Monday, November 7
9:00 AM–12:00 Noon
21st Century Approaches to Assessing Food Ingredient Safety
Consumers spend 25 cents of every consumer dollar on products regulated by the FDA. Of that amount, approximately 75% is spent on foods. The mission of CFSAN includes promoting and protecting the public’s health by insuring that the nation’s food supply is safe. This workshop will provide a number of recent initiatives aimed at food safety from the perspective of determining the safety of food ingredients. These initiatives will include the incorporation of computational approaches, efforts to modernize the approach to make GRAS determinations, and the integration of exposure modeling. These topics will be of interest to scientists engaged in safety assessment, because we are all consumers with an interest in food safety. Finally, the workshop will end with a presentation regarding the importance of effective communication to increase the impact of research findings through public engagement.
Drug-Induced Changes in Vascular Hemodynamics: Clinical and Drug Development Implications
The recent conclusions from the landmark Systolic Blood Pressure Intervention Trial (SPRINT) highlight the importance that small changes in blood pressure play a role in cardiovascular (CV)-related morbidity and mortality in patients. These findings are not only important clinically, but also serve to raise awareness of the importance of evaluation of vascular hemodynamics throughout drug development. While the SPRINT study demonstrates that lowering blood pressure can have cardiovascular benefits, this symposium will explore opportunities and considerations in the role by which drug-induced changes play in vascular hemodynamics. Specifically, this symposium will focus on the effects of hemodynamic compounds on blood pressure and vascular injury as assessed via nonclinical models and translational studies. Chronic treatment risks may be informed with data from new safety pharmacology-related methods that allow more options in CV safety study designs, especially in combination with repeat-dose toxicological studies. Additionally, computational and other novel approaches, including the incorporation of biomarkers, have enhanced the ability for the field to assess coronary hemodynamics and vascular injury.
Marijuana: Medical Friend or Illicit Foe?
Marijuana is, and will remain, in the news for the foreseeable future. The use of Cannabis sativa for medical and/or recreational purposes has existed for centuries. The first reference to medical use is considered to date from the third millennium in the writing of Chinese emperor Shen Nung. Though cannabis contains more than 60 identified cannabinoid components, Δ-9-THC (tetrahydrocannabinol) is regarded as the primary ingredient responsible for the majority of the pharmacologic and psychotomimetic effects of cannabis. Evidence supporting this comes from studies in which the effects of oral synthetic THC are directly compared to cannabis extracts containing matching doses of THC. In these studies, the effects of synthetic THC and cannabis extracts are very similar, arguing that THC is the main constituent responsible for most of the widely recognized properties of cannabis. This symposium addresses issues related to “legal” medical and recreational marijuana use versus clearly illicit use of marijuana and designer synthetic cannabinoids; provides a brief history of marijuana use; provides an overview of cannabinoid pharmacology and the effects/consequences of cannabis intoxication; the public health and medical issues of medical cannabis products; current issues of designer/synthetic cannabinoids; and cutting-edge academic research addressing implications of medical marijuana on patients.
Small Compartment Toxicity:‘CN VIII’: Hearing Loss, Tinnitus, and Balance Disorders
The emphasis of this workshop is on peripheral and central auditory toxicity. There are three independent targets of toxicity within the small compartment of the ear that lead to changes in the “quality of life” and functional capacity of mid- to late-life patients. Drug-induced cytotoxicity has been linked to over 135 current medications. One of the largest contributors to hospitalizations related to fall injuries in the elderly are disorders of vestibular function linked to progressive and drug-induced toxicities. Tinnitus affects 35 to 50 million adults, representing approximately 25% of the United States population, with 12 million seeking medical care, and two to three 3 million reporting symptoms that were “severely debilitating.” This workshop will begin with two brief presentations on the anatomy and functional physiology of the outer and inner ears, as a foundation for the next two presentations. Three experts in the fields of audition, vestibular disorders, and tinnitus will present the current theories into the pathological markers of oxidative damage and the current focus of medical intervention and recovery of function. The final speaker will address the current thinking of the US FDA on the preclinical assessment for ototoxicity and the hopes for the future.
2:00 PM–5:00 PM
Application of In Vivo and Ex Vivo Multimodality Imaging in Toxicology and Toxicologic Pathology
Imaging methods are established tools in biomedical basic science research with applications in drug discovery, pathology, and toxicology research. Contemporary imaging tools extend the ability of the toxicologist and toxicologic pathologist to comprehensively study whole animal and tissue structure, and function in tandem with metabolism and distribution of molecules, biomarkers, metabolites, peptides, drugs, etc.; and to correlate these chemical events with conventional histology at high resolution. These imaging tools provide for noninvasively conducting longitudinal studies in the same experimental animals, for monitoring gene expression, signal transduction, and tumor growth and therapy, and give us the ability to quantitate multiple tissue lesions in three dimensions. This workshop was prepared by the International Academy of Toxicologic Pathology and will provide practical applications of multimodality imaging for toxicologists and toxicologic pathologists.
