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2014 Continuing Education Courses

SR01 Combination Products: Toxicology and Regulatory Challenges Basic Book
AM02 Computational and Experimental Aspects of microRNAs in Toxicology Advanced Book
AM03 Current Trends in Genetic Toxicology Testing Basic Book
AM04 Elucidating Adverse Outcome Pathways (AOPs) for Developmental Toxicity Basic Book
AM05 Inhalation Studies: Challenges and Complexities Basic Book
AM06 Methodologies in Human Health Risk Assessment Basic Book
AM07 Nonclinical Animal Models Enabling Biopharmaceutical Advances in Translational Medicine Basic Book
PM08 Nanotoxicology: Past Achievements, Future Challenges, and Potential Solutions Basic Book
PM09 Epidemiology for Toxicologists: What the Numbers Really Mean Basic Book
PM10 Innovations in Methodologies for Inhalation Exposure and Interpretations of In Vivo Toxicity Advanced Book
PM11 Nonclinical Pediatric Drug Development: Considerations, Study Designs, and Strategies Basic Book
PM12 Stem Cells in Toxicology Basic Book
PM13 Translational Biomarkers in the Assessment of Health and Disease Advanced Book

Combination Products: Toxicology and Regulatory Challenges

SR01—CE Basic

Theme: Safety Assessment: Mechanisms and Novel Methods

Chairperson(s): Jon Cammack, AstraZeneca Biologics, Gaithersburg, MD, and Chandramallika (Molly) Ghosh, US FDA, Silver Spring, MD.

Sponsor(s):
Career Resource and Development Committee
Drug Discovery Toxicology Specialty Section
Medical Device Specialty Section

Therapeutic and diagnostic products that combine drugs, devices, and/or biological elements are termed and regulated by US Food and Drug Administration (US FDA) as combination products. Technological advances continue to merge product types and blur the historical lines of separation among traditional drugs, biologics, and medical devices. Concomitantly, US FDA’s medical product centers, the Center for Biologics Evaluation and Research (CBER), the Center for Drug Evaluation and Research (CDER), and the Center for Devices and Radiological Health (CDRH), are employing ever-evolving collaborative efforts to address the regulatory complexities of combination products. Because combination products involve components that would normally be developed and regulated under different types of processes and policies (and frequently submitted to different US FDA Centers), these products raise challenging development, regulatory, and review management questions. Differences in these pathways for each combination product type can impact the processes for all aspects of product development and management (especially preclinical testing), but also clinical investigation, marketing applications, manufacturing and quality control, adverse event reporting, promotion and advertising, and post-approval modifications. Trends and strategies for addressing the impact of overlapping technologies and evolving regulatory processes in developing a successful preclinical evaluation program will be highlighted. A regulatory overview of definitions and combination product examples, as well as a high-level review of US FDA’s final rule (effective July 22, 2013), will be included. A primary focus of the course is discussion of approaches in optimizing a preclinical program for a hypothetical drug-device combination product (e.g., a monoclonal antibody packaged in a prefilled syringe). Additionally, regulatory overview of the preclinical evaluation program will be provided. Future trends in combination product therapies will also be highlighted.

Overview of Combination Products. Thinh Nguyen, US FDA Office of Combination Products, Silver Spring, MD.

Overview of a Development Program for a Hypothetical Combination Product. Jon Cammack, AstraZeneca Biologics, Gaithersburg, MD.

Regulatory Overview of Preclinical Assessment of Combination Products. Chandramallika (Molly) Ghosh, US FDA, Silver Spring, MD.

Computational and Experimental Aspects of microRNAs in Toxicology

AM02—CE Advanced

Theme: Advancing Clinical and Translational Toxicology and Application of Biomarkers

Chairperson(s): Susan C. Tilton, Pacific Northwest National Laboratory, Richland, WA, and Tamara L. Tal, US EPA, Research Triangle Park, NC.

