Continuing Education Courses

All ACT Continuing Education courses (with the exception CE 3/live event only) are available for on-demand access until December 31, 2020. If you are a meeting registrant and would like to purchase additional additional CE courses, please email ACT Headquarters for assistance.

Thursday, November 12: 11:00 AM–2:30 PM Eastern Time

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.

11:00 AM–11:10 AM Introduction: Need for Proper Experimental Study Designs for In Vivo Studies
Pallavi B. Limaye, Sekisui XenoTech, LLC, Kansas City, KS

CE01-1 11:10 AM–11:50 AM The Use of In Silico and In Vitro Toxicology Data for the First In Vivo Study
Bennett J. Varsho, Charles River Laboratories Inc., Horsham, PA

CE01-2 11:50 AM–12:30 PM Practical Considerations in Designing PK Studies and the TK Portion of Toxicology Studies
Kelly A. Byrnes-Blake, Northwest PK Solutions, LLC, Sultan, WA

12:30 PM–1:00 PM Break

CE01-3 1:00 PM–1:35 PM How to Bridge the Gap from PK and Efficacy Studies to Designing a Toxicology Program
Scott E. Boley, Sinclair Research, Auxvasse, MO

CE01-4 1:35 PM–2:10 PM 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 Laboratories Inc., Horsham, PA

2:10 PM–2:30 PM Questions and Answers



Over the past 30 years, approaches to acute toxicology have at once changed remarkably and not at all. Advances in alternative in vitro and computational toxicology allow but largely do not require modern toxicologists to refine or replace some or all the components of the so-called acute toxicity six-pack. Data generated from initial acute toxicity studies may also be used to inform decisions for subsequent studies; thus, the order in which these studies is performed can bear upon the approach to or even necessity of subsequent studies. While many alternative in vitro and computational toxicology options exist, they vary widely in completeness, accuracy, sensitivity, specificity, power, and regulatory acceptability, all of which can influence adoption of alternatives by industry. Additional factors influencing user acceptance include budget, type of industry, sponsor experience, concern for animal welfare, concern over public perception, and heterogeneous interpretation of requirements by performing laboratories. Thoughtful application of nonanimal methodologies can prevent the most egregious of acute study outcomes and are required by international test guidelines.


Proper planning of the study design, and for the logistics involved, is critical for the success of PK and biodistribution studies and the TK portion of toxicology studies. The goal of each study must be considered when determining what species to use, what dose levels and dosing regimen should be chosen, what PK samples to obtain, and how the data will be analyzed. Additionally, assay development and qualification or validation timelines must be considered when planning for preclinical studies. This portion of the course will discuss the practical considerations of planning for and designing PK/TK studies and why the successful evaluation of PK is critical during the course of preclinical development.


Every toxicology program starts with short-term studies that are building upon prior studies that are either in vitro, PK, or efficacy. Starting with those types of studies and then designing toxicology studies can seem like a daunting challenge. Topics such as selecting the appropriate species, how to justify a dose for a dog if all you have are mouse data, how long the study should be, and which dose route should be used, among other questions, need to be addressed when starting a toxicology program. This presentation will walk you through the approaches used to take a program from the early studies into the regulatory phase. We will explore the challenges that often occur and use examples of how these were met and overcome.


Unless a product is intended for use in pregnant women or only in juvenile populations, developmental and reproductive toxicity (DART) and juvenile studies are typically conducted post the Investigational New Drug (IND) application. The International Conference on Harmonization (ICH) Safety (S) 5 Guideline for Reproductive (DART) Toxicology and the proposed ICH S11 Guideline on Nonclinical Paediatric Safety provide basic information for conducting these studies and various options that guide the approach to nonclinical testing to support the various phases of clinical testing. This presentation will focus on the use of information available from both pre- and post-nonclinical IND studies, dosage range studies in pregnant animals, and the use of Phase I clinical data to design adequate preliminary DART and juvenile studies. In addition, the unique aspects of test models, the animal welfare concerns for use in these studies, and the issues of ensuring adequate exposure will also be presented. An attendee should leave the presentation with the information required to evaluate the adequacy of the design of an in vivo or in vitro DART and/or juvenile toxicity study needed prior to using women of childbearing age in a clinical trial or testing in juveniles from birth to adulthood. The specifics required for protocol development are outlined in the Good Laboratory Practices Regulations. Combining the information provided in these documents provides significant information but does not cover the practical knowledge necessary to design and conduct these studies.

