Educational Support Provided by: GSK
Nonclinical safety assessment of a new molecule is a critical component prior to initiation of clinical trials. According to GLP regulations, the Study Director is the single point of study control and is responsible for study conduct and interpretation. The Study Director must be a scientist, project manager and great communicator, and possess regulatory knowledge for nonclinical study conduct. 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. This course will provide an innovative forum for learning and sharing details of study conduct and the roles of Study Monitors and Study Directors. It will focus on practical approaches to real-life challenges faced during study conduct and will provide insight on anticipating and analyzing potential problems to develop solutions to issues that arise during the conduct of a nonclinical study. Participants will advance their understanding of the roles of the Study Director and Study Monitor, the concepts of study design, protocol development, handling study issues, expectations for monitoring study conduct, and best practices for interpreting and communicating study data.
Each participant will follow a general toxicology study, from the initial design to reporting. Real-life examples and experiences will be used to build a base of knowledge and to manage expectations. This is a hands-on course, and attendees should be prepared to solve study-related problems in small groups, interpret data, and interact with course faculty and attendees.
Educational Co-Support Provided by: EPL, Inc. and American College of Toxicology
Nonclinical safety evaluation studies are essential to identify potential hazards, to determine an initial safe dose for first-in-human (FiH) trials and to develop subsequent dose escalation schemes. These studies aim to identify potential on- target or off-target toxicity and provide signals for clinical monitoring plan. According to the ICH S6 regulatory guidelines for biotherapeutics, species/model selection is crucial for performing safety assessment studies. A relevant species is defined as one in which the test material exhibits pharmacological activity due to the presence of the receptor or epitope. Commonly, cynomolgus monkeys, rats, or mice are used as relevant species for safety assessment of biotechnology-derived drugs. However, in cases where traditional species are unsuitable, engineered (usually transgenic and/or huMouse) models expressing human targets may be employed. Several huMouse or disease rodent models have been successfully used for early discovery and/or efficacy studies and have been used for FiH-enabling safety assessment studies along with the cynomolgus monkey for establishing margin of safety. By providing case study examples, this continuing education (CE) course is designed to help participants improve and enhance their skills on the factors to consider when selecting an appropriate transgenic and/or huMouse models for FiH-enabling programs.
This CE course will offer a comprehensive examination of the application of Artificial Intelligence (AI) in toxicology, emphasizing its transformative potential and challenges within regulatory decision-making. Participants will gain foundational knowledge of AI concepts, explore state-of-the-art methodologies for toxicology predictions, and examine case studies showcasing successful AI applications. Additionally, the course will address current barriers to AI adoption and discuss strategies to integrate AI innovations into regulatory practices. By the end of this course, participants will: Understand foundational AI concepts and methodologies as applied to toxicology; Evaluate the strengths and limitations of AI tools in regulatory contexts; Critically assess AI-based toxicology predictions and their implications; Explore ongoing developments, ethical considerations, and collaborative opportunities in AI-driven toxicology. The course aspires to empower attendees to leverage AI for improved toxicological assessments while addressing regulatory challenges, ultimately driving safer and more efficient decision-making processes.
Educational Co-Support Provided by: Charles River and SciLucent, Inc.
At the 2023 ACT meeting, a basic CE course on Juvenile Toxicology described the added value of ICH S11 in defining the need, timing and design of juvenile animal studies (JAS) to support the pediatric development of novel therapeutic candidates. Building on this foundation, the proposed advanced CE course on JAS will delve deeper into several key areas. The regulatory processes for Pediatric Investigation Plans (PIPs) by the European Medicines Agency (EMA) and Pediatric Study Plans (PSP) by the US Food and Drug Administration (FDA) will be compared, including options for seeking pediatric regulatory deferrals and waivers. The Weight of Evidence (WoE) approach will be discussed. The course will also focus on the key drivers that determine the depth of evaluations on developing organs in JAS. There will be a deep dive into specialized approaches to bone evaluation in juveniles, supported by a case study illustrating how nonclinical data led to the inclusion of specialized bone examinations. In addition, possible designs for neurotoxicity assessments in JAS will be discussed, covering options for neurobehavioral testing and both routine and enhanced neuro-histopathology evaluations. Before the course concludes with an interactive panel discussion, both EMA and FDA will give their regulatory perspective. EMA will present the regulatory alignment with pharma regarding JAS for 127 medicinal products and FDA will talk about case studies where ICH S11 recommendations had a significant impact on the regulatory outcome as well as examples of JAS with both aligned and divergent regulatory perspectives between EMA and FDA.
