Drug development has been changing considerably over the several past years. There has been an ever-increasing shift from the approval of primarily new chemical entities to protein therapeutics, such as monoclonal antibodies and
fusion proteins, as well as entities at the interface of chemicals and biologicals (e.g., oligonucleotides, protein-drug antibodies). In parallel to the emergence of these more novel agents, there has been considerable development
and application of emerging digital technologies, such as digital pathology, tissue image analysis, and machine learning. This session will provide a snapshot of considerations regarding the development and applicability of some of
these modalities and technologies to drug discovery and development. Specifically, this session will discuss development aspects of oligonucleotides and long-acting protein therapeutics and how machine learning and artificial
intelligence can utilize general pharmacology data to predict therapeutic liabilities or aid in the discovery of safer candidates. Nucleic acid–based and tumor-targeted therapeutic programs offer a unique opportunity to explore
consistencies and variances in the pharmacokinetic and toxicity profile. From a technology perspective, digital pathology will display how these tools and artificial intelligence approaches are being applied, and advantages and
disadvantages will be demonstrated via case examples. While these agents and technologies are not entirely new, their development and utilization are helping to more quickly bring safer and more directed medicines to patients.
Science is changing rapidly, and this session will help to ensure therapeutic safety scientists are prepared for drug discovery and development in the 21st century.
The safety assessment of excipients in drug products can be challenging when evaluating new formulations, new routes of administration, new indications (acute versus chronic), or new populations. Even with the publication of
guidance documents on nonclinical safety evaluation of pharmaceutical excipients, there are still numerous examples where drug developers meet unexpected challenges or obstacles, often attributable to improper characterization of
the risks and/or inadequate understanding of the regulatory requirements surrounding excipients. This Workshop provides some key concepts and practical approaches in assessing the safety of excipients from both a systemic and a
local toxicity concern. The Workshop will highlight challenges and limitations of the Center for Drug Evaluation and Research (CDER) Inactive Ingredient Database (IID), leveraging data in Master Files, novel routes of administration
(such as transdermal or topical delivery systems), and pediatric formulations. It will specifically include safety assessment of flavors in drug products and the limitations of various GRAS designations commonly submitted to support
the safety of excipients contained in investigational new drug products. This Workshop will also present industry and US Food and Drug Administration/CDER review division case studies that illustrate current and applicable
challenges and how to effectively design a robust approach to the safety of excipients in new therapeutic formulations.
Every day, we use water for drinking, bathing, cooking, and cleaning. We trust that those who oversee our water supply maintain its quality and that it is safe for our families’ use. Unfortunately, quality can be compromised when
water supplies are contaminated. Contamination has resulted from changes in water supply, delivery, and treatment procedures, as well as from natural disasters like floods and hurricanes and spills from industrial and mining sites.
Of interest to toxicologists is contamination from heavy metals and industrial or agricultural chemicals. This Symposium will highlight some of the recent contamination incidents—including the lead contamination of the Flint,
Michigan, water supply and industrial chemical contamination at Camp Lejeune in North Carolina and the Fox River in Wisconsin—and it will explore how the water supply was compromised and what health concerns resulted from the
contamination. Additionally, speakers will discuss the remedies to improve the water quality and how to avoid a future occurrence. Research into evaluating the exposure and risk to the population will presented.
Gene therapy is the introduction of nucleic acid(s) into a host cell to replace or repair a lost or mutated gene, or to introduce something novel altogether. Adeno-associated virus (AAV), a DNA parvovirus, is currently the most
commonly used vector for in vivo gene therapies for potential treatment or cure of life-threatening diseases. The purpose of this Symposium is to provide an overview of AAV-based gene therapies and the nonclinical studies that are
needed to support clinical trials. This Symposium will include a review of the AAV vector field and the current state of its clinical use, a case study of an ophthalmic AAV gene therapy, and a case study of the biodistribution and
toxicity profile of AAV gene therapy following CNS delivery. This Symposium will also discuss the challenges that industry has been encountering for AAV-associated gene therapies. The session will conclude with a panel discussion on
the need for harmonization and an ICH guidance on AAV-based gene therapy.
There has been an increased interest in and activity for the use of peptide therapeutics to treat a variety of human diseases, with innovative strategies for the development of biopharmaceutical pipelines. The number of peptide
drugs entering into the market has increased significantly despite inherent challenges of peptide instability and patient-friendly delivery. Disparities in interpretation and application of existing regulatory guidances to
innovative synthetic and conjugated products have resulted in challenges for both regulators and sponsors. This Symposium will cover different challenges in peptide therapeutic development, along with considerations of regulatory
challenges. The specific topics to be covered will include the following: (1) peptide therapeutic progress and future direction, and approaches to discover, optimize, assess, and deliver combination peptide therapeutics for
treatment of diseases; (2) toxicological considerations to deliver peptide drug-device combination products for efficient development and optimal patient benefit and adherence; (3) industry and regulatory perspectives on the
regulation of synthetic and conjugated peptide products, including exploration of regulatory classifications, interpretations, and application of existing guidances in determining nonclinical study requirements (ICH M3[R2] versus
ICH S6); and (4) discussion of the 2016 HESI working group assessment. Both industry and regulatory professionals will be included as presenters and discussion facilitators.