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.

11:00 AM–11:10 AM Introduction
Angélique Braen, Insmed, Bridgewater, NJ

CE02-1 11:10 AM–11:50 AM Dose, Formulation, Device, and Design Considerations to Conduct Inhalation Experiments
Philip J. Kuehl, Lovelace Biomedical, Albuquerque, NM

CE02-2 11:50 AM–12:30 PM Adverse or Nonadverse: Common Findings Observed in the Respiratory Track in Toxicity Studies
Torrie Crabbs, EPL, Inc., Morrisville, NC

12:30 PM–1:00 PM Break

CE02-3 1:00 PM–1:40 PM Tissue Culture Models and Exposure Systems to Study the Effect of Inhalable Drugs on Human Airway Epithelium In Vitro
Julia Hoeng, Philip Morris Products S.A., Neuchatel, Switzerland

CE02-4 1:40 PM–2:20 PM Regulatory Insights on Development of Drugs Targeting the Respiratory System
Luqi Pei, US Food and Drug Administration, Silver Spring, MD

2:20 PM–2:30 PM Questions and Answers



Inhalation drug delivery is a unique mixture of dose, formulation, and device that all intercalate together in the design and conduct of inhalation drug delivery experiments. While working knowledge and previous experience aid in the design of these experiments, each system is fit for purpose. When designing inhalation experiments, the scientific team will bring together information on the compound class (small molecule, peptide, protein, antibody, viral vector, lipid nanoparticle, etc.), proposed formulation (pressurized metered dose inhaler, dry powder, nebulizer, or soft mist inhaler), potential dose(s)/dose range, quantitative assays (HPLC, qPCR, plaque, etc.), collection methods (filter type, impinger, biosampler, condenser, etc.), and other considerations to develop the unique inhalation system. Each of these variables must be considered together with the scientific hypothesis being tested to determine the appropriate inhalation exposure experiment. Without careful large-scale consideration, the results of the test may not address the scientific question. This presentation will utilize a series of case studies to show the importance of early and careful consideration of these variables in the development of inhalation experiments. These case studies will span a wide range of studies, including small and large animal models, pharmacology and toxicity, alert and anesthetized systems, and novel exposure systems, all to highlight the importance of well-designed inhalation studies. The viewer will leave this presentation with a knowledge of how to approach inhalation study design and the importance of addressing each of these questions appropriately at each stage of drug development.


Histopathological evaluation of the respiratory tract is an important component of any toxicity study, especially inhalation studies. The respiratory system is complex and varies histologically from tissue to tissue. While most routine studies include evaluation of the trachea and lung, inhalation studies frequently add multiple sections of nasal cavity and larynx, and occasionally pharynx, as protocol-required tissues. Familiarity with common histopathologic findings in each of these tissues is critical to assist with the pathologist’s ability to determine adversity of the findings, which is influenced by not only the nature of the findings, but their severity (i.e., extent of tissue involvement). This presentation will provide examples of common histopathological findings frequently observed in the respiratory tract (nose, pharynx, larynx, trachea, and lungs) in toxicity studies, such as the presence of eosinophilic globules in the nasal cavity, squamous metaplasia throughout the respiratory tract, and accumulations of alveolar macrophages in the lung. For each, factors used to determine if the findings should be considered adverse or nonadverse will be discussed.


