Sunday, November 17

Continuing Education (CE) courses are 3.5 hours each and are held either Sunday morning (AM: 8:00 AM–11:30 AM) or Sunday afternoon (PM: 1:00 PM–4:30 PM). Preregistration is required, and seating is limited.

CE course registrants may switch to a different course without paying an additional course registration fee until November 10. After November 10, switching courses will be regarded as a separate registration, and an additional course fee will be required.

Continuing Education course books will be provided exclusively in electronic format and will be available to course registrants in advance of the Annual Meeting.

Morning Courses (AM) 8:00 AM–11:30 AM

Session Chairs: Scott E. Boley, Sinclair Research Center LLC, Auxvasse, MO;
Heather Dale, Covance, Inc., Madison, WI; and
Shawna L. Weis, ToxStrategies, Inc., Swampscott, MA

This Continuing Education course will review the essential aspects of the role and responsibilities of the Study Director. For Part A, the presentations will include topics relevant for Study Directors, including a review and history of GLP regulations, managing and addressing the challenges of multisite studies, and designing toxicology studies to meet evolving animal welfare expectations. This course is an excellent introduction for new Study Directors and a great refresher course for experienced Study Directors. All students who complete the course will receive a certificate for course participation, which can be used for continuing education credits.

CE01-1 8:00 AM–8:10 AM Introduction
Scott E. Boley, Sinclair Research Center LLC, Auxvasse, MO

CE01-2 8:10 AM–9:00 AM A Review and History of the GLP Regulations
Robin Guy, Robin Guy Consulting, LLC, Lake Forest, IL

CE01-3 9:00 AM–9:30 AM Managing the Challenges of a Multisite Study
Heather Dale, Covance, Inc., Madison, WI

9:30 AM–10:00 AM Break

10:00 AM–10:15 AM Managing the Challenges of a Multisite Study (Continued)
Heather Dale, Covance, Inc., Madison, WI

CE01-4 10:15 AM–11:00 AM Animal Welfare, the Institutional Animal Care and Use Committees, and Accreditation
Gary L. Borkowski, AAALAC International, Frederick, MD

11:00 AM–11:30 AM Problem-Solving and Discussion



This will be a brief introduction to the roles and responsibilities of Study Directors and will introduce the other concepts that will presented throughout the course.


Good laboratory practices (GLPs) are the regulations by which safety studies intended to support a regulatory submission are conducted. Often, Study Directors do not understand the historical perspective of GLPs or the ways in which they have been interpreted. This presentation will highlight aspects of the GLP regulations that directly affect the SD in conducting their studies.


Most studies are not conducted in a single location. It is common for the in-life portion to be conducted in one lab, and the bioanalytical, dose formulation analysis, histology, and biomarker assessments to be conducted at remote locations either of the same company or with different companies. Fragmentation of study activities presents communication, scientific, regulatory, and logistical challenges for ensuring GLP compliance and timeliness of study conduct and reporting. This presentation will help the Study Director understand how to manage these relationships and keep everyone working to achieve the same goal: a scientifically sound and compliant study suitable for review and acceptance by regulatory bodies.


This presentation will explain the importance of animal welfare in designing and conducting toxicology studies, how the Institutional Animal Care and Use Committee (IACUC) and Study Director can work together for successful nonclinical safety studies, and how AAALAC accreditation provides a global framework.

Session Chairs: Gary Burleson, Burleson Research Technologies, Inc., Morrisville, NC; and
Kenneth Hastings, Hastings Toxicology Consulting, LLC, Mount Airy, MD

The immune system consists of four major components: (1) mediators that call in and activate immunological cells; (2) cells mediating innate immunity; (3) effector cells responsible for cell-mediated immunity; and (4) cells that provide humoral immunity. In addition, the vast network of lymphoid cells interacts with both lymphoid and nonlymphoid cells as well as cellular products to create a functionally intact immune system. Positive and negative feedback control mechanisms govern many of the circuitous immune networks. If the normal function of a network of cell-to-cell or cell-messenger interaction is perturbed or altered, the host may risk disease or death. Either a decrease (immune suppression) or an increase (immune enhancement) in the interactions or production of cellular products may cause deleterious health effects. The physiologic ideal is a homeostatic network of interactions and cascade effects with the proper positive and negative controls. Many assays are available to evaluate potential immunotoxic effects of small molecule pharmaceuticals and chemicals. The advent of biologics, their species specificity, and changes and advances in that field have posed some unique challenges in assessing immunotoxicity. This course will introduce the immune system and information on how to utilize existing and novel assays to design a thorough immunotoxicology safety assessment that evaluates all three arms of the immune response: innate immunity, cell-mediated immunity, and humoral immunity.