Regional regulations on Good Laboratory Practices (GLP) have been published to ensure the quality and integrity of nonclinical laboratory study data that are intended to support clinical research or marketing permits for human
therapeutics. The US Food and Drug Administration (US FDA) promulgated GLP regulations in 1978 and the Organisation for Economic Co-operation and Development (OECD) followed with the publication of GLP Principles in 1981. Many
individual nations generated their own unique GLP regulations. Under the Mutual Acceptance of Data (MAD) System, data generated in toxicological testing in one OECD Member country are accepted in all other OECD Member countries.
However, several differences in national GLP regulations exist, not all countries are OECD Members, and not all laboratories conduct toxicological testing following US or OECD GLPs, generating hurdles for the acceptance of GLP data
in global drug development. The goal of this Workshop is to openly discuss the similarities and differences in GLP regulations and inspections from different countries and regions to facilitate identifying challenges when
outsourcing nonclinical GLP testing globally. In this Workshop, the speakers will share their experience and interpretations of GLP regulations and inspections from OECD Member countries (US, Canada, UK, Japan, Korea, and Germany),
Brazil (Latin America), Taiwan, and China, by covering (1) GLP roles and responsibilities; (2) testing facility personnel credentials and management responsibilities and training; (3) the quality assurance unit reporting process;
(4) SOPs formulation, approval, and enforcement; (5) animal welfare, ISO standards and quality systems, test article characterization, and regulatory inspections; and (6) current challenges in compliance. This Workshop will be of
interest to those seeking to understand differences and challenges when considering global outsourcing during drug development.
This session is a companion to the successful 2017 ACT Symposium “What to Do When Things Go Wrong.” This year, early career toxicologists from the pharmaceutical and biotechnology industries as well as the US Food and Drug
Administration will present a new set of challenging scenarios they have encountered in their respective roles and how they were resolved. Case studies will include challenges as a new pharmacology/toxicology reviewer, evaluating
nontraditional data in Good Laboratory Practices toxicology studies, navigating project team dynamics, unexpected pathology findings, and employment instability. Audience engagement and questions are highly encouraged.
Regulatory guidelines are currently evolving for juvenile animal studies (JAS) that support pediatric drug development and have particularly flexible requirements. The draft ICH S11 guidance aims to recommend an approach for the
nonclinical safety evaluation of medicines intended for pediatric populations. This guidance is vague about the extent of CNS assessments, which makes applying the guidance challenging for new drugs that may be neuroactive, such
as anesthetics. Nonclinical data in the published literature have indicated the vulnerability of the developing brain to anesthetics, driving a recent Safety Labeling Change (SLC) by the US Food and Drug Administration (US FDA)
and serving as an example for the relevance of JAS. The SLC, however, also highlights the regulatory challenges involved in developing new, potentially safer pediatric anesthetics. The goals of this session are to (1) examine the
current thinking laid out in the draft ICH S11 guidance pertaining to neurotoxicity, (2) discuss the available data on anesthesia-induced developmental neurotoxicity to inform future JAS design, (3) understand the regulatory
concerns for a new potentially neurotoxic drug, and (4) implement the principles of ICH S11 for a hypothetical new anesthetic seeking US FDA approval. To achieve these goals, we will bring together US FDA regulators who
participated in the ICH S11 guidance and the anesthetics SLC, academic researchers who characterized the anesthetic-induced developmental neurotoxicity, and industry research organizations with expertise in designing JAS. After
the session, attendees will have a better understanding of how to implement the ICH S11 guidance for a new drug with potential developmental neurotoxicity.
Immune tolerance is defined as the active homeostasis of the immune system to prevent inflammatory responses against antigens. Loss of immune tolerance to self-antigens can lead to various pathologies that result in tissue injury
and are collectively referred to as “autoimmune diseases.” In drug development, the goal of newly emerging immune tolerance therapies is to treat autoimmune disorders by restoring the regulatory capacity of the immune system. This
approach has the promise to substantially improve upon current standards of care, with even curative potential, but poses unique challenges in biology, translation, and safety characterization. This Symposium will feature four
speakers to give perspectives on immune tolerance: the state-of-the-science behind it; clinical and nonclinical safety challenges and examples of immune tolerance; an introduction on industry perspectives; and a regulatory
perspective regarding potential nonclinical toxicology issues and challenges. Finally, all speakers will convene for a joint panel discussion and Q&A session.