Educational Support Provided by: Charles River
This CE course will present interactive case studies from pharmaceutical development across the toxicology testing continuum and with a focus on neurotoxicology. Attendance will be organized into tables of 6-8 attendees, and volunteers will be requested to present their perspective to the audience. Participants will have the opportunity to discuss each case in subgroups and the moderators will then provide case outcomes from the various perspectives. The aspects that will be presented will include general toxicology study design for centrally delivered antisense oligonucleotide (ASO), developmental neurotoxicology, safety pharmacology, neuropathology, CNS biomarkers and regulatory strategies. The session will explore a wide range of therapeutic modalities and represent commonly encountered challenges in neurotoxicology. A strong emphasis on regulatory toxicology will allow session participants to gain practical knowledge in this rapidly involving space.
This CE course will focus on examining the various modalities, documents and timelines when submitting preclinical safety studies to enable clinical studies. Every year unsuccessful IND submissions result in delay of clinical onset, often due to lack of experience when submitting safety packages or due to inexperience of writing applications. Furthermore, several companies lack strategies and miss opportunities to advance translational research models, tools, and technologies to enable R&D efficiency. A robust regulatory strategy is essential to ensure development activities are aligned with regulatory requirements. The role of the toxicologist in this process is to ensure the nonclinical development program supports the proposed clinical trial. The International Conference on Harmonisation provides a framework for recommendations and regulatory expectations for the United States, Europe, Japan, Canada, and Switzerland. However, there are regional differences in requirements even within ICH regions. This course will provide an overview of regulatory expectations and recommendations for nonclinical safety assessment to support clinical trials in the United States as well as Europe, the United Kingdom, Australia, and Canada. We will review nonclinical submission requirements and opportunities for seeking regulatory input via formal meetings in these regions. In addition, we will highlight some common pitfalls that may lead to a clinical hold and best practices to ensure a successful regulatory submission.
Minipigs are a well-established nonrodent species in nonclinical safety assessment and device biocompatibility evaluation. However, many toxicologists have little, if any, first-hand experience designing and conducting toxicology studies in minipigs. This session is intended to improve our understanding of minipigs by 1) reviewing regulatory acceptance of their use; 2) providing basic information on their use in toxicology and safety pharmacology, and 23) offering forward-looking perspectives that could expand the use of minipigs as an alternative to dogs and NHPs in the future. The session will begin with basic descriptive overviews of technical and logistical considerations when working with minipigs (including micropigs and nanopigs) in repeat-dose toxicology studies and safety pharmacology studies. Comments on the current status of regulatory acceptance as well as on use with various drug modalities (small molecules, biologics, etc.) will be included. After this foundational instruction, the session will shift to more forward-looking discussions that will challenge attendees to consider potential future directions and opportunities for minipig use. This will include a description of hurdles that must be surmounted to assess the suitability of minipigs as a model for DART studies. The session will close with a talk highlighting the importance of immunology issues with minipigs in toxicity testing and a discussion of the value humanized minipigs could bring to nonclinical safety assessment programs. In summary, this session is intended to be both instructive and provocative. The initial talks will provide foundational knowledge for toxicologists seeking to gain familiarity with the current state-of-the-art with minipigs. The subsequent talks will be more thought-provoking for those who are looking to future possibilities for minipigs in drug discovery and development.