Sponsor(s):
Drug Discovery Toxicology Specialty Section
Mechanisms Specialty Section
Molecular Biology Specialty Section

MicroRNAs (miRNAs) are small noncoding RNAs that function as post-transcriptional regulators of gene expression. miRNAs are increasingly recognized for their importance in regulating mechanisms of disease and exposure, including those associated with nervous system development, cardiac function, metabolism and cancer. miRNAs and their transcriptional targets are highly conserved across species. They are also stable in plasma and urine as biomarkers of tissue-specific damage or response. Furthermore, miRNAs are unique in that not only can they be experimentally measured along with their inhibitory effects on transcript and protein levels, but their post-transcriptional regulation can also be computationally predicted based on sequence specificity and conservation across species. Given the overall importance of miRNAs in toxicology, it is necessary to understand both computational and experimental aspects of miRNAs for accurate miRNA quantification and discovery of the functional consequences of their disruption by chemical or drug exposure. The goal of the course is to provide toxicologists with a better understanding of miRNA biology (biogenesis, sequence, structure, function, and species similarities), the experimental and computational resources available for identification and target prediction and how these resources can be leveraged to identify mechanisms and biomarkers of toxicity.

Background on miRNA Biology and Relationship to Toxicology. Igor Pogribny, US FDA-NCTR, Jefferson, AR.

Experimental Methods for Measuring Circulating RNAs. Kai Wang, Institute for Systems Biology, Seattle, WA.

Computational Resources for miRNA Identification, Target Prediction, and Integration of Co-Expressed miRNAs and mRNAs. Susan C. Tilton, Pacific Northwest National Laboratory, Richland, WA.

Network and Pathway Analysis of miRNA Data. Richard J. Brennan, Sanofi, Waltham, MA.

Strategies for Developing miRNA Biomarkers of Toxicity. Karol L. Thompson, US FDA-CDER, Silver Spring, MD.

Current Trends in Genetic Toxicology Testing

AM03—CE Basic

Theme: Safety Assessment: Mechanisms and Novel Methods

Chairperson(s): B. Bhaskar Gollapudi, Exponent, Midland, MI, and Stephen Dertinger, Litron Laboratories, Rochester, NY.

Sponsor(s): Regulatory and Safety Evaluation Specialty Section

The scientific discipline of genetic toxicology has played an important role in the safety assessment of existing and new chemicals during the past four decades. This field has undergone significant changes during this time, not only in its regulatory applications, but also in the tools and technologies employed to identify adverse events. While the emphasis during the early years was on protecting germ cells and future generations from the deleterious effects of mutagenic agents, the focus shifted in later years towards identifying carcinogenic chemicals through the use of short-term assays. Furthermore, genetic toxicology tended to operate as a standalone discipline, generating qualitative data and placing little importance on dose-response analysis or integration with other toxicology measurements. The field is now in the midst of a sea change. Regulatory requirements across the globe are being harmonized, with emphasis on “3 Rs.” For example, recent changes to ICH and OECD testing guidelines promote the integration of genetic toxicology endpoints (e.g., Comet, micronucleus, and gene mutation) into repeat-dose general toxicology studies. This integrated approach benefits the interpretation of genotoxic findings by placing them in context with other toxicology data, including pharmacokinetics and pharmacodynamics. Additionally, regulatory initiatives such as REACH stress the importance of germ cell effects as part of a comprehensive assessment of genotoxicity. Guidelines for the study of mutations in germ cells of transgenic animals (OECD 488) have recently been finalized. Rapid advances in molecular biology are facilitating the integration of genomic biomarkers into standard toxicology studies to identify various classes of genotoxic agents (DNA reactive and DNA nonreactive). Finally, genetic toxicology is moving from a qualitative science to the quantitative assessment of dose-responses including the identification of point-of-departure (PoD) metrics to extrapolate effects to realistic human exposure levels. The course is designed to provide a comprehensive overview of recent changes and newly established practices in the field with emphasis on their application in safety assessments.

Introduction. B. Bhaskar Gollapudi, Exponent, Midland, MI.

Integration of Genetic Toxicology Endpoints Into Repeat Dose Studies. Stephen Dertinger, Litron Laboratories, Rochester, NY.

