Topics

Symposia and Workshop sessions are three hours each and are held Monday through Wednesday.


Monday,

Session Chairs: Raluca Kubaszky, Citoxlab, a Charles River Company, Laval, QC, Canada; and Brian J. Mulhern, SciLucent, LLC, Herndon, VA

Gene and cell therapy products are making strides in drug development, demonstrated by a rapidly growing number of such products in development and the recent approvals of products such as Kymriah®, Yescarta®, and Zolgensma®. Given the advancements and growing enthusiasm for these products, this symposium is focused on discussion of the latest hot topics and developing trends in the nonclinical safety assessment of gene and cell therapies. First, a case study of a genetically-modified cell therapy product will be presented to highlight strategies for the design and execution of a nonclinical program. Next, a framework for evaluating biodistribution and safety pharmacology of CRISPR/Cas9 gene-edited products will be discussed. Third, lessons learned from the development and approval of engineered T-cell therapies will be reviewed to shed light on the safe use and toxicity management of these products. Lastly, unique preclinical studies required to support clinical development of gene and cell therapies will be discussed.


1-1
9:00 AM–9:40 AM
Preclinical Hurdles for Genetically Modified Cell Therapy Programs
Shawna Jackman, Charles River, Horsham, PA
1-2
9:40 AM–10:15 AM
Preclinical Biodistribution and Safety Pharmacology Considerations for CRISPR/Cas9 Gene-Edited Products
Jonathan Phillips, Intellia Therapeutics, Inc., Cambridge, MA
10:15 AM–10:45 AM
Break
1-3
10:45 AM–11:20 AM
Engineered T-Cell Therapies: What Have We Learned from First-Generation Efforts?
Rafael Ponce, Shape Therapeutics, Seattle, WA
1-4
11:20 AM–12:00 Noon
Preclinical Studies Supporting Clinical Development of Gene and Cell Therapies: From Pharmacodynamics to Biodistribution, Stability, and Safety
Wolfgang Walther, EPO Berlin-Buch GmbH, Buch, BE, Germany

 


1-1

Cell and gene therapy products are on the cutting edge of drug development, providing ways to deliver drugs, alter biologic/genetic processes with long-lasting effects, and/or regenerate function. They also provide unique challenges to preclinical safety programs to support first-in-human trials, including evaluating the effects of ex vivo manipulation and demonstrating biological activity of products of human origin in animal models. To successfully develop and execute a program that meets regulatory expectations, consideration of the specific cell product attributes and intended indication is mandatory. Therefore, cell therapy preclinical safety programs require customized approaches with specialized animal models and/or hybrid efficacy/safety models and sensitive biomarkers of detection for biodistribution, engraftment, and/or expression. In this presentation, a genetically modified cell therapy product will be highlighted to discuss effective strategies for the design and execution of preclinical safety studies for these cellular therapeutics.


1-2

Highly specific genome editing promises to resolve the root cause of many genetic diseases. While precise editing can influence disease outcomes, other biological consequences may result. Effects of on-target editing can vary depending on cell type. For in vivo editing approaches, distribution of editing cargo will influence which cell types are subject to editing. Subsequent distribution of the edited cells can verify durable effects in specific tissue compartments. Experience with in vivo–edited transthyretin (TTR) will be used as an illustrative example. Outcomes of biodistribution studies can help formulate safety assessments and follow-up studies to evaluate the impact of editing. Toxicology studies can also be informed by biodistribution results indicating editing in unintended cell types. Preclinical model selection may present novel challenges for properly evaluating a CRISPR/Cas9 edited product. Model selection can aid in evaluating phenotypes associated with target biology, which can also support true safety pharmacology assessments. A framework for considering biodistribution and safety pharmacology for CRISPR/Cas9 gene-edited products is proposed in this discussion.


1-3

The successful marketing approval of two CD19 CAR T-cell therapeutics has established an important new option for treating otherwise intractable cancers. These products also represent the successful convergence of molecular, genetic, and cellular engineering efforts to reshape cellular functionality. This synthetic biology evolution continues with both the extension of the current technologies to novel cell types and the expansion of novel functionality into the T cell, with the hope of broadening and deepening responses in specific cancers. This talk will review the design of engineered TCR T cells and chimeric antigen receptor (CAR) T cells, with a focus on engineering and manufacturing aspects designed to confer specific pharmacology on the T cell. Lessons learned from translational biology and correlative analyses provide insight into process-, product-, and patient-specific factors that underlie both safety and efficacy. An understanding of key class-specific toxicities is emerging, which can inform the safe use and toxicity management of these therapies.


1-4

Gene therapy for treatment of cancer diseases has grown in importance over the last decade and has entered clinical application. This is reflected by the fact that more than 60% of all gene therapy trials are aiming at treatment of cancer and that their number is still increasing worldwide. In this regard, knowledge on safety, biodistribution, and clearance of vectors for gene therapy is essential. In cancer gene therapy, viral and nonviral vectors are well-established technologies for effective introduction of the respective transgenes. Particularly, nonviral vectors are of increasing attractiveness. This is due to new developments in vector design (minicircles, miniplasmids, minimalistic vectors, etc.) to improve vector transduction and stability as well as transgene expression, and transfer technologies (e.g., physical, liposomal, lipoplex technologies), which aid gene transfer to the tumor cells. Currently, 18% of gene therapy trials employ nonviral vectors. In vivostudies with cell line–derived xenograft (CDX) and patient-derived xenograft (PDX) models, and more importantly clinical gene therapy trials, generate important data on pharmacodynamics, biodistribution, clearance, and stability of nonviral vectors, as important parameters for efficient and safe application of such vectors for future clinical applications. Such data will have an impact on design and performance of future clinical gene therapy trials to better control vector use and to improve therapeutic efficacy in patients. Cell therapies are mainly based on human stem cells, for which the loss of tumorigenicity and teratogenicity has to be shown. Tumorigenicity and teratogenicity assays will be discussed, and case studies involving cell therapy products will be presented.

Session Chairs: Michael Santostefano, Merck & Co., Inc., Needham, MA; and
Debie Hoivik, Akebia Therapeutics, Cambridge, MA

Gene therapy for treatment of cancer diseases has grown in importance over the last decade and has entered clinical application. This is reflected by the fact that more than 60% of all gene therapy trials are aiming at treatment of cancer and that their number is still increasing worldwide. In this regard, knowledge on safety, biodistribution, and clearance of vectors for gene therapy is essential. In cancer gene therapy, viral and nonviral vectors are well-established technologies for effective introduction of the respective transgenes. Particularly, nonviral vectors are of increasing attractiveness. This is due to new developments in vector design (minicircles, miniplasmids, minimalistic vectors, etc.) to improve vector transduction and stability as well as transgene expression, and transfer technologies (e.g., physical, liposomal, lipoplex technologies), which aid gene transfer to the tumor cells. Currently, 18% of gene therapy trials employ nonviral vectors. In vivostudies with cell line–derived xenograft (CDX) and patient-derived xenograft (PDX) models, and more importantly clinical gene therapy trials, generate important data on pharmacodynamics, biodistribution, clearance, and stability of nonviral vectors, as important parameters for efficient and safe application of such vectors for future clinical applications. Such data will have an impact on design and performance of future clinical gene therapy trials to better control vector use and to improve therapeutic efficacy in patients. Cell therapies are mainly based on human stem cells, for which the loss of tumorigenicity and teratogenicity has to be shown. Tumorigenicity and teratogenicity assays will be discussed, and case studies involving cell therapy products will be presented.


2-1
9:00 AM–9:25 AM
Nucleic Acid Therapies: Safety Differentiators and Regulatory Considerations for Development
Natalie Keirstead, Merck & Co., Inc., West Point, PA
2-2
9:25 AM–9:50 AM
Small Molecules Targeting the mRNA Splicing Machinery: Lessons Learned on PD and Safety from Risdiplam
Lutz Mueller, F. Hoffmann-La Roche Ltd, Basel, BS, Switzerland
2-3
9:50 AM–10:15 AM
Deep Machine Learning for Drug Candidate Assessment and Optimization in Preclinical Safety
Friedemann Schmidt, Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, HE, Germany
10:15 AM–10:45 AM
Break
2-4
10:45 AM–11:10 AM
Emerging Clinical and Investigative Image Analysis Approaches and Applications in Computer-Assisted Diagnostic Digital Pathology
R. Mark Simpson, NIH/NCI, Bethesda, MD
2-5
11:10 AM–12:00 Noon
Utility of Digital Image Analysis in Preclinical Drug Development and an Introduction to Machine Learning: Parts I and II
Famke Aeffner, Amgen Inc., South San Francisco, CA; and Vanessa Schumacher, F. Hoffmann-La Roche Ltd, Basel, BS, Switzerland

 


2-1

Decades in the making, nucleic acid–based therapeutics are now beginning to deliver on their considerable promise to become a third significant modality class, alongside small molecule and biologic classes, with applications across many therapeutics areas. Several antisense oligonucleotide (oligos) drugs have already received regulatory approval and are on the market, and the first RNAi US FDA approval was granted in 2018. In addition, numerous mRNA and CRISPR therapeutic programs have entered clinical stages of development. Despite the commonality of being nucleic acid based, the safety profiles can differ, and broad generalizations of toxicity-related findings should be carefully considered. This presentation will provide an overview of some of the preclinical safety considerations from a development and regulatory perspective, with specific focus on mechanisms of toxicity and the pharmacology and toxicity studies that are recommended for inclusion in Investigational New Drug (IND) applications. Topics to be discussed include the commonalities and differences among nucleic acid–based therapeutics; current approaches to address specific and nonspecific toxic effects in nonclinical safety studies; and nonclinical regulatory considerations from FIH to carcinogenicity studies.


2-2

RNA as a drug target offers opportunities to modulate numerous cellular processes, including those linked to the so-called undruggable protein targets. Targeting RNA with small molecules may drastically expand the toolbox to design safe and efficacious medicine for almost any disease. Currently, approved protein-targeted drugs interact with fewer than 700 gene products, and an estimated 10%–15% of proteins are thought to be disease related. Altering the natural process of pre-mRNA splicing can change the formation of splicing products and influence the level of the corresponding protein products. Risdiplam, a small molecule RNA splice modifier, has been developed to interact with the RNA/protein splicing machinery to shift RNA splicing of the survival motor neuron 2 (SMN2) gene to include exon 7 and to generate a functional protein. This is expected to be disease modifying as the SMN1 gene is mutated and dysfunctional in patients with the rare spinal muscular atrophy (SMA) disease. The journey to arrive at this clinically efficacious small molecule involved surpassing safety and selectivity hurdles, which are unique in the combination of these challenges in drug development.


2-3

Patients, product manufacturers, and regulatory authorities share a demand for deep characterization of potential health risks associated with chemical or pharmaceutical products. Over the past several years, the classical toxicity testing of substances has therefore been increasingly complemented by in vitro and in silico methods. Machine learning, particularly deep learning, has been recognized as a key technology for artificial intelligence applications and digitalization. We will describe a deep learning (DL) framework implemented and broadly validated in support of drug research projects. Typical applications are the early identification of drug liabilities and contribution to understanding of liabilities, such as safety pharmacology, hepatobiliary metabolic toxicity, off-target mediated clastogenicity, and preclinical photo-safety. In our experience, DL often outperforms benchmark methods. Particularly, “Multitask”-DNNs can be tweaked to describe multiple endpoints simultaneously in a single framework, further improving the performance of individual models. Apparently this approach capitalizes on hidden trends or correlation even between orthogonal ADME-toxicology assays or endpoints. This feature can be particularly rewarding when working with small toxicology datasets. Our models are managed and deployed in the Google TensorFlow environment, which also enables broad application to novel research compounds.


2-4

Digital computational pathology, a high-velocity, rapidly progressing field disrupting classical diagnostics, has significant ramifications for clinical diagnosis and drug safety assessment. Whole-slide image (WSI)–based digital pathology systems (DPS) are basically composed of commercially available technology that enables a traditionally prepared pathology tissue section mounted on a glass slide to be optically scanned through digital image capture. This permits a user to then pan, magnify, and view the slide image from a database on a digital display monitor, analogous to conventional microscopy. Capabilities permit traditional pathology assessments to be accomplished using readily recalled image data from related studies for side-by-side comparisons. Additionally, remote telepathology consultation and image annotation can be executed in real time with colleagues having network access at other company sites. DPS are forecast to grow at a compound annual rate of 12.1% from 2016 to 2021. Drivers include rising cancer prevalence and increasing demand for telepathology consultations, as well as utilization for drug discovery and companion diagnostics. In addition to database organization and retrieval of histopathology images, the greatest impacts are anticipated to be due to image analysis and pathology informatics now merging into pharmaceutical research, computer-assisted clinical diagnostics, and education. While regulatory policy continues to prescribe conventional microscopy for traditional assessment of test article compound–exposed tissues from in vivo preclinical studies, this fact is likely to be impacted in the future, as examination of WSI moves further into the realm of patient primary clinical diagnosis. Notwithstanding current regulatory policy, discovery and nonregulatory studies benefit from DPS capacity to enable greater objectivity through more reproducible, quantitative computational data that can be generated from digitized images. Furthermore, there is a dynamic spectrum of data management and analysis capabilities for WSI providing the potential for image analysis automation and artificial intelligence applications in computational image data development that move beyond visual inspection of tissue alone. The objective of the presentation will be to indicate how WSI analysis technology is being validated for clinical and preclinical diagnosis, using example approaches and data that can be generated to inform discovery science.