The human respiratory tract is functionally and structurally heterogeneous, and the kinetics governing the transfer of gas or aerosol constituents from an inhaled volume of air to its epithelia are highly complex. Consequently, the physical conditions, as well as the amount and composition of an inhaled aerosol the epithelia of different respiratory tract regions experience vary strongly. Simulating this complexity for the purpose of in vitro aerosol exposure experiments poses a significant technical challenge. A new-generation in vitro aerosol exposure system, the Independent Holistic Air-Liquid Exposure System (InHALES), will be presented that structurally and functionally mimics the human respiratory tract, and therefore is expected to deliver human-relevant doses of inhalable substances to cell cultures representing different respiratory tract epithelia. The InHALES system, like the human lung, is able to, for example, breathe surrounding air under various breathing conditions, as well as operate with various medical inhalers. Sensory modules and microfluidic systems can be inserted into the system, allowing for the physical and chemical characterization of test-atmosphere and its evolution along the physiology-based model of the human respiratory tract. Human organotypic cell cultures can be inserted at various locations representative of the different compartments of the human respiratory tract, enabling pharmacological testing. The platform is extendable to biology-inspired microphysiological systems that emulate organ-organ cross talk. It will be demonstrated how human multi-organ chip co-cultures of bronchial lung cultures and liver spheroids are suitable for drug exposure studies and allow investigation of pharmacokinetic parameters, such as absorption, distribution, metabolism, and excretion. The most recent developments of multi-organ chip systems will be presented and are regarded as ground-breaking in preclinical validation of substances and have the potential to change and accelerate drug development significantly.


Regulatory nonclinical safety evaluation plays an important role in the development of inhalation drug products targeting the respiratory system. Most inhaled drugs are drug-device combination products with complex delivery systems. These products vary in formulations, clinical indications, and device characteristics: design, delivery mechanism, and performance. Inhalation toxicity studies characterize toxicity profiles of inhaled testing materials in animals. The profile includes assessments of local and systemic toxicity (when adequate systemic exposures are achieved) and toxicokinetics. These studies may also incorporate safety pharmacology endpoints. Studies of supplemental route(s) of administration (e.g., parenteral) may be necessary if inhalation delivery fails to demonstrate adequate systemic exposures. Such studies often reveal findings unique to inhaled materials in the respiratory system. These findings may differ among animal species. Some responses may not be relevant to humans. Regulatory scientists conduct safety assessments in submitted drug applications. They evaluate pharmacological and toxicological profiles of active pharmaceutical ingredients, excipients, and any other potential issues (e.g., metabolites, impurities, degradants, leachables, and extractables). They evaluate and interpret findings in these toxicology studies along with other relevant nonclinical data. They determine the adequacy of nonclinical data in support of the safety of intended clinical trials and registrations. Their decisions may vary depending on nonclinical findings, intended clinical use, and the risk/benefit analysis of the inhaled drug. This presentation provides a brief overview of regulatory safety evaluation at the US FDA.

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 the 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.

11:00 AM–11:05 AM Introduction
Natalie Holman, Eli Lilly and Company, Indianapolis, IN

CE03-1 11:05 AM–11:35 AM How to Propose and Review Safe Clinical Dose Using Nonclinical Safety Data
Hanan Ghantous, US FDA, Silver Spring, MD

11:35 AM–12:30 PM Case Study Reviews Breakout Groups

Case Study A: Considerations for FIH Clinical Trails When Disparate Results are Observed in Nonclinical Safety Studies
Group 1—Pharmaceutical
Facilitator: Nancy Kerzee, Sumitovant Biopharma, New York, NY

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

Group 3—Regulatory
Facilitator: Hanan Ghantous, US FDA, Silver Spring, MD

Case Study B: Considerations for FIH Clinical Trials When Seizure Liability Is Identified in Nonclinical Safety Studies
Group 4—Pharmaceutical
Facilitator: Natalie Holman, Eli Lilly and Company, Indianapolis, IN

Group 5—Pharmaceutical
Facilitator: Jeff Tepper, Tepper Nonclinical Consulting, San Carlos, CA

Group 6—Regulatory
Facilitator: Katie Sokolowski, US FDA, Silver Spring, MD

12:30 PM–1:00 PM Break

1:00 PM–1:20 PM Case Study A: Results from the Breakout Groups

1:20 PM–1:40 PM Case Study A: Actual Outcomes
Review Led by Natalie Holman, Eli Lilly and Company, Indianapolis, IN

