Symposia and Workshop sessions are three hours each and are held Monday through Wednesday. Mini-Symposia are 75 minutes each and will take place on Wednesday afternoon.
Chairpersons: Thomas Hudzik, GlaxoSmithKline, Collegeville, PA and Peyton Myers, Center for Drug Evaluation and Research, US FDA, Silver Spring, MD
The impact of opioid addiction has now been felt by the majority of households in the US. Opioid use underlies a high level of unnecessary mortality, and the number of deaths has been increasing each year since 1999, topping 65,000 in 2016. While addictive behavior is one of most well-studied areas in contemporary neuroscience, application of this knowledge must advance more quickly in order to stem the rise in mortality. This symposium examines this public health crisis from the perspectives of etiology, toxicology, neuroscience, enforcement, and experimental medicine.
Chairpersons: Sven Korte, Covance Preclinical Services GmbH, Münster, Germany and Xiaoyou Ying, Sanofi-Aventis US, Framingham, MA
In vivo imaging (IVI) technologies have become powerful tools in nonclinical drug development. They can aid investigating distribution of labeled compounds throughout the body, and they can help monitoring pathologies in animals selected for pharmacology or toxicity studies. This symposium will give an overview of the latest IVI technologies and their applications, including magnetic resonance imaging (MRI), computed tomography, single photon emission computed tomography, Dual-energy x-ray absorptiometry, optical coherence tomography, immunofluorescence optical imaging, and radiography. These technologies are applied in a broad range of studies that support drug development from early discovery to regulatory toxicology. A panel of leading experts from the pharmaceutical industry, academia, and US FDA will outline numerous case examples on how such technologies have been used in preclinical drug development, supporting pharmacology and toxicology. In addition animal models will be presented, such as brain injury, disease progression and for the efficacy of new therapeutics, which are followed with MRI. Last but not least, nonsystemic MRI-guided administrations in nonhuman primates will be highlighted. This symposium addresses to toxicologists, study monitors, pathologists, and regulators and will support them to successfully implement IVI technologies in preclinical studies, leading to improved study designs according to the 3 Rs principles.
Chairpersons: James Smith, Boehringer Ingelheim Pharmaceutical Inc., Ridgefield, CT and Shashi Ramaiah, Pfizer Inc., Cambridge, MA
Drug-induced toxicities to the gastrointestinal tract (GIT) encompass a multitude of diverse pathologies, reflecting the heterogeneity in physiological function in this system. Clinically, adverse drug reactions include: erosions to the upper GIT from nonsteroidal anti-inflammatory drugs (NSAIDs) and dose-limiting lower GIT safety concerns such as diarrhea or colitis due to chemotherapeutics and immuno-oncology therapies. This symposium will provide a forum for updates and discussion on the following topics: 1) quantitative, accessible GIT injury biomarkers and morphometric measurements to add mechanistic understanding to standard in life measurements and histopathology; and 2) systems toxicology approaches, to inform dosing and increase the confidence in the predictivity of preclinical studies.
Chairpersons: Kate Lane, Translate Bio, Lexington, MA and Patricia Ryan, Medimmune Inc., Gaithersburg, MD
Nucleic acid therapeutics offer one of the most potent strategies for the treatment of genetic disorders caused by single or multiple gene defects. These agents can achieve a high level of therapeutic success due to selective and targeted up regulation (by DNA) or down regulation (by antisense/antigene oligonucleotides). This update symposium will attempt to bring the ACT attendees some broad perspective on the field, followed by some recent approaches to tackle potential nonclinical issues. The symposium will start with a brief introduction of the salient features of the main nucleotide therapies. The next presentation will focus on mRNA therapies, and describe challenges and approaches for nonclinical safety testing. Following on there will be presentations detailing the potential immune stimulation challenges associated with certain nucleic acid therapies and in vitro methods to tackle them. The specific challenges associated with packaging/delivering some nucleic acid modalities will be discussed, highlighting new developments in nanoparticles/liposomes. Finally, efforts during the drug discovery stage to understand and derisk known toxicities associated with some siRNA delivery platforms will be described.
