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7:00am Registration (Open until 5:30pm)

8:00 Plenary Keynote Introduction
Edward G. Heidig, General Counsel and Deputy Secretary, Business, Transportation and Housing Agency

8:10 Risk Diagnosis for Disease Prevention
C. Thomas Caskey, M.D., F.A.C.P., Director and Chief Executive Officer, BrownFoundation Institute of Molecular Medicine, University of Texas Health Science Center
There are an increasing number of presymtomatic diagnostic options which include: genetic, imaging, and analyte technology. Examples of linking a specifi c diagnostic to a therapeutic decision and FDA approval have fueled the activity for personalized medicine. It must be appreciated that diagnostic capacity emerges far more rapidly than an approved safe therapeutic. Thus the personalized medicine goal has a bottle neck for broad utility. A strategy of studying approved drugs for maximal effi cacy is realistic and reasonable toward that goal since it is estimated that many approved drugs are effective in less than 50% of patients. These approaches will be discussed.

8:55 Disruption of the Pharmaceutical Industry: Moving from Products to Solutions
Theodore J. Torphy, Ph.D., Corporate Vice President & Head, Science & Technology, Johnson & Johnson
The pharmaceutical industry is bracing itself for a period of unprecedented challenges. This new era for our industry is being brought on by the confluence of several environmental factors, both internal and external to the industry, including; 1) non-sustainable increases in healthcare expenditures, 2) spiraling costs and decreasing productivity of R&D, 3) reimbursement driven by medical and economic outcomes, and 4) the proliferation and redistribution of healthcare outcomes information. Although all of these factors threaten to disrupt our industry, it is the evolving transparency in healthcare outcomes information that represents the most unsettling threat to our current business model, as well as the largest opportunity to transform our industry. For this transformation to take place, it is imperative that we change from an industry in which the sole mission is to provide products to one that provides broader, cost-effective solutions to areas of major healthcare needs.

9:40 Grand Opening Refreshment Break in the Exhibit Hall

11:00 Chairperson's Remarks
William B. Mattes, Ph.D., DABT, Director of Toxicology, The Critical Path Institute (invited)

11:10 Improving R&D Productivity Through Better Preclinical Decision Making and Science
B. Michael Silber, Ph.D., Senior Vice President and Head Safety & Technical Sciences (Preclinical Development), Roche Pharmaceuticals, LLC
We have considered all of the significant contributors to overall productivity, as measured by getting a new medicine to registration, regulatory approval and launch. The major contributors to attrition and survival include the confidence in rationale (CIR) and confidence in the safety (CIS) for the target, and CIR and CIS for the compound, impacting on success in each of the phases of discovery and development. Development strategies often assume success and build in significant front-loading and cost, but don’t take into account the probability of success. Significant increases in productivity are possible if flexible strategies to development are adopted early as opposed to one size fits all, which is the norm. This includes appropriate preclinical development strategies dependent on the early Phase I plans in the clinic. We have developed and applied a simulator-based model to R & D that suggests significant increases in productivity can be achieved without increases in budget. We will discuss what this means in preclinical development, with a focus on alternative strategies and plans. This approach will require fundamental re-thinking at senior levels to ensure success for this innovative approach. It will focus on developing the right package at the appropriate time to hypothesis testing and proof of concept.

11:55 Toxicity Testing in the 21^st Century: Opportunities for Pharmaceutical Risk Assessment
Daniel Krewski, Ph.D., MHA, Professor and Director, McLaughlin Centre for Population Health Risk Assessment, University of Ottawa
Current approaches to toxicity testing of environmental agents rely primarily on a complex array of studies that evaluate adverse effects in intact animals at high doses. Anticipating the opportunities that will be provided by recent scientific advances in cell and molecular biology, genomics, high-throughput robotics, bioinformatics, computational systems biology, and other disciplines, the National Research Council ‘s Committee on Toxicity Testing and Assessment of Environmental Agents developed a long-range vision for toxicity testing and a strategic plan for implementing that vision. This vision was designed to (i) develop a more robust scientific basis for assessing adverse health effects of environmental agents, (ii) provide broad coverage of chemicals, chemical mixtures, outcomes, and life stages, and (iii) reduce the cost and time of toxicity testing. In addition, the process envisioned would greatly reduce the numbers of animals used in toxicity testing. The main elements of the vision will be outlined in detail, and the potential applications of the vision to assessing the potential risks of pharmaceutical products examined.