8:00 AM–8:10 AM Introduction
Gary Burleson, Burleson Research Technologies, Inc., Morrisville, NC; and Kenneth Hastings, Hastings Toxicology Consulting, LLC, Mount Airy, MD

CE02-1 8:10 AM–8:50 AM Basic Immunology: Cells and Mediators of the Immune System
David McMillan, US FDA/CDER, Silver Spring, MD

CE02-2 8:50 AM–9:30 AM Basic Immunology and Immunotoxicology Testing
Peyton Myers, US FDA/CDER, Silver Spring, MD

9:30 AM–10:00 AM Break

CE02-3 10:00 AM–10:45 AM Immunosuppression
Hervé Lebrec, Amgen Inc., South San Francisco, CA

CE02-4 10:45 AM–11:30 AM Immunostimulation: Hypersensitivity Reactions—From Allergy to Infusion Reactions
Marc Pallardy, University Paris-Sud, Chȃtenay-Malabry, France



The immune system is a host defense system designed to protect against infection and disease. Extremely complex, this system consists of a diverse array of cell types (including lymphocytes, neutrophils, and monocytes) and proteins (including cytokines, antibodies, and complement proteins). This presentation will survey the major players in both innate and adaptive immunity and indicate how perturbations to these systems can affect human health and disease.


A thorough immunotoxicology safety assessment often requires an evaluation of all three arms of the immune response: innate immunity, cell-mediated immunity, and humoral-mediated immunity. Many historical assays are available to evaluate small molecule pharmaceuticals and chemicals, but mostly for immunosuppression. With the advent of biologics (and especially immunomodulators), the assays to evaluate the toxicities have created many unique challenges and opportunities for immunotoxicological evaluation. For both small molecules and biologics, immunotoxicity may be caused by various mechanisms and may involve only some arms of the immune system. Therefore, immunotoxicological safety assessments are often on a case-by-case basis and are driven by the science. With many assays available (both GLP and non-GLP), there are many tools across various species now available to provide a thorough immunotoxicology safety assessment.


The immune system is broadly categorized as innate and adaptive immunity, with innate immunity consisting of the nonspecific first set of responses and adaptive immunity (cell-mediated and humoral) providing a more delayed but exquisitely sensitive recognition. While the three arms of the immune response (innate immunity, cell-mediated immunity, and humoral-mediated immunity) are often described as separate arms and are different in their mechanism of action, synergy between them is critical in generating a fully effective immune response. Evaluating the function of these three arms of the immune system and immunosuppression in the context of an immunotoxicology safety assessment will be discussed.


Hypersensitivity is an exaggerated or inappropriate immune response resulting from exposure to an otherwise innocuous compound. These responses can be specifically directed to the compound, leading to allergy and mediated by antibodies or T cells. On the other hand, the innate immune system can be stimulated, leading to infusion reactions mostly supported by cytokines, prostaglandins, and vasoactive amines. Hypersensitivity responses and mechanisms will be reviewed. Testing strategies in the context of an immunotoxicity assessment and in vitro assays currently addressing the relevant adverse outcome pathways will be discussed.

Session Chairs: Krishna Allamneni, Turning Point Therapeutics, San Diego, CA; and
Marian Glynn, Tox Clarity, LLC, Napa, CA

Functioning effectively as a toxicologist to advance development of a new drug product requires a breadth of skills beyond classical scientific training. Before designing a toxicology study, critical data need to be obtained from colleagues in CMC, pharmacology, pharmacokinetics, clinical, and management roles. As data are generated, they need to be thoughtfully interpreted but also thoughtfully communicated to a range of audiences to guide decision making. This course will discuss how to initiate a toxicology program, how to communicate with team members to facilitate everyone’s progress toward the next milestone, and how to meet a range of challenges encountered in evaluating safety in diverse business contexts. The session will conclude with an interactive discussion of real-world examples.

CE03-1 8:00 AM–8:50 AM Getting Started: Delineating the Foundation with CMC, Pharmacology, Pharmacokinetics, and Clinical
Paramita Mookherjee, Omeros, Seattle, WA

CE03-2 8:50 AM–9:30 AM Staying Grounded on the Critical Path
Marian Glynn, Tox Clarity, LLC, Napa, CA

9:30 AM–10:00 AM Break

CE03-3 10:00 AM–10:45 AM Managing in a Matrix and Communicating Findings: When and How
Patricia C. Ryan, AstraZeneca, Gaithersburg, MD

CE03-4 10:45 AM–11:30 AM Lessons Learned in the Real World
Natalie S. Holman, Eli Lilly and Company, Indianapolis, IN; Kristina DeSmet, United Therapeutics Corporation, Research Triangle Park, NC; and Francis Wolenski, Takeda Pharmaceuticals, Cambridge, MA



The early days of drug discovery and development require give and take among key stakeholders. This presentation will discuss how toxicologists could (1) partner with CMC to define excipients, vehicles, homogeneity, stability, purity, and manufacturing similarity to the clinical product; (2) tag-team with pharmacology and pharmacokinetics to characterize target conservation, blood partitioning, extent of plasma protein binding, plasma stability, and in vitro metabolite profiling to enable informed selection of species, administration route, and dose ranges; (3) collaborate with CMC to estimate dosing needs to inform the scale of manufacturing campaigns; and (4) work with clinicians and project management to discern clinical intentions and enable clinical flexibility.


Shaping expectations is an essential skill to facilitate team success. The toxicologist can guide expectations by developing realistic timelines that align sound science with a company’s risk tolerance and by preparing the team for a range of outcomes. This talk will provide examples for how one set of regulatory goals may be met by a variety of strategies based on a range of corporate risk-tolerance levels and objectives. It also will discuss case studies of how both “aggressive” and “measured” timelines affect overall project success.