Chairpersons: William J. Brock, Brock Scientific Consulting, Montgomery Village, MD and Beatrice Setnick, INC Research, Raleigh, NC
Prescription opioid abuse continues to be an increasing North American concern and is associated with significant morbidity and mortality, including associated disease modalities. Risk mitigation strategies and abuse-deterrent formulations (ADF) are some targeted strategies to address the prescription opioid abuse epidemic. Abuse of opioid drug products is difficult to manage, requiring efforts on the part of all stakeholders. The US FDA guidance on abuses deterrent opioids describes the categories of evidence required to demonstrate the effectiveness of an ADF including laboratory, pharmacokinetic, human abuse potential, and epidemiological evaluations. Innovators continue to examine different approaches to developing ADFs, utilizing various formulation technologies and excipients to mitigate the inappropriate use these medications. The ADF program needs to examine the effectiveness of the formulation and the potential toxicity of added excipients intended to deter abuse. The recent case of Opana ER market withdrawal highlights the need to consider the safety of ADF formulations by the intended route of administration but also anticipate the safety profile by unintended routes of administration. This symposium will describe the issues of prescription opioid abuse, the nonclinical and clinical evaluation of abuse deterrent formulations targeted for pain or opioid maintenance treatment, and the toxicological considerations of those drug formulations.
Chairpersons: Kathleen Funk, EPL, Inc., Sterling, VA and Maralee McVean, Preclinical Research Services, Inc., Ft. Collins, CO
A number of issues may arise during the conduct of a study which can complicate interpretation of in vitro and in vivo datasets. Speakers will discuss the implications of differing interpretations and how to avoid complicating factors.
Chairpersons: David McMillan, US Food and Drug Administration, Silver Spring, MD and Drew Badger, Amgen, Inc., Thousand Oaks, CA
This is a joint workshop between ACT’s Early Career Professional Outreach committee and the American Board of Toxicology. The first half will feature a member of the American Board of Toxicology, who will discuss the history of the ABT, the value of DABT certification, information about the revised examination, test strategies/resources, and will answer questions from the audience. Other professional certifications (e.g., ATS, SPS, ERT, etc.) will be mentioned as part of this presentation. The second half will include four presentations from early career professionals in different fields: industry, government, consulting and CRO. Each speaker will briefly discuss their career trajectories thus far, networking successes, and the skills sets and experiences that have proven most beneficial to them. After each speaker has presented, all four will be brought to the stage for a panel discussion. Audience participation is strongly encouraged.
Chairpersons: Kathleen Funk, EPL, Inc., Sterling, VA and Maralee McVean, Preclinical Research Services, Inc., Ft. Collins, CO
Combination products are defined as devices which contain a drug or biologic (dependent on chemical or biological action action, e.g., drug-coated balloon, drug-coated stent, hormone-coated delivery system) or devices which are specifically designed to deploy a drug or biologic. These complicated products generally necessitate consultation with the appropriate regulatory agencies for categorization and determination of applicable development programs. The Office of Combination Products (OCP) works with other US FDA centers, CDER, CBER and CDRH, to establish and clarify regulatory approaches for these combination products and determine requests for designation and the appropriate development/toxicology pathway(s). This symposium will provide an overview of different types of combination products and challenges in defining the regulatory path forward and should be of value to anyone in the pharmaceutical and/or device development arena.
Chairpersons: Bert Haenen, Janssen Research and Development, Beerse, Antwerp, Belgium and Simon Authier, CitoxLab, Laval, QC, Canada
Adverse events associated with drug-induced CNS toxicity continue to be a leading cause of drug attrition, both in late preclinical drug development and during clinical evaluation. Monitoring of EEG signals in nonclinical species is of pivotal importance to assess the seizurogenic potential of a candidate drug. However, the use of EEG in toxicology remains one of the most challenging endpoints both from a study design and interpretation perspective. This workshop presents the second chapter on EEG assessments building on the foundations that were established at the 2016 ACT Annual Meeting. The workshop will present EEG related themes such as early derisking strategies, blood brain barrier permeability considerations and PK, CSF, brain tissue modelling, drug induced seizure demographics, inclusion of EEG in GLP repeated dose toxicology studies, and target engagement estimation using qEEG. Then, a reflection on the translational potential of EEG will be undertaken with considerations for neuroanatomical differences as well as the limitations of this methodology. Lastly, a regulatory perspective on convulsions in nonclinical studies will be provided from an US FDA standpoint.
Chairpersons: Ian Kimber, University of Manchester, Manchester, United Kingdom and Thomas Monticello, Amgen, Thousand Oaks, CA
The pharmaceutical and biotechnology industries continually review requirements and justification of the relevance of current testing strategies. Consortia that critically evaluate data and processes seek to promote best practices that may identify opportunities in the drug development process to apply the 3Rs (replacement, refinement, or reduction). This can result in the adoption of new or different approaches which may provide more predictive data and more efficient ways of working. Various industry consortia are currently discussing and reviewing data on a range of topics within regulatory toxicology programs. As each consortium is considering a distinct question, individual outputs and recommendations could be perceived to be conflicting. However, a complementary theme is embraced by all the consortia: exploring the most appropriate use of animals for the safety assessment of new medicinal products. This symposium will bring together scientists and regulators involved in four of the active consortia: IQ-DruSafe, EFPIA, Biosafe, and the NC3Rs, to discuss if separate recommendations can be aligned into useable approaches for future toxicology testing strategies, highlighting justification for the appropriate use of different species and opportunities for reductions in their use, without compromising patient safety.