Next-generation in vitro models can dramatically increase the physiological relevance of cell-based studies; however, amidst the hype, understanding the advantages and limitations of these systems can be akin to a trip down the
rabbit hole for investigative, safety, and regulatory toxicologists. While traditional nonclinical strategies have laid the foundation for much of the field of toxicology, some of these pioneering models are approaching, or have
reached, the limit of their utility. Replacing these approaches with advanced in vitro systems that incorporate the biological complexity that exists in vivo is the next big leap in furthering our understanding of the effects of
xenobiotics on human health. Next-generation in vitro models can help in lead selection and minimize attrition in the clinic due to unforeseen toxicities. Further, they can provide mechanistic data that facilitate the
identification, development, and use of biomarkers that work both in vitro and clinically. This session will examine cutting-edge in vitro models that are revolutionizing toxicology and include examples of their use to identify
new targets, decipher molecular mechanisms, and increase the efficacy and efficiency of xenobiotic toxicity testing. Speakers will present data demonstrating how human-derived 3D microtissues can be used to study
xenobiotic-induced liver, gastrointestinal, and airway toxicities and understand interindividual variability and effects on susceptible populations. In addition to presenting successful applications and translational value,
speakers will discuss the challenges, limitations, and potential drawbacks of their models to provide attendees with a fair and balanced understanding of these new approaches and their integration into toxicity testing paradigms.
The purpose of this Workshop is to provide participants with an overview of different approaches required for successfully transforming nonclinical toxicology results into a scientifically sound submission document. This session
will cover various aspects of authoring nonclinical reports, pharma/US Food and Drug Administration (US FDA) perspectives on writing regulatory documents for first-in-human clinical trials, and NDA/BLA submissions. The overall
focus will be on scientific quality of these documents and regulatory considerations for a successful submission. The first speaker will discuss key objectives of the session and will set the stage for subsequent presentations.
The second speaker will discuss key points to be considered in writing and reviewing scientifically sound, integrated nonclinical reports to effectively convey the study data to regulatory authorities. The third speaker will
discuss the overall pharma expectations and provide an overview of authoring the nonclinical package in support of first-time-in-human Ph1 submissions, including IND Module 2, investigators brochures (IB), and clinical protocols.
The third speaker will cover nonclinical aspects required at later stages of clinical development, including authoring US FDA biologics licensing applications (BLA) and similar regulatory submissions for marketing in other
geographical regions. The final speaker will present a US FDA reviewer’s perspectives on key aspects of IND/BLA submissions. This will be an advanced session for CRO and pharmaceutical attendees interested in improving their
understanding of the role of toxicologists in preparing nonclinical elements of regulatory submissions.
This session is designed and supported by the board of the Safety Pharmacology Society to update toxicologists on the latest developments within the associated field of safety pharmacology. It focuses on the increased application
and acceptance of functional endpoints within investigative and regulatory toxicology studies, but also the ongoing discussions into potential changes to regulatory guidelines in the future. Assessments of acute cardiovascular,
neurofunctional, and respiratory systems (the ICHS7A “core battery”) are generally performed as stand-alone studies within the IND-enabling package supporting first-in-human administration. In recent years, safety pharmacologists
have increasingly collaborated with toxicologists to incorporate these functional endpoints into toxicology studies, to provide additional information following repeat administration, or often to replace the stand-alone studies
altogether. Presentations will provide information highlighting current industry practices for including cardiovascular and CNS (functional observational battery) endpoints into toxicology studies, along with tips for successful
collaboration and potential drawbacks to consider. Further presentations will discuss the requirement and predictivity of safety pharmacology data, preparing for proposals to review and update ICHS7A/B guidelines in the future.
These include changes to cardiovascular data following the international CIPA initiative and the value of respiratory data, given the lack of translation to human clinical data. These topics will be presented for audience
discussion in conjunction with regulatory feedback.
In silico toxicology is poised to play an increasingly important role in hazard identification and characterization, including assessments of impurities, extractables, and leachables, as well as worker safety and transportation.
This session will outline the major drivers for such adoption as well as current obstacles in improving the quality of such assessments. One of the major impediments is the lack of commonly agreed protocols for performing an in
silico assessment. To this end, an international consortium was established to create in silico toxicology protocols for major toxicological endpoints, similar to test guidelines routinely used in the application of in vitro or in vivo methods. This session will outline progress toward creating such protocols as well challenges in the application of in silico methods for complex chronic endpoints. The session will include case studies describing how these
protocols are already being practically applied and the potential for future use cases.