Working in a cross-functional setting as a key team member poses challenges for toxicologists. Stakeholder management is critical and requires effective leadership skills. This talk will describe best collaboration behaviors for toxicology project leaders related to building trust, resolving differences of opinion, and communicating effectively. This presentation will discuss methods of focusing a team on important information and its implications, as well as the appropriate timing to allow for effective team decision-making. This includes decisions pre-IND regarding clinical trial design and manufacturing supplies, as well as decisions to support in-progress clinical trials. It also encompasses public release of information and interpretation of safety findings. Best practices for gaining internal alignment, managing key stakeholders, and communicating findings will be described, with case examples to illustrate these concepts.


To complement the instructional talks in this session, three early career project toxicologists will share examples and key learnings from their first several years in industry. Their perspectives span working in small, midsize, and large pharmaceutical companies. These talks will provide lessons learned under difficult circumstances, including how to successfully build personal relationships to help overcome the technical challenges of drug development. A panel Q&A session will follow the individual talks.

Session Chairs: Joel Bercu, Gilead Sciences, Inc., Foster City, CA; and
Timothy J. McGovern, US FDA/CDER, Silver Spring, MD

Pharmaceutical impurities are a natural part of drug development. Chemistry, manufacturing, and controls (CM&C) and toxicology experts work together to test and control impurities. Lack of control for impurities can result in concerns for both the safety and the quality of a pharmaceutical. Throughout pharmaceutical development, impurities are evaluated for mutagenic concern. Mutagenic impurities are typically controlled to lower levels than nonmutagenic impurities. Nonmutagenic impurities are controlled at or below the qualification threshold, and higher exposures may require additional animal testing. These presentations will describe the regulatory, scientific, and toxicological aspects of impurities. They will also discuss recent developments and scientific/regulatory changes on the horizon.

CE04-1 8:00 AM–8:30 AM Chemistry of Pharmaceuticals: How Impurities Get Introduced and Control Strategies for Limiting Exposure
Olivier Dirat, Pfizer Inc., Sandwich, United Kingdom

CE04-2 8:30 AM–9:00 AM Regulatory Aspects of Nonmutagenic and Mutagenic Pharmaceuticals
Timothy J. McGovern, US FDA/CDER, Silver Spring, MD

CE04-3 9:00 AM–9:30 AM Qualification of Impurities in Clinical Trials and Beyond
James Harvey, GlaxoSmithKline plc, Hertfordshire, United Kingdom

9:30 AM–10:00 AM Break

CE04-4 10:00 AM–10:30 AM Hazard Identification and Limits for Mutagenic Impurities
John Nicolette, AbbVie Inc., North Chicago, IL

CE04-5 10:30 AM–11:00 AM Pharmaceutical Impurities in the 21st Century: Scientific and Regulatory Developments
Joel Bercu, Gilead Sciences, Inc., Foster City, CA

11:00 AM–11:30 AM Panel Discussion



This presentation will introduce the chemistry aspects of pharmaceutical impurity management. Pharmaceutical impurities are a natural part of drug development. While controlling impurities is fundamental to high-quality and safe medications, patient exposure to impurities is unavoidable. In addition, degradation products occur over the shelf life of a drug and cannot be reduced further. While synthetic impurities can be reduced via reprocessing, synthetic chemistry design, or other techniques, reducing impurities to minuscule levels affects other quality attributes and increases environmental waste with little gain in the overall reduction of the impurities. Therefore, toxicology is needed to help develop safe levels of impurities and a practical target for CM&C.


This session will introduce the regulatory aspects of pharmaceutical impurities. Pharmaceutical guidance documents include the International Conference on Harmonisation (ICH) Q3 and ICH M7 Guidelines. ICH Q3A and Q3B discuss when to report, identify, and qualify impurities or degradation products in drug substances or drug products. Qualification is the process by which safety data are generated for the impurity or degradation product. ICH Q3C, Q3D, and M7 discuss further details about the toxicological limits and controls for solvents, metals, and mutagenic impurities, respectively. In these guidances, permitted daily exposures (PDEs) or acceptable intakes (AIs) for common solvents, metals, and carcinogenic compounds are provided. Regulatory feedback and case studies will be presented.


This presentation will discuss the practical aspects of impurity qualification throughout development. ICH Q3A and Q3B Guidelines do not apply for early-phase clinical trials. However, a collaborative effort among a few major pharmaceutical companies provided scientific advancement and guidance on qualification thresholds and processes for early-phase clinical trials. Then, when clinical trials exceed six months in duration, the qualification thresholds can be set to ICH Q3A and Q3B limits. This presentation will also show how an impurity typically is tested in a safety study and how to calculate a limit based on the result of the safety study.


This presentation will discuss the toxicologist’s role in identifying and controlling mutagenic impurities. In the synthesis of pharmaceuticals, it is not uncommon to identify a potentially mutagenic impurity. This is because a synthetic process is typically reactive, allowing molecules to combine to form the drug substance. The toxicologist typically identifies concerns for mutagenicity using computational tools and expert review. This predicted mutagen can be tested in the Ames to confirm the prediction. If predicted mutagenic or Ames positive, the impurity will be controlled below the threshold of toxicological concern (TTC) or compound-specific limit in cases where there are carcinogenicity data available. The TTC and AI are dependent on duration of exposure. Therefore, identifying and controlling mutagenic impurities is essential to limiting exposure to these potentially toxic compounds.