Educational Co-Support Provided by: Aclairo Pharmaceutical Development Group, Inc. and American College of Toxicology
The 2024 Nobel Prize in Physiology and Medicine was awarded to Victor Ambros and Gary Ruvkun for their discovery and description of microRNAs. This session will tell the story of the discovery of microRNAs and their broad gene regulatory functions, conservation across species, and their contribution to normal physiological processes. Importantly, the session will review their dysregulation, it's contribution to different pathological states and opportunities for therapeutic intervention. We will provide therapeutic context from a regulatory perspective and will discuss FDA guidance on Nonclinical Development of Oligonucleotide Therapeutics with a focus on small RNAS. Lastly two industry speakers will discuss their experience within the field of microRNA therapeutics; topics include microRNA therapeutics (mimics and microRNA inhibitors/anti-microRNAs), development of small interfering RNAs (siRNA, therapeutically similar to microRNA), and upregulation of microRNAs by antisense oligonucleotides.
Developmental and reproductive toxicity (DART) studies are generally not needed to support first-in-human clinical trials but are typically conducted to support continued clinical development and marketing approval. Animal studies used to support DART safety assessments include male and female fertility, embryo-fetal development (EFD), and pre- and postnatal development (PPND). Initial safety evaluation of male and female reproductive organs in nonpregnant animals are included as part of most general toxicity studies to inform risk of infertility prior to and throughout clinical development, as well as potential for clinical monitoring. Functional fertility studies and developmental toxicity studies (EFD and PPND) are usually conducted later to support enrollment of individuals of reproductive potential on clinical trials and to inform patient safety in the package insert of approved products. DART and genetic toxicity data is used to inform recommendations on egg and sperm preservation, pregnancy testing, contraception, and potential restrictions on egg and sperm donations in clinical protocols, informed consent documents and/or package inserts. This course will review when, what, and how DART data are used to support clinical trials and labeling from different perspectives including a nonclinical team representative, DART subject matter experts, pharma clinical lead and a FDA deputy director of safety
Educational Co-Support Provided by: Health and Environmental Sciences Institute and Instem
Nitrosamines (NA) are chemicals found as impurities in drugs and food, associated with genotoxicity risks, but their toxicity varies based on structure, bioavailability, and potency, which can further categorize them into sub-classes of molecules that are either deemed to be a cohort of concern (CoC), weak acting mutagens (non-CoC), or non-mutagens. Despite the significant experimental and regulatory progress to date, there remains a need to implement robust and sustainable safety assessment methods that protect public health from NA risks while ensuring uninterrupted access to essential medications. Mechanism-based genotoxicity risk assessment (MGRA) is being applied to evaluate nitrosamine risk in drug development, following adverse outcome pathways (AOPs) to incorporate new scientific understandings and technologies. MGRA enables the evaluation of diverse genomic damage endpoints to inform on nitrosamine-related genotoxicity both in vitro and in vivo. The symposium will discuss various MGRA approaches, including optimized 1.) Optimized Ames testing, 2.) error-corrected next-generation sequencing (ecNGS) for mutagenicity, 3.) alternative in vitro cellular models, advanced in vivo genotoxicity strategies,4.) (Q)SAR and quantitative mechanics-based modeling, and 5.) regulatory perspectives on nitrosamine risk assessment. A 15 min panel discussion at the end of the session will enable a Q&A discussion between the speakers and the audience members. The session targets professionals, trainees, and students in toxicological research, drug development, and regulatory risk assessment, including of impurities and nitrosamines.
Educational Co-Support Provided by: Charles River and American College of Toxicology
Oligonucleotide-based therapeutics (ONTs) are a rapidly growing class of RNA-based therapies that have the potential to treat a diverse range of diseases through a variety of mechanisms (e.g. mRNA degradation, splicing, inhibition of protein translation, etc.). Two common classes of ONTs leading to degradation of target messenger (m)RNA include small-interfering (si)RNAs and antisense oligonucleotides (ASOs). While each has a distinct mechanism of action, they both have the potential for hybridization-dependent off-target silencing. In the case of siRNAs this can occur through full or partial hybridization-dependent RISC-mediated silencing or seed-region binding resulting in micro (mi)RNA-like effects. On the other hand, ASOs are generally limited to full or partial hybridization-dependent RNase H1 silencing. In either case the off-target profile of the clinical candidate will likely differ in the nonclinical species (i.e. rodent or non-rodent) compared to that of the human. Therefore, a challenge often encountered during development of these ONTs is how to manage toxicities in nonclinical safety studies that may be specific to the model species and of unknown relevance to the human. In this session we aim to 1) provide an overview of hybridization-dependent off-target mechanisms and risk assessment opportunities, 2) rodent specific hybridization-dependent off-target associated toxicities and derisking strategies, 3) a pathology perspective of off-target associated lesions, and 4) regulatory perspective on hybridization-dependent off-target assessment.