2-5

Digital pathology and image analysis not only have impacted diagnostic pathology and academic research but also are commonly utilized in drug development research. This encompasses aspects such as target expression analysis via immunohistochemistry in human and animal tissues, analysis of early efficacy studies and toxicology studies, and digital pathology in the peer-review process. Most recent advances in this field have been driven by the application of machine learning and deep learning. These fields within artificial intelligence (AI) have been demonstrated to be powerful tools when it comes to histopathology. We will give an overview of cases where AI-powered tools can be useful in driving timely decision-making by generating robust and reproducible data and improving workflow efficiency. Using these examples, we will outline important points to consider regarding implementation of digital pathology, including aspects of collaboration, slide evaluation, image analysis, and AI. The presentation will be divided in two parts. Part I will focus on introduction of the topic, basic concepts, and the current state of digital peer review. Part II will focus on examples of machine learning tools and their use cases in pathology.

Session Chairs: Armaghan Emami, US FDA/CDER, Silver Spring, MD; and
Denis Roy, SciLucent, LLC, Herndon, VA

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 Ingredients 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 generally recognized as safe (GRAS) designations commonly submitted to support the safety of excipients contained in Investigational New Drug products. This Workshop will also present industry and US FDA/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.


3-1
9:00 AM–9:30 AM
US FDA Regulatory Requirements for Safety Evaluation of Excipients
R. Daniel Mellon, US FDA/CDER, Silver Spring, MD
3-2
9:30 AM–9:55 AM
Common Challenges and Pitfalls in Excipient Safety Evaluation: An Industry Perspective
Denis Roy, SciLucent, LLC, Herndon, VA
3-3
9:55 AM–10:15 AM
Case Studies (1): “Real-Life” Safety Evaluation of New Excipients in Dermal Patch (Topical Delivery System) Formulations
Armaghan Emami, US FDA/CDER, Silver Spring, MD
10:15 AM–10:45 AM
Break
3-4
10:45 AM–11:15 AM
History of Safety Assessments for Flavoring Ingredients in Foods
Timothy Adams, US FDA/CFSAN, College Park, MD
3-5
11:15 AM–11:40 AM
Excipients and Special Populations: Points to Consider—An Industry Perspective
Mitchell Friedman, Takeda Pharmaceuticals, San Diego, CA
3-6
11:40 AM–12:00 Noon
Case Studies (2): Safety Evaluation of Excipients, Including Flavoring Agents, Intended for Pediatric Patients
Jay Chang, US FDA/CDER, Silver Spring, MD

 


3-1

This introductory presentation will provide an overview of the regulatory expectations for drug product excipient safety assessment, including a discussion of the existing guidance document recommendations, limitations of the CDER IID and GRAS designations, and challenges faced by regulators when sponsors propose the use of new or novel excipients. This presentation will discuss the regulatory considerations in the qualification requirements for “new” excipients as defined by the existing guidance documents. The presentation will illustrate these challenges by drawing upon examples of challenges faced by both the Agency and sponsors of drug products during development, including reliance on the CDER Inactive Ingredients Database, GRAS designations, and attempt to leverage data in Drug Master Files (DMFs).


3-2

This presentation will provide an industry perspective on the challenges of meeting regulatory agency expectations to support the use of excipients in therapeutic products. The key aspects of excipient safety considerations and requirements will be integrated with real-life examples of development challenges, including novel excipients, reformulations, leveraging GRAS-listed excipients, use of novel or known excipients in delivery systems, and/or use in special routes of administration. Common mistakes/pitfalls companies encounter in leveraging safety information on excipients, including the use of regulatory precedents (e.g., approved products), literature information, and/or dietary/food safety databases (acceptable daily intakes [ADI], permissible daily exposures [PDE], and GRAS), will also be presented, along with practical approaches to avoid product development delays or regulatory issues.


3-3

As the use of dermal patches as a drug delivery system increases, toxicology assessments of drugs administered via this route play an important role in evaluating the potential local adverse effects to patients. This presentation provides a practical illustration of the regulatory requirements associated with development of drugs intended for this route and case studies that illustrate associated challenges as well as approaches to addressing complex scenarios when qualifying the safety of excipients. The presentation will also include a discussion on how to evaluate safety margins based on local and systemic toxicity of excipients.


3-4

Since 1960, the Flavor and Extract Manufacturers Association (FEMA) has supported an independent, continuous program of safety evaluation of flavoring substances. Under a US FDA contract, FEMA compiled safety data on all existing flavoring substances and organized these data into 69 monographs on congeneric groups exhibiting similar biochemical and toxicologic properties. In 1995, US FDA proposed a novel global flavor safety evaluation program to the Joint FAO/WHO Expert Committee on Food Additives (JECFA), which subsequently adopted the procedure in 1996. Flavors were first classified according to one of three classes of relative toxicity using the Cramer et al. (1978) Decision Tree (CDT). The intake of a substance is compared with the Threshold of Toxicological Concern (TTC) determined for its CDT class. If intake is below the TTC, a substance is concluded to be safe; if above the TTC, the substance is evaluated based on its data taken in the context of data for the congeneric group. To date, approximately 3,000 substances have been successfully evaluated and added to a global positive list of flavoring agents. An updated, expanded version of the CDT and new TTC values will provide an additional tool in safety evaluation of all chemical substances with low-exposure scenarios.


3-5

NMEs often behave differently in different populations, but what about excipients? This talk will focus on some of the considerations that should go into drug product design where special populations are involved. Pediatric and geriatric patients will be discussed, as well as other populations that may be adversely affected by excipients such as alcohols, DMSO, cyclodextrins, and propylene glycols. We’ll also delve into different routes of administration and how excipient use can and should be changed to accommodate these special use situations.


3-6

Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new active ingredients (which include new salts and new fixed combinations), new indications, new dosage forms, new dosing regimens, or new routes of administration are required to contain an assessment of the safety and effectiveness of the product for the claimed indication(s) in pediatric patients unless this requirement is waived, deferred, or inapplicable. Under the Food and Drug Administration Safety and Innovation Act (FDASIA), a pediatric study plan (PSP) must be submitted within 60 days of an End-of-Phase-2 (EOP2) meeting that outlines the pediatric studies planned or a request for a deferral, partial waiver, or waiver of studies. In addition, the PSP should specifically provide a justification for why nonclinical juvenile animal studies are or are not needed to support the pediatric drug development program, and this should include an assessment of the drug product excipients. This presentation will discuss the regulatory expectations for the nonclinical information needed to justify the safety of excipients intended for pediatric patients and provide examples of appropriate strategies to test these compounds, including flavoring agents, in juvenile animal studies to support dosing in this patient population.

Session Chairs: Vincent Murphy, STILLMEADOW, Inc., Sugar Land, TX; and
Mellessa M. Miller, University of Memphis, Bartlett, TN

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 be presented.


4-1
9:00 AM–9:25 AM
Lead (Pb) Exposure and Associated Adverse Health Outcomes during the Flint, Michigan, Water Crisis: Quantifying the “Unknown”
Siddhartha Roy, Virginia Polytechnic Institute and State University, Blacksburg, VA
4-2
9:25 AM–9:50 AM
The Impact of the Flint Water Crisis on Fertility
David Slusky, University of Kansas, Lawrence, KS
4-3
9:50 AM–10:15 AM
PBPK Modeling Contaminants of Concern in Drinking Water
Elaina M. Kenyon, US EPA/ORD/NHEERL, Research Triangle Park, NC
10:15 AM–10:45 AM
Break
4-4
10:45 AM–11:10 AM
Impact of PCB Contamination in Fox River Using Rodent Model Linking the Human Implications
Mellessa M. Miller, University of Memphis, Bartlett, TN
4-5
11:10 AM–11:40 AM
Reconstructing VOC-Contaminated Drinking Water Concentrations for Epidemiological Studies at US Marine Corps Base Camp Lejeune, North Carolina
Morris L. Maslia, M. L. Maslia Consulting Engineer, Peachtree Corners, GA
11:40 AM–12:00 Noon
Panel Discussion

 


4-1

Ever since a citizen science collaboration between Flint, Michigan, residents and the Virginia Polytechnic Institute and State University (Virginia Tech) research team exposed citywide water lead contamination in August 2015, there has been widespread concern regarding consumer exposure to lead during the Flint Water Crisis (FWC). The FWC was triggered when the City of Flint switched its water supply from Lake Huron to the Flint River in April 2014 without implementing federally mandated corrosion control treatment, causing a spike in lead levels in Flint’s tap water. It is acknowledged that water lead sampling approaches used violated federal law, rendering the available official data useless. The nearly complete lack of data on lead levels in Flint’s tap water and associated uncertainties with human exposure from April 2014 to August 2015 have ultimately led to intense speculation, proxy research, and controversy. Proxy research using blood lead measurements by Flint pediatricians, CDC, and others has tied the source water switch to a doubling of the percentage of children less than six years old with elevated blood lead (EBL; >= 5ug/dL) among other illnesses and deaths, in the now internationally acknowledged case of environmental injustice. Depending on the news source, one may gather that all Flint’s children were “poisoned” or that the persistent spotlight on FWC was tantamount to “toxicohistrionics.” Understanding what occurred during the FWC, therefore, remains of great scientific, social, political, and legal interest. This presentation will highlight a novel approach that utilizes routine monthly lead in sewage sludge (or biosolids) monitoring data to examine lead release to sewage via potable water. We successfully link lead in biosolids to water lead levels pre-, during, and post-FWC, which is consistent with the changes in children’s blood lead. The analyses confirmed expectations that other lead sources (i.e., paint, dust) were probably major contributors to blood lead at times other than summer 2014, even though higher lead in water persisted through at least October 2015, when public health interventions, including provisions for bottled water and lead filters, were implemented. Furthermore, we use an age-specific biokinetic model to mimic low, typical, and extreme lead exposure scenarios seen pre-, during, and post-FWC to estimate adverse health outcomes in young children and pregnant women. Finally, we use data and findings from historical events like the USA Today building miscarriage cluster (1987–1989) and Washington, DC, lead in drinking water crisis (2001–2004) to place the FWC in broader historical and public health context.


4-2

Flint, Michigan, switched its public water source in April 2014, increasing exposure to lead and other contaminants. We compared the change in the fertility rate and in health at birth in Flint before and after the water switch to the changes in other cities in Michigan. We found Flint fertility rates decreased by 12% and overall health at birth decreased. This effect on health at birth is a function of two countervailing mechanisms: negative selection of less healthy embryos and fetuses not surviving (raising the average health of survivors) and those that survived being scarred (decreasing average health). We untangle this and find a net of selection scarring effect of 5.4% decrease in birth weight. Due to long-term effects of in utero exposure, these effects are likely lower bounds on the overall effects of this exposure.


4-3

Physiologically based pharmacokinetic (PBPK) models are a well-accepted tool used by regulatory agencies for multiple risk assessment applications. These applications include exposure route extrapolation, exposure scenario extrapolation, and cross-species extrapolation. All of these extrapolation areas are key to performing credible, scientifically sound human health risk assessment, and frequently, all are performed in the process of developing health-protective exposure limits for pollutants in multiple media. In this talk, the utility of PBPK modeling will be illustrated using bromodichloromethane, a drinking water disinfection byproduct, as a case study. This model has multiple risk analysis applications, including multiroute exposure assessment, prediction of toxicity based on internal dose to target tissues, risk analysis for potentially susceptible subpopulations, and prediction of the effect(s) of changes in disinfection scenarios on tissue dosimetry and toxicity.


4-4

The Fox River in northern Wisconsin has accumulated a number of toxins due to waste disposal into the river for over 100 years. This buildup of toxic waste included arsenic, lead, mercury, and polychlorinated biphenyls (PCBs). However, the predominant contaminant in the water that posed the most threat to humans and the ecosystem was found to be PCBs. PCBs biomagnify as they move up the aquatic food chain as larger organisms consume PCB-contaminated food sources, and eventually, this includes humans who ate contaminated fish. Over time, this adversely affected the wildlife and ultimately impacted the human population that lived along the Fox River. Additionally, PCBs are very lipophilic and are stored in fatty tissue, resulting in their bioaccumulation. This fatty tissue accumulation allows for mammals to pass PCBs onto their young in utero and during lactation. This can affect the next generation, especially during critical windows of development that can have lasting implications into adulthood. Clinical studies and research using a developmental PCB-exposure model in rodents will connect the dots of the Fox River contamination and its human impact.


