Continuing Education Courses

Morning Courses (AM)

Session Chairs: Douglas A. Donahue, BD (Becton, Dickinson and Company), Research Triangle Park, NC;
and Pallavi B. Limaye, Sekisui XenoTech, LLC, Kansas City, KS

When assigned to complete their first in vivo toxicology study or studies, toxicologists sometimes do not know where to start the study design. This course will feature experts who will address this issue by discussing experimental study design for in vivo studies, including case studies (the good, the bad, and the ugly).The course will begin by discussing how to utilize in silico and in vitro data for first-in-use animal studies. What can be gleaned from these data? A pharmacokinetic/toxicokinetic (PK/TK) scientist will present best practices on PK/TK study design and how to utilize the data from a PK/TK study for future in vivo studies. Two further presentations will focus on long-term in vivo studies in multiple species and DART/juvenile toxicology studies.


Introduction: Need for Proper Experimental Study Designs for In Vivo Studies
Pallavi B. Limaye, Sekisui XenoTech, LLC, Kansas City, KS

CE01-1 The Use of In Silico and In Vitro Toxicology Data for the First In Vivo Study
Bennett J. Varsho, MB Research, Spinnerstown, PA

CE01-2 Practical Considerations in Designing PK Studies and the TK Portion of Toxicology Studies
Kelly A. Byrnes, Northwest PK Solutions, LLC, Sultan, WA

Break

CE01-3 How to Use Acute In Vivo Toxicology Data for Long-Term Study Design in Multiple Species
Scott E. Boley, Sinclair Research, Auxvasse, MO

CE01-4 Practical Considerations in the Design of In Vivo Reproductive, Developmental, and Juvenile Toxicity Studies: Meeting the ICH S5(R3) and S11 Guidelines
Alan M. Hoberman, Charles River, Horsham, PA

Panel Discussion

Session Chairs: Angélique Braen, Insmed, Bridgewater, NJ; and
Jacob McDonald, Lovelace Biomedical, Albuquerque, NM

There are many unique challenges to developing therapeutics via the respiratory route. Further, over the past decade, evolving trends in the respiratory field have resulted in advances to address delivery/formulation technology as well as novel drug categories such as gene therapy. The respiratory tract presents unique challenges for study designs, understanding of dose, efficiency of drug product, and interpretation of outcomes. Thus, this course is intended to update the toxicology community on the practical aspects of nonclinical (pharmacology, pharmacokinetics, and toxicology) animal studies when it comes to the design, dose, formulation, and device considerations. Further, this course will provide examples and interpretations on what is adverse and nonadverse in reference to histopathological findings in the respiratory tract. Also, state-of-the-art technologies and best practices for inhalable drug delivery to cell culture systems will be discussed. Putting it all together, regulatory insights will be shared by the US Food and Drug Administration (US FDA) regarding drug development by the respiratory route.


Introduction
Angélique Braen, Insmed, Bridgewater, NJ

CE02-1 Dose, Formulation, Device, and Design Considerations to Conduct Inhalation Experiments
Philip J. Kuehl, Lovelace Biomedical, Albuquerque, NM

CE02-2 Using Multi-scale Mechanism Based Mathematical Modeling to Understand Effects of Physiology in Pulmonary Drug Delivery, Pharmacokinetics, and Preclinical to Clinical Translation
Antonio Cabal and Timothy E. Johnson, Merck, North Wales, PA

CE02-3 Adverse or Nonadverse: Common Findings Observed in the Respiratory Track in Toxicity Studies
Torrie Crabbs, EPL, Inc., Morrisville, NC

Break

Adverse or Nonadverse: Common Findings Observed in the Respiratory Track in Toxicity Studies (Cont.)
Torrie Crabbs, EPL, Inc., Morrisville, NC

CE02-4 State-of-the-Art Technologies and Best Practices for Inhalable Drug Delivery to Cell Culture Systems
Julia Hoeng, Philip Morris Products S.A., Neuchatel, Switzerland

CE02-5 Regulatory Insights on Development of Drugs Targeting the Respiratory System
Luqi Pei, US Food and Drug Administration, Silver Spring, MD

Session Chairs: Natalie Holman, Eli Lilly and Company, Indianapolis, IN;
and Katie Sokolowski, US FDA, Silver Spring, MD