The International Conference on Harmonization (ICH) guidance documents outline nonclinical safety study requirements in pharmaceutical development. Waivers or modifications to these guidance documents may be granted in specific cases, such as substantial data from similar compounds, established clinical use, or well-understood mechanisms of action. Waivers must be scientifically justified and involve regulatory engagement assessed on a case-by-case basis to balance risk with safety and efficacy data. This symposium will discuss the nuances of waivers under ICH M3(R2), S6(R1), S9, S5(R3), and S1B(R1) and present case studies on submission approaches to health authorities. The first speaker will discuss strategies and case studies for waiving the requirement to perform in vivo embryofetal development (EFD) or enhanced pre-and postnatal development (ePPND) studies. The second will provide an overview of the carcinogenicity waiver industry experience to date, including case studies, best practices, and challenges encountered. The third will address the nonclinical safety strategy for T cell engaging bispecific (TCB) molecules, including case studies, and highlight the rationale for not conducting chronic toxicity studies and supporting first-in-human (FIH) studies. The final speaker will outline the pursuit of regulatory agreement on an unconventional in vitro safety package to support FIH trials within an oncology framework. Experts will share insights on interactions with regulatory bodies and submission strategies for modality-agnostic waivers, providing advanced guidance for toxicologists.
The requirement by FDA for the generation and submission of standardized CDISC-SEND-formatted toxicology study data has enabled the construction of large databases of toxicology study data that can be used to build predictive models. The Nonclinical Topics Working Group of the Pharmaceutical Users Software Exchange (PHUSE) has initiated a project to facilitate collaboration among regulators, pharmaceutical companies, contract research organizations, and software vendors to collaboratively develop open source software solutions to improve the fidelity and accessibility of these methods. More specifically, supervised machine learning models will be trained to detect and characterize patterns in toxicology study endpoints that are associated with the documented conclusions of expert toxicologists, e.g. target organs of toxicity, and then applied to streamline the interpretation of newly generated toxicology study data. Additional study interpretations, e.g. adversity of findings, NOAEL determination, clinical translatability, structure activity relationship – will be explored for development of predictive models. This symposium will provide an update on the progress of this project as well as perspective on the applicability of its deliverables from a diverse set of stakeholders.
Educational Co-Support Provided by: Altasciences and American College of Toxicology
Cell and gene therapies represent revolutionary advancements in modern medicine, offering the potential to treat diseases that were previously intractable. These therapies utilize complex techniques such as genetic modification, cell reprogramming, and targeted delivery systems. This allows for highly personalized and precision treatments across a wide spectrum of conditions, from genetic disorders to cancers, and beyond. Despite their promising potential, the intricate nature of these therapies introduces significant challenges and risks, particularly in predicting and managing adverse events. Adverse events can range from immunogenic reactions to unintended genetic consequences, highlighting the necessity for rigorous preclinical and clinical evaluations. Understanding and mitigating these adverse effects is essential for the safe and successful translation of these treatments from research to clinical application. The goal of this symposium is to highlight the lessons learned from both clinical and preclinical studies in the field of cell and gene therapies, to identify strategies to optimize the safety and efficacy of these cutting-edge modalities. Topics will include understanding the mechanisms of adverse events in gene therapy, emphasizing critical insights into safety profiles and efficacy assessments; preclinical development of a novel gene therapy using an AAV-delivered zinc finger transcriptional repressor to target and treat prion diseases via epigenetic mechanisms; latest methodologies to enhance T-cell receptor potency and safety, leveraging both in vitro and in silico techniques to prevent adverse effect in cell therapy; development and utilization of advanced mouse models to better evaluate new therapeutics, focusing on enhancing drug evaluation processes and accurate toxicity assessments.