Resurgence of Transgenic Animals in Genotoxicity Testing. Robert H. Heflich, US FDA-NCTR, Jefferson, AR.

Approaches to Genetic Toxicology Testing in the Era of Genomics. Matthew J. LeBaron, The Dow Chemical Company, Midland, MI.

Quantitative Assessment of Dose-Response in Genetic Toxicology Studies. B. Bhaskar Gollapudi, Exponent, Midland, MI.

Elucidating Adverse Outcome Pathways (AOPs) for Developmental Toxicity

AM04—CE Basic

Theme: Safety Assessment: Mechanisms and Novel Methods

Chairperson(s): Thomas B. Knudsen, US EPA, Research Triangle Park, NC, and George P. Daston, Procter & Gamble Company, Mason, OH.

Sponsor(s):
Regulatory and Safety Evaluation Specialty Section
Reproductive and Developmental Toxicology Specialty Section
Scientific Liaison Coalition

An Adverse Outcome Pathway (AOP) is a theoretical construct that integrates the biological plausibility and weight of evidence supporting a linkage between a Molecular Initiating Event (MIE) to adverse response at the individual or population level. Conceptually, an AOP spans multiple levels of biological organization and organizes the stepwise propagation of chemical disruption from MIE to toxicological outcome via a series of key events. Qualitatively, the concept of an AOP is basic to establishing plausible hypotheses and weight of evidence for chemical mode of action. This has practical use in the integration of high-dimensional data with knowledge of a complex biological system and focusing research planning on critical data needs identified as gaps in the AOP, thereby enhancing current risk assessment practices. Alternatively, development of more quantitative AOP constructs requires a framework to delineate causal relationships across a temporal series of events, and will support more realistic quantitative risk assessment. As AOPs are initially governed by signaling networks and metabolic processes, SNPs in key genes relevant to the AOP could point toward susceptible populations. The course will delve into the science of AOP elucidation from a system biology perspective, focusing on developmental processes and toxicities for early life stage susceptibilities. The presenters will each focus on making extensive use of current knowledge, informatics and data-mining tools to advance predictive toxicology.

Systems Pathway-Knowledge Tools for Constructing AOPs. Daniel L. Villeneuve, US EPA, Duluth, MN.

Constructing AOPs for Developmental Toxicities. Nicole Kleinstreuer, Integrated Laboratory Systems, Inc./NICEATM, NIEHS, Research Triangle Park, NC.

AOP Frameworks for Simulating Dysmorphogenesis. Thomas B. Knudsen, US EPA, Research Triangle Park, NC.

AOPs for Endocrine Signaling and Reproductive Development. George P. Daston, Procter & Gamble Company, Mason, OH.

AOPs for Developmental Neurotoxicity: Principles and Experimental Approaches. Alexey Terskikh, Sanford-Burnham Medical Research Institute, La Jolla, CA.

Inhalation Studies: Challenges and Complexities

AM05—CE Basic

Theme: New Science and Perspectives Surrounding Environmental and Occupational Exposures

Chairperson(s): Gregory L. Baker, Battelle, West Jefferson, OH, and Willie J. McKinney, Altria Client Services, Richmond, VA.

Sponsor(s): Inhalation and Respiratory Specialty Section

The successful execution of animal inhalation studies (e.g., acute, subchronic, and chronic) present many challenges and complexities not encountered with other routes of exposure. Five inhalation study challenges will be addressed: 1) Comparison of methods of exposure and potential impact on inhalation studies; 2) Using various test materials, generating simple atmospheres (e.g., exposures to gases, nanoaerosols, bioaerosols, micron-sized aerosols) and mixtures (e.g., semivolatile compounds and particles, tobacco smoke); 3) selection of the appropriate animal species (e.g., species specific dosimetry); 4) incorporating standard and novel toxicological endpoints; 5) deciding which regulatory guidance document or specifications (e.g., US EPA, US FDA, OECD, and NTP) to follow. The diversity of presenters’ backgrounds (government, contract research organization, industry, and academic), and depth of experience, will provide a broad and rich resource for the participants.