Chairpersons: Wally Hayes, Harvard University, Temple Terrace, FL and William Mattes, National Center for Toxicological Research, US FDA, Jefferson, AR
The “Reproducibility Project: Cancer Biology” not only stirred debate in the biomedical sciences but it raised this issue to a level of immediate concern. The project synopsis put together by Nosek and Errington described what replication means, how to judge whether “same” (or different) results emerge in a replication experiment, and how to interpret divergent results in original vs reproducibility studies. Others have suggested that reproducibility checks destroy discovery and stall efforts to translate promising research and is, therefore, a waste of money. A similar debate erupted when a Technical Comment exchange reported on the respective reproducibility project on psychology, even though the available data were far more extensive (100 experiments instead of just 5 preliminary ones) and had a massive participation of top psychologists (270 scientists and their teams) trying to reproduce results.
Chairpersons: Melissa Rhodes, Roivant Sciences, Raleigh, NC and Krishna Allamneni, Jazz Pharmaceuticals, Palo Alto, CA
The purpose of this workshop is to openly share regulatory feedback from various portions of nonclinical safety packages. A series of 20 minute talks will be given where case examples of interesting feedback from regulators will be discussed with time for audience questions/participation following each example. Examples will include carcinogenicity study interactions with ECAC, feedback on abuse liability packages, juvenile toxicology requests, and general toxicology questions on small and large molecules. It will also include examples where waivers for certain nonclinical studies were and were not accepted. The goal of this workshop is to encourage open dialogue amongst ACT industry and health authority members on current regulatory expectations in order to get medicines to patients more efficiently and potentially reduce animal usage across the industry.
Chairpersons: Paul Roney, Biomedical Advanced Research and Development Authority, Arlington, VA and Mercedes Serabian, Center for Drug Evaluation and Research, US FDA, Silver Spring, MD
The 21st Century Cures Act defines regenerative medicine (RM) therapy as a cell therapy, therapeutic tissue engineering product, human cell and tissue product, or any combination product using such therapies or products. The US FDA draft guidance “Expedited Programs for Regenerative Medicine Therapies for Serious Conditions” (Nov. 2017) includes genetically modified cells that lead to a durable modification of cells or tissues, in this definition. This symposium will highlight the innovative approaches employed for evaluating the safety profile of cell therapy-based RM products prior to administration in a first-in-human clinical trial. The first speaker will present the CBER Office of Tissues and Advanced Therapies perspective on preclinical considerations for translational development of RM products. The subsequent presentations will provide: some background on the investigational RM product; the preclinical program conducted to characterize proof-of-principle and safety to support a reasonable benefit/risk profile; the regulatory interactions from bench-to-bedside; and lessons learned. These advanced therapy products are rapidly advancing from the basic research/discovery phase to initial testing in individuals with existing medical conditions. Thus, this symposium will provide a timely comprehensive overview that emphasizes examples of these promising products, and provide a glimpse of their attributes, challenges, and clinical promise.
Chairpersons: Charles Miller, Elanco Alternative Innovation, Greenfield, IN and Rainer Helbig, Elanco Animal Health Inc., Basel, Switzerland
Veterinary drug development shares numerous similarities to human drug development. This symposium will highlight the basic approaches to assess the safety of veterinary medicinal products giving an overview of veterinary drug development and approval processes, current thinking on evaluating food safety, translational comparative medical research linking animal disease models to human drug development, requirements and conduct of juvenile animal studies and risk analysis of concurrent animal and human drug developent.
These topics are of interest to toxicologists engaged in safety assessments originating from different fields like pharmaceutical, chemical and pesticide industries. This workshop covers a breadth of knowledge that will help toxicologists in human pharmaceuticals by providing answers to many challenges in understanding the science and art of designing some of the complicated studies commonly used across the industry.