Drug-drug interactions (DDIs) are common in patients undergoing polypharmacy and may result in reduced therapeutic efficacy or enhanced toxicity. Although DDIs are largely preventable, they currently increase the number of outpatient visits and hospitalizations, increase the economic burden to healthcare systems globally, and some are responsible for patient deaths. Over the past 20 years, our understanding of drug disposition and the mechanisms by which coadministered drugs cause clinically relevant pharmacokinetic (PK) DDIs has markedly advanced. Due to the global nature of drug development, different expectations from various regulatory agencies can increase drug development cost, delay patient access to medications, and lead to inconsistent recommendations for healthcare providers. Following a succession of regional guidelines released over the past 28 years since the first DDI guidance was issued by the US Food and Drug Administration (FDA) in 1997, the International Council for Harmonisation (ICH) adopted its M12 guideline in May 2024. ICH M12 promotes a harmonized approach in conducting and interpreting enzyme- and transporter-mediated in vitro and clinical DDI studies during drug development. This session aims to : 1) summarize the in vitro tools and methods that are used to assess the potential for DDIs in light of ICH M12, 2) highlight how ICH M12 was developed and summarize its scope and where challenges remain, and 3) provide insight on the implications of ICH M12 in the design of successful clinical trials in the complex area of oncology drug development.
The advancement of next generation therapeutics, including oligonucleotides, cell therapies and gene therapies, to marketing authorization requires an understanding of developmental and reproductive toxicology (DART) to be included on the drug label. However, traditional DART approaches, including the route of administration, may be neither relevant nor feasible due to the complexity and novelty of these new medicines. Current regulatory guidance lacks clear advice on how best to evaluate DART and how to integrate traditional toxicology datasets to understand risk for reproductive potential or risk to a developing fetus for patients receiving these novel therapies. This symposium will discuss the challenges and potential strategies, including the feasibility of in utero dosing, to inform potential risk to patients receiving next generation drugs. Case studies will be presented to describe approaches that have been taken to derisk developmental and reproductive toxicity based on assessing route of administration, drug exposure, duration, genomic integration, and rare event analyses. Outcomes and interpretation of data will be discussed. Additionally, general considerations based on current FDA and EMA health authority policy for next generation therapies tested in DART studies will be presented.
For decades, preclinical toxicology was essentially a descriptive discipline in which treatment-related effects in vivo were carefully reported and used as a basis to calculate safety margins for drug candidates. To complement this time-consuming and costly assessment, gained insights into observed toxicity findings were translated into high-throughput in vitro enzymatic or cellular assays for the early detection of off-target activities or toxicity mechanisms in drug discovery. While these methods are invaluable for initial prioritization, the potential off-targets that can be monitored remain limited to hundreds, failing to account for the estimated 2,500 druggable proteins at risk across the entire proteome. In addition, they often fail in bridging toxicity observations between animal models and humans. As a result pharmaceutical companies are still faced with complex in vivo toxicity issues of which the mechanism, understanding of species relevance and translatability to humans is still hampered. In recent years, technological or NAMs (New Approach Methods) as AI/ML deep learning techniques, multi omics approaches in vitro and in vivo, high dimensional imaging and micro physiology systems are touted as game changers that promise to revolutionize pharmaceutical toxicology testing and address existing limitations in tackling in vivo toxicity challenges.
In this session, we will present an overview of the current technology landscape through case studies and explore the impact of ongoing technological advancements. The speakers will share real-world case studies that highlight difficulties encountered in traditional observational toxicology and examine whether the described technologies contribute to faster, safer, and more effective resolutions.
