Continuing Education Courses

Session Chairs: William J. Brock, Brock Scientific Consulting, LLC, Hilton Head Island, SC; and Heather Dale, Labcorp, Madison, WI

Educational Support Provided by Altasciences and Labcorp
Nonclinical safety assessment of a new molecular entity is a critical component prior to the initiation of clinical trials. According to GLP regulations, the Study Director is the single point of study control and has responsibility for overall study conduct. The Study Director must be a scientist, project manager, and great communicator, and must possess regulatory knowledge for the conduct of nonclinical studies. Study Directors and their projects are successful when they have support and coordination within the laboratory and collaboration and support from the Sponsor/Study Monitor and any external laboratories that might be involved in the study.

This course will provide an innovative forum for learning and sharing details of study conduct and the roles of Study Monitors and Study Directors at all toxicology career levels. It will focus on practical approaches to real-life challenges faced during study conduct and will provide insight on anticipating and critically analyzing potential problems to develop solutions to issues that often arise during the conduct of a nonclinical study. At the end of the course, participants will have advanced their understanding of the roles of the Study Director and Study Monitor in nonclinical studies, the concepts of toxicology study design, protocol development, handling study issues as they arise, expectations for monitoring study conduct, and best practices for interpreting and communicating study data.

In this course, each participant will follow a single study, from the initial design to reporting. Real-life examples and experiences will be used to build a base of knowledge and manage expectations. This is intended to be a hands-on course and attendees should be prepared to solve study-related problems through group work, participate in polling, work through data interpretation, and interact with course faculty and attendees.

Topics

• Role of the Study Director and Monitor
• Study Design and Assignment
• Protocol Development
• Study Initiation
• Study Conduct
• Unexpected Study Events
• Managing Multisite Study Events
• Data Interpretation and Reporting

• Scott E. Boley, Altasciences, Auxvasse, MO
• William J. Brock, Brock Scientific Consulting, LLC, Hilton Head Island, SC
• Heather Dale, Labcorp, Madison, WI
• Carolyn Dugan, Labcorp, Madison, WI
• Noel Horton, Inotiv, Mount Vernon, IN
• Heidi Hsieh, Labcorp, Madison, WI
• Vijay Kale, Bristol Myers Squibb, New Brunswick, NJ
• John Kapeghian, Preclinical Safety Associates, Spring, TX

8:00 AM–8:30 AM Welcome and Logistics

8:30 AM–8:50 AM You Were Awarded Some Studies Today

8:50 AM–9:30 AM Mise en place: Nuts and Bolts for a Study—Protocol Development

9:30 AM–10:00 AM Break

10:00 AM–10:45 AM Best Laid Plans of Mice and Men: Protocol Development and Study Initiation

10:45 AM–11:30 AM Getting a Study Off the Ground and Staying in the Air: Managing the Expected Unexpected

11:30 AM–1:00 PM Lunch on Your Own

1:00 PM–1:30 PM Mitigation: Toxicity is Intended and Deviations Will Happen!

1:30 PM–2:00 PM Study Conduct and Study Monitoring: Collaboration

2:00 PM–2:30 PM Data Interpretation and Study Results

2:30 PM–3:00 PM Break

3:00 PM–3:50 PM Group Data Evaluation and Report Writing

3:50 PM–4:30 PM Group Report Out and Final Questions and Answers: Panel Discussion

Session Chairs: Katie Sokolowski, Denali Therapeutics, South San Francisco, CA; and
Laura Erwin, Allucent, Waltham, MA

Educational Support Provided by Charles River
Drug-induced seizures are a major concern for central nervous system active pharmaceuticals during development. Currently, there are no guidelines for interrogating and mitigating seizure liability associated with new pharmaceuticals. Because of the risks to patient safety during clinical trials, the understanding of nonclinical characterization that informs the translation of risks to humans is an area of intense interest among drug developers and regulators. The goals of this session are to (1) understand the diverse mechanisms of seizures; (2) examine findings in nonclinical studies indicating seizure liability; (3) understand the elements of a pivotal nonclinical EEG study; and (4) implement the principles of risk mitigation to derisk seizure liability in clinical trials. To achieve these goals, we will bring together a practicing clinical neurologist with primary knowledge of patients experiencing seizures, a pharmaceutical consultant with expertise in identifying seizure liability in nonclinical studies, a director of a contract research organization with experience in designing nonclinical EEG studies, and a US FDA regulator to discuss mitigation strategies. After the session, attendees will have a better understanding of how to mitigate risks of pharmaceutical products that carry a seizure liability and understand the limitations of the current state of the art to inform research in this area.