While impurity guidelines have been available for over 20 years, recent activities have been formed to advance the toxicological science of impurities. The purpose of these efforts is to facilitate the manufacture of pharmaceuticals, reduce animal testing, and ensure the safe exposure of impurities. Current scientific achievements include developing common toxicological limits for pharmaceutical impurities, advancing QSAR evaluation of impurities, and establishing qualification thresholds during short-term clinical trials. This session will discuss some of these recent scientific achievements and current work. It will also discuss how scientific advancement can be used in practice to demonstrate the safety of impurities.

Session Chairs: Daniel J. Patrick, Charles River, Mattawan, MI; and
Noel D. Horton, Charles River, Mattawan, MI

It is well known that successful preclinical safety assessment studies depend on reliable and accurate data, which usually include critical contributions from anatomic and clinical pathology. There are numerous pathology publications that provide insights and recommendations that reliably improve pathology data and overall study outcomes when implemented. This Continuing Education course will present 10 of the most important pathology-related concepts, with practical recommendations that toxicologists can utilize in their preclinical studies. These concepts include using recommended anatomic and clinical pathology study designs, communicating information with the study pathologist before the evaluation, understanding what constitutes a properly trained toxicologic pathologist, following recommended histopathology evaluation practices, appropriately determining the adversity of pathology data, using pathology diagnostic terminology that is globally harmonized and Standard for Exchange of Nonclinical Data (SEND) compliant, knowing when and when not to use pathology historical control data, implementing pathology quality control measures such as pathology peer review, and following recommended pathology reporting practices. This course will be presented by globally recognized toxicologic pathologists who have actively promoted and authored publications on these topics.

CE05-1 8:00 AM–8:45 AM Recommended Anatomic and Clinical Pathology Study Designs and Prestudy Communication
Armando Irizarry, Eli Lilly and Company, Indianapolis, IN

CE05-2 8:45 AM–9:30 AM Prudent Practices for Picking Pathologists, Handling Histopathology, and Assigning Adversity
Brad Bolon, GEMpath Inc., Longmont, CO

9:30 AM–10:00 AM Break

CE05-3 10:00 AM–10:45 AM SENDing the Pathology Data We Have INHAND and Factors to Consider When Using Pathology Historical Control Data
Charlotte M. Keenan, C.M. Keenan ToxPath Consulting, Doylestown, PA

CE05-4 10:45 AM–11:30 AM Histopathology Quality Control and the Reporting of Pathology Data and Interpretations
James D. Fikes, Biogen, Cambridge, MA



This presentation will provide a basic understanding of the speaker’s perspective on how to effectively implement clinical pathology and anatomic pathology endpoints into nonclinical toxicity studies. Implementing pathology endpoints requires a clear understanding of the goals of the study, full awareness of regulatory guidance and scientific best practices, thoughtful planning and design of the studies, consideration of potential failure modes, and deliberate prestudy communication with study pathologists (clinical and anatomic). Addressing these areas will facilitate the successful completion of nonclinical toxicity studies that require the inclusion of pathology endpoints.


Pathology data are an essential element in toxicity risk assessment, so institutions should exercise care in selecting an apt pathology practitioner and suitable practices. Pathology diagnosis melds both objective knowledge and subjective experience. Proficiency in pathology requires appropriate training, success at which typically is attested by achieving status as a certified pathologist. Requirements for training and certification differ around the globe, and some pathways are more effective than others. The pathology dataset includes macroscopic (gross) observations, organ weights, clinical pathology values, and histopathologic diagnoses. Key variables in designing a pathology data acquisition strategy are the selection of nonblind versus blind evaluation and how to confirm the accuracy of pathology data, the choices of which differ depending on the study objective. Once pathology raw data are obtained, the last major consideration is how to appropriately integrate and interpret pathology findings as a means of determining which, if any, changes are adverse. Important concepts are that findings are adverse only if they cause harm to the animal and that an interpretation of adversity applies solely to the test species and only under the specific conditions of the study. The best interpretations are possible when pathologists are fully acquainted with pertinent information before making their diagnoses and adversity calls.


There are numerous benefits of consistent pathology diagnostic terminology, including allowing toxicologists to compare findings across studies and programs. There has been broad interest in utilizing published International Harmonization of Nomenclature and Diagnostic Criteria (INHAND) terminology for SEND (Standard for Exchange of Nonclinical Data) submissions to the US FDA. To date there has been wide acceptance of INHAND nomenclature, based on input from industry and government toxicologists as well as information technology specialists. Examples of harmonized terminology, how it can be accessed, and how it can be mapped to SEND controlled terminology will be provided. Pathology diagnoses from control animals from previous studies (historical control data, HCD) can greatly help differentiate test article effects from spontaneous/background lesions; however, HCD also has many limitations with which toxicologists should be familiar. Some factors to consider include when and when not to use it, where to obtain it, and how variables such as pathology practices, including necropsy and trimming procedures and applying diagnostic criteria, can affect study data and HCD.


