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Early Stage Drug Safety Strategies and Risk Management: Maximizing opportunities towards achieving clinical success

NEW YORK, Oct. 26, 2011 /PRNewswire/ -- announces that a new market research report is available in its catalogue:

Early Stage Drug Safety Strategies and Risk Management: Maximizing opportunities towards achieving clinical success

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.


• 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?

Table of Contents

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

To order this report:

Pharmaceutical Industry: Early Stage Drug Safety Strategies and Risk Management: Maximizing opportunities towards achieving clinical success

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Nicolas Bombourg
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Intl: +1 805-652-2626

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