8:00 AM–8:10 AM Introduction
Laura Erwin, Allucent, Waltham, MA

CE2-1 8:10 AM–8:30 AM Clinical Description and Mechanisms of Seizures
Judy Liu, Brown University, Providence, RI

CE2-2 8:30 AM–8:50 AM Identifying Seizure Liability in Nonclinical Studies
Marcus Delatte, Allucent, Cary, NC

CE2-3 8:50 AM–9:10 AM General Design Elements of a Nonclinical EEG Study
Simon Authier, Laval, QC, Canada

CE2-4 9:10 AM–9:30 AM Risk Assessment: Management and Mitigation of Pharmaceutical Products with Seizure Liability
Katie Sokolowski, Denali Therapeutics, South San Francisco, CA

9:30 AM–10:00 AM Break

CE2-5 10:00 AM–10:30 AM Active Practice 1: Identify Seizure Liability in Nonclinical Studies
Breakout Teams

CE2-6 10:30 AM–11:00 AM Active Practice 2: General Design Elements of a Nonclinical EEG Study
Breakout Teams

CE2-7 11:00 AM–11:30 AM Active Practice 3: Risk Management and Mitigation of Drug Products with Seizure Liability
Breakout Teams

CE2-1

This talk will illustrate the clinical picture of the different types of seizures (provoked and unprovoked; partial vs. generalized) to understand the impact of seizures on patients as well as the various causes of seizures: brain lesions, E/I imbalance, physiological (dehydration, diabetes, etc.). We envision this talk to provide images of MRIs with brain lesions and EEG tracings that are definitive for seizures. The learning objectives of this talk are to (1) define seizures and how they are identified and managed in the clinic; (2) examine various causes of seizures; and (3) understand why seizures are adverse to patients.

CE2-2

This talk will discuss nonclinical findings that are indicative of seizure liability and appropriate approaches to characterize risks. Many drug classes carry seizure liability which may trigger preliminary studies, such as kindling studies, to understand risks prior to conducting a repeat-dose toxicology study. A description of premonitory signs of seizure in dose-range findings and repeat-dose toxicology studies will be discussed. Finally, this talk will briefly discuss when nonclinical EEG studies are warranted and how to leverage the data from the general toxicology studies to design an informative EEG study. Learning objectives of this talk will (1) set up a drug development program for drugs in a class with seizure liability; (2) identify seizure liability in nonclinical studies; and (3) examine the elements from general toxicology studies that inform the pivotal EEG study.

CE2-3

Designing a nonclinical EEG study is key to defining a NOAEL to seizures. This talk will build on the previous talk by integrating the nonclinical data from general toxicology studies into the elements of an EEG study, including PK profile, dose-response, and clinical observations. It will describe the essential elements, including video monitoring for behavioral analysis, use of electromyograms (EMG), and EEG trace recordings definitive of seizures. Finally, it will explore how to describe the seizures detected with EEG in the study to inform seizure risk, including the onset and duration of seizure events, characteristics of EEG tracings, and species sensitivities. The learning objectives of this talk are (1) the use of information from general toxicology studies to inform EEG study design; and (2) interpreting EEG study data to define a NOAEL.

CE2-4

This talk will focus on applying risk management strategies to drug development programs that present seizure liability. The risk/benefits for certain indications and points to consider while weighing the risk/benefits will be discussed (e.g., patient population and underlying disease, inability to distinguish drug-induced seizures, reasonable benefit to patients, and use of healthy volunteers). Clinical trial designs to mitigate risks will be discussed (e.g., PK stopping criteria, exclusion criteria, sentinel dosing, in-clinic monitoring, and mitigation). The learning objective of this talk is to implement the principles of risk mitigation in a nonclinical toxicology package by (1) understanding the discussion points to consider during risk/benefit analysis; and (2) understanding mitigation strategies in clinical trials.