Pharmaceutical labeling is used primarily for communicating important information to allow for the safe and effective use of approved products in patients for various indications. Although intended primarily for health care
providers, the product label is used by a variety of audiences, including patients. Thus, nonclinical data should be conveyed in a clinically meaningful way to ensure that its relevance to the intended patient population is
communicated clearly. The US Food and Drug Administration regulations, including the Physician Labeling Rule (PLR) and the Pregnancy and Lactation Labeling Rule (PLLR), and guidance provide direction on the requirements for the
content and format of labeling for human prescription drug and biological products. This Workshop will introduce sections of the label covered by the PLR and PLLR, describe relevant guidance, and focus on presenting data in
clear language, with an emphasis on relevance to the prescribing health care professional and patient. Although all sections of the label that may contain (or reference) nonclinical data will be covered, the presentations and
discussion will focus on communicating risk in specific populations (Sections 8.1, 8.2, 8.3, 8.4) as well as communicating nonclinical toxicology data (carcinogenicity, genotoxicity, fertility, and other animal toxicology and/or
pharmacology) (Section 13) in labeling. The session will describe what, where, and how nonclinical information should be included in pharmaceutical product labeling and will conclude with a small group breakout session that will
discuss practical aspects of writing an informative label as well as considerations for best practices in labeling.
This Workshop is presented by the ACT Early Career Professional Outreach (ECPO) Subcommittee. As we advance through our career, we benefit from building professional relationships and receiving mentoring from our peers, senior
colleagues, managers, and friends, inside and outside our organization. This interactive Workshop will discuss the why, when, and how of developing and building such relationships, with anecdotal case studies and examples shared
by early and advanced career professionals. The goal of this Workshop is to provide tools for attendees to build, develop, and maintain effective and successful mentoring relationships as a toxicologist. The first part of the
Workshop will consist of talks by an experienced manager at pharmaceutical company, a career mentor, and an early career mentee sharing the highlights of a successful professional and mentoring relationship. The roles of each
relationship and avenues to maximize the helpful feedback obtained from a good mentor will be outlined. The second half will consist of three short presentations highlighting challenging case studies where a mentor’s advice has
been instrumental: how a mentor can help evaluate and influence career choices, how to effectivity talk with a manager about professional and personal goals, and how to seek a mentor outside your organization. The talks will be
followed by a panel discussion at the end during which all speakers will offer on-site mentoring. Audience participation is strongly encouraged.
A challenge to all toxicologists is working out what study findings are actually adverse or nonadverse for humans, resulting in generation of a toxicology study No-Observed-Adverse-Effect-Level (NOAEL). This session will discuss
why setting a NOAEL is not always straightforward, not only for small molecules but also for biopharmaceuticals. It will introduce examples of study findings considered adverse and nonadverse and how the former can halt or delay
clinical development depending on a number of factors. Case studies will be presented, as will presentations on how US Food and Drug Administration and EU regulators assess adverse and nonadverse findings to allow clinical
studies to commence and drug marketing approvals to succeed, along with the process that allows dialogue with the regulators. Discussion will take place around how decisions defining adverse findings and the NOAEL in final study
reports can occur and who should be involved in the process.
The CDISC Standard for Exchange of Nonclinical Data (SEND) provides a data model for nonclinical datasets supporting regulatory submissions, standardized data exchange between organizations, and enhanced data
visualization/analytics. SEND dataset submissions are required by the US Food and Drug Adminiatration (US FDA) for general toxicity and carcinogenicity studies initiated after December 17, 2016 (for NDAs/BLAs/ANDAs), or December
17, 2017 (for INDs). Between the publication of the SEND Implementation Guide (IG) version 3.0 in 2011 and the first SEND submission requirement in December 2016, considerable SEND experience was gained through the collaborative
work of larger pharmaceutical companies, contract research organizations, the US FDA, and SEND technology vendors. Currently, implementation is particularly challenging at smaller companies, even as strategies continue to extend
and mature across the pharma landscape. While uncertainties around SEND requirements and interpretation of guidance documents continue to create implementation challenges, sponsors and sponsor partners have worked
collaboratively to generate best practices that enhance processes of managing the creation, sharing, storage, and submission of SEND datasets. Additionally, these organizations continue to keep current with new data standards
guidance, vendor tools, and IGs for SEND. Importantly, as with the US FDA, sponsors and sponsor partners are leveraging SEND by implementing new data warehouse strategies for efficient SEND dataset analyses per study or across
targets that aspire to enable smarter drug development through more robust data evaluation. In this Workshop, representatives from small and large pharmaceutical companies and the US FDA will provide perspectives on experiences
encompassing SEND implementation challenges, management, and enhanced utilization (visualization/analyses) of SEND data.