CE03-2 1:40 PM–2:00 PM Case Study B: Results from the Breakout Groups

2:00 PM–2:20 PM Case Study B: Actual Outcomes
Review Led by Katie Sokolowski, US FDA, Silver Spring, MD

2:20 PM–2:30 PM Closing Comments
Katie Sokolowski, US FDA, Silver Spring, MD
Natalie Holman, Eli Lilly and Company, Indianapolis, IN



The goal of this presentation is to introduce critical considerations for reviewing IND-enabling toxicology packages for FIH clinical trials, setting up the info to consider during interactive breakout case study review. The presentation will briefly cover starting dose guidance and the principles of FIH nonclinical safety review: Do dose, duration, and route of administration used in the nonclinical studies support the proposed clinical trial? Using the start dose guidance, is the starting dose acceptable? Identify the target organs and toxicities. Are they relevant to humans? Are they monitorable? Are they reversible? What impact does this have on the adjudication of “safe to proceed”?

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 11:00 AM–11:30 AM Target Animal Safety: Not Just a Toxicology Study
Phyllis B. Malpas, Zoetis, Kalamazoo, MI

CE04-2 11:30 AM–12:00 Noon Hazard and Exposure Assessments Required for Human User Risk of Veterinary Pharmaceuticals
Jay Harriman, Boehringer Ingelheim Animal Health, Duluth, GA

CE04-3 12:00 Noon–12:30 PM Environmental Risk Assessment of Veterinary Pharmaceuticals
Duane Huggett, Boehringer Ingelheim Animal Health, Duluth, GA

12:30 PM–1:00 PM Break

CE04-4 1:00 PM–1:30 PM Human Food Safety, Part 1: Hazard Characterization
Tong Zhou, US FDA, Rockville, MD

CE04-5 1:30 PM–2:00 PM Human Food Safety, Part 2: Risk Management
Kimberly Lombardi, Elanco Animal Health, Greenfield, IN

2:00 PM–2:30 PM Questions and Answers



Target animal safety (TAS) is integral to any compound approved for animal health. In this session, we will examine the theory and practice of TAS that ensures that only compounds with a well-understood safety profile that supports the field regimen enter the market. We will explore International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products (VICH) Guidelines (GL43) for pharmaceuticals for our basic understanding. We will also look at the ways that we adapt pharmaceutical methods to biopharmaceuticals such as monoclonal antibodies. To that end, we will review the contexts of toxicological response across small and large molecules and learn how we build the safety database in exploratory studies to where we can construct a design for pivotal studies that is individualized to the specific compound. We will explore the many challenges to the successful design and conduct of TAS studies, including (1) the types of studies that are covered under TAS; (2) the number and type of variables that are collected, analyzed, and interpreted in most TAS studies, including challenges from biometrics, data visualization, and control of bias; (3) interpretation of abnormal observations, ascribing dose relationships and how these observations may be reflected in labeling; and (4) working with CROs: the importance of collaboration between the Study Director and the associated Principal Scientists and Contributing Scientists and the critical relationship with the Sponsor case studies: (a) CRO versus in-house: finding the right CRO that understands that a 90-day dog toxicology study is not a three-month TAS study; and (b) regional regulatory challenges for TAS.


Successful registration of an Investigational Veterinary Pharmaceutical Product (IVPP) requires the demonstration of product safety under the proposed conditions of use. Because humans may be accidentally or unavoidably exposed to IVPP before, during, or after administration to animals, a human user risk assessment is required to demonstrate adequate safety for these products. Safety is assessed based on the active pharmaceutical ingredient’s (API) toxicologic hazard profile. Reasonable worst-case exposures for all potential human exposure scenarios are matched with the most conservative health hazard endpoint from similar duration laboratory animal toxicity studies to define a margin of exposure (MOE). The MOE is regarded as acceptable and the exposure is regarded as safe when the MOE exceeds the uncertainty or safety factor associated with extrapolating laboratory animal data to humans. Regulatory guidelines promote consistency in these User Risk Assessments (URAs) and include both default values as well as product-specific exposure and hazard values for use in evaluating potential human user risk. Guidelines from the US and EU that dictate the safety development programs during development of globally registered veterinary products will be discussed. Case studies will include a companion animal oral product, topical product, and injectable product.


