Symposia and Workshop sessions are three hours each. The Program Committee is actively working with chairs and speakers to provide an optimized scientific program. Topics are subject to change.
Session Chairs: Maggie Liu, Pfizer Inc., San Diego, CA; and Judith Prescott, Merck & Co., Inc., West Point, PA
Severely debilitating or life-threatening indications (SDLTs) include conditions in which life expectancy is short or quality of life is greatly diminished despite available therapies. As such, the medical context for SDLT indications is comparable to advanced cancer and the benefit versus risk assessment and development of SDLT therapeutics should be modeled on that for advanced cancer therapeutics. A streamlined development approach would allow patients with SDLTs earlier and continued access to new, potentially beneficial therapeutics. While there are regulatory guidelines for advanced cancer therapies and for therapies for rare diseases (which include some, but not all, SDLTs), as well as regulatory programs primarily employed to expedite late development for serious conditions, there is minimal, and no global, guidance to facilitate early development and availability of SDLT therapeutics for patients with limited therapeutic options. In light of this high unmet need, a global guideline is needed to facilitate streamlined development of non-oncology SDLT therapeutics. While much of this is focused on therapeutics for SDLT conditions, it should be noted the development of vaccines for SDLT indications with urgent medical need and no adequate preventatives should similarly apply a streamlined approach. This Symposium will (1) introduce a proposed streamlined development approach for non-oncology SDLT conditions across therapeutic areas, (2) discuss potential criteria defining the scope applicable to global guidance, (3) discuss industry case examples of the development of COVID-19 vaccines and therapeutics during the current pandemic; (4) provide regulator perspective and description of current efforts on SDLT guidance development, and (5) incorporate patients’ perspectives on benefit/risk considerations when living with SDLTs.
Session Chairs: A Wallace Hayes, University of South Florida College of Public Health, Temple Terrace, FL; and Peter Pressman, The Daedalus Foundation, San Clemente, CA
E-cigarettes are battery-powered devices that generate an aerosol for inhalation by heating a liquid formulation (e-liquid) to temperatures ranging from 40° to 300°C, while most vaping products are not battery powered and may not require heating. In its 2018 report on Public Health Consequences of E-Cigarettes, the US National Academies of Sciences (NAS) stated that there is conclusive evidence that completely substituting e-cigarettes for combustible tobacco cigarettes reduces users’ exposure to numerous toxicants and carcinogens present in combustible tobacco cigarettes. However, given their relative novelty, conclusive long-term clinical studies on the health consequences of e-cigarettes and vaping products are not yet available. Research involving both types of products is challenging and complex, mostly because of the numerous and rapidly evolving variety of technology and designs, as well as the multiplicity of e-liquid flavors and solvents that are on the market. Notably, the absence of standardized assessments makes research data difficult to interpret and compare. These considerations highlight the urgent need to harmonize research protocols, starting with production guidelines and moving on to vapor generation and physicochemical characterization methods, as well as nonclinical and clinical exposure studies. The specificities of the products constitute challenges to toxicity testing and require the development of ad hoc assessment frameworks, equipment, and methods. In so doing, the objective evaluation and verification of existing evidence must occur and, ultimately, lead to the formulation of standardized methods to test such products.
Session Chairs: Krishna Allamneni, Turning Point Therapeutics, San Diego, CA; and Jeffrey Moehlenkamp, Aclairo® Pharmaceutical Development Group, Inc., Vienna, VA
How does a project have the best chance to survive through internal decision-making to successful launch? A lot of data must be brought forth from discovery or conception to the development phase in a timely manner for a particular project to move forward. Contracts, legal, project management and monitoring, toxicokinetic, toxicology, pathology, immunogenicity or ADA, and bioanalytical experts all have critical/pivotal roles. The intracompany and possibly external PIs as well as potential partners all play their role in moving a project forward, or alternatively, stalling it. So, what are the key functions that need to be lined up for the correct decision-makers and elements to be in place to make the decision of Go or No-Go? This Workshop will explore the planning and timing of key events in drug development. This session is designed for early career toxicologists to be aware of this critical non-toxicology skill needed to lead and/or contribute to a successful nonclinical safety assessment program. Decision-making skills may not have been part of the graduate school’s curriculum, but these are critical to employ along with organizational ability, teamwork, leadership, problem solving, and collaboration in the context of competing regulations, interests and expertise, and prioritization, so toxicologists could lead from any seat no matter the role in the team. The course focuses on keeping the patient and the entire program in the forefront by engaging the executive function in decision-making.