CE2-5

This is a group activity that is designed to reinforce concepts discussed in CE2-2 through active practice. Active practice will be conducted in small teams (5–10 people per team) sitting at tables within the master room. The master instructor will provide general direction from the podium to all teams in the room. Team instructors will float from table to table to stimulate discussion and provide additional direction as needed. The group activity will be a discussion of 1–2 case studies that highlight the principles covered in CE2-2. At each table, all course participants will be provided with a printed cheat sheet of key concepts covered in CE2-2 to use during the group activity. This group activity will be followed by an anonymous electronic poll to all course participants through a phone app downloaded during the Introduction with Laura Erwin. The poll questions will address challenging situations on the CE2-2 topic (i.e., “gray area” questions with no correct answers.) The poll will serve as a temperature read on the way toxicologists approach nonclinical findings and potentially identify areas of research to improve the state of the art.

CE2-6

This is a group activity that is designed to reinforce concepts discussed in CE2-3 through active practice. The group activity will be a discussion of 1–2 case studies that highlight the principles covered in CE2-3. At each table, all course participants will be provided with a printed cheat sheet of key concepts covered in CE2-3 to use during the group activity. This activity will be followed by a poll to all course participants that address challenging situations on the CE2-3 topic.

CE2-7

This is a group activity that is designed to reinforce concepts discussed in CE2-4 through active practice. The group activity will be a discussion of 1–2 case studies that highlight the principles covered in CE2-4. At each table, all course participants will be provided with a printed cheat sheet of key concepts covered in CE2-4 to use during the group activity. This activity will be followed by a poll to all course participants that address challenging situations on the CE2-4 topic.

Session Chairs: Thulasi Ramani, PTC Therapeutics, Inc., South Plainfield, NJ; and
Scott Manetz, AstraZeneca, Gaithersburg, MD

Educational Support Provided by
AstraZeneca and the American College of Toxicology

Nonclinical safety studies are typically conducted with the objective to provide an assessment of the toxicity profile of a pharmaceutical. Such a profile may encompass multiple different types of animal studies, or not! Some types of animal studies may not be warranted for a specific program or may only require a limited evaluation if scientifically justified. The goal of this course is to provide a practical perspective on regulatory writing of a dossier(s) using the weight of evidence (WOE) approach for carcinogenicity, drug abuse liability, and pediatric safety assessments. This course will provide a discussion of key data elements to consider and strategy options with case studies and examples. Additionally, FDA experience with a dossier(s) including WOE arguments will be discussed.

8:00 AM–8:05 AM Introduction
Thulasi Ramani, PTC Therapeutics, Inc., South Plainfield, NJ

CE3-1 8:05 AM–8:45 AM Carcinogenicity WOE Assessment Overview: Principles and Methods
Scott Manetz, AstraZeneca, Gaithersburg, MD

CE3-2 8:45 AM–9:30 AM Drug Abuse Liability WOE Dossier
Paul Kruzich, PTC Therapeutics, Inc., South Plainfield, NJ; and David Compton, PTC Therapeutics, Inc., South Plainfield, NJ

9:30 AM–10:00 AM Break

CE3-3 10:00 AM–10:45 AM Nonclinical Pediatric Development: One Size Doesn’t Fit All
Susan Laffan, GlaxoSmithKline, Collegeville, PA

CE3-4 10:45 AM–11:20 AM Weighing the Weight of Evidence: A CDER Perspective
Ronald Wange, US FDA, Silver Spring, MD

11:20 AM–11:30 AM Interactive Panel Discussion

CE3-1

This talk will cover aspects of preparing a carcinogenicity weight of evidence assessment for a small molecule or biotherapeutic and engagement of regulatory agencies. This will include how to build a weight of evidence assessment and review of key resources, including literature and relevant guidance documents. Secondly, the talk will briefly review the process for submission of draft carcinogenicity study protocols to the CDER/FDA Carcinogenicity Assessment Committee (CAC; generally reviewed for the appropriateness of the protocol from CDER’s perspective on approaches to testing, including the study type, doses employed, and other design issues). Finally, it will review and discuss some real-world carcinogenicity assessment case studies.