12:40pm Technology Spotlight (Sponsorship Available)

1:10 Walk & Talk Luncheon in the Exhibit Hall

2:15 Chairperson's Remarks
Joy Cavagnaro, Ph.D., DABT, RAC, President, Access BIO

2:20 Overview
William B. Mattes, Ph.D., DABT, Director of Toxicology, The Critical Path Institute

2:40 From Publication to Practice: Interlaboratory Validation of Microarray and QPCR-based Signatures for Predicting Carcinogenicity in the Rat
Mark Fielden, Ph.D., DABT, Discovery and Investigative Safety, Non-Clinical Drug Safety, Roche Palo Alto LLC
Interlaboratory evaluation of putative biomarkers is essential for their validation prior to use, however, the majority of efforts to date are limited to single publications and/or analytical platforms, thus limiting their general applicability. Based on hepatic changes in gene expression, the Carcingenicity Working Group of the Critical Path Institute has validated biomarkers of non-genotoxic carcinogens across companies and are working towards developing a QPCR-based platform for larger deployment and tier 2 validation. It is anticipated that the interlaboratory validation and widely accessible platform will provide industry with a valuable tool to evaluate the potential for molecules to induce tumors in the rat, thus providing essential information for early human risk assessment and assist in compound prioritization and selection.

3:00 Mechanistic Cardiac Modeling: Concepts and Utility in Drug Development
Anna Georgieva, Ph.D., Associate Director, Modeling & Simulation, and Ruben Bibas, Ph.D., Biology Modeler, Modeling & Simulation, Novartis Inc.
Blockade of the delayed rectifier potassium channel current, I(Kr), has been associated with drug-induced QT prolongation in the electrocardiogram and life-threatening cardiac arrhythmias. However, it is increasingly clear that compound-induced interactions with multiple cardiac ion channels may significantly affect QT prolongation that would result from inhibition of only I(Kr). A complete experimental pre-clinical assessment of the pro-arrhythmic potential of all drug candidates may not be feasible due to multi-factorial processes that are also time-dependent and highly non-linear. Here, we present an example of a systems-based integrative modeling approach to characterizing risk carried by pharmaceutical compounds based on limited preclinical data.

3:20 Advances in Liver Toxicity Testing: What's on the Horizon?
Holly L. Jordan, DVM, PhD, Dipl. ACVP, Director of Clinical Pathology, Safety Assessment, GlaxoSmithKline
Current approaches to evaluation of liver injury in drug safety testing rely extensively on histopathologic and clinicopathologic assessment in preclinical species. These standard elements successfully predict the potential for hepatotoxicity in the clinical setting in only about half of the cases. Through comprehensive, collaborative efforts, such as the Hepatotoxicity Working Group in the Predictive Safety Testing Consortium of the Critical Path Institute, a number of novel preclinical and clinical biomarkers of liver injury have been proposed and are currently under evaluation worldwide. These candidate predictive markers are designed to address general hepatotoxicity or in some cases, very specific types of liver injury. Modalities under investigation encompass a variety of technologies, including new and/or modified serum enzyme assays and gene expression panels with an emphasis on non-invasive or minimally invasive testing that can be applied to preclinical species and humans.

3:40 SDAR: Spectrometric Data Activity Relationship Modeling
Dan Buzatu Ph.D., Research Chemist, National Center for Toxicological Research, FDA
A brief introduction to a class of novel and highly accurate modeling methods capable of predicting chemical and biological properties for substances based on chemical spectral information. This includes chemical reactivity, biological activity, and toxicity. The presentation will include a discussion regarding the fundamental concepts behind the principle, several examples of published SDAR models, and advancements to the original technique that increase predictive accuracy.

3:55 Modeling and Assaying Dioxin-Like Biological Effects for Both Dioxin-Like and Certain Non-Dioxin-Like Compounds
Jon Wilkes, Ph.D., Research Chemist, National Center for Toxicological Research, FDA
Quantitative spectrometric data-activity relationship (QSDAR) models were used to correlate ¹³C NMR data to World Health Organization Toxic Equivalency Factors (TEFs) of the 29 polychlorinated dioxin-like compounds (PCDDs, PCDFs, or PCBs) for which non-zero TEFs have been defined. The best QSDAR models predicted TEFs of 0.037 and 0.004, respectively, for 1,3,7,8-tetrachlorodibenzo--dioxin (TCDD) and 1,2,3,4,7-pentachlorodibenzo--dioxin (PeCDD), both of which are among the 390 congeners for which zero value TEFs are assumed. A QSDAR model of Relative Potency (REP) values estimated the corresponding values as 0.115 and 0.020. Both models indicated that these two congeners are likely to exhibit significant dioxin-like toxicity. We used a luciferase gene expression in vitro assay based on mouse liver cells to determine experimental REPs of 0.027 and 0.013, respectively, for 1,3,7,8-TCDD and 1,2,3,4,7-PeCDD. The corresponding QSDAR-estimated and gene-expression assayed values were in close agreement with the predicted values demonstrating that SDAR prediction followed by a relatively inexpensive in vitro assay could be used to nominate a few candidates among hundreds for expensive in vivo evaluation.

4:20 Reception in the Exhibit Hall (Sponsorship Available)

5:00 - 6:00pm Break-out Discussions in the Exhibit Hall