Session Chairs: David Clarke, Lilly Research Laboratories, Indianapolis, IN; and Helen Prior, National Centre for the Replacement, Refinement & Reduction of Animals in Research (NC3Rs), London, United Kingdom
For biotherapeutics with multiple pharmacologically relevant species, short-term toxicology studies (generally IND-enabling studies supporting Phase I trials) should be performed in a rodent and a nonrodent. ICH S6(R1) outlines options justifying when only one species may be sufficient for subsequent longer-term toxicology studies (e.g., up to six months dosing duration). These options include that “the toxicity profile in the two species is comparable in the short term,” or that “findings are understood from the mechanism of action of the product.” In these cases, the rodent species should be considered to progress to the longer-term studies, unless there is scientific rationale for using nonrodents instead. A key decision for progression to longer-term studies in one or two species revolves around the “similarity” of toxicities between the species identified in the short-term studies. However, definitions of “similar toxicity profile in two species” remain vague; there is lack of clarity on how to apply this in practice and whether the absence of toxicity in two species constitutes a “similar” toxicity profile as outlined in ICH S6(R1). As a consequence, Sponsors may continue to use two species to avoid regulatory risk and potential delays in development timelines. Such decisions represent missed opportunities for applying the 3Rs and reducing animal use, particularly of NHPs, during drug development. This session will highlight case studies from industry to share examples of decisions to reduce to one species for longer-term toxicology studies and regulatory perspectives to highlight any common themes or experience that could be applicable for use in future decision-making.
Session Chairs: William B. Mattes, US Food and Drug Administration, Jefferson, AR; and Peyton Myers, US Food and Drug Administration, Silver Spring, MD
Tox21 focuses on modernizing toxicology for the 21st century. Part of that effort is to evaluate the 3Rs and encourage development and eventual regulatory acceptance of alternative systems that can meet regulatory requirements for public health. Although many in vivo systems are used for regulatory decision-making, alternative models can play a crucial role for toxicologists in both risk assessment as well as efficacy evaluation. In this session, we will discuss multiple in vitro or in silico platforms that are being developed or are in use for risk assessment for the cardiovascular system, hepatic system, and skin sensitization. Next, we will discuss how in vitro assessments may help pave the way for further advancements in efficacy for rare and ultra-rare diseases. Lastly, the impact of inter-individual variability between cells lines based on individual donors will be discussed. The in vitro and in silico platforms in this session will describe both successes and ongoing challenges for both regulators and industry as the community moves toward an ever-increasing in vitro world.
Session Chairs: Tracey Spriggs, GlaxoSmithKline Consumer Healthcare, Warren, NJ; and R. Daniel Mellon, US FDA, Silver Spring, MD
The world of cannabis-based medicinal and consumer products is rapidly expanding. Products containing cannabidiol (CBD) are virtually everywhere, currently including in foods, dietary supplements, cosmetics, and even clothes. Navigating the legal landscape of CBD-containing products has been challenging, particularly since the passage of the 2018 U.S. Agriculture Improvement Act (aka, the Farm Bill), which made products derived from hemp (cannabis-based products that contain less than or equal to 0.3% THC on a dry weight basis) no longer controlled substances under the Controlled Substances Act (CSA). Regardless, CBD-containing products are still subject to the same laws and requirements as US Food and Drug Administration (US FDA)–regulated products that contain any other substance. Although US FDA has approved a single cannabidiol drug product (Epidiolex) in 2018, this drug product is indicated for two severe pediatric forms of epilepsy and requires very clear labeling recommendations to delineate the risk:benefit of the drug product for that indication. Despite widespread marketing of CBD-containing products, there are known safety concerns and many unknown questions about the safety and pharmacology of CBD. This session will detail the current legal status of CBD and other important considerations for products derived from cannabis. An overview of the known pharmacology and toxicology of CBD will be provided, and a case example presented. This session will describe the existing concerns regarding widespread use of these products and outline regulatory recommendations for the development of CBD-containing and other cannabis-based drug products for marketing approval.