Chairpersons: Zaher Radi, Pfizer Worldwide R&D, Drug Safety R&D, Cambridge, MA and Vishal Vaidya, Pfizer Worldwide R&D, Drug Safety R&D, Cambridge, MA
Understanding the science of kidney injury with respect to pathophysiology, mechanisms and biomarkers of nephrotoxicity, and alternative models that allow human translation of preclinical data is very critical for pharmaceutical drug development, chemical hazard risk assessment, and consumer health industries. The objective of this symposium is to provide current state, innovation and anticipated regulatory changes as it relates to kidney efficacy, and safety risk assessment. The symposium will cover basic, yet relevant renal general physiology and drug/chemical-induced pathology and case examples to illustrate recent advances in biomarkers and emerging technologies bridging the preclinical to clinical gap. Specifically, the four talks will highlight: 1) basic kidney histologic anatomy, physiology, and toxicologic pathology; 2) mechanisms of drug-induced renal toxicity and their interpretations; 3) translational biomarkers for early detection of kidney injury; and 4) application of kidney-on-a-chip microphysological system for kidney safety and regulatory assessment. The symposium is intended as an update of the current and future states to toxicologists in the pharmaceutical, and chemical industries, and regulatory agencies.
Chairpersons: Erin Hines, US Environmental Protection Agency, Research Triangle Park, NC and Peyton Myers, US Food and Drug Administration, Silver Spring, MD
Disaster preparedness and response is a complex paradigm with multiple supporting partners including industry, federal agencies, and environmental health consultants. Technical expertise in exposure science, toxicology, human and ecological risk assessment is needed during the incident response as well as post-incident. Within industry, teams that employ toxicological tools are used at all levels of preparedness and response including environmental functional teams and the safety, fire, and health team. Environmental health consultants use toxicological tools to prepare for and support natural disaster response and recovery. Preparedness models are employed to align, integrate and improve an organization‘s readiness and response obligations. Emergency response network and Incident Management Assistance team supports readiness, response and recovery activities with boots on the ground in response to natural disasters. The federal research enterprise serves an important role in disaster response. Multiple approaches that include exposure monitoring, epidemiological studies, rapid toxicology screening, and informatics tools are used to investigate public health implications of natural disasters. Federal agencies also support readiness, response, and recovery from natural disasters and work with the scope of superfund sites. Together these supporting partners all work on various facets of preparedness, readiness, response and recovery when faced with natural disasters like a hurricane.
Chairpersons: Tim McGovern, Center for Drug Evaluation and Research, US FDA; and Melissa Rhodes, Roivant Sciences, Raleigh, NC
Chairpersons: James MacGregor, Toxicology Consulting Services, Bonita Springs, FL and Kenneth Hastings, Mount Airy, MD
It is widely believed that natural and organic products are inherently safer and more healthful than those produced using synthetic chemicals and pesticides. However, plants have evolved to make their own pesticides, naturally resistant organic plants have elevated levels of these endogenous pesticides, many of the “natural antioxidants” sought by consumers have the same chemical and physiological properties as “artificial preservatives,” and, most importantly, botanical alternatives to pharmaceutical products are often adulterated and potentially dangerous. Regulation of the complex chemical constituents in botanical products is difficult scientifically, and the laws and regulations governing product safety allow sales of botanical supplements and plants bred to elevate endogenous pesticides without the safety testing required of food additives, pesticides, and pharmaceuticals. The session will address these issues, with a focus on the chemical complexity of natural products, the limitations of the current regulatory structure for assessing endogenous chemical constituents (especially the impact of regulatory burden of proof on product safety), and the issue of botanical supplements safety.
Chairpersons: Michael Leach, Pfizer Inc., Cambridge, MA and Diann Blanset, Boehringer Ingelheim, Ridgefield, CT
The selection of the dose of a new molecular entity (NME) to be administered to humans for the first time (FIH starting dose) is a critical aspect of drug development. In 2016, IQ convened a Working Group (WG) to evaluate the use of Minimal Anticipated Biological Effect Level (MABEL) in selection of the FIH starting dose. This mini symposium will review the output from this WG, beginning with how first-in-human (FIH) starting doses have been selected historically, and then review how the current MABEL thought process came about, including a discussion of the 2017 European Medicines Agency’s (EMEA) guidance on FIH and early clinical trials. This will be followed by results of a survey the IG Working Group conducted in 2017 to determine recent (2012–2017) experience by pharma companies using MABEL approaches, accompanied by several illustrative case studies. Next, a review of the various current methods for calculating MABEL will be provided. Then the recommendations of the IQ Working Group will be presented. After the presentations, there will be an interactive panel discussion where attendees will be able to discuss their experiences and present their opinions regarding the use of the MABEL approach in selecting FIH starting doses.