CE3-2

New chemical entities that contain CNS penetrating properties (i.e., crosses the blood-brain barrier) should be evaluated for abuse liability as part of the drug product safety package. Data from studies investigating chemistry, pharmacology, pharmacokinetics, nonclinical and clinical behavior, and abuse-related adverse events in clinical trials are all relevant components of the drug abuse liability assessment (DALA). These DALA data are then compiled and provided to the FDA for evaluation by the FDA Controlled-Substance Staff (CSS) during the development process (e.g., by End-of-Phase 2 [EOP 2] meeting) as well as during the application for marketing approval. The DEA then determines the appropriate scheduling and control, if needed, under the Controlled Substance Act. In this course, you will learn what data are used to compile a DALA, how drugs are scheduled and controlled, and how to determine when to submit a DALA to the FDA. In many cases, the DALA is provided to the FDA early in development during an EOP2 meeting and may require an update as a “living document” prior to submission with the marketing application. Case examples and audience discussion/participation will be incorporated with an emphasis on various strategies available to project teams.

CE3-3

With the goal to get more medicines available to pediatric patients sooner and safer, pediatric development is occurring earlier in the drug development process as there are specific regulatory processes required for pediatric development. This course will define terms of waivers and deferrals for pediatric plans and outline the contents included in regulatory dossiers for the FDA’s pediatric study plans (PSPs) and the EMA’s pediatric investigative plans (PIPs), as well as contrast the regulatory expectations on timing. Next, the relatively new ICH S11 guidance on nonclinical support of pediatric development will be reviewed, which details the WOE framework for the decision of whether a dedicated juvenile animal study is warranted. This is decided on a case-by-case basis customized to the specifics of the age of the intended pediatric patients and the attributes of the medicine in development (e.g., toxicity profile on developing organ systems, pharmacologic target, modality, etc.), all of which need to be incorporated in the WOE rationale captured in the dossier. Lastly, case studies will be shared to demonstrate a variety of situations.

CE3-4

FDA regulations require that sponsors submit nonclinical data to support the clinical development and marketing of drugs and biologics. With limited exceptions (e.g., products developed under 21 CFR 314.600-650 for drugs; 21 CFR 601.90-95 for biologics—often referred to as the “Animal Rule”) the precise nature of what constitutes adequate nonclinical data is not defined by the regulations, but rather by guidance documents that reflect the FDA’s current thinking. This presentation will provide an overview of FDA guidance that supports the use of WOE in various safety assessments, and the CDER’s experience in reviewing WOE dossiers.

Session Chairs: Tom Steinbach, EPL, Inc., Research Triangle Park, NC; and
Bhupinder Bawa, AbbVie, North Chicago, IL

Educational Course Provided by Society of Toxicologic Pathology
Digital pathology and artificial intelligence (AI) are transforming all aspects of health care—including drug development. This CE course aims to introduce this technology to toxicologists and toxicologic pathologists and highlight promises and pitfalls. To illustrate the power of digital pathology and AI, the session concludes with presentations highlighting practical applications, presented by colleagues with hands-on experience.

CE4-1 8:00 AM–8:30 AM Digital Pathology Applications in Toxicologic Pathology
Tom Forest, Merck & Co., Inc., Kenilworth, NJ

CE4-2 8:30 AM–9:00 AM Introduction to Artificial Intelligence and Machine Learning
Tom Steinbach, EPL, Inc., Research Triangle Park, NC

CE4-3 9:00 AM–9:30 AM General Uses of AI in Drug Development of Partnerships Formed by Pharma with AI Companies in the Pathology Space
Bhupinder Bawa, AbbVie, North Chicago, IL

9:30 AM–10:00 AM Break

CE4-4 10:00 AM–10:30 AM Implementation: Preparing Pathology Data for ML Experiments
Jürgen Funk, Hoffmann LA Roche Ltd, Basel, Switzerland

CE4-5 10:30 AM–11:00 AM Implementation: IT Infrastructure Requirements for Computational Pathology
BK Kang, Novartis Institutes for Biomedical Research, Basel, Switzerland

CE4-6 11:00 AM–11:30 AM Artificial Intelligence-Driven Quantification of Rodent Cardiomyopathy
Deb Tokarz, EPL, Inc., Durham, NC

CE4-1

This talk will provide an overview of the historical use of digital pathology for nonclinical image evaluation, current developments in the wide adoption of digital pathology for GLP use in nonclinical toxicology studies, and perspectives on the implementation of machine learning into GLP workflows on the horizon. Considerations for evaluating the suitability of a digital pathology system for GLP use will be a focus.