Introduction. Willie J. McKinney, Altria Client Services, Richmond, VA.

Comparison of Whole Body vs. Nose-Only Exposure. Robert F. Phalen, University of California Irvine, Irvine, CA.

Test Materials for Inhalation Studies. Gregory L. Baker, Battelle, West Jefferson, OH.

Inhalation Studies—Test Subjects and Dose Predictions. Michael J. Oldham, Altria Client Services, Inc., Richmond, VA.

Toxicological Endpoints in Inhalation Studies. Jack R. Harkema, Michigan State University, East Lansing, MI.

Regulatory Guidance for Inhalation Studies. Mark A. Higuchi, US EPA, Research Triangle Park, NC.

Methodologies in Human Health Risk Assessment

AM06—CE Basic

Theme: Enhancing Strategies for Risk Assessment

Chairperson(s): Qiyu (Jay) Zhao, US EPA, Cincinnati, OH, and M.E. (Bette) Meek, University of Ottawa, Ottawa, ON, Canada.

Sponsor(s):
Biological Modeling Specialty Section
Regulatory and Safety Evaluation Specialty Section
Risk Assessment Specialty Section

This course provides an overview of more advanced aspects of chemical risk assessment, following up from a successful CE course on basic principles offered at the Annual Meeting in 2013. This new course will focus on methodologies, which incorporate increased use of biological and chemical specific data as a basis to provide more accurate estimates of risk. In addition, it will address evolving areas such as problem formulation as a basis to better target toxicity testing and tailor assessments to the needs of risk management. The course will feature presentations and discussions focusing on the value of mode of action analysis for characterization of hazard, the fundamental tenets of physiologically based pharmacokinetic (PBPK) model development and implementation, use of benchmark dose (BMD) models to identify points of departure, and use of chemical specific adjustment factors to address inter- and intraspecies uncertainty and variability. The principles and key components of these methodologies will be illustrated with applied case examples from the regulatory risk assessment arena.

An Overview of Advanced Aspects of Risk Assessment. M.E. (Bette) Meek, University of Ottawa, Ottawa, ON, Canada.

Mode of Action Analysis. M.E. (Bette) Meek, University of Ottawa, Ottawa, ON, Canada.

Benchmark Dose Modeling. Qiyu (Jay) Zhao, US EPA, Cincinnati, OH.

Physiologically Based Pharmacokinetic and Pharmacodynamic Modeling. Hugh A. Barton, Pfizer, Inc., Groton, CT.

Nondefault Uncertainty Factor Values. John C. Lipscomb, US EPA, Cincinnati, OH.

Nonclinical Animal Models Enabling Biopharmaceutical Advances in Translational Medicine

AM07—CE Basic

Theme: Advancing Clinical and Translational Toxicology and Application of Biomarkers

Chairperson(s): Thomas M. Monticello, Amgen Inc., Thousand Oaks, CA, and Vivek Kadambi, Millennium, Cambridge, MA.

Sponsor(s):
Clinical and Translational Toxicology Specialty Section
Comparative and Veterinary Specialty Section
Toxicologic and Exploratory Pathology Specialty Section

A fundamental theme in drug discovery and nonclinical development is the utilization of appropriate animal models that are predictive for efficacy or adverse events in humans administered a novel biopharmaceutical. The accurate prediction of human adverse effects using nonclinical animal toxicology studies remains a major goal in drug development and relies on appropriate animal models. Essential attributes for an appropriate animal model include similar target distribution, target pharmacology, systemic pharmacokinetics, metabolism, and distribution to those of humans. Utilization of the most appropriate animal model aligns with the 2011 US FDA Strategic Plan to advance regulatory science and modernize toxicology in order to enhance product safety and develop better models of human adverse responses. The Preclinical Safety Leadership Group (PSLG) of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) is creating a contemporary industry-wide database to determine accuracy with which the interpretation of nonclinical safety assessments in animal models correctly predicts human risk. The course will present considerations for the selection of an appropriate animal model for nonclinical safety, the use of animal models of disease in safety testing, emerging use of the minipig in safety testing, data from an industry-wide nonclinical to clinical translational database, and the use of animal safety data in the design and conduct of clinical trials. Output from the course will help identify advances and remaining gaps in the utilization of animal models in biopharmaceutical development.