Approaches to Safety Assessment of Combination Therapeutic Agents
This workshop will highlight the basic tenets of approaches to assess the safety of therapeutic agents used in combinations, whether intentionally so developed or based on overlapping use patterns, and highlight specific case study experience in therapeutic areas such as cardiovascular disease and diabetes. While ICH M3(R2) provides basic guidance, combination toxicology (or safety pharmacology) programs are often (and appropriately) designed on a case-by-case manner based on an informed understanding of potential drug-drug interactions regarding mechanisms of action, drug disposition, and target organ characteristics. Regulatory agencies often request nonclinical combination studies, and rich conversations ensue about the specific goals for, and design of, these studies. Finally, the discussion will explore whether these nonclinical combination studies significantly inform or alter clinical practice.
Toxicology Evaluation of Drugs Administered via Uncommon Routes: Intranasal, Intraocular, Intrathecal/Intraspinal and Intra-Articular
As the need for nasal, ocular, spinal, and articular therapeutic compounds increases, toxicology assessments of these drugs play an important role in human safety. This symposium will outline the local and systemic evaluation to support safety during the development of these drugs in nonclinical models with some case studies: selecting two appropriate species for the intended route conducting nonclinical studies that closely mimic the intended use with adequate duration functional assessment, if deemed necessary; evaluation of local tissues with special histological staining procedure evaluations of systemic toxicity; and safety margin assessments based on local toxicity and systemic toxicity.
Why Do Promising Therapies Stall in Development and How Can We Move Them Forward?
The purpose of the symposium is to outline reasons that molecules fail to progress to market and the principles of risk-benefit decisions that can drive the molecule through development. Discussions will include global strategies involved to push a promising molecule to market, what to do when the molecule stalls out in its = progress to market, and options for rescuing the molecule and pushing it forward again. Innovative partnerships that bring stalled drugs back into clinical development will also be addressed, as well as a regulatory perspective on common reasons for a molecule to fail in its forward progress. Using examples from the private and public domain, discussion will center on how to repurpose a molecule, the usefulness of having a third-party advisory committee intercede with the sponsor and regulatory agency, and when more science is needed.
Tuesday, November 8
9:00 AM–12:00 Noon
Early Career Professionals' Forum: Current Topics in Applied Toxicology
The objective of this symposium is to highlight novel methodologies, or investigative topics, in toxicology presented by early career professionals. The range of topics will be quite broad and will center around pharmacology/toxicology aspects common to pharmaceutical development of small or large molecules, or specialty biologics.
FDA CDER’s Pharmacology/Toxicology Coordinating Committee and Associated Subcommittees
The FDA CDER Pharmacology/Toxicology Coordinating Committee (PTCC) is comprised of the Office of New Drugs Associate Director (OND AD) for Pharmacology and Toxicology, Office Associate Directors, and all supervisory pharmacologists and toxicologists. The PTCC is responsible for providing advice and recommendations to the OND AD on policy and guidance development, as well as other communications, to ensure high-quality regulatory reviews and to promote consistency across the Center. The PTCC also charters subcommittees (SCs) focused on the pharmacology/toxicology subdisciplines that review technical issues and monitor scientific developments in specialty areas. These SCs are comprised primarily of pharmacology/toxicology reviewers and management staff based on expertise and interest in the subject matter of the SC and may be supplemented by adjunct of other disciplines or ad hoc members from other Centers. This symposium will include talks that highlight the organization and functions of the PTCC as well as discuss the role and activities of some of the active SCs including Biologics, Genetic Toxicology/Computational Toxicology, Pharmacokinetic and Toxicokinetic, Neurotoxicity Assessment, Nonclinical Safety Testing for Pediatric Drugs, and Reproductive and Developmental Toxicology.
Toxicity and Efficacy Biomarkers in Preclinical Toxicology
Toxicity and efficacy biomarkers, for use in candidate development decisions and regulatory applications, have been and will continue to be a priority of the pharmaceutical and chemical industries as well as regulatory bodies. This symposium will provide attendees with an update on the development of novel toxicity biomarkers, present strategy for implementing translational toxicity and efficacy biomarkers, and highlight considerations and challenges when developing and validating biomarker immunoassays. Topics will include identification of novel biomarkers, using microRNAs as an example, the perspective of regulatory authorities on qualification of biomarkers, successes and challenges in qualifying novel skeletal muscle biomarkers and identification and testing in a preclinical setting of efficacy biomarkers with potential applications to the clinic.
2:00 PM–5:00 PM
Clinical Holds: Regulatory and Industry Perspectives and Practical Considerations
A clinical hold is an order issued by the US FDA to the sponsor of an Investigational New Drug (IND) application to delay a proposed clinical investigation, or to suspend an ongoing investigation in the interest of patient safety. From the sponsor’s perspective, a clinical hold is a significant event in the development cycle of a drug, and is highly undesirable as it can delay or halt the progress of a program. This workshop will present the regulatory perspective on clinical holds, sharing the contextual thinking, causes and process for these orders, as well as a perspective from the sponsor’s side. Both perspectives will include high-level examples. Participants will have an opportunity to examine three case studies and determine clinical hold status and potential paths to resolve the hold issues.