Educational Support Provided by: atai Life Sciences
Mental health concerns are rising globally. Psychedelics represent a novel treatment strategy for many of these disorders. This session will address the toxicity testing of psychoactive/psychedelic drugs by presenting examples of data-driven nonclinical toxicity testing by considering the specifics of the individual molecule, indication and treatment regimen. While psychedelics are a “hot topic” currently, the approach to thinking through the toxicology methods / regulatory strategy, is applicable to all novel molecules with activities that might compromise study execution. This symposium will focus on multiple different pharmacologies that are grouped into “psychedelic” and interrogate the overlap of pharmacologic on-target (dissociative) effects and toxic/ NOAEL dose levels. Speakers will address depression, anxiety, and opioid-use-disorder programs and individually focused on: A classical 5-HT2A psychedelic, A serotonergic-biased active enantiomer, and A non-serotonergic dissociative drug. In addition to the, the session will also address the CRO-side challenges of study execution and implantation of new methods to address questions of specific concern at the FDA. The session will then close with a panel discussion focused on the challenges and solutions different programs have found in the context of: Schedule 1 drug testing, different regulatory expectations around the world, the potential utility (or impediment) of historical information in the literature. The nonclinical safety assessment of these psychoactive drugs provides a great opportunity to look at the interplay of guidance documents, different global regulatory expectations, and drug-specific decisions around the appropriate studies and species for nonclinical safety testing.
This symposium will explore the evolving regulatory and scientific landscape surrounding new approach methodologies (NAMs), with a focus on the latest contributions from key industry organizations. Attendees will gain insights into the efforts of the Biotechnology Innovation Organization (BIO), the IQ Microphysiological Systems (MPS) Affiliate, the NC3Rs (National Centre for the Replacement, Refinement), and the European Federation of Pharmaceutical Industries and Associations (EFPIA) to advance the application of NAMs in research and regulatory frameworks. Highlights include case studies from the BIO NAMs Taskforce, showcasing the replacement of laboratory animals in regulatory filings, foundational work by the IQ MPS Affiliate on integrating MPS into drug development, and EFPIA’s recent publication on the progress and potential of NAMs. Additionally, the NC3Rs will present an overview of their collaboration with the Medicines and Healthcare Products Regulatory Agency (MHRA) and the Association of the British Pharmaceutical Industry (ABPI) focused on integrating NAMs into the development of new medicines. This session will provide a comprehensive overview of industry initiatives driving innovation in NAMs.
Educational Support Provided by: Eli Lilly and Co., Inc.
The development of biologic therapeutics requires developmental and reproductive toxicity (DART) studies to support post investigational new drug (IND) development in clinical trials that include women of childbearing potential (WOCBP) and/or to reduce the intensity of contraceptive requirements. Non-human primates (NHPs) tend to be the only pharmacologically relevant species for most biologics and the latest shortage of monkeys poses timing and financial challenges for the industry. Other biologics may not have pharmacological activity in NHPs or any animal species. To mitigate the challenges and limitations, approaches on using transgenic mice and/or surrogate molecules to leverage the assessment of reproductive and developmental liability of biologics will be discussed. Experience of the speakers in the use of transgenic models or surrogate molecules for DART testing and regulatory acceptance worldwide. Presentations will include the preliminary work that is involved in establishing/characterizing a transgenic model or surrogate molecule including the timing and extent of the characterization of the model or molecule. The issue of sufficient Historical Control Data (HCD). The success or failure of the program. Were NHPs studies eventually conducted or still deemed necessary and the translation of the results to the product label. Perspectives from regulatory agencies and case studies from the pharmaceutical industry will be presented in this session.
This session is a companion to the ACT Symposium from 2017 “What to Do When Things Go Wrong” and 2019 “Keep Calm and Carry On: Challenging Case Studies”, where early career professionals will present case studies with unanticipated situations. Four professionals in different areas (consulting, industry, and regulatory) will state the issue they experienced, the impact of the issue, handling/management of the issue, and how this issue was resolved (either positively or not). This year we will hear from a pathologist that observed unexpected findings in control animals, a consultant derisking a nonclinical program with misidentified clinical observations that resulted in a clinical hold, a consultant performing risk assessments of heavy metals in feminine products, and an experienced toxicologist on challenges in drug review process. We will also have an open panel discussion with an industry veteran to answer questions about navigating as an early career professional. Audience engagement and questions are highly encouraged!
This Symposium is being presented in collaboration with the ACT Early Career Professional Subcommittee.