Introduction. Thomas M. Monticello, Amgen Inc., Thousand Oaks, CA.

What Constitutes a Relative Animal Model in Translational Medicine? Rakesh Dixit, MedImmune Inc., Gaithersburg, MD.

Use of Animal Models of Human Disease for Nonclinical Safety Assessment of Pharmaceuticals. Sherry J. Morgan, Abbvie, North Chicago, IL.

The Minipig As a Nonrodent Species in Nonclinical Safety Testing and Where Are We Now? Niels-Christian Ganerup, Ellegaard Göttingen Minipigs A/S, Dalmose, Denmark.

Nonclinical to Clinical Translational Safety Database Initiative. Vivek Kadambi, Millennium, Cambridge, MA.

Utilization of Nonclinical Animal Data in the Conduct of Human Clinical Trials. John T. Sullivan, Amgen Inc., Thousand Oaks, CA.

Nanotoxicology: Past Achievements, Future Challenges, and Potential Solutions

PM08—CE Basic

Theme: New Science and Perspectives Surrounding Environmental and Occupational Exposures

Chairperson(s): Saber Hussain, US Air Force, Wright-Patterson AFB, Dayton, OH and David B. Warheit, DuPont Haskell Laboratories, Newark, DE.

Sponsor(s): Nanotoxicology Specialty Section

Nanomaterials (NM) possess tremendous promise to advance consumer, military, and medical applications due to their unique physicochemical properties, such as enhanced surface area, tunable size, modifiable surface chemistry, and particle reactivity. However, these same properties have made NMs a potential health hazard, thus giving rise to the field of nanotoxicology (NT), which has become a prominent player in toxicological advancement and research over the past decade. Initial NT studies were limited by a lack of both available materials and characterization tools. Through advances in material science, enhanced capabilities have been developed that allow for the synthesis of distinctive NMs and the ability to accurately evaluate their characteristics. Taking advantage of these developments, NT has made remarkable progress in evaluating the hazards of NMs and correlating specific properties, such as size, shape, coating, and composition, to observe cytotoxicity. However, even with these numerous advances, there are still a number of constraints plaguing the field of NT. One principal area of concern is the development of procedures that account for new NT facets; including NM behavior in a physiological environment, varied aggregate structure, role of ionic dissolution, and realistic modes of exposure. Another limitation is the need for new and more powerful characterization tools. Recently, the question of dosimetry has become a forefront topic and whether a universal, conceptual standard should be adopted, such as mass, surface area, or particle number. Arriving at a consensus on this issue is critical for the establishment of NM exposure limits and risk assessment metrics, which are significantly lacking. To accomplish accurate risk assessment and regulatory evaluations, NT will have to develop a means to improve the correlation of in vitro data to in vivo predictions, via enhanced cell models, relevant dosages (low vs. high), and realistic exposure scenarios. This CE course will evaluate where NT stands, by highlighting key research successes, identifying challenges facing the field today, and exploring solutions to overcome current limitations.

Introduction and Overview. Saber Hussain, US Air Force, Wright-Patterson AFB, OH.

Importance of Robust Nanomaterial Characterization as a Necessary Prerequisite for Evaluating the Results of In Vivo Nanotoxicity Studies. David B. Warheit, DuPont Haskell Laboratories, Newark, DE.

Nanotoxicology: What Has Been Done for the Past Decade. Laura Braydich-Stolle, US Air Force, Wright-Patterson AFB, OH.

Dosimetry Issues and Relevance for Risk Assessment. Christin Grabinski, US Air Force, Wright-Patterson AFB, OH.

Unresolved Challenges: Biological Models and Future Directions Overcome These Challenges. Kristen Comfort, University of Dayton, Dayton, OH.

Occupational Hazards and Risks in the Workplace: Where We Stand. Charles Geraci Jr, NIOSH, Cincinnati, OH.