Many of the critical data points in repeat toxicology studies are generated during the histopathologic examination of tissues, so accuracy in the description, interpretation, and reporting of histopathology data is crucial for safety assessment. This presentation will outline activities contributing to the overall quality of the diagnoses and interpretation of histopathology observations, followed by recommendations to optimize the incorporation of pathology findings in the study report and the integration of pathology observations with other study results. Included in the discussion will be an overview of the histopathology assessment process, what constitutes histopathology raw data, pathology peer review, good laboratory practice considerations related to peer review, pathology working groups, and best practices for pathology reports.

Afternoon Courses (PM) 1:00 PM–4:30 PM

Session Chairs: Scott E. Boley, Sinclair Research Center LLC, Auxvasse, MO; Heather Dale, Covance, Inc., Madison, WI; and Shawna L. Weis, ToxStrategies, Inc., Swampscott, MA

This Continuing Education course will review the essential aspects of the role and responsibilities of the Study Director. Part B will concentrate on the science involved in toxicology studies and will help attendees understand how to evaluate data generated. Presentations will be made regarding immunotoxicology, biomarkers, anatomic pathology, and regulatory expectations for an IND package. This course is an excellent introduction for new Study Directors and a great refresher course for experienced Study Directors. All students who complete the course will receive a certificate for course participation, which can be used for continuing education credits.

CE06-1 1:00 PM–1:45 PM Immunotoxicology
Jennifer Tichenor, Charles River, Reno, NV

CE06-2 1:45 PM–2:30 PM Biomarkers in Safety Assessment Studies: Integration of Traditional and Emerging Endpoints
Adam Aulbach, Charles River, Mattawan, MI

2:30 PM–3:00 PM Break

CE06-3 3:00 PM–3:45 PM The Art and Science of Anatomic Pathology
Kenneth A. Schafer, Greenfield Pathology Services, Inc., Greenfield, IN

CE06-4 3:45 PM–4:30 PM US FDA Reviewer’s Quest for the Message: Regulatory Review of an IND
John Dubinion, US FDA/CDER/OAP, Silver Spring, MD



An increasing number of therapeutics that affect the immune system, either through design or as a side effect, are in development. Study Directors should have the skills to evaluate and interpret these data in the context of the overall safety interpretation of a compound. This presentation will provide a foundation for understanding how to evaluate the effect of a test article on the immune system of the animal—from cytokines to immunophenotyping results and anti-drug antibody formation.


Using biomarkers as a clinical pathology endpoint has become a routine practice following the recent emergence of a variety of safety assessment biomarkers that can be used to characterize organ- and pathophysiologic-specific toxicity. This session will focus on using traditional and newly emerging biomarker endpoints, with an emphasis on their appropriate application and study design principles. Case examples that combine the use of biomarker data with other study endpoints (e.g., in-life and pathology) will be used to highlight the importance of a comprehensive and integrated approach to contemporary clinical pathology assessment.


Anatomic pathology assessments are often a black box for those who are not pathologists. This presentation will demystify what an anatomic pathologist does in the evaluation of a toxicology study and will explain why things are done in particular ways. This presentation will also provide an overview of an anatomic pathology report; clarify what Study Directors should look for in a quality report to get the most out of a pathologist’s contribution; and explain how the anatomic pathology assessment should be tied in with other aspects of a nonclinical study, including in-life observations and clinical pathology.


An IND is submitted to the US FDA to request permission to test a potential therapeutic in human clinical trials. The package claims that the potential therapeutic is safe and efficacious. The US FDA reviews the primary data supporting safety and efficacy and determines the accuracy of these claims. This presentation will help Study Directors understand the structure of the review team and their interactions, describe a common review process and the necessity for a targeted review approach, and provide general best practices for submitting an IND. 

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Session Chairs: Simon Authier, Charles River, Laval, QC, Canada; and
Raluca Kubaszky, Charles River, Laval, QC, Canada

This Continuing Education course is intended to be an overview of the nonclinical testing practices and paradigms for gene and cell therapy products, with perspectives from industry, CROs, and the US FDA. Gene and cell therapies are emerging as important modalities to treat a variety of human diseases. Recent advances have led to important scientific breakthroughs including numerous successful approvals. The time is ripe to review basic concepts in gene and cell therapy, discuss technical approaches and unique analytical testing methods, provide an overview of nonclinical safety testing strategies and share the US FDA/CBER perspective on gene and cell therapies. This Continuing Education course is intended to be an overview of the nonclinical testing practices and paradigms for gene and cell therapy products, with perspectives from industry, CROs, and the US Food and Drug Administration.