An evaluation of the environmental safety for a veterinary pharmaceutical is a pivotal part of a successful regulatory dossier. For veterinary pharmaceuticals, global regulatory guidance documents available through the VICH outline the process to generate environmental risk assessments (ERA). VICH GL6 and GL38 outline the Phase I and II veterinary ERA process for geographic regions, such as Europe, Australia, and the United States. The Phase I process determines the potential exposure in the environment and whether a Phase II assessment is needed. The Phase II assessment outlines a tiered process with environmental studies aimed at understanding the fate in different matrixes (e.g., soil, sediment, water) and toxicity (e.g., aquatic, terrestrial) of the veterinary pharmaceutical. These data aid in the determination of a predicted environmental concentration and a predicted no effect concentration, which are used to derive a risk quotient (RQ). Additional testing or approaches may help refine the RQ, or if necessary, risk mitigation measures can be considered. In addition to the traditional ERA process, a separate evaluation of persistence, bioaccumulation, and toxicity (PBT) of the veterinary pharmaceutical is often needed. The type of evaluation is based on the intrinsic properties of the compound rather than exposure in the environment following use of a product. This presentation will discuss the relevant environmental guidance documents, the Phase I and II ERA process, the key environmental fate and ecotoxicity studies, and PBT assessments and will conclude with several environmental case studies.


This part of the course will provide an overview of the human food safety evaluation of animal drugs for use in food-producing animals during the pre-market approval, with focus on hazard characterization of animal drug residues. Guidances for Industry related to human food safety assessment—in particular, toxicology testing—will be discussed. The human food safety assessment is to ensure that the residue of a new animal drug in or on food, when consumed, presents a reasonable certainty of no harm to human consumers. The assessment is conducted from the perspectives of toxicology, residue chemistry, and microbial food safety. In general, the toxicology evaluation determines a safe level for humans based on toxicology data extrapolated from the surrogate laboratory animal studies. For a noncarcinogenic compound, an acceptable daily intake (ADI) and safe concentrations for each edible tissue for total drug residue are established. For carcinogenic compounds, regulators must evaluate the concentration of a residue of carcinogenic concern in a specific tissue and in the total human diet that represents no significant increase in risk of cancer to the human consumer. Residue chemistry evaluation assigns the marker residue, target tissue, tolerance, withdrawal period, and/or milk discard time and establishes a practical regulatory method for analyzing tissue residues. Microbial food safety evaluation is to ensure that the proposed conditions of use for all uses of antimicrobial new animal drugs for food-producing animals are adequate to guard against the emergence and selection of antimicrobial resistance among bacteria of public health concern.


For drugs registered for use in food-producing animals, regulatory agencies use stringent risk-based approaches based on the toxicological properties of the drug and potential worst-case human exposure to drug residues through food consumption. Potential human exposure to drug residues through food is estimated by regulatory authorities by using either “consumption factors” of edible tissues or a “food basket” approach. Further, regulatory agencies use different programs for assessing and managing human food safety risks. This presentation will explain the various sets of standards relevant for registration of a drug in multiple geographies. Moreover, regulatory agencies add various “safety factors” to the computations of human drug exposure from residues to further mitigate the likelihood of humans consuming food products derived from treated animals being exposed to relevant levels of drug residues. Typical computations and considerations factored into the establishment of codified regulatory drug tolerances/maximum residue limits will be discussed. The presentation will also cover regulatory surveillance mechanisms, which are in place globally to ensure human food safety and may influence trade of edible tissues.