Educational Co-Support Provided by: Neurocrine Biosciences, Inc. and American College of Toxicology
Artificial intelligence (AI) is revolutionizing toxicology, transforming it from an observational science into a data-rich discipline capable of addressing complex challenges in drug and chemical safety assessment. By leveraging advancements in machine learning, deep learning, and the growing availability of toxicological data, AI is enhancing predictive toxicology, risk assessment, and mechanistic research. This session provides an overview of key developments in AI-enabled toxicology, from early expert systems and quantitative structure-activity relationships (QSARs) to recent breakthroughs with deep neural networks. It highlights emerging trends and opportunities while addressing critical limitations, such as sparse datasets, high-dimensional challenges, and the risk of overgeneralization in AI models. The responsible integration of AI—through interpretable, human-centered tools and multidisciplinary collaboration—offers immense promise for advancing toxicology and regulatory science. However, it must complement ongoing efforts to strengthen primary evidence generation and critical appraisal. By thoughtfully navigating these advancements, AI can accelerate safer outcomes for human health and the environment. This session is a follow up to the keynote talk given by Dr Weida Tong in 2024, and is designed to address some of the questions raised by attendees during that opening session.
Educational Support Provided by: Roundtable of Toxicology Consultants
Many toxicologists consider consulting an alluring and viable career option with work-from-home benefits, flexibility, and perceived freedom for early- to late-career professionals. Toxicology consulting is a rewarding career, but it is not for everyone. Dedication and persistence are required along with motivation to solve problems and work diligently with clients, laboratories, the regulatory community, non-toxicologists and project teams. In this interactive workshop, we will compare career options for toxicologists as independent consultants or members of consulting organizations. The challenges for independent consultants can be daunting but are surmountable. This workshop will outline how to start and build a consulting practice to ensure success. This workshop will answer common questions: “how do I start”, “how much should I charge” and “what do I need to do?” The initial presentation will describe “how do I begin” with real-world challenges for a consulting practice and will address consulting rate, fees, liability insurance, bank accounts, accounting, and day-to-day operations. Subsequent presentations will describe consulting for solo practitioners, a small group practice, and a large consulting group, as well as developing niche consulting practices. A final presentation will discuss myths and misconceptions that keep toxicologists from choosing consulting – mostly marketing. A panel discussion will address questions, case studies, dealing with clients, and providing regulatory and scientific feedback to clients.
Educational Support Provided by: Eli Lilly and Co., Inc.
Recent advancements in molecular targeting technologies have led to a renewed interest in radiopharmaceuticals, particularly radioligand therapies for oncology, due to the potential to deliver cytotoxic radiation selectively to cancer cells while minimizing damage to healthy tissues. Compared to other targeted therapies, radiopharmaceutical therapies can be personalized by radionuclide imaging and deriving individual patient tumor and normal organ radiation absorbed doses. Radiopharmaceuticals generally require fewer cycles to elicit a response and are generally well tolerated relative to traditional chemotherapies. Unfortunately, the relatively short half-lives of radionuclides, measured in hours or days, make their deployment for cancer therapy challenging. This symposium will explore the unique safety, logistical, translational, and regulatory considerations associated with the development of this oncolytic modality. The goals of this session are to 1) provide a basic overview of various radiopharmaceutical constructs and commonly used radionuclides in cancer therapy, 2) discuss nonclinical studies required for the registration of a novel radiopharmaceutical product, 3) present study design considerations for the safety evaluation of non-radioactive constructs, 4) discuss the design and conduct of biodistribution studies with the radioactive construct and the logistical challenges associated with their execution, 5) present how organ-level dosimetry estimates are extrapolated to humans based on dosimetry data obtained from nonclinical biodistribution studies, and 6) discuss the regulatory requirements for the development of radiopharmaceutical products. The audience will gain a basic understanding of the development of radiopharmaceuticals and translational dosimetry. The speakers will elaborate on terminology associated with radiation wherever applicable and present case studies wherever possible.
