels vs. Importance in Drug Metabolism
- Exhibit 2.24 CYP2D6: Correlation between Genotype and Phenotype
- Exhibit 3.1 Creating Commercial Value through Technology Breakthroughs
- Exhibit 3.2 Animal Model Companies
- Exhibit 3.3 ADME/Tox Assay Technology Companies
- Exhibit 3.4 Toxicogenomics & Toxicoproteomics Companies
- Exhibit 3.5 DNA Microarray Technologies
- Exhibit 3.6 Protein Microarray Technologies
- Exhibit 3.7 In Silico ADME/Tox Companies
- Exhibit 3.8 Absorption and Elimination of Toxicology Platform Companies
- Exhibit 3.9 Lilly Toxicology-Driven Attrition.(5 of Total) 1993-2004: CS to FHD Phase
- Exhibit 4.1 Sources of Adverse Drug Events
- Exhibit 4.2 Recent Safety-based Drug Withdrawals.(since 1980)
- Exhibit 4.3 Distribution of Withdrawn Drugs by Year Withdrawn
- Exhibit 4.4 Distribution of Withdrawn Drugs by Year Approved
- Exhibit 4.5 Safety-based NME Withdrawals.(by Approval Year) in 5-year Cohorts
- Exhibit 4.6 Prescription Drug Market Withdrawals—The Link to Gender
- Exhibit 4.7 Estimated Revenues of Cholesterol Lowering Drugs—2001
- Exhibit 4.8 Metabolism by CYP450 Enzymes
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