First-in-human (FIH) clinical trials rely heavily on nonclinical data for safety assessment. Before initiation of FIH studies, the industry toxicologist and regulatory toxicologist play a similar role in identifying safety signals in the data and informing key aspects of the clinical protocol to minimize risk to human subjects. This is accomplished through critical data review and translational evaluation, identification of NOAELs and a safe starting dose, appropriate representation of nonclinical findings in informed consent documents, and mitigation strategies such as additional clinical monitoring, exclusion criteria, and exposure limitations. This course invites early and mid-career toxicologists to review and discuss FIH IND-enabling toxicology packages from the perspective of both the industry toxicologist and regulatory reviewer. In breakout groups facilitated by industry or regulatory experts, participants will determine if data in two case studies are sufficient to support specific clinical trial designs, and what, if any, additional risk mitigation should be implemented. The course is designed for participants to (1) apply regulatory toxicological principles to review of full FIH nonclinical safety profiles, (2) identify and defend a NOAEL/LOAEL, (3) calculate a safe starting dose, and (4) de-risk safety signals. The course will conclude with a discussion of case outcomes, highlighting industry and regulatory toxicology considerations/strategies to ensure safety in FIH clinical studies.


Introduction
Natalie Holman, Eli Lilly and Company, Indianapolis, IN

How to Propose (and Review) Safe Clinical Plans Using Nonclinical Safety Data
Hanan Ghantous, US FDA, Silver Spring, MD

Case Study Reviews Breakout Groups

Case Study A: Under Review
Group 1—Pharmaceutical
Facilitator: Nancy Kerzee, Sumitovant Biopharma, New York, NY

Group 2—Regulatory
Facilitator: Armaghan Emami, US FDA, Silver Spring, MD

Case Study B: Considerations for FIH Clinical Trials When Seizure Liability Is Identified in Nonclinical Safety Studies
Group 1—Pharmaceutical
Facilitator: Natalie Holman, Eli Lilly and Company, Indianapolis, IN

Group 2—Regulatory
Facilitator: Katie Sokolowski, US FDA, Silver Spring, MD

Break

Case Study A: Results from the Breakout Groups

Case Study A: Actual Outcomes
Review led by Hanan Ghantous, US FDA, Silver Spring, MD

CE03-2 Case Study B: Results from the Breakout Groups

Case Study B: Actual Outcomes
Review led by Katie Sokolowski, US FDA, Silver Spring, MD

Closing Comments
Katie Sokolowski, US FDA, Silver Spring, MD
Natalie Holman, Eli Lilly and Company, Indianapolis, IN

Session Chairs: Jay Stallons, Elanco Animal Health, Greenfield, IN;
and Emmanuelle Kuntz, Elanco Animal Health, Basel, Switzerland

Safety assessment in veterinary drug development involves unique regulatory requirements, necessitating the application of several fields of toxicology. This course will highlight the basic aspects of safety assessment required for registration of a new veterinary medicine. This will include human user safety, target species tolerability, environmental fate and toxicology, and human food safety. This introductory course will be of interest to toxicologists in the pharmaceutical, chemical, and contract research industries to provide background on the regulatory and technical framework for veterinary drug development and approval.


CE04-1 Target Animal Safety: Not Just a Study
Phyllis Malpas, Zoetis, Kalamazoo, MI

CE04-2 Hazard and Exposure Assessments Required for Human User Risk of Veterinary Pharmaceuticals
Jay Harriman, Boehringer Ingelheim Animal Health, Duluth, GA

CE04-3 Environmental Risk Assessment of Veterinary Pharmaceuticals
Duane Huggett, Boehringer Ingelheim Animal Health, Duluth, GA

Break

CE04-4 Human Food Safety, Part 1: Hazard Characterization
Tong Zhou, US FDA, Rockville, MD

CE04-5 Human Food Safety, Part 2: Risk Management
Kimberly Lombardi, Elanco Animal Health, Greenfield, IN

Discussion

Session Chairs: Kristina Howard, US Food & Drug Administration, Silver Spring, MD;
and Peyton Myers, US Food & Drug Administration, Silver Spring, MD

Humanized mice are chimeric animals made by injecting/implanting human cells/tissues into severely immune-compromised mice. They represent a new type of animal model, allowing human cells and their receptors to be tested in an in vivo system with more physiologically relevant responses than in vitro models and permit interactions with other nonhumanized organ systems. This session will describe and define different immune and hepatic humanized mouse models, including types of models and the mice that can be used, how these models have been used in studies to date, and the advantages and limitations of these models. Emphasis will be placed on giving the attendees the ability to understand how to select a specific model for studies, study design, and data analysis. In addition, data from a variety of studies will be presented.


