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 Humanized rodent models, in which key enzymes responsible for metabolism have been replaced by their human counterparts, may also be suitable for use in candidate selection.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?