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 11:00 AM–11:40 AM Introduction to Humanized Mice
Kristina Howard, US Food & Drug Administration, Silver Spring, MD

CE05-2 11:40 AM–12:20 PM Characterization of Humanized Immune System Mice as Preclinical Models of Immune Modulation
Michael Oropallo, Merck & Co., Inc., West Point, PA

12:20 PM–12:30 PM Questions and Answers

12:30 PM–1:00 PM Break

CE05-3 1:00 PM–1:40 PM Using Immune Humanized Mice to Evaluate Immunostimulatory Adverse Events
Jungeun Sung, US Food & Drug Administration, Silver Spring, MD

CE05-4 1:40 PM–2:20 PM Hepatic Mouse Models
Jeannette Connerney, Precigen, Inc., Germantown, MD

2:20 PM–2:30 PM Questions and Answers



The range of methods and mouse strains available to make immune humanized mice is broad and can create confusion when choosing a model to study biological drugs. This presentation will provide an in-depth background into the available strains and methods (PBMC, CD34, BLT) used to make immune humanized mice, including their advantages and limitations. Humanization of immune cell subsets will be compared between models, with general aspects of model use, including study design, also presented.


Immune modulation using checkpoint inhibitors is rapidly becoming an important treatment modality in oncology. One drawback of these drug products is that few animal models can be used to understand the potential adverse effects induced by this type of immune system modulation. This presentation will review data from checkpoint inhibitor drug studies using different immune humanized mouse models to compare and contrast the utility of each model.


In recent years, development and clinical use of biologics has increased significantly because of their ability to effectively treat immune-mediated diseases and cancer. However, adverse reactions, including cytokine release syndrome (CRS) and immunogenicity to biologics triggering the formation of anti-drug antibodies (ADAs), remain concerns. This presentation will review models to evaluate CRS in vivo and will present recent data on the ability of immune humanized mice to produce antibodies in response to immune stimulation and potential to form ADA.


Hepatic mice are produced through the injection of human hepatocytes into severely immune-compromised mice that have murine hepatocytes eliminated through one of several methods. This presentation will compare and contrast the different mouse strains used to make hepatic mice and the advantages/disadvantages of each of these models and methods. Data from a range of studies, including drug metabolism and toxicity, will be discussed.

Friday, November 13: 11:00 AM–2:30 PM Eastern Time

Session Chairs: William Salminen, Tolmar, Inc., 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 11:00 AM–11:45 AM Overview of Nonclinical Study Contracting and Monitoring: Outline and Goals of the Course
William Salminen, Tolmar Inc., Sarasota, FL

CE06-2 11:45 AM–12:30 PM Laboratory Qualification, Requests for Proposals (RFPs), and Study Contracting
Andrew Emanuel, Aronnax Inc. (Camargo Research Group),, Montreal, QC, Canada

12:30 PM–1:00 PM Break

CE06-3 1:00 PM–1:40 PM 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 1:40 PM–2:20 PM Good Laboratory Practices: Test-Article and Dose Formulation and Bioanalytical Method Development, Validation, and Analysis
William Salminen, Tolmar Inc., Sarasota, FL

2:20 PM–2:30 PM Questions and Answers



This presentation will provide a high-level overview of nonclinical study contracting and monitoring. An outline and goals of the course will be presented. The presentation will provide various examples of where nonclinical studies have gone wrong and why monitoring of contracted or internally conducted studies is critical to receiving successful studies and study reports that will pass scientific and regulatory scrutiny, particularly for pivotal GLP safety and toxicology studies for regulatory submissions.


This presentation will cover the process of laboratory qualification from quality assurance, GLP compliance, and scientific aspects. The process of generating and sending out Requests for Proposals (RFPs) to CROs will be covered. Finally, lab selection and the formal contracting process will be covered. This presentation will cover key areas that need careful oversight and that can lead to delays in getting studies started.


This presentation will cover the critical aspects of study start-up and day-to-day study monitoring, including to test-article supply, analysis, and logistics; dose formulation and bioanalytical method development; protocol development and finalization; day-to-day data review; interactions with the Study Director and other scientists at the CRO; drafting main and subreport reviews; and report finalization. This presentation will cover on-site study monitoring and the various study phase visits that can benefit from on-site study monitoring. This presentation will also cover GLP compliance and key study aspects that typically require oversight and input by the study monitor to ensure GLP compliance and regulatory acceptance of the study.