Session Chairs: Natalie S. Holman, Eli Lilly and Company, Indianapolis, IN; and Lauren Mihalcik, Amgen, Silver Spring, MD
Oligonucleotide therapeutics such as short interfering RNAs (siRNA) represent a promising class of molecules to reach targets that conventional small and large molecules cannot. With the recent approval of the first siRNA therapies and many more in development, it is critical to understand the specific challenges in profiling the toxicity of these unique drug candidates. In this session, leaders in the siRNA therapeutics field from pharma, biotech, and government will discuss components of IND-enabling toxicity studies, current best practices, ambiguities, and regulatory perspectives related to siRNA therapies. Importantly, exciting advances in siRNA (i.e., targeting extra-hepatic tissues) will also be discussed.
Session Chairs: Christopher Ellis, US FDA/CDER, Silver Spring, MD; and Tacey White, Aclairo Pharmaceutical Development Group, Inc., Vienna, VA
Evaluating the safety of pharmaceutical products used during lactation is a topic that has garnered substantial interest over the last several years. Although driven primarily by the implementation of the US Food and Drug Administration (US FDA) Pregnancy and Lactation Labeling Rule (PLLR), which provides requirements for the content and format of labeling for human prescription drug and biological products that may be used during lactation, this has also been a topic of recent discussions related to proposed updates to ICH S5(R3). Pharmaceutical labeling communicates important information, allowing for the safe and effective use of approved products in patients, with the PLLR providing specific requirements for the labeling of pharmaceuticals that may be used during lactation (in Section 8.2) in regard to (1) the presence or absence of the drug in milk; (2) the known or predicted effects on the breastfed child from drug exposure through milk; and (3) the effects of the drug on milk production. The extent to which animal data can or cannot inform human risk assessment in these three areas has been a topic for considerable debate. This Workshop will begin by providing an overview of lactational physiology and mechanisms of drug excretion into milk (focusing on similarities and differences between humans and animals used for toxicologic assessment) as well as lactational study designs. The Workshop will also provide perspective and discussion on the usefulness of animal lactation–related data for human risk assessment purposes, as well as considerations for communicating risk in the US prescribing information (USPI).
Session Chairs: William B. Mattes, US FDA National Center for Toxicological Research, Jefferson, AR; and Richard D. Beger, US FDA National Center for Toxicological Research, Jefferson, AR
Metabolomics is the comprehensive study of the biochemicals present in cells, tissues, and body fluids, collectively called the “metabolome.” Importantly, its ability to query accessible biofluids (blood, urine, feces, etc.) gives it a unique ability to examine system-wide status and responses in animal, clinical studies, and even in vitro studies. Indeed, an individual’s metabolic state provides a close representation of overall health status and reflects what has been encoded by the genome and modified by diet, environmental factors, and the gut microbiome. This session will highlight several studies showing the power and promise of metabolomics to query normal and pathological states in both nonclinical and clinical settings.
Session Chairs: Mary Ellen Cosenza, MEC Regulatory & Toxicology Consulting, LLC, Moorpark, CA; and Paul Baldrick, Covance, Harrogate, United Kingdom
The potential for direct or indirect adverse effects on the immune system is an established component of nonclinical testing to support the safe use of new drugs. ICH S8 established testing recommendations, and immune safety–related assessments are routinely conducted for a variety of therapeutic modalities not necessarily in scope of ICH S8. How these assessments can be used to inform clinical development continues to evolve. This session will review key developments in this arena and will include a review of ICH S8 and other relevant regulatory documents. Regulatory perspectives from the US and EU will be provided by regulatory agency scientists.
Session Chairs: Patricia Ryan, AstraZeneca, Gaithersburg, MD; and Justine Cunningham, Sana Biotechnology, San Francisco, CA
Genetic therapies, once heralded and later maligned by setbacks, are now astounding the world with clinical proof of their potential to cure patients with devastating diseases. Today, genetic therapies encompass a wide array of delivery (viral and nonviral) and mechanistic approaches, offering novel ways to replace or modify affected genes. The novel mechanisms of genetic therapies have opened pathways to rethink traditional preclinical approaches, bringing opportunities to shed old ideas while embracing the challenges to de-risk these products. The challenges that toxicologists have had to consider involve how to leverage hybrid study designs for combined safety/efficacy studies, evaluate vector persistence, predict for immunogenicity, de-risk for off-target genotoxicities, address risks for germ line transmission, and scale to humans from a single species. As developers look to expand the therapeutic potential of gene therapies, new toxicologists will be challenged with addressing these key questions to demonstrate safety and tolerability. The goal of this Symposium is to learn how successful gene therapy developers have navigated the preclinical space to enable clinical entry and to identify where the new challenges lie ahead.