CE05-1 Introduction to Immune Humanized Mice and Their Application, Benefits, and Drawbacks
Kristina Howard, US Food & Drug Administration, Silver Spring, MD

CE05-2 Using Immune Humanized Mice to Understand Immune Modulation
Michael Oropallo, Merck & Co., Inc., West Point, PA

Break

CE05-3 Using Immune Humanized Mice to Evaluate Immunostimulatory Adverse Events
Jungeun Sung, US Food & Drug Administration, Silver Spring, MD

CE05-4 Hepatic Mouse Models
Jeannette Connerney, Precigen, Inc., Germantown, MD


Afternoon Courses (PM)

Session Chairs: William Salminen, Camargo Pharmaceuticals, Sarasota, FL;
and Rebecca Barry, RTI International, Research Triangle Park, NC

This course will provide the attendee with practical guidance for designing, contracting, monitoring, and reporting nonclinical/toxicology studies. This encompasses pharmacology (including safety pharmacology), pharmacokinetic, and toxicology studies. The main focus of this course will be on studies that must comply with good laboratory practices (GLPs) for regulatory submissions; however, the guidance is also applicable to studies that do not need to comply with GLPs since general advice on running sound scientific studies is provided. This course will cover all aspects of a study, from initial laboratory selection through protocol development, conduct of in-life functions, and final reporting of the study. The idea for this course came out of the frustration of trying to find resources on contracting, monitoring, and receiving sound GLP toxicology study reports from Contract Research Organizations (CROs) and internal company laboratories. Often, a given laboratory would excel in some areas but fall short in others. This course aims to provide an overview of all aspects of study contracting and monitoring so that the Contracting Scientist clearly understands how all the pieces fit together, has an understanding of where studies can go wrong, and has guidance on the conduct and oversight of a study to ensure they receive the highest-quality study possible, especially pivotal GLP safety/toxicology studies for regulatory submissions.


CE06-1 Overview of Nonclinical Study Contracting and Monitoring and Goals and Outline of the Course
William Salminen, Camargo Pharmaceuticals, Sarasota, FL

CE06-2 Laboratory Qualification, Requests for Proposals (RFPs), and Study Contracting
Andrew Emanuel, Camargo Research Group (CRG), Montreal, QC, Canada

Break

CE06-3 Critical Aspects of Study Start-Up, Day-to-Day and On-Sight Study Monitoring, and Study Reporting
Rebecca Barry, RTI International, Research Triangle Park, NC

CE06-4 Good Laboratory Practices: Test-Article and Dose Formulation and Bioanalytical Method Development, Validation, and Analysis
Monica Whitmire, Catalent Pharma Solutions, Middleton, WI

Session Chairs: Pramila Singh, Charles River Laboratories, Evreux, France;
and Mark Vezina, Charles River Laboratories, Montreal, QC, Canada

Eye disease and the loss or impairment of vision because of toxicities are serious conditions that affect health status and quality of life. This course will provide detailed information on how to design nonclinical studies for ocular therapies and for non-ocular therapies that may have unintentional, off-target ocular effects. Designing ocular development packages, from proof of concept and efficacy studies to safety and translational studies, will be discussed in detail by experienced Contract Research Organization professionals specialized in nonclinical ocular testing methods, including current standards for evaluation of structure, function, and physiology of the eye. Specific studies to support the nonclinical development program for ocular therapies—including small molecules, biologics, novel gene therapies, and both permanent and refillable ocular devices—will be described by pharmaceutical and biotech professionals working on some of the latest and most novel ocular therapy products. Particular attention will be placed on pivotal nonclinical safety studies and points to consider about what is essential in a nonclinical data package for a range of ocular therapeutic modalities. This course will cover approaches that can ensure translational benefits are realized from the nonclinical program to clinical trials. Actual case examples will be taken from current ocular therapeutic product development programs and what has proven to be essential to support clinical trials for these promising therapies.


CE07-1 Designing Nonclinical Studies to Support Clinical Trials for Ocular Indications
Margaret Collins, Charles River Laboratories, Reno, Nevada

CE07-2 How to Design Pivotal Safety Studies for Non-ocular Therapies When Off-Target Ocular Effects Are Expected
Mark Vezina, Charles River Laboratories, Montreal, QC, Canada

Break

CE07-3 Critical Success Factors When Working with Gene Therapy Products for Ocular Diseases
Kali Stasi, Novartis Institutes for BioMedical Research, Cambridge, MA

CE07-4 Points to Consider for Ocular Permenant and Refillable Drug/Device Combination Nonclinical Toxicology and Biocompatibility Strategies
Vladimir Bantseev, Genetech Inc., South San Francisco, CA