This presentation will cover the key aspects of ensuring that the test article used on a GLP study meets the GLP requirements. In addition, dose formulation analytical method development, validation, and samples analysis under GLPs will be covered. Finally, a high-level overview of bioanalytical method development, validation, and sample analysis under GLPs will be presented.

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.

11:00 AM–11:05 AM Introduction

CE07-1 11:05 AM–11:45 AM Pharmacology and Molecular Mechanisms of Drugs of Abuse
Michael Klein, Controlled Substance Scientific Solutions, LLC, Chevy Chase, MD

CE07-2 11:45 AM–12:30 PM Role of Abuse Testing in the Development of CNS Drugs
David J. Heal, DevelRx Ltd, Nottingham, UK, and University of Bath, Bath, UK

12:30 PM–1:00 PM Break

CE07-3 1:00 PM–1:40 PM Conducting a Successful Human Abuse Potential Study and Integration with Other Clinical Data
Edward Sellers, University of Toronto and DL Global Partners Inc, Toronto, ON, Canada

CE07-4 1:40 PM–2:20 PM Regulatory Perspective on Abuse Potential Assessment and the Drug Scheduling Process
Dominic Chiapperino, US Food and Drug Administration, Center for Drug Evaluation and Research, Silver Spring, MD

2:20 PM–2:30 PM Questions and Answers



Understanding the mechanisms underlying the abuse of drugs is crucial to identifying drugs with abuse potential. The neuropharmacology of narcotics, stimulants, depressants, and hallucinogens will be discussed. Differences in the addiction profile between drug classes and drugs in the same class will be highlighted.


This talk will focus on the nonclinical studies the US FDA recommends be conducted to assess abuse potential. Details on the design, conduct, and timing of the battery of studies will provided. In addition, there will be a discussion on other custom, but relevant, studies that can be used to provide further insight on the abuse potential of a drug.


The Human Abuse Potential study is integral in assessing the abuse potential of a drug. This talk will discuss when a Human Abuse Potential study is needed, general trial design, using animal data to inform study design, outcome measures, and data analysis. The presentation will also address how physical dependence can alter abuse potential and how abuse-related data from safety and efficacy clinical trials can be used in the overall assessment.


The US FDA representative will give an overview of the drug scheduling process and provide recommendations on engaging the US FDA during drug development and preparing the abuse potential section of an NDA. A discussion of the Eight Factor Analysis and the drug scheduling process will be provided, and case studies will be highlighted.

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) and will 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.

CE08-1 11:00 AM–11:35 AM Introduction to Toxicokinetics (TK)
Suman Mukherjee, Merck & Company, Inc, West Point, PA

CE08-2 11:35 AM–12:10 PM Exposure Multiples: Finding the Best Path through Development
Holly Dursema, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT

12:10 PM–12:30 PM Questions and Answers

12:30 PM–1:00 PM Break

CE08-3 1:00 PM–1:35 PM Toxicokinetics in Developmental and Reproductive Toxicology Studies
Jack Valentine, Merck & Company, Inc, West Point, PA

CE08-4 1:35 PM–2:10 PM New Biological Entity (NBE) Toxicokinetics
Ming Cheng, Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT

2:10 PM–2:30 PM Questions and Answers



This presentation will cover the basic principles of small molecule TK, including the parameters that are measured in TK. The importance of collecting blood/plasma/serum samples at appropriate time points to ensure accurate estimation of TK parameters will be discussed. Interpretation of TK data, including assessment of accumulation, dose proportionality, sex difference, and change in disposition between single dose and repeat dosing, will be covered, as well as how these factors affect the design of toxicology studies. The causes of variability in TK data, the impact of variability in TK data, and approaches to manage TK data variability in toxicology studies will be addressed. Practical examples will be included throughout the presentation.


Toxicology study design during development transitions through various phases as the potential toxicity of a compound is evaluated. In parallel, health authorities have expectations of dose levels and their corresponding exposure that are generally based on ICH Guidelines. Achieved multiples of exposure may be a result of using a maximum feasible dose, maximum tolerated dose, or limit dose, or by using special considerations for carcinogenicity studies. These margins are often determined by the characteristics of the compound and frequently change dependent on the phase of development. The impact of protein binding on margins of exposure and its impact on safety remains an open debate and will be discussed briefly. Case studies will be provided for illustration.