CE07-1 1:00 PM–1:45 PM An Introduction to Gene and Cell Therapy
Patricia C. Ryan, AstraZeneca, Gaithersburg, MD

CE07-2 1:45 PM–2:30 PM GLP Analytical Assays for Gene and Cell Therapy Products: Strategies and Success Factors
Philippe Ancian, Charles River, Évreux, France

2:30 PM–3:00 PM Break

CE07-3 3:00 PM–3:45 PM Nonclinical Development Challenges and Strategies for Gene and Cell Therapy Products: An Industry Perspective
Brian J. Mulhern, SciLucent, LLC, Herndon, VA

CE07-4 3:45 PM–4:30 PM Preclinical Considerations for Gene and Cell Therapy Products: A CBER Perspective
Abigail L. Shearin, US FDA/CBER, Silver Spring, MD



According to a recent review article published in Science (Dunbar et al., 2018), the field of cell and gene therapy has finally come of age. Gene therapy, defined as introduction, modification, or removal of DNA to treat disease, is a promising area of biomedical research that, despite notable setbacks, has finally begun to bear fruit after over 50 years of diligent and dedicated research. Cell therapy, the administration of living cells to restore a cell population or as carriers to deliver a therapeutic cargo, is a rapidly advancing treatment modality. Cell and gene therapy are frequently applied in combination, such as through the use of viral vectors to engineer T cells to express tumor-specific chimeric antigen receptors (CAR) for potent antitumor activity. This approach, sometimes described as ex vivo gene therapy, has lead to several recent US FDA approvals, including Kymriah, CD19-specific CAR T cells. Meanwhile, in vivo gene therapy has also celebrated recent successes, including the 2017 approval of in vivo delivery of therapeutic adeno-associated virus (AAV) vectors to the retina to treat congenital blindness (Luxterna, Spark Therapeutics). Finally, genome editing technologies offer an exciting new tool for precise gene addition, correction, or ablation that is in its earliest phases of development and poised to deliver advanced therapies for patient care over the next decade. This presentation will review the history of cell and gene therapy, provide definitions, and describe the various types of treatment modalities that encompass cell and gene therapy, including their disease settings, as well as the unique challenges they pose for translational research and development.


CEll and gene therapies (CGT) have become druggable with products such as Glybera, Strimvelis, Yescarta, and Kymriah being approved by the US FDA. Technologies are progressing at an impressively fast pace, with applications across a wide range of therapeutic indications, such as cancer, monogenic, cardiovascular, infectious, visual, and/or neurological conditions/diseases. Program-specific endpoints and technologies are major drivers in establishing the nonclinical testing strategy for CGT. The high level of analytical method customization needed in CGT may come with special considerations in the context of regulatory submission. This session will present and discuss the various technical approaches and tools available for CGT products safety assessment and their implementation in the successful conduct and completion of nonclinical studies. Elements of the presentation will encompass considerations for study design, animal models, immune-conditioning prior to treatment for cell therapies, and contamination control for gene therapies, as well as analytical challenges with GLP compliance for some aspects of the study. Successful assay deployment, including flow cytometry, ELISPOT, qPCR, and/or immunohistochemistry (IHC/ISH), requires careful scientific and regulatory support, as no regulatory guidance exists for the analytical validation typically required to support such programs. Finally, CGT case studies will be presented to illustrate potential paths and tactics relevant to this emerging field.


Gene and cell therapies offer promising and lasting treatments for a wide variety of diseases, which has led more and more sponsors to develop drugs in this field. Designing a nonclinical safety program to support development of gene and cell therapies can be uniquely challenging, as the classical nonclinical testing paradigms (ICH M3 and S6) generally do not apply to these products. This presentation will provide an overview of the considerations specific to nonclinical safety testing for gene and cell therapies, and case studies will be included to illustrate challenges associated with these products and strategies for effective program design.


The conduct of clinical trials for investigational cell and gene therapy (CGT) products is guided by the Code of Federal Regulations (CFR) Title 21, Part 312, to ensure the safety and rights of human subjects in all phases of clinical investigation. According to 21 CFR 312.23(a)(8), the sponsor needs to provide sufficient information derived from pharmacology and toxicology studies to support a conclusion that the proposed clinical trial is reasonably safe and scientifically feasible. The preclinical testing platform to evaluate the safety and effectiveness of each investigational CGT product can vary based on the biological properties of the product, the proposed clinical trial design, and other factors. The regulatory review of these products employs a weight of evidence, science-based, tiered approach to determine the potential benefits and risks of an investigational CGT product in the planned clinical context of use. These considerations are discussed in detail in the “Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products,” which was released by the US FDA Center for Biologics Evaluation and Research (CBER) in November 2013. This presentation will provide an overview of the current US FDA/CBER considerations for preclinical development programs assessing the safety and activity of CGT products.

Session Chairs: Kate E. Lane, Translate Bio, Lexington, MA; and
Todd Page, Eli Lilly and Company, Indianapolis, IN

There are myriad opportunities to meet with regulators during all stages of drug development—from early discussions before any formal submission to formal meetings at prescribed stages of development. Across the various regions (the US, the EU, and China), there are important differences in timing of submission, submission content, meeting expectations, and regulatory feedback. This session will take a step-by-step approach, focusing on the US, the EU, and China separately, allowing time for questions after each session. The final presentation will bring together some general principles of meeting preparation, etiquette, and tips for a more successful and effective interaction. The session will wrap up with a panel discussion.