Session Chairs: Reem Elbekai, Otsuka Pharmaceutical Development and Commercialization, Rockville, MD;
and William Brock, Brock Scientific Consulting, LLC, Montgomery Village, MD

As America continues to struggle with the opioid epidemic, it is more prudent than ever to ensure the abuse potential of CNS active drugs are adequately characterized. The Guidance on the Assessment of Abuse Potential of Drugs was released in January 2017 and provides detailed recommendations on the conduct of clinical and nonclinical studies to allow a thorough evaluation to support scheduling in accordance with the Controlled Substances Act (CSA) and to inform labeling. In this session, speakers from industry and US Food and Drug Administration will review underlying pharmacological mechanisms that may lead to the abuse of a product; discuss which products are likely to require assessment for abuse potential; provide details on type, design, and timing of the nonclinical studies; provide an overview of human abuse studies and other supporting clinical trial data; and discuss how scheduling decisions are made under the CSA.


CE08-1 Pharmacology and Molecular Mechanisms of Drugs of Abuse
Michael Klein, Controlled Substance Scientific Solutions, LLC, Chevy Chase, MD

CE08-2 Building the Nonclinical Safety Package to Address Abuse Potential
David J. Heal, DevelRx Ltd, Nottingham, UK, and University of Bath, Bath, UK

Break

CE08-3 Conducting a Successful Human Abuse Potential Study and Leveraging Data from Other Clinical Trials
Edward Sellers, University of Toronto and DL Global Partners Inc, Toronto, ON, Canada

CE08-4 The US FDA’s Role in Drug Scheduling and the Eight Factor Analysis
Dominic Chiapperino, US Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, MD

Session Chairs: Holly D. Dursema, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT;
and Suman Mukherjee, Merck & Company, Inc, West Point, PA

Toxicokinetics (TK) is often rightly viewed as a means to measure exposure in animals to further understanding of adverse effects and to use in comparison to human exposure to gauge safety. However, there is more to TK than meets the eye. The intent of this course is to educate participants on the nuances of TK that could affect how they design their toxicology studies. The first presentation will cover basic principles of small molecule TK and review factors that may affect study design and interpretation of results, including variability. The second presentation will walk participants through small molecule development and discuss how exposure multiples can affect study design at various phases. This will include how to utilize guidance documents and provide examples on how compound characteristics can affect results. How protein binding may/may not affect evaluation of multiples of exposure will be discussed. The third presentation will discuss TK in development and reproductive toxicology (DART) studies, addressing topics such as study design and exposure in pregnant versus nonpregnant animals. The fourth presentation will focus on new biological entities (NBEs), discuss common NBE toxicology/TK and bioanalytical strategies, and possible effects of anti-drug antibody formation on exposure and toxicology. Oligonucleotides will be used as an example of alternate modalities to illustrate flexibility in measurement and interpretation of TK results.


CE09-1 Toxicokinetics Introduction
Suman Mukherjee, Merck & Company, Inc, West Point, PA

CE09-2 Exposure Multiples: Finding the Best Path through Development
Holly Dursema, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT

Break

CE09-3 Toxicokinetics in DART Studies
Jack Valentine, Merck & Company, Inc, West Point, PA

CE09-4 Toxicokinetics of NBE and ATMP
Ming Cheng, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT

Session Chair: Tara P. Arndt, Covance, Madison, WI

Biologic drug modalities are rapidly expanding in number and complexity, and this expansion has been accompanied by the observation of equally complex effects, both expected and unexpected, in nonclinical safety studies. The increasing emphasis on immunotherapeutic agents has further complicated matters, such that interpreting clinical pathology data has become a challenging endeavor requiring heightened comprehension of immunology and a working understanding of responses that may be qualitatively or quantitatively different between species. This session will cover clinical pathology alterations common to various biotherapeutics, using didactic presentations, mechanistic discussions, and case examples to deliver a comprehensive discourse on this challenging topic.


CE10-1 Effects of Biologic Drug Modalities on Peripheral Blood Cells
Nancy E. Everds, Seattle Genetics, Bothell, WA

CE10-2 Immunogenicity and Immune Complex Disease in Preclinical Safety Assessment Studies: Challenges for Assessing Human Safety
John L. Vahle, Eli Lilly & Company, Indianapolis, IN

Break

CE10-3 Complement Activation: Cause and Effect
William Siska, Charles River Laboratories, Thousand Oaks, CA

CE10-4 Immunophenotyping and Cytokines: Considerations and Case Examples
Ellen W. Evans, Independent Consultant, Waterford, CT