Abstract
Summary
About $70 million (20%) of the total R&D costs per drug are spent on ADME/Tox failures.
Preclinical toxicity is one of the major bottlenecks in drug development. In particular, the ability to predict the safety of a drug in the preclinical stage, prior to human testing, has been one of the major bottlenecks in drug development. Current approaches have serious limitations in their ability to predict toxicity in humans, and thus invite substantial risk not only in terms of patient welfare, but also in terms of the cost of late-stage clinical trial failure. The integration of novel and traditional approaches to preclinical toxicity assessment will have a major impact on the ability to predict compound behavior in humans, reduce clinical trial failure, and cut both risk and cost in drug development.
Scope
D&MD's Market Analysis Report, Managing Toxicology for the Future: Improving Predictive Power Through Integrated Technologies, discusses the critical challenges associated with ADME/Tox testing during pharmaceutical R&D, including the requirements for:
- New strategies to minimize toxicity-related drug failures aimed at improving R&D productivity and pharmaceutical risk management.
- Breath of expertise in multiple disciplines to deal with a complex and fragmented technology landscape, such as "omics" technologies and in silico approaches.
- Integrative activities that combine new and old approaches to assess drug safety in a highly regulated and risk-aversive environment.
- Industry-wide collaborative efforts to build the necessary research infrastructure for toxicology, including toxicology databases and computational models.
Table of Contents
Chapter 1: Introduction: Industry Environment
- Focus of the Report
- The Pharmaceutical Industry: A Historical Perspective
- The Problem-The Increase in R&D Costs
- Industrialization of Drug Discovery
- The Trend Toward Pulling Risk Upstream
- The Three Bottlenecks of Pharmaceutical R&D
- 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