CE08-1 1:00 PM–1:45 PM Meeting with the US FDA: Preparation, Documentation, Timing, and Planning for Success
Arianne Motter, US FDA/CDER, Silver Spring, MD

CE08-2 1:45 PM–2:30 PM Meetings with EMA: Preparation, Timing, Submissions, and Planning for Success
Leslie Dowling, Real Regulatory Ltd, Ely, United Kingdom

2:30 PM–3:00 PM Break

CE08-3 3:00 PM–3:35 PM Regulatory Meetings with Chinese Regulators, a Non–US FDA, Non–EMA Regulator: Rules, Timing, Preparation, Documentation, and Tips for Success
Lijie Fu, National Shanghai Center for New Drug Safety Evaluation and Research, Shanghai, China

CE08-4 3:35 PM–4:15 PM General Principles for Successful Regulatory Meetings
Thomas Class, Translate Bio, Lexington, MA

4:15 PM–4:30 PM Panel Discussion



For those meeting with the US FDA, this session will cover the range of meetings offered by the various US FDA centers, as well as important timing considerations, general expectations, and tips for a successful meeting. How to prepare for, conduct, and follow up after the meeting will be discussed. In addition, common questions and pitfalls will be presented to help attendees learn how to get the most out of a meeting.


This presentation will cover the range of EMA meetings, from early to late phases of medicinal product development, including timelines, required documentation, general expectations, and tips for success. Consideration for pediatric investigation plans will also be discussed.


This talk will cover the range of regulatory meetings with Chinese regulators, a non–US FDA, non–EMA regulator. The new rules, important timing, general expectations, tips for success, appropriate level of submission detail, how much data to include and how they should be presented, and common questions and pitfalls will be discussed, with ideas and suggestions for framing data positions.


The speaker will present a general overview of best practices that apply to regulatory meetings around the world, highlighting important regional differences, preparation of briefing documents, premeeting preparations, expectations for conducting successful meetings, and outcomes.

Session Chairs: Holly D. Dursema, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT; and
Tracy M. Williams, Eli Lilly and Company, Indianapolis, IN

This course will provide an overview of safety assessment of metabolites in pharmaceutical drug discovery and development while incorporating key contemporary topics. The objective of this course is to provide participants with an understanding of current guidance, safety implications of metabolites, approaches for metabolite assessment, and key challenges. After providing the groundwork of existing guidance, basic concepts of new chemical entity (NCE) metabolism will be discussed. This will include metabolic considerations for nonsmall molecules (e.g., linkers). Challenges that may be encountered with disproportionate human metabolites will be reviewed and relevant case studies provided. A US FDA perspective on safety assessment of metabolites, along with case studies, will be presented. The course material will ensure participants are familiar with guidance expectations and the challenges that may be encountered in metabolite assessments.

1:00 PM–1:10 PM Introduction
Tracy M. Williams, Eli Lilly and Company, Indianapolis, IN

CE09-1 1:10 PM–1:50 PM Metabolites in Drug Discovery and Development: Current Guidance
Suman K. Mukherjee, Merck & Co., Inc., West Point, PA

CE09-2 1:50 PM–2:30 PM Metabolic Considerations for NCEs and Nonsmall Molecules
Kenneth C. Cassidy, Eli Lilly and Company, Indianapolis, IN

2:30 PM–3:00 PM Break

CE09-3 3:00 PM–3:40 PM Metabolites in Practice: Examples and Case Studies
Holly D. Dursema, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT

CE09-4 3:40 PM–4:20 PM Metabolites: US FDA Perspective
Carol M. Galvis, US FDA/CDER, Silver Spring, MD

4:20 PM–4:30 PM Q&A and Closing Remarks



The groundwork of this course will be laid by covering the relevant guidelines related to metabolite evaluation. Approaches from the various guidelines and papers will be integrated, including a brief history of the MIST guidance. The focus will be on key points and clarification of the ICH Q&A.


Basic concepts of new chemical entity metabolism, including CYPs and transporters, and what it means to a toxicologist will be discussed. This presentation will also provide the perspective of the drug disposition department and what role they play following discovery of a major human metabolite. This talk will include metabolic considerations for nonsmall molecules (e.g., linkers).


Although in vitro metabolite evaluation occurs early in drug discovery and development, major human metabolites that require safety assessment are confirmed during conduct of clinical trials. A typical timeline of major metabolite confirmation will be presented and will include practical use of the guidelines. Case studies will be used to illustrate the types of challenges that could be encountered and how to respond. This talk will expand from major metabolites to disproportionate or unique metabolites and how qualification may be approached.


The US FDA perspective on the assessment of human metabolites will be shared. General considerations and timing in drug development are affected by a number of factors, including timing of human metabolite discovery in relation to clinical trial phase and whether the metabolite is major, disproportionate, or unique. The speaker will discuss case studies to provide insight into the regulatory decision-making process regarding human metabolites.

Session Chairs: Timothy J. McGovern, US FDA/CDER, Silver Spring, MD; and
LaRonda L. Morford, Eli Lilly and Company, Indianapolis, IN

Numerous nonclinical-related ICH guidances are currently under development, undergoing revisions, or developing question and answer documents to clarify issues. In this session, speakers will provide background information regarding the current ICH guidances S1, S7B/E14, M7, S5, and S11 and will update the audience on current activities of the Expert Working Groups. These include a new S11 guidance addressing the need for and conduct of juvenile animal studies, a newly developed Concept Paper on clinical QT assessments, a Q&A document for ICH M7 as well as addition of new compounds to the Addendum, a revised S5 guidance on developmental toxicity, and a current exercise evaluating the need for two carcinogenicity studies (S1).