Epidemiology for Toxicologists: What the Numbers Really Mean

PM09—CE Basic

Theme: New Science and Perspectives Surrounding Environmental and Occupational Exposures

Chairperson(s): Nancy B. Beck, American Chemistry Council, Washington, DC, and Julie E. Goodman, Harvard School of Public Health and Gradient, Cambridge, MA.

Sponsor(s):
Occupational and Public Health Specialty Section
Regulatory and Safety Evaluation Specialty Section
Risk Assessment Specialty Section

Twenty-first Century risk assessment relies on data from multiple lines of evidence. High quality human epidemiology data are generally preferred for regulatory decision-making, but the body of evidence often includes animal toxicity, in vitro, in silico, animal dosimetry, and human exposure data. The quality of individual epidemiology studies can be highly variable and dependent on study design as well as other critical factors that sometimes cannot be controlled for. For risk assessors to fully understand the implications of epidemiology evidence, they must understand how the overall integration of toxicity and mechanistic data with human epidemiology findings facilitates science-informed decision-making. A sufficient understanding of the epidemiology data is a necessary starting point for appropriately integrating all the available information. The course is geared towards the toxicologist who is trying to determine how to appropriately evaluate, use, and integrate epidemiology data in a weight-of-evidence evaluation or risk assessment. Attendees first will be given a basic overview of epidemiology, with a focus on different epidemiology study designs and their strengths and weaknesses. Attendees will also gain an understanding of exposure assessment and biomonitoring, and how this information is used and evaluated in epidemiology studies. Additional learning objectives of the course: How to determine when an association may be supportive of a causal relationship and what confidence intervals mean; how to use trend information; how to evaluate and understand adjustments that are made for potential confounding factors; and how to evaluate several epidemiology studies on the same topic, particularly in light of available toxicity and mechanistic data. Finally, attendees will learn to integrate all types of data streams with a real example. Attendees will leave the course with a stronger understanding of how to interpret and use epidemiology data in their weight-of-evidence analyses and risk assessments, and how epidemiology can help inform regulatory decision-making.

Setting the Stage. Nancy B. Beck, American Chemistry Council, Washington, DC.

Overview of Epidemiologic Studies. Michael Goodman, Emory University, Atlanta, GA.

Exposure Assessment and Biomonitoring in Epidemiologic Studies. Sorina Eftim, George Washington University School of Public Health and Health Services and ICF International, Fairfax, VA.

When an Association Indicates Causation. Julie E. Goodman, Harvard School of Public Health and Gradient, Cambridge, MA.

A Case Study Showing How Toxicology Complements Epidemiology for Informing Human Risk. James S. Bus, Exponent, Midland, MI.

Innovations in Methodologies for Inhalation Exposure and Interpretations of In Vivo Toxicity

PM10—CE Advanced

Theme: New Science and Perspectives Surrounding Environmental and Occupational Exposures

Chairperson(s): Urmila Kodavanti, US EPA, Research Triangle Park, NC, and Juergen Pauluhn, Bayer HealthCare, Wuppertal, Germany.

Sponsor(s):
Inhalation and Respiratory Specialty Section
Regulatory and Safety Evaluation Specialty Section

The respiratory system presents most diverse structural and cellular heterogeneity suited to handle complicated aspects of air liquid interface such as the direct exposure of the delicate cellular and capillary surfaces to the atmosphere and the encounter of lung epithelial cells to complex mixtures of particles and gases. Not only the respiratory depositions of inhaled substances vary regionally but also the regional responses generated by the respiratory tract. Recently the field of inhalation technology and respiratory toxicology has seen revolutionary growth because of the emergence of the use of nanomaterials and renewable energy sources creating new environmental challenges. Moreover, the paradigm shift of toxicology testing to high throughput screening has led to the development of novel inhalational approaches for cells. The course will cover the recent advances in inhalation methodologies for various types of emerging inhalants and focus on generation of atmospheres for in vivo and in vitro toxicity assessment. These aerosols will include gas and particulate emissions from vehicles using old and new energy sources, forest fires, coal combustion, manufactured nano materials and mixtures formed from atmospheric aging. The dynamic of physicochemical composition of such mixed aerosols will be discussed to allow for identification of causative constituents and lung site-specific injuries. Structural differences in the respiratory tract of rodents and large mammals, including humans, impacting dosimetry will be discussed. Respiratory system heterogeneity between humans and animals, and their differential neurohumoral mechanisms will be discussed to aid in interpretation of inhalational hazard for humans. This course will be useful for those involved in air pollution toxicology, nanotoxicology, novel drug delivery systems, pulmonary toxicology, and risk assessment.