4-5

A US government health agency, the Agency for Toxic Substances and Disease Registry (ATSDR), conducted five epidemiological studies to determine whether volatile organic compound (VOC)–contaminated drinking water exposures at US Marine Corps Base Camp Lejeune, North Carolina, were associated with increased health risks to children and adults. These health studies required information, data, and knowledge of contaminant concentrations in drinking water, at monthly intervals, delivered to family housing, barracks, and other facilities within study areas. Because concentration data were limited or unavailable during much of the contamination time frame (1950s–1985), the historical reconstruction process was used to quantify estimates of monthly mean contaminant-specific concentrations. Examples of results show reconstructed (simulated) tetrachloroethylene (PCE) concentrations reached a maximum monthly average value of 183 micrograms per liter (µg/L) compared with a one-time maximum measured value of 215 µg/L and exceeded the current US EPA maximum contaminant level (MCL) of 5 µg/L during the period of November 1957 to February 1987 at the Tarawa Terrace water treatment plant (WTP). Reconstructed trichloroethylene (TCE) concentrations reached a maximum monthly average value of 783 µg/L compared with a one-time maximum measured value of 1,400 µg/L during the period from August 1953 to December 1984 at the Hadnot Point WTP (also exceeding the current US EPA TCE MCL of 5 µg/L). The epidemiological studies would not have been able to evaluate exposure-response relationships without the monthly mean drinking water concentrations produced by the historical reconstruction process. The ability to evaluate chemical-specific associations and exposure-response trends, rather than simply comparing exposed to unexposed, greatly enhanced the impact of these studies and the evidence they provided.


Session Chairs: Michael Bolt, Pfizer Inc., Cambridge, MA; and
Laurence Whiteley, Pfizer Inc., Cambridge, MA

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.


2:00 PM–2:05 PM
Introduction
Michael Bolt, Pfizer Inc., Cambridge, MA
5-1
2:05 PM–2:35 PM
Recombinant AAV-Mediated In Vivo Gene Transfer as a Platform for Drug Delivery: The Principles, Approaches, and Challenges
Guangping Gao, University of Massachusetts Medical School, Worcester, MA
5-2
2:35 PM–3:05 PM
Nonclinical Safety Evaluation of CPK850 for Treatment of RLBP1 Retinitis Pigmentosa
Timothy K. MacLachlan, Novartis, Cambridge, MA
3:05 PM–3:35 PM
Break
5-3
3:35 PM–4:05 PM
Biodistribution and Toxicity Profile of an Intrathecally Administered AAV Gene Therapy
Branka Grubor, Biogen, Cambridge, MA
5-4
4:05 PM–4:25 PM
Regulatory Expectations for Gene Therapy, Regulatory Guidelines, and Learnings from Industry Experience
Laurence Whiteley, Pfizer Inc., Cambridge, MA
5-5
4:25 PM–4:45 PM
Are the Current Gene Therapy Guidance Documents Relevant for Gene Therapy 2.0?
Joy Cavagnaro, Access BIO, L.C., Boyce, VA
4:45 PM–5:00 PM
Panel Discussion

 


5-1

Since the first proof of concept human application in the early ’90s, the field of gene therapy has now entered a stage of unprecedented revolution for clinical translation and commercialization. Gene therapy can be accomplished through in vivo and ex vivo approaches by gene replacement, for loss-of-function genetic diseases; gene silencing, for gain-of-function genetic disorders; gene editing, for any genetic diseases; and gene addition, for treating acquired diseases. The design and selection of vehicles used to deliver the genetic payload, called vectors, are key elements for successful genetic therapies. The progress of human gene therapy in the past decades has been primarily driven by vector technology platform development. Among the current variety of vectors available for in vivo gene therapy, recombinant adeno-associated virus (rAAV) stands out for its high efficiency, stability, and low immunogenicity/toxicity profiles. AAV is a common benign residential virus that can persist in primate tissues for the lifetime of the host without integration into the host genome and pathological consequences, holding great promise for multiple gene therapy applications. Several recombinant AAV-derived gene therapy drugs have been approved by European and US regulatory authorities for commercialization, including the AAV2-based drug, Luxturna (Spark Therapeutics) for treating a childhood blindness and the AAV9-based Zolgensma (AveXis) for treating spinal muscular atrophy. This presentation will provide an overview of the key principles, history, current challenges, and future directions of human gene therapy, with a focus on rAAV gene therapy, and showcase AAV capsid discovery and engineering to modulate target tissue tropism and biodistribution profiling, therapeutic gene expression cassette design and optimization, rAAV transduction biology, and examples of AAV gene therapy development—from proof of concept preclinical studies to translational studies in large animal models to first-in-human clinical evaluation.


5-2

Retinitis pigmentosa is a form of retinal degeneration usually caused by genetic mutations affecting key functional proteins. We have previously demonstrated efficacy in a mouse model of RLBP1 deficiency with a self-complementary AAV vector carrying the gene for human RLBP1 under control of a short RLBP1 promoter (CPK850). In this communication, we describe the nonclinical safety profile of this construct as well as updated efficacy data in the intended clinical formulation. In Rlbp1-/- mice dosed at a range of CPK850 levels, a minimum efficacious dose of 3x107 vg in a volume of 1 mL was observed. For safety assessment in these and Rlbp1+/+ mice, optical coherence tomography (OCT) and histopathological analysis indicated retinal thinning that appeared to be dose dependent for both Rlbp1 genotypes, with no qualitative difference noted between Rlbp1+/+ and Rlbp1-/- mice. In a nonhuman primate study, RLBP1 mRNA expression was detected and dose-dependent intraocular inflammation and retinal thinning were observed. Inflammation resolved slowly over time and did not appear to be exacerbated in the presence of anti-AAV antibodies. Biodistribution was evaluated in rats as well as from satellite animals in the nonhuman primate study. The vector was largely detected in ocular tissues as well as at low levels in the optic nerve, superior colliculus, and lateral geniculate nucleus, with limited distribution outside of these tissues. These data suggest that an initial subretinal dose of ~3x107 vg/mL CPK850 could safely be used in clinical trials.


5-3

This presentation will discuss the nonclinical development of an AAV gene therapy for treatment of a neurodegenerative disease. Differences in the biodistribution, transduction efficiency, and toxicity profile in nonhuman primates (NHP) will be described depending on the route of administration, dose level, volume, and animal age. Data suggest that at a physiologically feasible injection volume and regardless of age, transduction efficiency in the spinal cord motor neurons via intrathecal delivery is superior with intra cisterna magna (ICM) injection when compared with lumbar puncture (LP). Transduction efficiency results between NHP studies with AAV-GFP versus our AAV gene therapy on day 21 or 28 post-injection are in agreement, indicating that NHP studies with a reporter gene can be valuable in exploring routes of administration and translating efficacious dose levels from animal disease models. To confirm biodistribution, transduction durability, and potential toxicity in an NHP study with the selected dose and route of administration, testing the clinical candidate with at least one time point beyond that used in studies with AAV-GFP can be considered. Histopathology findings associated with intrathecal delivery of our AAV gene therapy consisted of asymptomatic sensory neuronopathy characterized by neuronal cell body degeneration in dorsal root ganglia and trigeminal ganglia accompanied by axonal degeneration of the dorsal funiculi in the spinal cord and axonal degeneration of peripheral nerves. These histopathologic effects, which were observed independent of the route of administration, emerged between day 14 and 28, plateaued by day 90, and did not progress by day 180 post-injection.


5-4

The EMA and US FDA have published multiple guidance documents that support the development of gene and cell therapies. With the recent approval of several AAV gene therapeutics and many programs in phase 3 development, there is increasing industrial experience and interactions with worldwide regulatory authorities. This presentation will provide an overview of regulatory guidelines and results from an industrial survey, conducted by the EFPIA Gene Therapy Working Group and IQ Pharmaceutical Consortium, on nonclinical development, and regulatory interactions for AAV gene therapeutics.


5-5

The current guidance for developing gene therapy–based products is consistent with the case-by-case approach introduced in the late ’90s for advancing protein-based pharmaceuticals into the clinic. Although flexible, this approach incorporates the basic toxicological principles that underlie the traditional, standardized preclinical testing paradigm (i.e., similar principles, different practices). The current guidance has served well to advance hundreds of both ex vivo gene-based cellular therapies and in vivo gene therapy–based products, including nonviral vectored therapies, into clinical trials. This includes the various more recent gene-editing modalities. The intended goal is that the preclinical program for each investigational gene therapy product should be individualized with respect to scope, complexity, and design to maximize the predictive value of these studies for clinical safety and therapeutic activity. The unintended goal of developers, albeit necessary, has been to maximize the predictive value of the program acceptable to a regulatory agency. As we continue to advance the novelty of products in this field (e.g., novel vectors, dual vectors, use of more than one promoter and/or multiple transgenes in a single vector), as well as more novel routes of administration and delivery approaches, are we really asking for a standardized preclinical testing paradigm? Designing successful programs is both science based and experience based. Would case studies be more valuable to understand best practices for current products in development and also serve as a reference point for the next generation of products?

Session Chairs: Jessica Hawes, US FDA/CDER, Silver Spring, MD; and
Doris Zane, Intarcia Therapeutics, Inc., Hayward, CA

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 of genotoxicity testing requirements. Both industry and regulatory professionals will be included as presenters and discussion facilitators.


6-1
2:00 PM–2:25 PM
Addressing the Challenges of Peptide Drug Discovery and Delivery: Combination Peptide Therapeutics to Treat Metabolic Diseases
Paul Feldman, Intarcia Therapeutics, Inc., Durham, NC
6-2
2:25 PM–2:50 PM
Toxicological Considerations for Peptide Drug-Device Combination Products
Doris Zane, Intarcia Therapeutics, Inc., Hayward, CA
6-3
2:50 PM–3:15 PM
Peptide Drug Hunter: The Third Wave of Intracellularly Targeted Peptide Therapeutics
Tomi Sawyer, Merck & Co., Inc., Southborough, MA
3:15 PM–3:45 PM
Break
6-4
3:45 PM–4:10 PM
Genotoxicity Assessment of Peptide/Protein Therapeutics: Perspectives from a HESI Working Group
Zhanna Sobol, Pfizer Inc., Groton, CT
6-5
4:10 PM–4:35 PM
Nonclinical Studies Supporting Investigational and New Drug Applications for Peptides
Jessica Hawes, US FDA/CDER, Silver Spring, MD
4:35 PM–5:00 PM
Panel Discussion

 


6-1

There has been surgent interest and activity in the use of peptide therapeutics to treat a variety of human diseases. Approaches to discover, optimize, assess, and deliver combination peptide therapeutics for treatment of metabolic diseases will be presented. Target selection utilizing observations resulting from Roux-en-Y gastric bypass surgery and rigorous preclinical assessment of peptide singleton and combinations will be reviewed. Peptide optimization is conducted to select for highly in vivo selective and potent peptides, and optimized peptide combinations are preclinically assessed to achieve maximal therapeutic benefit. Additionally, various considerations to deliver peptide combinations for efficient development and optimal patient benefit and adherence will be presented.


6-2

Given the inherent physical properties of amino acid polymers and poor stability, delivery of peptide therapeutics to their intended therapeutic targets represents a particularly challenging obstacle. Various toxicological considerations to deliver peptide drug-device combination products for efficient development and optimal patient benefit and adherence will be examined. A brief overview of toxicological expectations, including regulatory requirements, for combination products will be presented. Case study examples and experience with peptide drug-device combination therapeutics, including multipurpose study designs to minimize further animal testing, will be discussed.


6-3

This lecture will present a historical overview of clinical development activities for this important molecular drug class. It will highlight recent peptide drug approvals that illustrate different design features that have been key to their development. Next, the clinical stages of peptidic drugs in development and the targeted therapeutic areas will be discussed to illustrate the emerging peptide drug pipeline. Recent advances in the conceptualization, manufacture, and delivery of peptides, such as peptide delivery modalities, novel conjugations, and non-natural amino acids, that potentially enable new areas of clinical application will be discussed.


6-4

Peptide/protein biotherapeutics fall in a gray area between biologics and small molecules when it comes to genotoxicity testing. Perspectives from the Health and Environmental Sciences Institute (HESI) Genetic Toxicology Technical Committee (GTTC) workgroup on synthetic and conjugated peptide therapeutics will be presented. In 2016, the HESI GTTC working group published the article “Genotoxicity Assessment of Peptide/Protein-Related Biotherapeutics: Points to Consider before Testing” in the international journal Mutagenesis. The presentation will discuss the gaps in current regulatory guidelines and provide the workgroup’s opinion on specific case examples.


6-5

Challenges and considerations for peptide therapeutic products will be presented from a regulatory perspective. Disparities in interpretations and application of the existing International Council for Harmonisation (ICH) guidances ICH M3(R2) and ICH S6 to synthetic and conjugated peptide therapeutic products will be explored. Regulatory perspectives and rationale regarding nonclinical studies evaluating genetic toxicology and metabolic characterization will be discussed in further detail with case study examples. The impact of the March 2020 implementation of the Biologics Price Competition and Innovation Act on peptide-related product classifications will be clarified based on the most recent US FDA Q&A draft guidance.

Session Chairs: Pedro L. Del Valle, US FDA/CDER, Silver Spring, MD; and
Bettina Donato, Intertek Group plc, Sacramento, CA

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 FDA promulgated GLP regulations in 1979 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.