Current Issues in Evolving Regulatory Systemic Toxicology Study Design and Conduct
The pivotal and usually most important gatekeeping studies for drugs (and other new molecules with human systemic exposure) entering and subsequently advancing in clinical development are repeat dose GLP systemic (general) toxicology studies performed in one or two species and ranging from 14 days to 9 months of repeat test material administration. While there have been improvements in design details over the past 60 years, incorporation of new technologies and lessons learned have been limited and slow. This symposium will review design changes to-date, and then specific proposals for improvement (Use of Recovery Groups–Or Not, Changes in Blood Sampling Methods to Reduce Animal Usage in Rodent Studies, Multihousing of Animals to Provide Social Enrichment, Incorporation of New Biomarkers in Clinical Pathology, and Formulation, Route and Regimen for Nonclinical Studies for Improved Success in the Clinic) presented by individual experts. An open discussion of potential improvements in studies will follow. Practicing toxicologists and all those responsible for the planning, design, execution and analysis of nonclinical safety evaluation programs for drugs and other regulated products, or for ensuring the safety of such products, would benefit from this symposium.
Immune Complex Disease in the Preclinical Evaluation of Protein Therapeutics
Protein biotherapeutics are often human or humanized to maximize their therapeutic effect and minimize the potential immunogenicity in the clinic. With this structure, they are also inherently foreign to the animal species used for preclinical safety evaluation. In preclinical studies, an immune response against such a test article can lead to the formation of immune complexes (ICs), lattice-like networks of multimeric antibody/antigen complexes, which may also contain complement fragments. Depending on numerous factors, including size, these complexes can be benignly cleared from circulation or can cause severe clinical and anatomic pathologies. Such toxicities, unrelated to the pharmacologic activity of the therapeutic, can confound the interpretation of the safety of the molecule. This symposium will focus on describing the nature of ICs and IC formation, the hematologic and anatomic pathophysiologies associated with IC disease, and in-life and postmortem diagnostic approaches. Numerous case examples will be presented and the relevance to humans will be addressed.
Wednesday, November 9
9:00 AM–12:00 Noon
EEG Assessments in Nonclinical Drug Development: Strategic and Practical Considerations
Electroencephalography (EEG) investigations are required for a number of nonclinical drug safety studies. EEG may be applied to all stages of drug development from discovery to late-stage GLP toxicology studies, based on specific considerations and program requirements. Seizure liability, sleep disturbance/drug-induced insomnia, and stimulatory/sedative effects are only a few potential justifications for the addition of EEG in rodent or nonrodent neurotoxicology studies. This symposium will discuss major considerations related to EEG investigations with a pragmatic approach focused on drug development. Study design, species selection, interpretation of adverse events, regulatory considerations, safety margins and translation from animals to humans will be presented as they relate to nonclinical central nervous system testing. Drug safety evaluation based on EEG is a unique and complex task that requires integration and interpretation of a wide range of data. This symposium will aim to provide key concepts in the planning, execution, and interpretation of nonclinical EEG studies.
Current Topics in Neurodegenerative Disease Pathogenesis and Drug Development
This symposium will present an array of current topics in neurodegenerative disease pathogenesis and drug development with an emphasis on Parkinson's Disease (PD), beginning with a perspective from veterinary pathologist David Malarkey, a person living well with PD. The subsequent scientific presentations will include current concepts in PD pathogenesis (protein misfolding and the spreading hypothesis), development challenges associated with anti-amyloid antibody therapeutics (amyloid related imaging abnormalities; ARIA-E, ARIA-H), neurobiology of traumatic brain injury, and approaches to target and therapeutic modality selection in Parkinson's Disease research.
Long-Term Effects following Acute Exposure to Organophosphorous Nerve Agents
The use of the Organophosphorous Nerve Agent (OPNA) sarin in the Middle East raises concerns about the sequelae of OPNA poisoning. Although the acute lethal effects of OPNAs are well described, the nonlethal short- and long-term effects remain unclear. Immediately after exposure, OPNA intoxication leads to a progression from miosis to seizures and status epilepticus, and then to death due to respiratory failure. If one survives this cholinergic crisis, there is usually damage to the brain. Beyond these neuropathological effects, there are reports of long-term effects that may be pathophysiological and/or behavioral. These effects may be observed months to years after the initial acute exposure. The goal of this symposium is to discuss the nonlethal shortand long-term effects from acute OPNA exposure in humans and animals. Topics to be discussed include the neuropathological changes induced by OPNAs and the short- and long-term functional deficits associated with the acute exposures. The symposium will conclude with a summary of a systematic review of the evidence for long-term effects of sarin in humans and animals, and how the results can inform the need for medical countermeasures, and how animal models can be refined for the therapeutic discovery and development.
Wednesday, November 9
1:30 PM–4:30 PM