Inhalation Exposure Methodologies of Rodents and Nonrodents. Juergen Pauluhn, Bayer HealthCare, Wuppertal, Germany.

Aspects of Inhalation Studies with Complex Mixtures—Aerosol Generations, Chemistry, and Exposure. Jacob D. McDonald, Lovelace Respiratory Research Institute, Albuquerque, NM.

Inhalation Exposure Methodologies for Manufactured Nanomaterials. Bean T. Chen, NIOSH, Morgantown, WV.

The Use of Environmental Irradiation Chambers to Test Health Effects of Controlled Air Atmospheres. Kenneth G. Sexton, University of North Carolina at Chapel Hill, Chapel Hill, NC.

Methodologies to Conduct In Vitro Exposures to Aerosols and Vapors. Mark A. Higuchi, US EPA, Research Triangle Park, NC.

Nonclinical Pediatric Drug Development: Considerations, Study Designs, and Strategies

PM11—CE Basic

Theme: Safety Assessment: Mechanisms and Novel Methods

Chairperson(s): Kary E. Thompson, Bristol-Myers Squibb Company, New Brunswick, NJ, and Elise M. Lewis, Charles River Laboratories, Horsham, PA.

Sponsor(s): Reproductive and Developmental Toxicology Specialty Section

Although nonclinical and clinical testing needs for drugs for pediatric populations have been discussed for more than 40 years, there is no default approach to evaluating safety in this age group. Over the last decade there has been a heightened awareness of the differences between the pediatric and adult patient, and these differences are being addressed by the pharmaceutical and healthcare industries, as well as the governmental and regulatory bodies that sanction the development and testing of drugs for children. As regulatory demands evolve for nonclinical safety assessments in juvenile animals, industry leaders are developing innovative ways to meet the regulatory expectations and to overcome the challenges associated with pediatric drug development. Many practical issues regarding nonclinical testing in immature animals have been surmounted, using novel and/or adapted approaches. There are considerations related to the differences in regional guidelines (US FDA, EU, and Japan), therefore development of appropriate information for submission to worldwide agencies is critical. History and experience provide the best scientific arguments as to why juvenile animals can be useful. There are numerous examples of drugs that have identified findings in various species, including information regarding kinetic and toxicity differences that highlight considerations regarding nonclinical testing models. Additionally, there are unique challenges associated with nonclinical juvenile toxicity testing for biopharmaceuticals, including selection of appropriate animal models, immunogenicity, dose selection (toxicity vs. pharmacology), and relevant endpoints. Developing a juvenile animal program requires an appreciation of the complexity of the nonclinical strategies to enable pediatric trials and an overview of the historical perspective and the current approaches to evaluating safety during this unique period of life.

Introduction. Elise M. Lewis, Charles River Laboratories, Horsham, PA.

US FDA Regulatory Perspective on Pediatric Product Development. Karen Davis-Bruno, US FDA, Silver Spring, MD.

EU Pediatric Regulation (EC) No 1901/2006: Impact on Nonclinical Development Plans. Jacqueline Carleer, Belgian Federal Agency for Medicines and Health Products, Brussels, Belgium.

Nonclinical Strategies to Support Pediatric Trials. Kary E. Thompson, Bristol-Myers Squibb Company, New Brunswick NJ.

Juvenile Toxicity Studies: What Can We Do? Susan B. Laffan, GlaxoSmithKline, King of Prussia, PA.

Biologics Juvenile Toxicity Testing: Exploring Options to Address the Challenges. Gary J. Chellman, Charles River Laboratories, Reno, NV.

