Declining industrial productivity has forced companies to urgently address the areas of drug development that are most likely to lead to the failure of a new compound. Innovations are required that can support the earlier termination of drugs which will be toxic in humans and cause rare events that are unlikely to be identified in clinical trials. Major pharma companies have subsequently begun to implement an array of new technologies for drug safety prediction into the discovery phases of research.
’Early Stage Drug Safety Strategies and Risk Management’ is a report published by Business Insights that identifies the new predictive technologies which can facilitate the earlier termination of potentially unsuccessful compounds. Emerging approaches in key areas such as hepatotoxicity, nephrotoxicity and cardiotoxicity are examined, and the collaborative efforts of academia and technology developers in driving the discovery of safety predictive methods and biomarkers are reviewed. This report evaluates the latest innovative predictive technologies being introduced into pre-clinical and early clinical development phases and also explores the potential cost savings and challenges associated with their implementation.
Key Findings
Future improvements in drug discovery will include the modeling of a wider range of toxicities, such as hepatotoxicity, and formations of reactive metabolites that might lead to idiosyncratic toxicity. Developments in high-throughput technologies, systems biology and bioinformatics have also enabled virtual modeling for whole organs.
High-content screening is increasingly important for identifying toxicity endpoints in a drug discovery setting. The methods use automated microscopy with image analysis to measure the effects of compounds on cell health. Improvements are required in the cell types used and the number of toxicity endpoints that can be studied reliably.
Novel in vivo models are now available including zebrafish screens, which are suited for use at the lead optimization stage or earlier. Humanized rodent models, in which key enzymes responsible for metabolism have been replaced by their human counterparts, may also be suitable for use in candidate selection.
Pharmacometric modeling and simulation and novel study methods such as adaptive designs are increasingly being applied in drug development to make the most of the data collected and to guide the choice of dose for clinical application.
Use this report to
• Assess key technologies for predicting drug safety in the earliest stages of discovery and clinical development with this report’s comprehensive analysis of emerging approaches across in silico, in vitro and in vivo preclinical technologies.
• Identify which companies are leading the field in safety prediction for new drugs, understand the strategic implementations for large pharma companies and examine the role of public-private consortia in solving key issues within this field of predictive safety.
• Discover the extent to which predictive safety technologies can provide potential cost savings and improvements in attrition rates and assess the challenges and risks associated with the implementation.
• Understand the latest strategies to improve safety evaluation in early clinical development with this report’s analysis of the latest approaches in exploratory and Phase I clinical trials.
Explore issues including
The impact of failure; Declining productivity in the pharma industry has intensified the need to create innovative solutions to reduce new compound failures. The current likelihood of a project progressing from Phase 1 to approval is roughly 20%, although in some therapeutic areas this may be as low as 8%.
The importance of collaboration; Sharing information and expertise across companies can drive the field forward in a way that is impossible for these organizations individually. Biomarker data from some of the major consortia has been submitted to regulators, and this represents significant progress, most notably within the field of renal toxicity.
Better predictive animal models; Rodent and non-rodent models used in drug development are expensive and the results do not always translate well to the human situations. A survey carried out in 1999 reported a true positive concordance rate between animal and human data of 71% for rodent and non-rodent species (63% for non-rodents and 43% for rodents alone).
The need for early assessment of key clinical attributes; Exploratory trials are particularly useful for gaining early insight into human ADME characteristics including mass balance, metabolite and absolute bioavailability parameters that would not traditionally be collected until Phase 2 or later. These studies use microdoses and can explore more candidates at a lower cost than a traditional ’First in Man’ study.
Discover
• Which technologies are leading the way in predicting potential safety problems in the earliest stages of drug discovery and development as possible?
• What are the contributions of in silico, in vitro, and in vivo methods in the non-clinical stages of drug development?
• What are the goals of public-private consortia in driving the discovery of methods and biomarkers and how much have they achieved to date?
• How can the data collected in early human clinical trials be improved to better inform decision-making about potentially safe candidates?