2:00 PM–2:05 PM
Introduction
7-1
2:05 PM–2:30 PM
US Application of GLP Regulations
Barbara Munch, Munch GLP Consulting, Greenwood, SC
7-2
2:30 PM–2:50 PM
Application of the OECD GLP Guidelines
Jordan Burns, Charles River, Edinburgh, EL, United Kingdom
7-3
2:50 PM–3:15 PM
Taiwan Application of GLP Principles
Charlene Chen, QPS Taiwan, New Taipei, TW, China
3:15 PM–3:45 PM
Break
7-4
3:45 PM–4:10 PM
GLP Regulations for Nonclinical Studies and ISO Standards for Testing in Accredited Laboratories in Brazil and Latin America
Elizabeth de Souza Nascimento, University of São Paulo, São Paulo, SP, Brazil
7-5
4:10 PM–4:35 PM
Differences and Challenges of Nonclinical GLP Testing in China When Considering Global Outsourcing for Global Submissions during Drug Development
Susan (Xuehua) Cheng, Covance Inc., Pudong, SH, China
4:35 PM–5:00 PM
Questions and Discussion

 


7-1

This talk will focus on US FDA and contrast with the Medicines and Healthcare Products Regulatory Agency UK (MHRA) regulations and OECD principles. Conduct of nonclinical toxicology studies is becoming more complicated because many test articles have unique characteristics that require analysis at niche laboratories. While multisite study conduct has always been a part of the US FDA GLP regulations, work placed outside the US requires understanding of the similarities and differences between those countries’ regulations. Consideration of the US and UK GLP laws, and comparison with the OECD GLP principles, shows that it is possible for firms to claim compliance of work performed in that country and OECD guidelines. Topic examples include circumstances of when QA audits are shared, when it is acceptable to amend a closed study, and difference in regulatory inspections. The latter follows the US FDA Compliance Program Guidance Manual (CPGM), revised in 2018, and the MHRA Schedule 2 Inspection Procedures. Current challenges include compliance certificates, enforcement of guidance (e.g., MHRA GxP Data Integrity), differing expectations regarding management oversight of risk and enforcement of OECD guidance, and conduct of a non-GLP phase on a GLP study.


7-2

Advances in communication in a rapidly changing world, travel, and technology make it easier to outsource drug development globally. This can be a huge benefit for business and advancement of drug development, but it can pose a risk for regulatory compliance. The OECD GLP Principles are very robust, but their application and interpretation can present certain challenges when outsourcing studies or phases of studies. Careful consideration needs to be taken due to differences between the OECD and US FDA GLP guidelines and differences in interpretation of OECD guidelines by different GLP Monitoring Authorities (MAs) in OECD countries. This presentation aims to provide the audience with a high-level overview of the OECD GLP guidelines (as adopted by the UK) and address the main differences between these, other OECD countries—such as Canada, France, and the Netherlands—and the US FDA GLPs, providing advice on conducting multisite studies with contributions from OECD countries. The most important difference is the OECD defined roles and responsibilities of study personnel and management, which needs to be fully understood before working with sites outside the US. Another critical difference to keep in mind is that OECD MAs have expectations that test item (test article) characterization can be conducted to non-GLP standards. The recent OECD test item characterization document will be referred to as well as updated guidance on data integrity from the MHRA that focuses on the expectation that study directors have detailed knowledge on how electronic data are generated, captured, and archived.


7-3

Taiwan FDA (TFDA) implemented GLP regulations for nonclinical laboratory studies to ensure the quality and commissioned testing activities started in 2016. But TFDA GLP regulations had been put into practice in 2006. Test facilities may apply for accreditation, and once accredited, the test facilities are required to follow the TFDA “Good Laboratory Practice for Nonclinical Laboratory Studies.” There are eight sections in the TFDA GLP regulations: (1) general, (2) organization and personnel, (3) facilities, (4) instruments, (5) operations, (6) test items and references, (7) test plans and execution of tests, and (8) records and reports. The content of the above regulation is comparable to that of international regulations, such as OECD and US FDA GLP. Taiwan is working to become an OECD Member, and TFDA has been working to establish international cooperation relationships with other countries in terms of Good Laboratory Practice for Nonclinical Laboratory Studies. Currently, there are 13 GLP-accredited laboratories in Taiwan. In 2017, TFDA held a “Seminar on Malaysia Pharmaceutical Products GLP Regulations and Principle” to enhance the exchange of information and promote the national cooperation. This talk will elaborate on the current status and future plans of GLP accreditation in TFDA, as well as compare the differences between GLP regulations in Taiwan with UK MHRA regulations, OECD GLP, and US FDA and how those differences can be overcome for global submissions. The challenges and advantages to conducting a GLP-compliant study in Taiwan as part of a multisite study will also be discussed.


7-4

Quality systems in Brazilian test laboratories have been discussed and implemented since 1994 but significantly recognized and accredited after 2000 by national and international organizations. In Brazil, nonclinical studies supporting regulatory submissions, requested by regulatory agencies, such as health, environmental, and agriculture, need to be conducted under GLP rules, by laboratories formally recognized by the National Institute of Metrology, Quality and Technology (INMETRO). In 2011, INMETRO, obtained full adherence to OECD acts related to mutual acceptance of data for chemical evaluation, including nonclinical environmental safety and human health tests for pesticides, their components, and the like. In 2015, the scope was expanded to include veterinary products, feed additives, cosmetics, pharmaceuticals, sanitizers, wood preservatives, and remediators. Thus, Brazil, as a nonmember country of the OECD but with full adherence to its regulations, fulfills duties as recommended by MAD. INMETRO is responsible for inspecting GLP laboratories according to OECD/GLP, as the Brazilian GLP principles are a translation of those of the OECD. There are currently 47 GLP laboratories recognized by INMETRO. Such laboratories keep records of the professional competencies of the personnel involved in carrying on the studies conducted according to OECD Test Guidelines for Chemicals that can be detailed in specific SOPs. Depending on the scope of the laboratory, SOPs for all aspects of GLP must be followed. This presentation will focus on the GLP requirements allowing studies, conducted in Brazil and other Latin American countries, to be accepted by health and environmental regulators adhering to UK MHRA, US FDA, and OECD principles.


7-5

GLP regulations in China were published and implemented to ensure the quality and integrity of nonclinical studies supporting clinical research or marketing approval in China. GLP regulations in China in principle follow the GLP guidelines from the US FDA and the Organisation for Economic Co-operation and Development (OECD). However, there are differences between GLP regulations of China and those of the rest of the world, including OECD and US FDA, such as test facility management (TFM) approval for protocols/reports, additional requirements for animal facility, or requirements for QAU lead. In 2017, Chinese FDA (now National Medical Products Administration, or NMPA) published updated GLP regulations, and major changes were made, including removing the responsibility for TFM approvals, adding requirements on multisite study, computer system, pathology peer review, and sponsor responsibility. New GLPs are more aligned with US FDA and OECD GLP regulations but include requirements from Chinese FDA regarding nonclinical study design, which presents challenges when outsourcing studies in China or studies conducted elsewhere with intention of Chinese submissions. Studies have been rejected for not following Chinese GLP regulations/study guidelines. There are approximately 60 GLP laboratories recognized by NMPA. The regulations in China are evolving, which becomes a challenge for multinational companies as well as biotech companies planning to conduct studies in China. This presentation will discuss interpretation of Chinese GLP regulations; how they differ from UK MHRA, OECD, and US FDA; and how they can be overcome for global submissions.

Session Chairs: Natalie S. Holman, Eli Lilly and Company, Indianapolis, IN; and
Tracy M. Williams, Eli Lilly and Company, Indianapolis, IN

This session is a companion to the successful 2017 ACT Symposium “What to Do When Things Go Wrong,” in which speakers discussed their experiences with test article limitations, publication feedback, formulation challenges, resolution of concerns as regulators, communications as a study director, and unanticipated toxicities on day 1 of a study. This year, early career toxicologists from the pharmaceutical and biotechnology industries as well as the US FDA 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 GLP toxicology studies, navigating project team dynamics, unexpected pathology findings, and employment instability. Audience engagement and questions are highly encouraged!


2:00 PM–2:05 PM
Introduction
8-1
2:05 PM–2:30 PM
Strategies for When the Buck Stops with You
Francis Wolenski, Takeda Pharmaceuticals, Cambridge, MA
8-2
2:30 PM–2:55 PM
Nontraditional GLP Toxicology Study Designs and Challenges for the Project Toxicologist
April O’Connell, Gilead Sciences, Inc., Foster City, CA
8-3
2:55 PM–3:15 PM
Supporting Mature Drug Products: Risk Mitigation and Regulatory Strategy
Kristina DeSmet, United Therapeutics Corporation, Research Triangle Park, NC
3:15 PM–3:45 PM
Break
8-4
3:45 PM–4:05 PM
Starting Out at a Start-Up
Chanel Griggs, RAI Services Company, Winston-Salem, NC
8-5
4:05 PM–4:25 PM
An Eye-Opening Experience for an Early Career Pathologist: On-Target Ocular Toxicity—Or Is It?
Jessica Grieves, Takeda Pharmaceuticals, San Diego, CA
8-6
4:25 PM–4:45 PM
The Learning Curve of a First-Year Pharm/Tox Reviewer at the US FDA
Julie Castaneda, US FDA/CDER, Silver Spring, MD
4:45 PM–5:00 PM
Discussion

 


8-1

Congratulations—you have worked hard in your career and are now at the point where the problem is your problem! There will always be unforeseen and difficult situations, but now, when something goes wrong, your colleagues look to you for a resolution. Both what you do and how you act can be equally important. The talk will highlight five key principles for dealing with problems: (1) put patients first, (2) identify the information gaps, (3) ask partners for help, (4) determine what can and cannot be fixed, and (5) communicate at the right time. Examples of things going very wrong will be presented, including a fatal tumor on a chronic study, an assay ruined by a disgruntled employee, and a loss of data integrity. In these real-world situations, the five principles were applied at various points to cut through many different opinions and find the path to the best outcome.


8-2

GLP toxicology protocols in support of IND-enabling activities include basic study endpoints guided by an array of ICH Guidelines and health authority recommendations. However, case-by-case needs for novel targets benefit from unique, functional toxicity endpoints or investigative toxicology assays. The requirement to fully assess the safety of novel targets presents not only challenges but also opportunities for the project toxicologist. Clearly defined data collection and evaluation procedures plus diligent oversight for these complex studies may identify critical toxicity signals that would otherwise have been missed and likely enhance the review and acceptance of the toxicology program by health authorities.


8-3

Supporting mature drug products is not as straightforward as one would expect. Toxicological challenges can arise postmarket that require significant time and resources. Two case studies on mature drug products will be presented, along with the risk mitigation plan and regulatory strategy developed to overcome the toxicological challenges. The first case study will describe global expansion of a reformulated drug product with a novel excipient, and the second will describe a postapproval change in drug substance manufacturer that resulted in a change in specification of a potentially genotoxic degradation product.


8-4

Your first job after graduate school seems like the most important career move since deciding to go to school. Who you work for and what you do could have the potential and impact to shape the rest of your career. Working for a biotech start-up company can be either a very exciting or a very risky experience. The speaker will share some experiences of working at a biotech start-up, including (1) accepting a high-risk, high-reward position; (2) dealing with job loss early in one’s career; and (3) reentering the job market with only six months of postgraduate experience.


8-5

After a few years as a toxicologic pathologist, the steepness of the learning curve finally starts to flatten out. You are the program pathologist for a high-priority/high-profile program gearing up for candidate selection. Accurate characterization of target organ toxicities is in your hands, and there is no time to waste. Gulp! Previous nonclinical studies have been performed with this asset, so as you sit down with your cup of coffee to start peer review of a repeat-dose rat study, you think you know what to expect. But wait! Are your eyes deceiving you, or is that a retinal lesion? This is a new and unexpected finding! What does this mean for the program? How can you, the toxicologist, and the rest of the project team work together with urgency to derisk this liability as the program hurtles toward the next stage gate with all eyes on you?


8-6

You finally land your dream job in the federal government but are now faced with dealing with work that is directly related to the well-being and health of many. No other job has prepared you for the work you are about to do. As a brand-new reviewer, how can you make an informed decision and at the same time follow the clues in a sea of data to make a vital decision that could potentially help or harm many human beings? This speaker will walk through interesting and difficult case studies faced as a first-year pharmacology/toxicology reviewer at the US FDA and how to overcome the many obstacles in a brand-new job.



Tuesday,

Session Chairs: Katie Sokolowski, US FDA/CDER, Silver Spring, MD; and
Jennifer Shing, AbbVie Inc., North Chicago, IL

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 FDA and serving as an example for the relevance of JAS. The SLC 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 supported the US FDA internal discussions during development of the ICH S11 guidance and those involved specifically in the anesthetic agent SLC, academic researchers who characterized 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.