CE4-2

This talk will cover some basic concepts of artificial intelligence and machine learning, including definitions of key concepts. He will look at the role of data and how it impacts machine learning. Some examples of the use of AI in pathology will be used to illustrate important points. Finally, there will be a short discussion on the potential impact of AI on the profession of toxicologic pathology. These concepts will help set the stage for follow-on talks that more specifically cover AI in toxicologic pathology.

CE4-3

This talk will provide a high-level overview of applications of AI and machine learning (ML) in drug discovery and development. Most pharmaceutical companies are investigating AI across their R&D value chain with an objective to essentially increase R&D efficiency. Current data in the public domain and published literature on trends and investments made by pharmaceutical companies in AI/ML space will be discussed. The second half of the talk will be focused on AI/ML applications and collaborations in pathology and more specifically in toxicologic pathology. Finally, a strategy for successful external collaboration and building an internal AI research-based expertise will be discussed.

CE4-4

This talk will cover all aspects of the preparation of pathology data for ML experiments with a special focus on microscopic findings. The principles of data FAIRification will be described. Points to consider in the selection of the most suitable slide scanner, the selection of suitable studies, scanning of slides, entering metadata, and other necessary prerequisites including quality control will be reviewed. The link between the slide scans, study metadata, and microscopic findings with its interoperability boundaries will be discussed. It will also show that there are still steps that must be done manually and there are limitations with regard to full automation. Finally, it will give an outlook on what experiments could be done with these data.

CE4-5

This talk will provide an overview of the technical factors that need to be considered before applying machine learning, with specific regard to IT infrastructure, computer hardware, etc. The vision is to enable toxicologists and toxicologic pathologists to return to their departments and know what to ask for in terms of hardware and IT infrastructure.

CE4-6

Rodent progressive cardiomyopathy (PCM) is a common background finding that can mask or mimic cardiotoxicity. This talk will present a practical application of deep learning for the development of a computer algorithm that detects and quantifies histologic features of PCM in rat heart. The process of testing this algorithm against a panel of toxicologic pathologists will be discussed. The goal of this algorithm is to provide sensitive and consistent quantification of PCM features to aid the pathologist in differentiating spontaneous findings from test article-related cardiotoxicity.

Session Chairs: Sarah Gould, Charles River Laboratories, Auvergne Rhone Alpes, France; and
Deborah Novicki, DL Novicki Toxicology Consulting LLC, Boston, MA

Medicine is evolving and the science of toxicology needs to evolve with it to ensure the safety of medicine. Regulatory guidelines provide support but cannot be all-encompassing and can fall behind the science. Conducting a toxicology program to support a safety evaluation requires consideration of the product, endpoints, timing, and for in vivo studies, species selection. How do we navigate our way through this advancing medicinal world, which includes a range of modalities: antibodies, oligonucleotides, vaccines, cell and gene therapy, and ensure an appropriate toxicology evaluation of key risks? We also must consider the 3R’s and an additional R for relevance, where there may be one or no relevant species. We aim to make this an interactive learning session using different approaches and expand upon a slide deck. We have pulled together a team of panelists with key expertise across the diverse modalities who will facilitate learning using various tools, including case studies, questions, and interactive media to encourage audience participation. By the end of the session, the audience will be given information to encourage critical thinking about species selection and designing a toxicology program for each of the different modalities mentioned above.

CE5-1 1:00 PM–2:00 PM Toxicology: The Challenges of Species Selection across Classic and Novel Modalities
Sarah Gould, Charles River Laboratories, Saint Nuelles, France

CE5-2 2:00 PM–2:30 PM Panel and Interactive Session: Toxicology: How Different Medicinal Modalities Impact Species Selection

Development of an Oligonucleotide Drug: Species Selection Considerations for Toxicological Assessment
Moderator: Joanna Harding, AstraZeneca, Cambridge, United Kingdom

2:30 PM–3:00 PM Break

CE5-2 3:00 PM–4:15 PM Panel and Interactive Session: Toxicology: How Different Medicinal Modalities Impact Species Selection (Continued)

Multiple Modalities, Species Selection, Including Animal Models for Disease
Moderator: Joy Cavagnaro, Access Bio, Boyce, VA

Selection of Biologically Relevant Animal Species/Models: A Cell/Gene Therapy Case Study
Moderator: Kate Dabirsiaghi, US FDA, Baltimore, MD