CE10-1 1:00 PM–1:30 PM ICH S7B/E14
Hugo M. Vargas, Amgen Inc., Newbury Park, CA

CE10-2 1:30 PM–2:00 PM ICH M7: Recommendations for the Evaluation of DNA-Reactive Impurities and Current Activities
Aisar Atrakchi, US FDA/CDER, Silver Spring, MD

CE10-3 2:00 PM–2:30 PM The ICH S5(R3) Revision to “Detection of Toxicity to Reproduction for Human Pharmaceuticals”
Alan M. Hoberman, Charles River, Horsham, PA

2:30 PM–3:00 PM Break

CE10-4 3:00 PM–3:30 PM ICH S1: Reevaluating Traditional Carcinogenicity Testing
Timothy J. McGovern, US FDA/CDER, Silver Spring, MD

CE10-5 3:30 PM–4:00 PM ICH S11: Nonclinical Safety Testing in Support of Pediatric Medicines
LaRonda L. Morford, Eli Lilly and Company, Indianapolis, IN

4:00 PM–4:30 PM ICH General Discussion



The newly published Concept Paper from the ICH S7B/E14 Implementation Working Group for the first time highlights how nonclinical data could inform the implementation and interpretation of clinical QT assessments. The Concept Paper also mentions the need for consistent quality standards and best practices in the nonclinical study execution so that there is sufficient confidence in the data. This presentation will describe the Concept Paper and give examples of potential Q&As to S7B and E14 as well as describing areas of focus for nonclinical best practices.


The ICH M7 guidance on DNA-reactive impurities was finalized in 2014. Since then, an Addendum (R1) was finalized in 2017 to provide acceptable daily intakes (ADIs) or permitted daily exposures (PDEs) for 14 commonly experienced impurities. The examples in the Addendum provide approaches that can be used for developing compound-specific acceptable limits above the threshold of toxicological concern (TTC). This presentation will provide an overview of the M7 safety recommendations and discuss issues that have arisen since the guidance was implemented. Case examples will be provided. In addition, current activities of the M7 Expert Working Group (EWG), including developing a question and answer document and a second Addendum of impurities with calculated ADIs or PDEs, will be discussed.


The International Conference on Harmonisation (ICH) Safety (S)5 Guideline for the detection of toxicity of human pharmaceuticals to male and female fertility, embryo-fetal development, and the eventual growth and development of the next generation was the first ICH guidance safety document to be accepted and promulgated by all ICH member countries. Developed in the early 1990s and issued in 1994, the ICH S5 guidance has harmonized the procedures for evaluating the hazard of a new pharmaceutical to allow for a scientifically based rationale for testing while significantly reducing the number of animals required to conduct these evaluations. Harmonizing the multitude of international guidelines for testing a new pharmaceutical to prevent another thalidomide tragedy was the major impetus for the initial guidance. However, since 1994 we have seen the introduction of new types of pharmaceuticals, therapies, and medical devices that need to be evaluated for their potential hazard to reproduction, embryo-fetal development, and postnatal growth and development. Our ability to measure the absorption, distribution, metabolism, and excretion (ADME) and exposure in our animal models and humans has also increased and become more routine. As newer ICH guidance documents were issued for these new types of pharmaceuticals, principally large biologic molecules and other molecules to treat cancers, the issue of reproductive and developmental toxicity and timing for the need to have the hazard information was peripherally addressed in these guidance documents. Finally, as our knowledge of developmental biology increases and trends toward the molecular basis of development, the potential tools that we have to evaluate hazard reproductive and developmental toxicity continue to evolve. The changes that have been implemented since the inception of the ICH S5 Guideline and how they will be incorporated into the pending revised guidance will be reviewed and discussed.


The ICH S1 Guidelines (A, B, and C) were originally published in the years spanning 1995 to 1997; a revision to S1C, R2, was finalized in 2008. In 2012, the ICH Steering Committee endorsed a Concept Paper that proposed “to introduce a more comprehensive and integrated approach to addressing the risk of human carcinogenicity of pharmaceuticals, clarify and update, without compromising safety, the criteria for deciding whether the conduct of a two-year rodent carcinogenicity study of a given pharmaceutical would add value to this risk assessment.” This presentation will provide a brief overview of current ICH recommendations, discuss the primary objectives of the current EWG, and provide an update on the status of the EWG effort. The presentation will also review US FDA recommendations regarding preparing and submitting Special Protocol Assessments (SPA) to the Executive Carcinogenicity Assessment Committee (ECAC) and will provide case examples of scenarios that prevent ECAC concurrence with dose selection.


Regional guidances (US, EMA, MHLW) related to the nonclinical safety assessment of pediatric drug products have been available over the last decade, and ICH Guideline M3(R2) provides some harmonized recommendations. However, conflicting recommendations on major aspects of development exist and present challenges in defining a single nonclinical study plan that satisfies all regulatory regions. This topic was endorsed by the ICH Steering Committee in 2014, and since then, an Expert Working Group (EWG) has been meeting to develop harmonized approaches to address these concerns and draft a Step 2 draft guideline that was published in September 2018. This presentation will provide background on issues related to nonclinical testing for pediatric products and key challenges leading to the formation of the ICH EWG, as well as providing an overview of the S11 Step 2 document.