9:00 AM–9:15 AM
Introduction
Katie Sokolowski, US FDA/CDER, Silver Spring, MD
9-1
9:15 AM–9:45 AM
Content and Intent of the ICH S11 Guidance
Darren Fegley, US FDA/CDER, Silver Spring, MD
9-2
9:45 AM–10:15 AM
Overview of the Neurotoxic Effects of Anesthesia on the Developing Brain
Ansgar Brambrink, Columbia University, New York, NY
10:15 AM–10:45 AM
Break
9-3
10:45 AM–11:15 AM
Regulatory Perspective on Drugs with Developmental Neurotoxicity
Newton Woo, US FDA/CDER, Silver Spring, MD
9-4
11:15 AM–11:45 AM
Design of Juvenile Animal Studies to Identify Developmental Neurotoxicity Using the Draft ICH S11 Guidance
Alan M. Hoberman, Charles River, Horsham, PA
11:45 AM–12:00 Noon
Panel Discussion

 


9-1

This talk will serve as an introduction to the ICH S11 guidance by covering the contents and intentions of the guidance with an emphasis on neurodevelopment. This talk will also discuss the evolution of regulatory standards over time and provide a brief overview of the experience of the US FDA with the design and outcome of JAS that supported guidance development. It will briefly discuss topics covered in the guidance, such as determining the need for additional nonclinical safety investigations and considerations for pediatric-first/only development with no indication in adults, as well as general considerations for study design. Practical application of these general considerations will be addressed in detail by the final speaker, who will apply the ICH S11 guidance in a proposed study to investigate the toxicity of a hypothetical anesthetic drug.


9-2

This talk will introduce the nonclinical and clinical data associated with anesthetics. Here, general anesthetic and sedation drugs will serve as examples of currently marketed drugs with risks to the developing brain. Animal data accumulating for the past 15 years have suggested that sedatives and anesthetics cause neurotoxicity. Molecular, cellular, and behavioral analyses of the brain after anesthetic or sedative exposure in young animals have revealed neurotoxicity in several species, which has been replicated in many labs. Initial studies involving administration of NMDA receptor antagonists to the postnatal day (PND) 7 rat found widespread apoptotic cell death and neurodegeneration in the developing brain. These findings of neurotoxicity in rodents were later reproduced using GABA receptor agonists and observed in numerous brain regions, including the hippocampus, thalamus, cerebellum, and cerebral cortex. Moreover, a variety of manifestations of neurodegeneration have been detected, such as impaired neurogenesis, impaired glial development, synaptic loss, and altered dendritic spine morphology. To investigate functional outcomes of general anesthesia, many studies have revealed impairments in recognition memory, fear learning and avoidance memory, and spatial learning and memory in rats, as well as abnormal social behaviors. Strikingly, cognitive deficits arising from anesthesia exposure have been demonstrated to persist into adulthood in rodents. While the girth of data was generated in rodent models to initially characterize anesthetic-induced neurotoxicity, the data generated in nonhuman primates served as the basis for details specified in the SLC for anesthetics. Similar to rodents, neurotoxicity induced by an array of general anesthetics has been observed in fetal and postnatal nonhuman primates. The presentation of functional deficits in primates, such as impaired cognitive function and altered emotional reactivity, seems to depend on prolonged and/or repeated neonatal exposures and may not be detectable until the animals are over a year old. While there have been dedicated clinical studies to investigate the effects of anesthesia on the developing brain, confounding factors and the low number of children exposed for durations greater than three hours make the nonclinical data invaluable. The information in this talk will provide the basis for the juvenile animal study design discussed in the final talk.


9-3

To illustrate the relevance of JAS to pediatric drugs, this talk will describe the process of integrating the nonclinical and clinical data available for anesthetics and the ultimate determination to issue an SLC for anesthetics. Despite the SLC, anesthetics are essential pediatric medicines that are widely used. Because anesthetic agents are essential drug products that always carry certain risks and it is not clear if any one drug is safer than another based on their pharmacology, it may be possible to develop new and even safer anesthetics. Therefore, any new drug development program for an anesthetic agent will require testing for the potential for developmental neurotoxicity. This talk will discuss some of the lessons learned from the anesthetic class of drugs, including some of the data that led to the SLC and issues that arise during drug development of an anesthetic. The presentation will also discuss what a sponsor should think about when drafting their initial pediatric study plan (iPSP) and what types of things to address in their JAS.


9-4

This talk will focus on the application of the ICH S11 Guideline to design a juvenile animal study using the example of a new anesthetic drug. The design of the study would take into consideration the nonclinical data available for anesthetics while addressing US FDA concerns of developmental neurotoxicity. Study design considerations will be presented, including dose and species selection, age of animals in relation to the intended pediatric population, route of administration, and endpoints. Evaluation of CNS function using behavioral tests, learning and memory tests, and neuropathology will be discussed. Study design considerations for anesthetics can be broadly applied to other neuroactive compounds seeking pediatric indications.

Session Chairs: Zaher Radi, Pfizer Inc., Cambridge, MA; and
David McMillan, US FDA/CDER, Silver Spring, MD

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; an introduction on industry perspectives; clinical and nonclinical safety challenges and examples of immune tolerance; 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.


10-1
9:00 AM–9:50 AM
State-of-Science of Immune Tolerance, and Trending Therapeutic Concepts for New and Differentiated Mechanisms of Action
David Wraith, University of Birmingham, Birmingham, WMD, United Kingdorm
10-2
9:50 AM–10:05 AM
Industry Perspective on Immune Tolerance
Zaher Radi, Pfizer Inc., Cambridge, MA
10:05 AM–10:35 AM
Break
10-3
10:35 AM–11:25 AM
Tolerogenic Immunity: A Pro or Foe? Clinical Safety Challenges and Regulatory T-Cell Therapies
Megan Levings, University of British Columbia, Vancouver, BC, Canada
10-4
11:25 AM–11:40 AM
A Regulatory Perspective on Immune Tolerance
David McMillan, US FDA/CDER, Silver Spring, MD
11:40 AM–12:00 Noon
Panel Discussion

 


10-1

Immune tolerance, or lack of immune response to self, is not the default state of the immune system, but rather an actively maintained homeostasis. A combination of genetic risk factors and environmental exposures results in loss of this homeostasis in individuals with autoimmune disease, and the specific self-antigens to which tolerance is lost determine the target organ(s). Important cellular players in maintenance of antigen-specific tolerance are regulatory T lymphocytes (Treg). There are a variety of Treg phenotypes, but two of the most important are those that express the transcription factor FoxP3 and utilize a variety of cell contact–dependent suppressive mechanisms, and TR1 cells, identified primarily by the production of the anti-inflammatory cytokine IL-10. A number of novel therapies for autoimmune disease are in development that have demonstrated therapeutic efficacy and the ability to expand FoxP3+ Treg and/or TR1 cells in preclinical animal models. Antigen-specific therapies in development include peptide and protein antigens delivered alone or via nanoparticle formulations in the presence or absence of immunomodulatory small molecules. The current state-of-the-science of these novel therapies, several of which have now advanced to human clinical testing, will be discussed, as well as remaining challenges in the translation of preclinical models to human disease and important safety considerations when developing immune-modulatory and antigen-specific therapies.


10-2

This presentation will provide a brief introduction on industry perspective on immune tolerance using a DruSafe industry survey. This will cover various aspects of immune tolerance, ranging from therapeutics in this space to drug design to toxicology studies design and challenges.


10-3

Regulatory T cells (Tregs) function to regulate immune responses and maintain immune tolerance. When harnessed as a cell-based therapy, Tregs have the potential to control harmful immune responses without altering healthy immune responses, such as those to infections. Moreover, they can be genetically modified to enhance specific properties, such as antigen specificity, ability to respond to cytokines, and effector functions. However, safety limitations of this approach include the risk of nonspecific suppression and/or conversion of Tregs into inflammatory effector T cells. In vitro and in vivo models to study the possible protolerogenic effects as well as safety risks will be discussed.


10-4

A thorough understanding of the immune system is becoming increasingly important in the field of drug development. Immune tolerance poses some interesting challenges for regulatory agencies as well as pharmaceutical companies, particularly as they pertain to drug exposure and efficacy. This presentation will provide an overview of the expectations surrounding the toxicology package for such modalities, a regulatory perspective on issues involving immune tolerance, and some of the challenges faced in drug development.

Session Chairs: Marie Fortin, Jazz Pharmaceuticals plc, Ewing, NJ; and
Shaun McCullough, US EPA, Chapel Hill, NC

Next-generation in vitro models can dramatically increase the physiological relevance of cell-based studies; however, amid 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.


11-1
9:00 AM–9:10 AM
Through the Looking Glass: Exploring New Frontiers
Marie Fortin, Jazz Pharmaceuticals plc, Ewing, NJ
11-2
9:10 AM–9:40 AM
Utilizing In Vitro Mechanistic and Cytotoxicity Assays on Multiple Platforms to Improve the Prediction of Hepatotoxicity
Christopher Strock, Cyprotex, Watertown, MA
11-3
9:40 AM–10:15 AM
Breaking the Barrier: Using a Novel In Vitro Organotypic Airway Trans-epithelial Exposure Model to Study the Depth of Inhaled Chemical Toxicity
Shaun McCullough, US EPA, Chapel Hill, NC
10:15 AM–10:45 AM
Break
11-4
10:45 AM–11:20 AM
Next-Generation Gastrointestinal Organoids to Predict Drug-Induced Diarrhea
Matthew Wagoner, Takeda Pharmaceuticals, Cambridge, MA
11-5
11:20 AM–11:55 AM
Translational Assessment of Kidney Injury Using Kidney-on-a-Chip and Quantitative Systems Pharmacology (QSP)
Murat Cirit, Javelin Biotech, Woburn, MA
11:55 AM–12:00 Noon
Concluding Remarks
Marie Fortin, Jazz Pharmaceuticals plc, Cambridge, MA

 


11-1

The integration of next-generation in vitro models into toxicology research and testing has allowed us to push the frontiers of our understanding of toxicology. This ever-changing in vitro assay landscape offers a world of opportunities to ask, and reliably answer, toxicological questions. The goal of this introductory presentation is to provide the attendees with a broadened knowledge of the realm of in vitro toxicity testing by briefly highlighting additional examples of the use of human-derived organoids and microtissues. The unique translational potential of these models will also be presented, along with perspectives for their integration into integrated approaches to testing and assessment (IATA).


11-2

Hepatotoxicity remains a significant challenge in drug development that results in attrition of drugs occurring in clinical trials and post-approval. This is due to the lack of predictivity of animal models for many of the causes of hepatotoxicity as well as an inability to properly identify these liabilities in the animals. It is therefore important to properly understand and test for as many mechanisms of drug-induced liver injury (DILI) as possible and understand how these contribute to the overall liability of a drug to ensure the ability to identify the risks and issues as they develop. Here we will show that evaluating compounds for mechanistic liabilities and cytotoxicity using assays on multiple platforms and cell types will increase the prediction of DILI and allow for selection of safer compounds to move forward into later-stage testing. We demonstrate the value of High Content DILI assays in both 2D and 3D formats with primary and immortalized cells for both cytotoxicity as well as mechanistic characterization of these liabilities. The importance of mitochondria-relevant endpoints is shown with the SeaHorse mitochondrial function assay as well as high content assays such as mitochondrial biogenesis and mitochondrial potential assays. Combining these endpoints with reactive metabolite determination as well as the transporters, BSEP and MRP2, further increases the predictive power for DILI prediction. The additive value of these endpoints will be demonstrated using case studies to illustrate the importance of multi-endpoint in vitro toxicity assessment.


11-3

The toxicity of inhaled xenobiotics is often attributed to oxidative stress and inflammation; however, the specific underlying cellular and molecular mechanisms remain to be fully understood. Bridging this gap will require the use of robust and broadly applicable in vitro organotypic models to provide insight into the role that the different cell types within the airway microenvironment play in exposure effects and susceptibility. We hypothesized that exposure of an intact epithelial barrier to an inhaled toxicant would cause oxidative stress and the induction of a proinflammatory response in underlying airway fibroblasts, a cell type crucial to maintaining tissue homeostasis in the airway. To test this hypothesis, we constructed a “trans-epithelial” exposure model (TEEM) to recapitulate an in vivo exposure of the airway microenvironment by incorporating an intact human bronchial epithelial cell (HBEC) layer to separate human lung fibroblasts (HLF) from the exposure material while also allowing assessment of the direct and trans-epithelial effects of toxicant exposure in the HBEC and HLF, respectively. Time course (2–24 hours) analysis of exposure outcomes following exposure of the TEEM to the model toxicant diesel exhaust particulates (DEP) demonstrated that the kinetics and magnitude of oxidative stress–responsive gene expression are similar between the two cell types; however, peak proinflammatory gene induction in HLF was delayed, but more prolonged in HLF relative to HBEC. Genes involved in glutathione homeostasis and hydrogen peroxide (H2O2) signaling (NQO1, TRX1, PTGS2, and GCLM1) were also alternatively regulated in response to DEP exposure, and their induction was attenuated by pretreatment with the antioxidants N-acetyl-cysteine (NAC) and ascorbic acid. Further, pretreatment of HLF with antioxidants led to an attenuation of both oxidative stress–responsive and proinflammatory gene expression in DEP-exposed HBEC. The findings presented here demonstrate that while receiving no direct exposures, HLF are both a target and a mediator of the effects of inhaled chemical exposures. Further, this readily accessible in vitro organotypic model of the human airway microenvironment allows for the identification of xenobiotic exposure effects beyond the epithelium, as well as the investigation of their underlying cellular and molecular mechanisms.