Human-Specific Immunostimulants and Tumor Antigens Encoded in a Nucleic Acid Vaccine Delivered in a Vehicle with a Novel Component: A Test Case Presenting Multiple Challenges (and Opportunities) for Nonclinical Strategy and Species/Models Selection
Moderator: Deborah Novicki, DL Novicki Toxicology Consulting LLC, Boston, MA

CE5-3 4:15 PM–4:30 PM Wrap-Up

CE5-1

The first part of this course will provide background information using slides to set the scene to begin the discussion about species selection in a toxicology program, guidelines, and 3Rs, in consideration of the evolving medicinal modalities, such as mAbs, vaccines, oligos, small molecules, and cell and gene therapies. The course will consider critical thinking, human psychology, and how different modalities may impact species selection, as well as how guidelines can help or hinder them. The course will also introduce the panel and get to know the audience using various media.

CE5-2

This will be an interactive learning session that expands upon a standard slide deck and Q&A format. A panel of key experts with expertise across the modalities will facilitate learning and generate discussion. Interactive media will be used, including case studies to discuss challenges and encourage audience team participation. Case studies will include a selection of species for different medicinal modalities—including mAbs, oligos, vaccines, small molecules, cell and gene therapy (e.g., gene therapy targets against a human protein with species homology over 80% in rats, NHP's, mini pigs and dogs). What will a first-in-human toxicology program look like and what is the rationale of the species selection? What was the rationale used for selecting the studies and species? How does this fit with or deviate from the guidelines and which guidelines were used? Does this strategy support the 4Rs? What are the challenges? Consideration of translation to humans will also be discussed.

CE5-3

This will be a wrap-up session for any final questions and will pose the next question: what happens if there are no relevant species to consider or other publications that can be supportive of a toxicology program (e.g., Marlowe et al., 2017)? What future changes may be envisioned? Audience participation and interactive survey media will also be used.

Session Chairs: Mansi Krishan, Meta Platforms, Inc., Broomfield, CO; and
Douglas A. Donahue, GlaxoSmithKline, Research Triangle Park, NC

Educational Support Provided by Becton, Dickinson and Company and the American College of Toxicology
The regulatory landscape for the safety evaluation of medical devices and combination products is rapidly evolving. Chemical characterization, utilizing extractable or leachable (E/L) substances studies, of materials and/or the drug are important steps in the overall risk assessment to ensure patient safety. E/L substances of toxicological concern are risk assessed using hazard assessment, exposure assessment, dose-response assessment, and risk characterization. This continuing education course is designed for new or “seasoned” toxicologists wanting (1) an overview of the fundamentals of risk assessment; (2) regulatory review considerations for submissions to the US FDA/CDHR that contain a chemical(s) of concern, and its toxicological risk assessment; and (3) identification of case examples where compounds of toxicological concern are present. This course is designed to provide a hands-on training opportunity to attendees on risk assessment of E/L substances using hypothetical case studies based on real-life examples. After the speaker presentations, each breakout group will be assigned one of the two hypothetical case studies and the attendees in break-out groups will be requested to determine their approaches for successful regulatory submission. Prior to the end of the course, a summary of the case examples will be provided to the attendees. Upon completing the course, the attendees will have a good understanding of general chemical characterization strategy, scenarios when a risk assessment is warranted, different risk assessment approaches for substances of toxicological concern, and will be equipped with the necessary tools to conduct and/or support successful regulatory submission of biocompatibility data.

Moderators:

• Douglas A. Donahue, GlaxoSmithKline, Rockville, MD
• Bernard Gadagbui, Toxicology Excellence for Risk Assessment (TERA), Cincinnati, OH
• Mansi Krishan, Meta Platforms, Inc., Broomfield, CO
• Daniel Nazarenko, Precision Biosciences Inc., Durham, NC
• Jan Oberdoerster, W.L. Gore and Associates, Inc., Elkton, MD
• Sharmilee Sawant, Becton, Dickinson and Company, Clovis, CA
• Alan Stokes, GlaxoSmithKline, Collegeville, PA

CE6-1 1:00 PM–1:45 PM Risk Assessment 101
Bernard Gadagbui, Toxicology Excellence for Risk Assessment (TERA), Cincinnati, OH

CE6-2 1:45 PM–2:30 PM Chemical Toxicological Risk Assessment, The US FDA/CDRH’s Perspective on Best Practices to Consider
Alan Hood, US FDA/CDRH, Silver Spring, MD

2:30 PM–3:00 PM Break

CE6-3 3:00 PM–4:10 PM Break-Out Groups: Identification of the Compounds of Toxicological Concern, Application of Risk Assessment Approaches, and Case Examples
Leigh Ann Burns Naas, Magnolia Consulting Services, LLC, Traverse City, MI

CE6-4 4:10 PM–4:30 PM Conclusion: Review of the Risk Assessments from the Breakout Groups and Any Additional Questions
Jan Oberdoerster, W.L. Gore and Associates, Inc. Elkton, MD

CE6-1

An overview of risk assessment strategies is sufficient to allow the attendees to complete the case examples.