Session Chairs: Norman Kim, Relay Therapeutics, Cambridge, MA; and Hanan Ghantous, US FDA, Silver Spring, MD
As a part of the US Food and Drug Administration (US FDA) Center for Drug Evaluation and Research’s (CDER) initiative to modernize the New Drugs Regulatory Program, the Office of New Drugs (OND) was restructured in November 2019. Approved changes in OND created offices that align interrelated disease areas and divisions that provide more focused areas of expertise. Changes increased the number of OND offices that oversee Review Divisions from six to eight and culminated in increasing the number of OND clinical divisions and realigning nonclinical Review Divisions. Six newly restructured pharmacology-toxicology divisions include: Division of Pharm/Tox for Infectious Diseases (DPT-ID); Division of Pharm/Tox for Neuroscience (DPT-N); Division of Pharm/Tox for Cardiology, Hematology, Endocrinology and Nephrology (DPT-CHEN); Division of Pharm/Tox for Immunology and Inflammation (DPT-II); Division of Pharm/Tox of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine (DPT-RPURM); and Division of Hematology/Oncology Toxicology (DHOT). The Symposium will present responsibilities of Associate Directors of Pharm/Tox, as well as an overview, roles and responsibilities, structure/procedures, and indication coverages of each Pharm/Tox Review Division. Potential uncertainties and questions from Sponsors will be outlined and addressed. The Symposium will also include other recent changes, including the Integrated Review process of NDA/BLA and its Summary approval, which incorporates pivotal safety studies in consideration of the risk-benefit for the indication.
Session Chairs: Laura Lotfi, Charles River Laboratories, Senneville QC, Canada; and Julie Douville, Charles River Laboratories, Senneville QC, Canada
Computational and artificial intelligence (AI) tools for predicting toxicity have been envisaged for their considerably high impact on the rate of compound discovery and lead candidate selection in drug research and development. The pharmaceutical and biotech industry as well as Contract Research Organizations (CROs) supporting these programs are in constant search of novel approaches to accelerate transition of drug molecules from laboratory benches to patients. It has been shown that robust tools and sophisticated system algorithms can be exhaustively applied to optimize detection of early safety endpoints to aid in determination of first-in-human dose. One of the various AI approaches that can be used to assist with regulatory communications, impacting clinical decisions and reducing the number of animal models used at these stages, is physiologically based pharmacokinetic (PBPK) modeling. Related publications and regulatory submissions have risen dramatically in recent years. This Symposium will provide attendees with an update on the cutting-edge applications in PBPK and related predicting software and present strategies for implementing PBPK and intelligent modeling in the program design of a drug candidate. It will also highlight considerations and challenges in regulatory submissions and risk assessments. Topics will include an introduction to use of PBPK in drug research, the perspective of regulatory authorities on the validation of such a technology, and successes and challenges in Investigational New Drug (IND) application submissions using this technology, focusing on case-based examples.
Session Chairs: Maralee McVean, Inotiv, Fort Collins, CO; and Kathleen Funk, Experimental Pathology Laboratories, Inc., Sterling, VA
This Symposium will focus on juvenile bone toxicity, i.e., the design of juvenile animal studies to adequately assess bone toxicity, the usefulness of biomarkers, the imaging modalities to assess bone structure, the interpretation of the significance of bone effects, and relevant regulatory issues. The first speaker will cover study design and interpretation of the data in the context of ICH Guidelines. The second speaker will address in depth how micro-CT applications can be used to evaluate skeletal elements and bone growth in embryo-fetal development (EFD) and pre- and postnatal development (PPND) studies as well as juvenile toxicology studies, while the third speaker will describe the various tools that can be used to monitor bone toxicity, healing, and remodeling, and how they relate to or drive study design. A regulatory perspective on the assessment of juvenile bone toxicity and the potential concerns about adverse skeletal effects in the pediatric population will be presented by the fourth speaker.