11-4

Though drug-induced gastrointestinal toxicities rank among the most common clinical side effects, the vast majority of GI toxicities go undetected until they are administered in vivo, where toxicologists are faced with uncertain translation of intestinal toxicity among species. Recent advances in organoid and microtissue development promise to enhance the predictivity and translation of our in vitro assays, though little work has been done to validate these models. Here we will present our efforts to compare and validate intestinal organoid and transwell microtissue systems using an array of clinical compounds. Our results suggest that intestinal organoids allow for robust comparison of intestinal sensitivity across species. We also find that human transwell intestinal microtissues are a robust and sensitive in vitro tool for the detection and derisking of drug-induced diarrhea.


11-5

Drug-induced kidney injury, a major cause of acute kidney injury, results in progressive kidney disease and is linked to increased mortality in hospitalized patients. Primary injury sites of drug-induced kidney injury are proximal tubules. Clinically, kidney injury molecule-1, an established tubule-specific biomarker, is monitored to assess the presence and progression of injury. The ability to accurately predict drug-related nephrotoxicity preclinically would reduce patient burden and drug attrition rates, yet state-of-the-art in vitro and animal models fail to do so. Our work demonstrates the use of kidney injury molecule-1 measurement in the kidney microphysiological system as a preclinical model for drug toxicity assessment. To show clinical relevance of toxic response, we utilize quantitative systems pharmacology (QSP) computational models for in vitro-in vivo translation of the experimental results and to identify favorable dosing regimens for one of the tested drugs.


Session Chairs: Subramanya Karanth, AstraZeneca, Gaithersburg, MD; and
Deacqunita Diggs, US FDA/CDER, Silver Spring, MD

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 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, Investigator’s Brochures (IB), and clinical protocols. The fourth 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.


12-1
2:00 PM–2:10 PM
Introduction
Subramanya Karanth, AstraZeneca, Gaithersburg, MD
12-2
2:10 PM–2:40 PM
How to Write a Scientifically Sound Nonclinical Report
Janice Lansita, ToxStrategies, Inc., Kennett Square, PA
12-3
2:40 PM–3:15 PM
Sponsor Expectations: How a Well-Written Nonclinical Report Can Help to Author IND, IB Modules, and Clinical Protocol
Jessica Lynch, Janssen Research & Development, Spring House, PA
3:15 PM–3:45 PM
Break
12-4
3:45 PM–4:20 PM
So You’re Filing to Go to Market: What to Expect
Scott Manetz, AstraZeneca, Gaithersburg, MD
12-5
4:20 PM–5:00 PM
US FDA Reviewer’s Perspectives on Regulatory Submissions (IND, IB, NDAs/BLAs)
Deacqunita Diggs, US FDA/CDER, Silver Spring, MD

 


12-1

This talk will introduce the key objectives of the Workshop. Authoring regulatory documents has unique challenges. Initial groundwork for a regulatory submission starts with a well-written, integrated nonclinical study report that effectively conveys study details and outcomes to regulatory authorities. Generally, several collaborators are involved in nonclinical studies, and a clear, open communication between the stakeholders is needed to prepare quality study reports. An overview of different approaches required for authoring a scientifically sound regulatory document will be presented.


12-2

This talk will highlight the challenges associated with complex datasets and writing scientifically sound, integrated nonclinical reports. The nonclinical study report captures the important details of a nonclinical study, which include the procedures, methods, results, subreports, data interpretation, and conclusions. Writing the nonclinical study report begins with analyzing the data to determine which results should be discussed and highlighted. This is generally the most challenging aspect of writing the report, especially when early mortality has occurred, findings are numerous, or it is unclear whether observed effects are treatment related (or all of the above!). This presentation will walk through data analysis, organization of the results in a report, data interpretation, and the review process. Finally, a clear conclusion that defines the outcome of the study (e.g., maximum tolerated dose [MTD], no-observed-adverse-effect level [NOAEL], severely toxic dose in 10% of rodents [STD10], or highest nonseverely toxic dose [HNSTD] in nonrodents) is essential for regulatory submissions. Often, nonclinical reports for regulatory submission can run more than 1,000 pages and are the key dataset that regulatory bodies use to support initial clinical trials. This presentation will assist toxicologists in writing and reviewing nonclinical reports to ensure that the study details and essential data interpretation are conveyed to regulatory authorities.


12-3

The IND, IB, and clinical protocol are living regulatory documents that not only support the application of a new drug candidate for first-in-human clinical trials but will continue to evolve until the corresponding New Drug Application is approved. Due to the importance of these documents throughout the development process, it is critical to have a clear goal and organized structure to these documents prior to the first submission. The first step to writing a clear, concise nonclinical overview and subsequent nonclinical sections (pharmacology, pharmacokinetics, and toxicology) is to have clear integrated study reports from both internal and external sources. This talk will give an overview of how to work with internal and external collaborators to prepare quality study reports and how to utilize these results to draft key regulatory documents for IND submission.


12-4

This talk will cover nonclinical aspects of a US FDA BLA and similar regulatory submissions for marketing in other geographical regions. This will include review of available key resources, including guidance documents. We will also review the recent changes to pregnancy and lactation labeling and specific nonclinical language from various regional labels (or equivalent) of some more recently approved biologics.


12-5

This presentation will focus on a US FDA reviewer’s perspectives on essential elements to be included in the INDs, IBs, and NDAs/BLAs. Points that will be addressed include the review process of these submissions. Examples of good submissions and those needing improvement will be shared.

Session Chairs: Brian Roche, Charles River, Ashland, OH; and
Marie-Luce Brodzinski-Rosseels, UCB Biopharma Sprl, Braine-l’Alleud, BW, Belgium

This session is designed 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 ICH S7A “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 ICH S7A/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.


13-1
2:00 PM–2:25 PM
Introduction and Perspectives on Safety Pharmacology Endpoints within Toxicology Studies
Helen Prior, National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), London, GLD, United Kingdom
13-2
2:25 PM–2:50 PM
Implanted Telemetry in Toxicology Studies: A Retrospective Analysis by the HESI Consortium
Simon Authier, Citoxlab, a Charles River Company, Laval, QC, Canada
13-3
2:50 PM–3:15 PM
Inclusion of Neurofunctional Assessments in Toxicology Studies
Stephanie Born, Merck & Co., Inc., West Point, PA
3:15 PM–3:45 PM
Break
13-4
3:45 PM–4:10 PM
Drug-Induced QTc Prolongation and Torsades de Pointes (TdP): Evolving ICH S7B in Light of Emerging Data
Jean-Pierre Valentin, UCB Biopharma Sprl, Braine-l’Alleud, BW, Belgium
13-5
4:10 PM–4:35 PM
Translation of Respiratory Safety Pharmacology Findings
Sabina Paglialunga, Celerion, Tempe, AZ
13-6
4:35 PM–5:00 PM
A Regulatory Perspective of Safety Pharmacology Data in Toxicology Studies
Amy Avila, US FDA/CDER, Silver Spring, MD

 


13-1

The integration of functional safety pharmacology assessments into toxicology studies has long been advocated (and endorsed within regulatory guidance), although not widely adopted, often due to practical difficulties (e.g., the location of safety pharmacology and toxicology teams or laboratories) as well as perceptions around data quality. Recent technological advancements, trends toward outsourcing of studies, escalation of biotherapeutics in development, and sharing of experience have encouraged wider acceptance of these approaches. Benefits include the ability to correlate functional with pathological/toxicological data in the same animal, capture delayed onset effects, and provide additional data to investigate whether effects observed after a single dose persist, intensify, or diminish on repeated dosing. If these combined studies are performed instead of an acute safety pharmacology study (generally the case for biotherapeutics and oncology products, but examples for small molecules are also available), this provides a 3Rs benefit of an overall reduction in animals within the package. Ideally, additional measurements should be noninvasive and not be detrimental to the conduct and primary purpose of the toxicology study. The most common measurements (cardiovascular and neurofunctional parameters) in nonrodent and rodent toxicology studies will be described in the following presentations.


13-2

The use of implanted telemetry in toxicology studies has increased in recent years, driven by ethical considerations and the intrinsic value of safety pharmacology assessments after repeated dosing. Data obtained from vehicle-treated groups in toxicology studies were analyzed and compared with nonimplanted animals to assess the impact of implanted telemetry on a broad range of toxicology endpoints and across commonly used species, including dogs, nonhuman primates, and rats. Interpretation of safety pharmacology data obtained in repeat-dose toxicology studies is often perceived as a challenge due to potential procedural interferences. Analysis strategies will be discussed, with a review of potential success factors and pitfalls. While implanted telemetry in toxicology has gained increasing industry and regulatory acceptance, circumstances that may favor stand-alone designs will also be discussed.


13-3

An assessment of central nervous system (CNS) function is required as part of the ICH S7A safety pharmacology core battery and may be needed for molecules governed by ICH S6 or ICH S9 if the target is expressed in the CNS or effects on the CNS are expected/predicted. Within our organization, a functional observational battery (FOB) is routinely incorporated into the rodent first-in-human enabling repeat-dose toxicity study. Following the FOB assessment after the first dose, these animals continue on study within the cohort of animals used to assess toxicity and/or toxicokinetic endpoints. This integrated approach to the assessment of CNS function has largely replaced the need for stand-alone FOB studies, has reduced animal usage and study costs, and has been broadly accepted in our regulatory submissions. This presentation will share practical information related to the incorporation of FOBs in toxicity studies and the advantages gained in utilizing this approach.


13-4

ICH S7B and E14 describe the nonclinical and clinical risk assessment strategies, respectively, to inform the potential risk for proarrhythmia of a drug and contribute to the design of clinical investigations. Since the implementation of these Guidelines in 2005, there has been no drug withdrawn for an unacceptable risk of TdP, and most drugs evaluated clinically nowadays are negatives, largely due to “hERG-centric” discovery screening strategies. Over the past several years, emergent data (e.g., CiPA, JiCSA) have increased our mechanistic understanding of drug-induced QTc prolongation and TdP. Consequently, guidance is needed regarding best practices for the design, conduct, analysis, interpretation, presentation, and reporting of in silico, in vitro, and in vivo nonclinical assays in order for these assays to influence nonclinical and clinical evaluation. Although ICH E14 identifies nonclinical data as a factor that can be used to reduce the need for a TQT study, there has been no consensus on how nonclinical data can be used to influence the design and/or interpretation of a clinical QT assessment. That said, there are several clinical scenarios that could benefit from high-quality nonclinical data, such as clinical QT assessments that are confounded by issues like heart rate changes, inability to test a sufficiently high multiple of the clinically relevant exposure to waive the positive control, and when a TQT study is not feasible in healthy volunteers. On the other hand, ICH S7B recommends “follow-up studies” to inform the integrated risk assessment if a drug blocks the hERG current or prolongs the QT interval. These could include evaluating drug effects on additional ionic currents, and the use of in vitro and in vivo assays. Newer assays and technologies such as in silico ventricular models and human primary and induced pluripotent stem cell–derived cardiomyocytes can provide insights into the relative proarrhythmic liability of drugs. Therefore, guidance is needed on when and how these novel approaches could play a role in determining the proarrhythmic risk to inform clinical development.


13-5

Prior to first-in-human exposure, most new chemical entities must undergo a series of preclinical evaluations. ICH S7A safety pharmacology Guidelines, adopted in 2001, include respiratory assessments as part of the core battery. Now, nearly two decades following the finalization of ICH S7A Guidelines, several questions arise regarding the effectiveness of these in vivo respiratory assessments to identify a potential clinical concern. Therefore, an industrywide nonclinical-to-clinical translational database was created by IQ/DruSafe to determine how safety assessments, including respiratory system in animal models, translate to first-in-human clinical risk. Specifically, how well do preclinical studies predict human risk? Are safety pharmacology respiratory endpoints sufficient to detect drug liability? To address these questions, this presentation will review the safety pharmacology data from the IQ/DruSafe database for respiratory endpoints, focusing on 2x2 contingency tables results (true positive, false positive, true negative, false negative). Additionally, the presentation will highlight case examples from industry and provide a historical overview of respiratory concordance studies.


13-6

There is precedent for the inclusion of in vivo safety pharmacology functional endpoints in general toxicology studies based on ICH guidance, including ICH M3(R2), S6, S7A, and S9. However, currently there is no ICH or US FDA guidance describing how to design such studies. This presentation will provide general suggestions, from a regulatory perspective, on the design and conduct of evaluating safety pharmacology endpoints in general toxicology studies. Initially, thoughtful consideration should be made based, in part, on the type of new drug (small molecule, biologic, anticancer pharmaceutical) and the drug’s pharmacodynamic and pharmacokinetic profile when considering whether to include safety pharmacology endpoints into general toxicology studies. Safety pharmacology evaluations may be incorporated into single or repeat-dose toxicology studies, or as part of follow-up toxicity studies. The assessment of safety pharmacology as part of general toxicology studies should provide rigor similar to that in stand-alone safety pharmacology studies. Therefore, the design of the general toxicology study should be carefully considered when including safety pharmacology endpoints with respect to species selection, timing of assessments, incorporation of all necessary endpoints, doses, dosing procedures, data quality, etc. Lastly, case studies will be presented with examples of when safety pharmacology endpoints were successfully incorporated into general toxicity studies and when stand-alone studies were used for a more adequate assessment of safety.