CE6-2

Biological evaluation of medical devices often includes characterizing chemicals that a patient or user could be exposed to when the device contacts the body. The chemical toxicological risk assessment process includes identification of harms that chemicals elicit, derivation of tolerable exposure levels, and estimation of chemical exposure doses. In this presentation, participants will learn CDRH’s perspectives related to best practices to consider when conducting these critically important toxicological risk assessment activities, as well as how toxicological risk assessment fits within the overall medical device risk management process. Participants will learn key terms and definitions, fundamental principles, and types of toxicological data that are useful in the assessment of chemical toxicological risks. The information presented will help guide the risk assessor in determining whether medical device chemicals are present at a tolerable level.

CE6-3

Breakout groups where case examples will be presented.

CE6-4

Review of breakout groups, providing an overview of the risk assessment for each case study and an interactive discussion.

Session Chairs: Jessica Graham, Genentech, Inc., South San Francisco, CA; and
Ray Zhang, Neuron23, Inc., South San Francisco, CA

This course is endorsed by the ACT Early Career Professional Subcommittee. In the pharmaceutical industry, project toxicologists (PTs) characterize the inherent hazards of a molecule to support a risk-benefit assessment that ensures patient safety while occupational toxicologists (OTs) focus on worker safety in the context of drug development, manufacturing, and in the clinical setting. Oftentimes, the OT will provide risk assessments for product quality-related matters including impurities, degradants, and extractables and leachables. Collectively, this discipline, known as Product Quality and Occupational Toxicology (PQOT), is performed by a dedicated group within an organization or wholly outsourced to a service provider. Close collaboration between the PT, OT (or analogous counterparts), and other key stakeholders are critical for the progression of development candidates and patient and worker safety throughout the drug’s lifecycle. The goal of this workshop is threefold: (1) to demystify the PQOT process for PTs and provide awareness of current and new strategies; (2) to create a dialog between parties and optimize development timelines by enabling smoother transitions and anticipating potential issues; and (3) to obtain perspectives on PQOT challenges that will inform future working group efforts. Speakers will present an overview of the fundamentals of pharmaceutical occupational toxicology plus current and emerging strategies for derisking mutagenic impurities, nonmutagenic impurities, and extractables and leachables. Live polling will be utilized to provide practical exercises and elicit feedback from the audience to understand the breadth of challenges, opinions, and approaches.

1:00 PM–1:05 PM Introduction
Jessica Graham, Genentech, Inc., South San Francisco, CA; and Ray Zhang, Neuron23, Inc., South San Francisco, CA

CE7-1 1:05 PM–1:45 PM Optimizing Information Sharing: Occupational Toxicology Engagement with Project Toxicologists
Andrew Maier, Cardno ChemRisk, Cincinnati, OH

CE7-2 1:45 PM–2:30 PM Risk Assessment of Mutagenic Impurities: Strategies for the Project Toxicologist
Mark W. Powley, Merck & Co., Inc., Rahway, NJ

2:30 PM–3:00 PM Break

CE7-3 3:00 PM–3:35 PM Nongenotoxic Impurities: Strategies for Qualification
Mayur Mitra, Genentech, Inc., South San Francisco, CA

CE7-4 3:35 PM–4:15 PM Extractables and Leachables: Current Topics and Strategies
Melisa Masuda-Herrera, Gilead Sciences, Foster City, CA