Early Stage Drug Safety Strategies and Risk
Management: Maximizing opportunities towards achieving clinical success. Executive Summary 10
Introduction 10
Modeling and simulation in drug discovery 11
Novel in vitro technologies for predictive safety testing 12
Novel in vivo methods in for non-clinical safety assessment 12
Current initiatives in preclinical drug safety 13
Strategies to improve safety evaluation in early clinical development 14
Challenges and cost saving opportunities 16
Chapter 1 Introduction 18
Summary 18
State of the industry 19
Drug attrition 20
Innovation in drug safety 21
Report outline 28
Chapter 2 Modeling and simulation in drug discovery 32
Summary 32
Introduction 33
Molecular modeling 34
Structure-toxicity relationships 35
Epix Pharmaceuticals’ in silico discovery platform 37
Chemoinformatic methods 38
Collaborative projects 41
Biosimulation 42
Virtual models of whole organs 43
Conclusions 45
Chapter 3 Novel in vitro technologies for predictive safety testing 48
Summary 48
Introduction 49
Toxicogenomics and systems biology 50
Commercial platforms 53
Cell-based assays 56
Stem cells 61
Conclusions 65
Chapter 4 Novel in vivo methods in for nonclinical safety assessment 68
Summary 68
Introduction 69
Zebrafish 70
Whole animal imaging and microscopy 73
Humanized rodent models 79
Conclusions 80
Chapter 5 Current initiatives in preclinical drug safety 84
Summary 84
Introduction 85
The Predictive Safety Testing Consortium 86
The International Life Sciences – Health and Environmental Sciences
Institute 88
The InnoMed PredTox project 89
The Innovative Medicines Initiative 92
Additional consortia 93
The Chemical Effects in Biological Systems Database 93
The Japanese Toxicogenomics Project 93
Liver Toxicity Biomarker Study 94
Consortium for Metabonomic Toxicology 94
Other European funded initiatives 95
ACuteTox 95
Reprotec 96
Predictomics 96
CarcinoGenomics 97
Conclusions 97
Chapter 6 Strategies to improve safety evaluation in early clinical development 100
Summary 100
Introduction 101
Exploratory clinical trials 102
Other applications of AMS 106
Industry uptake 108
Regulatory status 108
The future for AMS-based studies 109
Technologies 109
Linking pharmacology data to microdose studies 109
Improving safety evaluation in Phase 1 110
Biomarkers in Phase 1 clinical trials 110
Pharmacogenomics and rare, idiosyncratic adverse events 115
Pharmacometrics – modeling and simulation to improve Phase 1 safety 116
Optimizing early clinical trial design 119
QT in Phase 1 121
The Thorough QT Study 121
Timing of the TQT study 124
Intensive QT studies in early Phase 1 124
Costs and decision making 125
Conclusions 125
Chapter 7 Challenges and cost saving opportunities 128
Summary 128
Introduction 129
Implementation of new technologies 129
New technologies, new risks 132
Qualifying biomarkers 133
Translational medicine 135
’Fail early, fail often’ 136
Conclusions 141
Chapter 8 Appendix 142
Primary research methodology 142
Acknowledgments 143
Index 144
Glossary 145
Glossary 145
Bibliography 148
Endnotes 153
List of Figures
Figure 1.1: Pharma industry productivity decline (1995-2007) 19
Figure 1.2: Reasons for drug attrition 24
Figure 1.3: The place of innovative safety evaluation strategies in drug discovery and development 25
Figure 1.4: Serious adverse events: research priorities 26
Figure 2.5: In silico methods contribute to the earliest stages of drug discovery 33
Figure 2.6: The Safety Intelligence Program from BioWisdom 39
Figure 2.7: Examples of assertions in the Safety Intelligence Program from BioWisdom 40
Figure 3.8: Novel in vitro methods and their use in drug discovery and development 50
Figure 3.9: A typical toxicogenomics workflow in the pharma industry 52
Figure 4.10: Novel in vivo methods and their use in drug discovery and development 70
Figure 4.11: Whole body microPET images through a rat showing 18F-FDG distribution 75
Figure 5.12: Study design and investigations used in the InnoMed PredTox project 90
Figure 6.13: The ’learn and confirm’ model of drug development 101
Figure 6.14: The place of innovative technologies in early clinical safety assessment 102
Figure 6.15: Comparison of midazolam pharmacokinetics at microdose and therapeutic dose levels in the CREAM study 105
Figure 6.16: Proposed decision tree for integration of pharmacogenetic studies in early drug development 115
Figure 6.17: Information utilized in model-based drug development 118
Figure 6.18: Key attributes of a thorough QT study 123
Figure 7.19: Success rate improvements from increasing investment in technologies for early safety prediction 139
List of Tables
Table 1.1: Failure rates at each stage of clinical drug development 20
Table 1.2: Drugs withdrawn from the market in the US between 1998 and April 2008 21
Table 3.3: Examples of companies providing platforms for toxicogenomics 53
Table 3.4: Examples of companies offering integrated software suites for the analysis of toxicogenomic data 55
Table 3.5: Examples of contract laboratories offering HCA cytotoxicity screening 59
Table 3.6: Examples of companies offering stem cells for toxicity testing 63
Table 4.7: Advantages and disadvantages of zebrafish for toxicity screening 71
Table 4.8: Companies offering zebrafish toxicity screening products and services 72
Table 4.9: Advantages of molecular imaging of whole animals for preclinical studies 76
Table 4.10: Manufacturers of molecular imaging equipment and probes 77
Table 4.11: Companies developing transgenic models for ADMET testing 79
Table 5.12: Biomarker candidates identified by the InnoMed PredTox project 91
Table 6.13: Companies offering AMS services 103
Table 6.14: Advantages and disadvantages of AMS-based microdosing studies 104
Table 6.15: Advantages and disadvantages of using AMS for mass balance and absolute bioavailability studies 107
Table 6.16: Core list of validated genomic biomarkers involved in ADME 112
Table 6.17: Examples of valid genomic biomarkers in drug labels 113
Table 6.18: Pharmacometric consultancies 119
Table 7.19: Definitions and examples of safety biomarkers with different levels of qualification134
Table 7.20: Success rate improvements from increasing investment in technologies for early safety prediction 137
Table 7.21: Success rate improvements from increasing investment in technologies for early safety prediction 140
Other selected research from the 'Biotechnology' category:
Biotechnology: Global Industry Guide
Early Stage Drug Safety Strategies and Risk Management: Maximizing opportunities towards achieving clinical success
Other selected research from the 'Drug Discovery' category:
Biosimilars and Follow-On Biologics Report: The Global Outlook 2009-2024
Translational Medicine - Drug Development Transformed? (Market Focus)