Session Chairs: Catrin Hasselgren, Genentech, Inc., South San Francisco, CA; and
Joel Bercu, Gilead Sciences, Inc., Foster City, CA

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 as 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.


14-1
2:00 PM–2:25 PM
How to Improve the Acceptance and Defendability of In Silico Methods
Catrin Hasselgren, Genentech, Inc., South San Francisco, CA
14-2
2:25 PM–2:50 PM
How In Silico Methods Are Being Used to Support Regulatory and Industrial Decisions Today
Joel Bercu, Gilead Sciences, Inc., Foster City, CA
14-3
2:50 PM–3:15 PM
Protocols to Support the In Silico Prediction of the Acute Effects
Candice Johnson, Leadscope, Inc., Columbus, OH
3:15 PM–3:45 PM
Break
14-4
3:45 PM–4:10 PM
Progress toward Predicting Repeated-Dose Toxicity
Raymond Tice, RTice Consulting, Hillsborough, NC
14-5
4:10 PM–4:35 PM
Case Studies in the Application of In Silico Toxicology Protocols
Elena Lo Piparo, Nestlé, Lausanne, VD, Switzerland
4:35 PM–5:00 PM
Panel Discussion

 


14-1

In silico methods are used in a number of situations in industry and academia, as well as in regulatory and governmental organizations. Depending on the use case, different levels of confidence in the predictions are required. It is likely that the number of endpoints and application areas will expand in the near future to assess regulated chemicals on the basis of different toxicological endpoints. Thus, the application of quality-driven standards will play an increasingly important role in the use and adoption of such methods. A central element of any quality-driven approach is a protocol so the results can be generated, recorded, communicated, archived, and then evaluated in a consistent and reproducible manner. This presentation will introduce the current landscape of in silico toxicology and describe the formation of an international consortium including regulators, government agencies, industry, academics, model developers, and consultants across many different sectors to develop harmonized approaches to applying in silico predictions. The consortium initially developed a protocol framework that outlines how to select, assess, and integrate in silico predictions alongside experimental data for defined toxicological effects or mechanisms. This includes a new methodology for establishing the reliability of this assessment. A hazard assessment framework for systematic integration and assessment of these toxicological effects or mechanisms to predict specific endpoints as well as assess the confidence in the results is also part of this framework. These protocols are being created for a number of major toxicological endpoints, including genetic toxicity, skin sensitization, carcinogenicity, acute toxicity, reproductive toxicity, and developmental toxicity. This presentation will outline the protocol framework, and the concepts will be exemplified using a recently completed genetic toxicity in silico protocol as well as the initial steps taken toward an applied protocol dedicated toward transportation of chemicals.


14-2

This presentation will outline how in silico methods can support a variety of regulatory and product development decisions. The ICH M7 Guideline for pharmaceutical impurities provides a valuable use case for the successful adoption of in silico methods. Here, the use of in silico methods is driven by the need for a high-throughput approach to assess the DNA-reactive mutagenic potential for large numbers of pharmaceutical impurities, including situations where it is not possible to easily obtain sufficient quantities of the test material. The ICH M7 Guideline states that (Q)SAR methodologies can be used for this assessment, and it outlines that predictions from two methodologies are required (expert rule based and statistical based) and an expert review is warranted in situations where there are conflicting results. In support of the adoption of ICH M7, a number of articles have been published that provide critical support for Guideline implementation, validating that in silico methods are fit for purpose for this application and describing protocols for implementation of the (Q)SAR assessment. An increasing number of regulatory guidelines describe the potential for use of in silico methods as a part of hazard assessment. Examples include the European Union’s REACH, Cosmetics Directive, and EFSA residue definition for dietary risk assessment of plant protection products; the US FDA ENDS, PBPK, and environmental assessment guidelines; and the US EPA Toxic Substance Control Act regulation. This presentation will outline the drivers and benefits for using in silico methods and discuss the breadth of regulatory guidelines where in silico methods are now acceptable. The presentation will also enumerate criteria for successful adoption of in silico solutions based on the experience implementing the ICH M7 Guideline, including (1) outlines drivers and benefits for using in silico methods, (2) discusses the breadth of regulatory guidelines where in silico methods are acceptable, (3) presents industrial use cases where in silico methods have been successfully applied, and (4) enumerates criteria for successful adoption of in silico solutions.


14-3

A paradigm shift in toxicology toward a mechanistic evaluation of toxicological processes has fostered growth in the evaluation of the sensitization endpoint, as well as the irritation/corrosion and acute toxicity endpoints, albeit to a lesser extent. In silico analyses of these endpoints play an important role in evaluating the weight of evidence (WOE) indicated by nontesting methods and support decision-making. To improve the reproducibility and transparency of in silico use, protocols were developed for the sensitization, irritation/corrosion, and acute toxicity endpoints. Mechanistic information and observed effects are assembled in an evaluation framework in which in silico predictions and existing testing data are integrated to derive an assessment of major endpoints. The data integration may take the form of a defined approach (DA), in which rules and procedures are used to integrate adverse outcome pathway (AOP) informed predictions. In other instances, data integration may involve a WOE assessment. In all cases, the prediction of an endpoint is assigned a confidence score (a measure of reliability, relevance, and completeness of information). In this presentation, elements of the sensitization, irritation/corrosion, and acute toxicity protocols are used to illustrate how existing AOPs, integrated approaches to testing and assessment (IATA), and DA are used to derive an in silico assessment and an associated measure of confidence.


14-4

Prediction of repeated-dose toxicity using alternative methods is the focus of considerable international effort. This presentation will highlight the progress toward the prediction of chronic effects, with a focus on carcinogenicity, using a combination of in silico methods and experimental data. This will include a description of how computational models and in vitro data covering both genotoxic and nongenotoxic mechanisms alongside models predicting in vivo outcomes can be integrated to support these predictions. This presentation will also describe how ADME data and/or predictions as well as ‘omics information can be integrated into the predicted outcomes. In addition, the presentation will describe the alignment of this initiative with other projects, such as the Joint FAO/WHO Expert Committee on Food Additives (JECFA) project to update the guidance on evaluation of the genotoxicity of chemical substances in food as part of their effort to evaluate the carcinogenicity of food use pesticides and herbicides and the National Institute of Environmental Health Sciences/National Toxicology Program initiative to better characterize carcinogenicity mechanisms.


14-5

In silico toxicological protocols are starting to be used to support risk assessments. For food applications, the ultimate goal is to obtain quantitative toxicity predictions that can be used to establish a margin of exposure (MoE), which informs on the safety concern. In practice, the process begins with an assessment of all relevant hazard-related information available (e.g., mechanisms, DNA reactivity, alerts for developmental toxicity) using a combination of available and in-house data as well as different in silico predictions. This information is important for selecting the most appropriate quantitative toxicological prediction in order to calculate the MoE. When all information has been merged, data reliability is determined through a new reliability scoring method. Therefore, the protocol outlines the confidence associated with the final results after analyzing the completeness, reliability, and relevance of all the information. This presentation will describe the use of the protocols to support the safety assessment of real-world case studies (food ingredients, contaminants, and packaging migrants) and how the principles outlined in the protocols can be practically used to perform hazard identification and characterization. It will explain how the rules and principles outlined in the protocol are used to predict and assess the confidence for some toxicological endpoints (such as mutagenicity and reprotoxicity) as well as the role of expert review throughout the complete process. The benefits associated with the use of in silico protocol principles and the lessons learned from this process will be also illustrated.



Wednesday,

Session Chairs: Christopher Ellis, US FDA/CDER, Silver Spring, MD; and
Christopher Bowman, Pfizer Inc., Groton, CT

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 FDA 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 panel discussion regarding practical aspects of writing an informative label as well as considerations for best practices in labeling.


15-1
9:00 AM–9:25 AM
Overview of Current Regulations and Guidance for Including Nonclinical Data in Prescription Drug Labeling
Mukesh Summan, US FDA/CDER, Silver Spring, MD
15-2
9:25 AM–9:50 AM
Using Nonclinical Data to Communicate Human Pregnancy Risk
Dinesh Stanislaus, GlaxoSmithKline plc, Collegeville, PA
15-3
9:50 AM–10:15 AM
Communicating Risk for Use in Specific Populations: Pediatric Use and Lactation
LaRonda L. Morford, Eli Lilly and Company, Indianapolis, IN
10:15 AM–10:45 AM
Break
15-4
10:45 AM–11:10 AM
Use of Nonclinical Data to Communicate Risk in Females and Males of Reproductive Potential
Christopher Bowman, Pfizer Inc., Groton, CT
15-5
11:10 AM–11:35 AM
Communicating Nonclinical Toxicology Data in Labeling
Ilona Bebenek, US FDA/CDER, Silver Spring, MD
15-6
11:35 AM–12:00 Noon
Panel Discussion: Practical Aspects and Considerations for Best Practices in Labeling

 


15-1

On January 24, 2006, the US FDA issued final regulations governing the content and format of prescribing information (PI) for human drug and biological products. The rule is commonly referred to as the Physician Labeling Rule (PLR) because it addresses prescription drug labeling that is used by prescribers and other health care providers. The goal of the PLR content and format requirements as described at 21 CFR 201.56 and 201.57 is to enhance the safe and effective use of prescription drug products by providing health care providers with clear and concise PI that is easier to access, read, and use. The PLR format also makes PI more accessible for use with electronic prescribing tools and other electronic information resources. Similarly, the Pregnancy and Lactation Labeling Rule (PLLR) requires changes to the content and format for information presented in prescription drug labeling to assist health care providers in assessing benefit versus risk and in subsequent counseling of pregnant women and nursing mothers who need to take medication, thus allowing them to make informed and educated decisions for themselves and their children. This presentation will provide a general overview of the PLR, with specific emphasis on the PLLR.


15-2

Communicating the risk to a human pregnancy is central to the PLLR. It is not always clear what hazards identified in animal reproduction studies would constitute a relevant risk of importance to a human pregnancy. As hazard communications that would be included in the risk summaries would vary depending on the context of the observations, there are no clear rules. Therefore, examples and hypothetical scenarios will be utilized to provide an appreciation for what may be appropriate to include in a product label. The discussion will revolve around the importance of species concordance, exposure multiples, maternal toxicity, and types of hazards. Appropriate ways to communicate these risks will be explored.


15-3

Communicating risk information, based on animal toxicology data, contributes to the safe and effective use of approved pharmaceutical products. This presentation will provide unique considerations for communicating risk in clear language for specific populations (Sections 8.2 and 8.4) based on the PLLR and the recent US FDA guidance “Pediatric Information Incorporated into Human Prescription Drug and Biological Product Labeling” (2019). Practical aspects of writing an informative label and several case examples will be described.


15-4

A new, dedicated section of United States Package Insert (USPI) communicates risk to females and males of reproductive potential. The inclusion of this section in the USPI is optional and dependent on the presence of reproductive risk. At the time of new drug approval, the presence of reproductive risk is typically based on nonclinical data but would also account for any available clinical data. There are three possible subsections, including pregnancy testing, contraception, and infertility. Data in pregnant animals and genotoxicity testing are primarily used to determine whether risk communication includes pregnancy testing or contraception. Data from repeat-dose toxicity and fertility studies in animals are usually used to determine whether communication of infertility risk should be included. There is limited guidance on how nonclinical data should be used; thus, there is much inconsistency and variability across the USPI of approved products. Therefore, different product profiles will be used as examples to describe how this new section of the USPI is used to communicate risk in females and males of reproductive potential, including a scientifically based rationale for male and female contraception.


15-5

This presentation will focus on communication of nonclinical toxicology data (carcinogenicity, genotoxicity, fertility, and other animal toxicology and/or pharmacology) in Section 13 of a pharmaceutical label. Federal regulations, content requirements, and format, as well as case examples, will be discussed with respect to each subsection. In addition, special considerations for each subsection will be discussed.


15-6

The panel will discuss specific considerations related to Section 8 and/or 13 of labeling and will answer questions from the audience. Specific questions will be provided to help direct the discussion.

Session Chairs: Saurabh Vispute, Pfizer Inc., Groton, CT;
Jessica Sapiro, Allergan, Irvine, CA; and Caroline Moore, San Diego Zoo Global, San Diego, CA

This interactive Workshop is presented by the ACT Early Career Professional (ECP) Subcommittee. As we advance through our careers, we benefit from building professional relationships and receiving mentoring from our peers, senior colleagues, managers, and friends, inside and outside our organization. The why, when, and how of developing and building such relationships, with anecdotal case studies and examples shared by early and advanced career professionals, will be discussed. 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 will consist of talks by an experienced manager at a 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 of the Workshop 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 during which the speakers will offer on-site mentoring. Audience participation is strongly encouraged.