Regulatory agencies require rigorous testing of chemical entities in nonclinical species for embryonic and developmental toxicities prior to administration to women of childbearing potential. The primary objective of toxicokinetic study conduct during developmental and reproductive toxicity testing is to describe the systemic exposure of the test article(s) achieved in pregnant and lactating animals and to bridge the relationship between dose and toxicity in maternal animals and their developing embryos and/or fetuses. The design of toxicokinetic studies varies among pharmaceutical companies. The goal of this presentation is to discuss the guidelines and study designs for toxicokinetic assessment in developmental and reproductive toxicity testing for pharmaceutical drug development through background material and case studies.


The toxicology/TK studies of new biological entities (NBEs) and new chemical entities (NCEs) differ in many aspects, such as study design, study duration, and dose regimens. In addition, some biochemistry or immunology studies generally are conducted to understand NBE toxicology findings. This talk will discuss common NBE toxicology\TK strategies. It also will talk about the general bioanalytical strategy for TK since different assays (total versus free) and various platforms (LC/MS and enzyme-linked immunosorbent assay) have been widely utilized to measure NBEs. Immunogenicity is a critical phenomenon for NBEs, which can cause reduced exposure and immune-complex related adverse effects. The presentation will talk about how to interpret anti-drug antibody (immunogenicity) data and how to correlate ADA with drug exposure and toxicology findings. In addition, a brief discussion of considerations for alternate modalities will be provided using oligonucleotides as an example, to demonstrate a different approach to TK measurement and highlight the need for flexibility.

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.

CE9-1 11:00 AM–11:45 AM Effects of Biologic Drug Modalities on Peripheral Blood Cells
Nancy E. Everds, Seattle Genetics, Bothell, WA

CE9-2 11:45 AM–12:30 PM Immunogenicity and Immune Complex Disease in Preclinical Safety Assessment Studies: Challenges for Assessing Human Safety
John L. Vahle, Eli Lilly & Company, Indianapolis, IN

12:30 PM–1:00 PM Break

CE9-3 1:00 PM–1:40 PM Complement Activation: Cause and Effect
William Siska, Amgen, Sparks, NV

CE9-4 1:40 PM–2:20 PM Immunophenotyping and Cytokines: Considerations and Case Examples
Ellen W. Evans, Independent Consultant, Waterford, CT

2:20 PM–2:30 PM Questions and Answers



The interpretation of clinical pathology results from nonclinical studies using biotherapeutics requires knowledge of traditional and novel toxicologic clinical pathology concepts. This talk will focus on some of the ways that biologics can impact peripheral blood cells. Hematologic effects related to the pharmacology of the test article may result in expected changes in blood cell counts or may uncover unexpected species differences in pharmacologic action. Unintended hematologic effects of test articles may be caused by interactions of the CDR of the test article with nontarget molecules. Other hematologic changes include those that are class effects of new modalities or that occur secondary to activation of biologic cascades.


Biotherapeutics are often immunogenic in preclinical safety species; however, the consequences of the anti-drug antibody response can vary from minimal impact to near complete loss of exposure to morbidity and mortality secondary to immune complex disease. This talk will briefly review the development of anti-drug antibodies in preclinical safety studies and the potential impacts on study outcomes. Basic principles of immune complex disease will be reviewed, followed by a summary of the more common clinical and anatomic pathology manifestations of immune complex disease in toxicity studies of biotherapeutics. A weight of evidence approach to detecting and confirming immune complex disease will be emphasized. Case studies will be used to illustrate the challenges in determining the clinical relevance and regulatory impact of these types of findings.


This talk will discuss activation of the complement system in nonclinical studies of biotherapeutics, with a focus on pathophysiology, clinicopathologic sequelae, and practical testing considerations.


This discussion will concentrate on the use of cytokines and immunophenotyping endpoints in safety evaluation of biologic modalities, including case studies.

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