4:15 PM–4:30 PM Discussion

CE7-1

OTs apply the principles and methods of toxicology to assess potential risks from agents encountered at work. An important component of occupational risk assessment is the availability of an exposure control target such as a hazard band or health-based exposure limit (HBEL). For workplace assessments, the HBEL often takes the form of an occupational exposure limit (OEL). OELs are airborne concentrations to which employees can be exposed and not experience pharmacological or toxicological effects. Several organizations publish expert-group-derived OELs for pharmaceuticals and industrial chemicals; examples include Workplace Environmental Exposure Levels (WEELs^©) and Threshold Limit Values (TLVs^©). Traditionally, pharmaceutical industry OTs focused on worker safety, and relied, in part, on studies conducted pursuant to standard test guidelines, supplemented with other specialized toxicity testing methods. It is also common for the OT to rely on expertise from project toxicologists charged with supporting patient safety. To facilitate such interactions shared understanding is needed of the different assessment scopes supporting a given drug product through its life cycle. In many organizations, human health risk assessment responsibilities for OTs have expanded to include product quality-related assessments creating an even closer potential engagement among toxicologists with differing roles. Such assessments include the evaluation of impurities in pharmaceuticals during manufacturing and toxicology support for quality excursions. This session covers a brief history of occupational toxicology, key differences in considerations between OTs compared to project toxicologists, and strategies for optimizing engagements among toxicologists involved in various aspects of drug development, safety assessment, and manufacturing.

CE7-2

Pharmaceutical synthesis involves the use of chemicals (reagents, solvents, etc.) that may lead to known or potentially mutagenic impurities in the drug substance or product. To maximize patient safety, ICH M7 was developed to provide a harmonized framework for evaluating and controlling mutagenic impurities. The evaluation of mutagenic potential leverages in silico modeling supported by expert knowledge and/or genotoxicity testing. Results of these evaluations are ultimately used to classify impurities as nonmutagenic or mutagenic. Nonmutagenic impurities are controlled based on ICH Q3A/B principles. In contrast, mutagenic impurities are limited to levels associated with negligible cancer risk (i.e., 1 in 100,000 excess cancer risk) through the application of control strategies described in ICH M7. An initial evaluation of the synthetic route, including actual and potential impurities as well as degradation products, is routinely conducted starting with the first clinical batch. Additional evaluations are needed as the synthesis is refined during clinical development through to the finalization of commercial chemistry. Depending on the organizational model, the overall process may rely on project toxicologists, computational toxicologists, genetic toxicologists, occupational toxicologists, process chemists, analytical chemists, and/or regulatory affairs. Given the collaborative nature of the process, effective communication is critical to support regulatory submissions and avoid delays in development timelines. This presentation will review (1) the ICH M7 framework for assessment and control of mutagenic impurities; (2) components of an optimal collaborative process; and (3) lessons learned since the adoption of the guideline. Case examples will be included to emphasize practical strategies.

CE7-3

Pharmaceutical impurities are generally qualified in standard toxicology studies. In some instances, such as when a new impurity is identified or impurity is observed at higher levels than originally qualified, dedicated impurity qualification studies may need to be conducted. Current guidelines do not specify details about species selection, recommended study design, and the exact study duration of an in vivo impurity qualification study that would support the clinical use of a specific duration. This results in various study designs being used throughout the industry. To better elucidate and understand current practices and procedures in nonmutagenic impurity qualification, an IQ DruSafe Impurity Working Group surveyed member companies, leveraged the survey learnings, and provided harmonized study designs for impurity qualification. Harmonized study designs were created with a focus on patient safety while emphasizing the 3Rs (replacement of animal studies, reduction of animal use, and refinement of study designs), which have the potential to result in a 90% reduction in animal usage. Awareness of current practices, challenges, and strategies throughout the pharmaceutical industry in the area of impurity qualification is key to proper study design. The utilization of the harmonized study designs proposed offers benefits including improvements from a 3Rs, cost, and resource perspective. This session covers learnings from industry on impurity qualification study best practices as well as presents the harmonized study designs. This session will also solicit feedback on what areas of impurity qualification would benefit from further focus moving forward.

CE7-4

Current ICH guidelines (Q3A–Q3D, M7) address many specific types of impurities to be controlled, e.g., residual solvents, DNA reactive (mutagenic) impurities, and elemental impurities. Extractables and Leachables (E&Ls) are an obvious gap. This session will provide background on E&Ls, including their hazard evaluation and current risk assessment practices. Also covered will be an overview of ICH Q3E and emerging topics and strategies in the area of E&Ls. This session will also solicit feedback on what areas of E&L strategies, evaluation, and assessment would benefit from further focus moving forward.