Antibody-drug conjugates (ADCs) are a promising cancer treatment that expands the therapeutic index of conventional chemotherapy agents by conjugating potent cytotoxic agents to highly specific monoclonal antibodies (mAbs) to increase efficiency and delivery of cytotoxic agents to targeted cancer cells. The Food and Drug Administration (FDA) have approved 13 ADCs covering 16 indications, including several types of breast cancer, non-small-cell lung cancer, bladder cancer, classic and non-Hodgkin lymphoma, and more. While ADCs are designed to minimize damage to healthy cells, side effects are still common in patients, and many ADCs have failed during the clinical development phase due to their adverse toxicities which might be missed in the non-clinical phase testing. Common side effects observed in the clinics, such as peripheral neuropathy and multi-organ toxicities (e.g. eye, lung, liver), are largely recapitulated in preclinical models, and analysis indicates that certain types of payloads are related to certain types of toxicities. Further analysis demonstrates that toxicities are often shared by different ADCs that deliver the same cytotoxic payload, independent of the targeted antigens (i.e., off-target toxicity) or cancer types. This mini-symposium will (1) highlight the nonclinical to clinical challenges of ADC treatment-related common adverse events (ie. peripheral neuropathy, ocular, lung, and liver toxicities); (2) summarize current in vivo non-clinical study requirement and alternatives from regulatory aspect, and (3) examine fundamental mechanisms contributing to ADC-related adverse effects and explore the suitability of various animal models and new approach methodologies to understand and mitigate ADC toxicity in nonclinical development.
Educational Co-Support Provided by: SciLucent, Inc. and American College of Toxicology
FDA interactions are an important part of the drug development process. Several formal meetings between sponsors and FDA are available to provide an opportunity for the Agency to provide input on drug development plans or to discuss any issues that may have arisen during development. Successful meetings take time and planning. Understanding the goals of the meeting is a first step. Questions should be clearly defined and the information to support the data should be available and provided in the Briefing Package to enable FDA to respond. This mini symposium will discuss best practices for a successful FDA meeting from both an industry and a regulator’s perspective. Case studies will be presented that highlight successful meetings and ways to avoid common pitfalls.
A traditional part of the final afternoon of the ACT Annual Meeting is the Hot Topics Symposium. Each year this session includes a variety of topics from leading experts focusing on late-breaking regulatory or scientific advances related to toxicology.
Educational Support Provided by: Eli Lilly and Co., Inc.
Endogenous substances are often present as impurities in biologic therapeutics due to the nature and method of manufacturing. There are many classes of endogenous compounds, including fatty acids, amino acids, nucleic acids, sugars, vitamins, enzymes and others (e.g., urea). While these compounds may be present endogenously, increased levels can lead to adverse effects; thus, appropriate exposure thresholds are necessary. Thresholds are not readily available for many of the endogenous compounds. Due to the number and diversity of compound classes, a single threshold is not appropriate. This session will present the different types of exposure thresholds including permitted daily exposure (PDE), acceptable daily exposure (ADE), acceptable daily intake (ADI) that are often used interchangeably to describe daily exposure limits, general approaches used when setting an appropriate exposure thresholds and their importance. Specific considerations for setting exposure thresholds for endogenous compounds will be discussed. After a discussion of methodology and special considerations for setting exposure thresholds for endogenous compounds, four example endogenous compound classes will be presented: 1) fatty acids; 2) amino acids; 3) sugars; 4) enzymes. Some of the classes like fatty acids and amino acids have been studied more extensively and other classes are a work in progress. Specifically, special considerations for each class and class- or compound-specific limits where available will be discussed. Following discussion of class-specific thresholds, challenges and limitations to the proposed approach will be presented. Useful links for the reference materials will be provided. While the scope of the presentation is for parenteral route of administration, other routes of exposures will be touched upon.
Educational Support Provided by: AstraZeneca
Intranasal therapies and vaccines have been around for centuries and regained interest during the SARS-CoV-2 pandemic. In addition to being a site of disorders and infections, the nasal cavity offers access to the rest of the respiratory system, vasculature, brain, and immune system. The nose poses an interesting challenge specifically for immune-activating conditions because it first serves as a barrier to the external environment. It is by ‘putting the nose to the grindstone’ that intranasal therapies are advancing. This symposium will address in vitro and in silico models for nasal drug development; how allergens affect the interplay between neural and immune systems; and the case study of a recent intranasal program for influenza vaccination.