Session Chairs: Kristina Howard, US Food & Drug Administration, Silver Spring, MD; and Florence Burleson, Burleson Research Technologies, Inc., Morrisville, NC
Hypersensitivity reactions are highly complex and comprise a wide range of molecules, proteins, and cells, but it is well established that mast cells and basophils are key contributors during these reactions. These cells are markedly different in how and why they are activated and display remarkable heterogeneity across tissues and species, which impacts our ability to use models to predict their likelihood. Drug hypersensitivity is also known as infusion reaction or drug allergy and remains a critically underinvestigated topic of study. Drug hypersensitivities are often unpredictable and are associated with a high mortality risk because these reactions are often sudden, severe, and not necessarily directly related to dose or pharmacological action of the drug. Unfortunately, preclinical screening for drug allergy/hypersensitivity remains difficult and nonroutine, since reactions may present in specific tissues, only occur in some individuals, or involve tissue-resident cells. This Workshop will discuss challenges in assessing preclinical drug hypersensitivity by providing an introduction into the biology of hypersensitivity followed by speakers addressing in vitro methods, animal models to study in vivo mechanisms, and ex vivo approaches to screen for drug allergies, concluding with a panel discussion addressing current limitations and challenges and future directions.
Session Chairs: Joseph A. Francisco, Altasciences, Seattle, WA; and Jane J. Sohn, US FDA, Silver Spring, MD
Session Chairs: Ray Zhang, Theravance Biopharma, South San Francisco, CA; and Zhechu Peng, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT
This interactive Workshop is presented by the ACT Early Career Professional (ECP) Subcommittee. Career paths are often nonlinear and complex, presenting unique hurdles along the dizzying array of career trajectories within the subdisciplines of toxicology. Despite these challenges, major career transitions can elevate your career in toxicology at all stages, from graduate school to retirement. Traditionally, career paths in toxicology include positions typically starting out of graduate school with well-defined career milestones, such as US Food and Drug Administration (US FDA) pharm/tox reviewer, regulatory toxicologist, or research toxicologist in big pharmaceutical or biotechnological sectors. The nontraditional career paths navigate outside these well-established avenues and converge with less common toxicology applications, such as emergency response, emerging scientific fields, and specialized pharmaceutical industry occupational health. In this interactive Workshop, five case studies will be presented on successful traditional and nontraditional toxicology career trajectories. Both early and advanced career speakers will share their responses to obstacles and opportunities encountered during their professional journey and provide advice that can be incorporated into your own career advancement goals. The key components to creating and enhancing your own unique career in toxicology will be discussed, including the types of transitions, self-reflection and timing, and the usefulness of major transitions encountered in a variety of career trajectories. After the case studies, there will be an interactive question and answer panel with active audience participation where you can ask questions on how to craft your own distinctive and applied toxicology career through successful transitions.
Session Chairs: Vincent Murphy, Sillmeadow, Inc, Sugar Land, TX; and Arianne Motter, US FDA/CDER, Washington, DC
The incidence of food allergies and intolerances has increased over time. This Symposium will examine the issues and possible causes of the increase and the hypotheses behind the rapid rise in rates. Mechanisms of food allergy and intolerance, methods of identification of food allergies or intolerance, and various treatment paradigms will be described. Regulatory strategies of assessing allergenic risk with a focus on novel proteins and the data used for evaluation in regulatory submissions will be presented from a regulatory and safety consultant. A representative of the International Food Information Council will discuss communication of valid scientific data to the public and debunking misconceptions as to food allergies and intolerances.
Session Chairs: Douglas Ball, D&B ChemTox, LLC, Southbury, CT; and Kim Li, Amgen Inc., Thousand Oaks, CA
Extractables and leachables (E&L) are nondrug-related impurities potentially present in drug-device combination products from the container closure system, manufacturing equipment, and/or delivery device. E&L impurities need to be identified, reported, and qualified. In some cases, a leachable is identified as a known and/or suspect sensitizer. Screening of sensitizers is challenging, as no thresholds to mitigate the risk have been developed for medical devices or drugs. In some cases, elimination of the potential sensitizer is possible (e.g., replacement of a critical component that leaches the sensitizer); however, in cases where elimination is not possible, pragmatic approaches using threshold concepts may be useful. This Symposium will provide current approaches on the safety assessment of potential sensitizers in drug-device combination products.