Stem Cells in Toxicology

PM12—CE Basic

Theme: Biomarkers for Exposure Assessment, Safety Evaluation, and Translational Medicine

Chairperson(s): Erik J. Tokar, NIEHS, Research Triangle Park, NC, and Michael P. Waalkes, NIEHS, Research Triangle Park, NC.

Sponsor(s): Stem Cells Specialty Section

Stem cells are revolutionizing toxicological research and remain an area with tremendous potential. Recently, research on stem cells has generated tremendous public and professional interest. However, some areas of toxicological research have lagged behind in the integration of stem cells as a concept in toxicant-induced disease etiology. We will describe the utility and suitability of the assorted types of stem cell models (i.e. embryonic, fetal, progenitor, induced pluripotent, immortalized stem cell lines, etc.) for various research purposes, including disease modeling, drug discovery and toxicity testing in order to describe the potential applications of stem cells in toxicological research. This important overview of stem cells will highlight their nomenclature, properties, and their roles in the genesis of various diseases.

Introduction. Erik J. Tokar, NIEHS, Research Triangle Park, NC.

The Concepts and Methods for Stem Cells. Erik J. Tokar, NIEHS, Research Triangle Park, NC.

Stem Cells in Carcinogenesis. Michael P. Waalkes, NIEHS, Research Triangle Park, NC.

Applications of Stem Cells for Toxicology and Regenerative Medicine, Aaron B. Bowman, Vanderbilt University Medical Center, Nashville, TN.

Stem Cells in Safety Testing. Kyle L. Kolaja, Cellular Dynamics International, Montclair, NJ.

Translational Biomarkers in the Assessment of Health and Disease

PM13—CE Advanced

Theme: Advancing Clinical and Translational Toxicology and Application of Biomarkers

Chairperson(s): Vishal S. Vaidya, Harvard Medical School, Boston, MA, and Donna I. Mendrick, US FDA, Silver Spring, MD.

Sponsor(s): Association of Scientists of Indian Origin Special Interest Group

Biomarkers serve as quantitative measures of chemical exposures and biologically effective doses, early warning signals of biologic effect, predict outcome in a patient with disease, and identify who will respond to an intervention and whether the intervention is working. The current era of scientific discovery has brought seemingly limitless opportunities for improvements in medical care. Translational biomarkers that can be measured in blood or urine in both experimental animals and man are of particular interest. Given the importance to the clinical, pharmaceutical, and regulatory communities motivated by more specific and timely diagnoses, early intervention and safer therapies, clinically useful biomarkers have evolved over time, reflecting the scientific and technologic progress made over the centuries. An increasing number of clinically relevant tests and procedures are available to estimate organ injury and guide treatment. The use of molecular signals in the assessment of health and disease is not new; however, the concept of what constitutes a useful biomarker has evolved considerably in the past two to three decades given the advanced enabling technologies, deeper molecular understanding of disease, and the advent of a regulatory framework for biomarker qualification. Our panel experts will highlight the potential of these biomarkers over a wide variety of applications spanning preclinical-clinical safety in liver and kidney, to disease monitoring in cancer. The panel will also demonstrate the application of translational biomarkers in clinical trial design. Coordinated efforts at biomarker discovery and validation as well as technologies for biomarker measurement will help ensure that the ultimate goal of safer drugs, a cleaner environment, and improved patient outcomes are realized.

Introduction. Donna L. Mendrick, US FDA, Silver Spring, MD.

Discovering Cancer Biomarkers: From Diagnosis and Prognosis Through Therapy. Marsha A. Moses, Children’s Hospital Boston, Harvard Medical School, Boston, MA.

Kidney Safety Biomarkers: From Proteins to MicroRNAs. Vishal S. Vaidya, Harvard Medical School, Boston, MA.

Liver Safety Biomarkers: A Comprehensive Evaluation in Human Subjects. Jiri Aubrecht, Pfizer, Inc., Groton, CT.

Application of Biomarkers in Clinical Trial Design, Federico Goodsaid, Vertex Pharmaceuticals, Washington, DC.