16-1
9:00 AM–9:10 AM
Introduction
Saurabh Vispute, Pfizer Inc., Groton, CT
16-2
9:10 AM–9:30 AM
Managing Your Career Progression: A Manager’s Insight
Laura Andrews, AbbVie Inc., Worcester, MA
16-3
9:30 AM–9:50 AM
A Career Mentoring Relationship: A Resource to Maximize Growth and Development
Kristina Chadwick, Bristol-Myers Squibb Company, New Brunswick, NJ
16-4
9:50 AM–10:15 AM
Back to School for Advanced Degree and Beyond: How to Maximize Career Development through Mentoring
Jessica Sapiro, Allergan, Irvine, CA
10:15 AM–10:45 AM
Break
16-5
10:45 AM–10:55 AM
Case Study: How to Seek a Mentor Outside Your Organization
Caroline Moore, San Diego Zoo Global, San Diego, CA
16-6
10:55 AM–11:05 AM
Case Study: Balancing Professional and Personal Goals and Why Honest and Open Dialogue Is Important
Saurabh Vispute, Pfizer Inc., Groton, CT
16-7
11:05 AM–11:15 AM
Case Study: How Your Mentoring Relationship Can Help You Evaluate and Influence Your Career Transitions and Choices
Krista Greenwood, INDS, Inc., Ann Arbor, MI
11:15 AM–12:00 Noon
Interactive Discussion

 


16-1

The introduction will briefly orient the audience with the Workshop Session. Specifically, this presentation will serve as an introduction to goals of a relationship and the various types of relationships that will be discussed. This Workshop will cover key components of building an effective mentoring relationship; aspects of evaluating relationships, including self-assessment/peer assessment; perspectives of early career and advanced career professionals; interactive on-site mentoring; and information about the ACT Mentorship Program.


16-2

This talk will discuss the role of a manager in career progression and how a manager acts as a catalyst for career development. A great manager possesses strong leadership skills that are passed on to employees and both attracts them and stimulates growth. A manager brings different attributes to the table that may not have been appreciated during a graduate or postdoc period. While a manager is responsible for the goals and performance of their function and the people in that function, there is an added accountability upward to senior management for project performance and overall attainment of business goals. A good manager can be instrumental in defining and building critical characteristics of successful toxicologists, including inquisitiveness, patience, attention to detail, strong verbal and written communication skills, ability to work on diverse teams, and business acumen. Each employee has unique skills, and a strong, healthy employee-manager relationship may define how an employee grows as a successful toxicologist. Critical characteristics that make an employee successful in their daily job functions and how to develop a rapport with a manager will be shared. Good toxicologists in industry may become managers themselves, and key steps early career professionals can take to become a people manager and/or functional area manager in the future will be provided.


16-3

Mentorship is a relationship in which a more experienced or more knowledgeable person helps guide a less experienced or less knowledgeable person. By definition, anyone can be a mentor at any stage of their life or career. A career mentor focuses on professional development and assistance. A mentee can have multiple mentors throughout their career as needs and situations evolve. This talk will begin by discussing the role of a mentor and a mentor-mentee relationship. A mentor helps guide a mentee in reaching their career goals and aspirations. The mentor-mentee relationship shares common traits with many other types of relationships, including respect, strong communication, vulnerability and establishment of trust, and authenticity. This relationship is one that typically involves a long-term, ongoing commitment and a genuine investment in helping the other person accomplish desired goals and grow. A manager can provide mentorship by providing advice to help the employee develop, but in many cases, that will be associated with the organization’s priorities. A career mentor not associated with performance evaluation can focus on providing advice in the best interests of their mentee. Following the discussion of this type of relationship, examples of topics a mentor and mentee can discuss that are applicable to early career scientists will be provided, including honing communication skills, managing stress, navigating difficult situations, working with challenging individuals, developing leadership skills, and transforming from trainee to early and mid-career professional.


16-4

This session will discuss how mentoring can advance your career. Managerial relationships and career mentoring relationships apply to any individual’s career. The first part of this talk will provide insights on how to be a good mentee, whether that is working with a career mentor or attributes that will drive a manager to provide mentorship. Subsequently, the speaker will share a predoctoral biopharma experience working in the toxicology group that led to a toxicology career. The role of a manager in helping to foster this career path yet providing skills to make independent choices will be described. Critical transferable skills acquired during the technician experience—including multidisciplinary teamwork; defending oneself and one’s beliefs; networking internally within an organization and externally in the community; developing a positive attitude with big-picture, holistic thinking; and working with a manager—will be delineated. The speaker will explain the role of transferable, interpersonal, and scientific skills in an academic doctoral degree setting, and the value of obtaining a career mentor during graduate training will be emphasized. An application of the skills acquired throughout the speaker’s career will be shared. Lastly, insights on when to consider further growth and what those opportunities may look like in a drug development toxicology career will be discussed.


16-5

This case study will outline how a mentor can impact early career transitions at a time when you may feel overwhelmed with the options (or lack of options) available to you.


16-6

This case study will discuss how using effective communication skills with your mentor can not only streamline your professional goals but also ensure you have the time and energy to meet your personal goals, too.


16-7

This case study will elaborate on how developing a network of mentors outside your current position and reaching out of your comfort zone can take your career path in new directions. This can help you rationally evaluate options and redirect you if first (or second or third) choice ideas don’t succeed as anticipated. This talk will also briefly outline the ACT Mentorship Program and how mentees can benefit from your own career progression.

Session Chairs: Paul Baldrick, Covance Inc., Harrogate, NSN, United Kingdom; and
Mary Ellen Cosenza, MEC Regulatory & Toxicology Consulting, LLC, Moorpark, CA

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 FDA 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.


9:00 AM–9:05 AM
Introduction
Mary Ellen Cosenza, MEC Regulatory & Toxicology Consulting, LLC, Moorpark, CA
17-1
9:05 AM—9:20 AM
Handling Adverse and Nonadverse Toxicology Findings
Paul Baldrick, Covance Inc., Harrogate, NSN, United Kingdom
17-2
9:20 AM 9:50 AM
Generating, Interpreting, and Communicating Adverse and Nonadverse Pathology Data from Animal Toxicity Studies
Brad Bolon, GEMpath Inc., Longmont, CO
17-3
9:50 AM–10:15 AM
How Adverse and Nonadverse Findings Have Affected Product Development
Melissa Rhodes, Dance Biopharm Inc., San Francisco, CA
10:15 AM–10:45 AM
Break
17-4
10:45 AM–11:15 AM
An MHRA Perspective on Handling Adverse and Nonadverse Toxicology Findings
Ian Waterson, Medicines and Healthcare Products Regulatory Agency, London, GLD, United Kingdom
17-5
11:15 AM–11:45 AM
A US FDA Perspective on Handling Adverse and Nonadverse Toxicology Findings
Tessie P. Alapatt, US FDA/CDER, Silver Spring, MD
11:45 AM–12:00 Noon
Panel Discussion

 


17-1

The role of toxicology testing is to screen out toxic molecules and to identify adverse findings that are of a safety concern in the clinic, allowing appropriate monitoring. However, 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 NOAEL. This presentation will introduce examples of the study findings considered adverse and nonadverse and how an understanding of “expected pharmacology,” mechanism of action not relevant to humans, and species-specific and other situations are vital in characterizing findings.


17-2

Anatomic and clinical pathology diagnoses are professional interpretations in which objective observations are judged in the context of prior individualized experience. To optimize diagnostic consistency, pathologists define adverse as “harm” and nonadverse as a lack of harm in relation to effects to a test species for a given study. Adverse findings may be identified in subreports (clinical data, pathology data, etc.) and/or the final study report, but the NOAEL should be established at the level of the overall study report. Decisions defining adverse findings and the NOAEL in final study reports should combine the expertise of all contributing scientific disciplines to provide the clearest and most concise “weight of evidence” (WOE) foundation for science-based decision-making.


17-3

The determination of findings being adverse or nonadverse can significantly affect a compound’s developability. Adverse findings can halt or delay clinical development depending on a number of factors, including the type of finding, monitorability, reversibility, clinical indication, and therapeutic index (exposure margin). However, adverse findings are not the only consideration in product development. Nonadverse findings can lead to significant alterations in clinical development plans, biomarker analyses, or inclusion/exclusion criteria. Furthermore, both adverse and nonadverse findings may require in-depth scientific justifications for health authorities. This presentation will provide case studies of how adverse and nonadverse findings in toxicology studies affected product development.


17-4

The talk will deal with two aspects of handling adverse and nonadverse toxicology findings—first during a submission for a clinical trial authorisation (CTA) application and second reporting new toxicology findings to the Agency while a clinical trial is ongoing. The talk will also cover what the Agency considers to be adverse and nonadverse, risk mitigation processes, and how sponsors can liaise with the Agency to receive advice or discuss findings.


17-5

This presentation will give an update on how adverse and nonadverse findings in toxicology testing are assessed from a US FDA perspective from review of data submitted to the Agency. Examples will be presented from across drug classes, and how they are evaluated from a safety perspective will be discussed. It will be shown how agreement on their interpretation for risk assessment occurs with sponsor companies.


Session Chairs: Joseph A. Francisco, Charles River, Woodway, WA; and
Jane J. Sohn, US FDA, Olney, MD


18-1
2:00 PM—2:40 PM
TCR 2.0: Reviewing Experience with Methods to Detect Off-Target Binding of Monoclonal Antibodies
Timothy K. MacLachlan, Novartis, Cambridge, MA
18-2
2:40 PM 3:15 PM
Regulatory Considerations for Human Gene Therapy Products Involving Genome Editing by CRISPR/Cas: A CBER Perspective
Sandhya Sanduja, US FDA/CBER, Silver Spring, MD
3:15 PM–3:45 PM
Break
18-3
3:45 PM–4:20 PM
Investigating the Molecular Potentiation of Cutaneous and Systemic Damage Inflicted by Co-Exposure to Solar UV Radiation and Chlorination Stress Originating from Swimming Pool Disinfectants
Georg T. Wondrak, Univeristy of Arizona, Tucson, AZ
18-4
4:20 PM–5:00 PM
TBA
Valerie E. Ryder, NASA, Houston, TX

 


18-1

Monoclonal antibodies and derivatives thereof have become a mainstay pharmaceutical modality. A primary benefit of these proteins is their highly targeted nature which can reduce the incidence of side effects in patients. It is critical however to ascertain the specificity of antibodies prior to human clinical trials, and several country and worldwide guidances direct sponsors to evaluate this. For the last two decades, the primary technique for determining specificity has been the immunohistochemistry (IHC) based “Tissue Cross Reactivity” assay (TCR), where the candidate antibody is panned across 32 tissues to look for unexpected staining. In the last few years however, other array-based platforms have emerged that allow for screening the majority of the human membrane proteome, indicating a viable alternative and/or addition to the IHC methods. Additionally, a “Q&A” to the ICH S9 guidance in 2018 indicated that TCR assays are not required in most situations for oncology biotherapeutics. The preclinical advocacy arm of the Biotechnology Industry Organization, “Biosafe”, has conducted a survey of 26 BIO member companies to understand current sponsor experience with the IHC and array techniques for determining antibody specificity. In the last ten years, more than 650 IHC TCR assays have been conducted largely on full length mAbs with varying impacts on programs. Protein/cell arrays have been utilized by a third of the companies surveyed and are gaining familiarity and comfort with the platform—initial experience with recent versions of these arrays has been largely positive and are integrating new modalities such as scFvs from CAR-T therapies. ICH S6R1 guidance offers sponsors the option to use alternatives to IHC to determine antibody specificity—while most sponsors are not prepared to eliminate the IHC method, growing experience with these alternatives may allow them to confidently choose one with or without IHC in the future. Details on sponsor responses and experience will be shared in this session.


18-2

Over the past decade, interest in human genome editing as a therapeutic modality for the treatment of human disease has increased exponentially. While the potential benefit of this technology is apparent, the risks are not as well understood. Thus, the transition of these gene therapy products to clinical trials requires comprehensive characterization of product risks and how they can be mitigated. This presentation will describe the existing regulatory framework to assess the safety and activity profiles of CRISPR/Cas-based gene edited therapeutic products to enable administration in early-phase clinical trials. This presentation will provide a general overview of CBER/OTAT considerations for preclinical proof-of-concept and safety assessment of these novel products.


18-3

Hypochlorous acid (HOCl) is the active oxidizing principle released by standard swimming pool disinfectants used on a global scale, but the health consequences of human exposure inflicted by HOCl remain largely unknown, posing a major public health concern relevant to populations around the world. Environmental exposure to solar ultraviolet (UV) radiation is a causative factor in skin photocarcinogenesis, and immune suppression is a key mechanism underlying detrimental effects of acute and chronic UV exposure. Our preliminary data indicate that HOCl exposure greatly potentiates the genotoxicity of solar UV photons thought to originate from oxidative DNA base modifications caused by this potent electrophile. Moreover, we have observed that the key modulators of UV-induced systemic immunosuppression, cutaneous dendritic cells (Langerhans cells), are hypersensitive to the cytotoxic effects of HOCl, suggesting a potentiation of immunotoxic effects of solar UV, relevant to skin barrier function, systemic inflammatory disease, and carcinogenesis. Our ongoing research explores the molecular potentiation of UV-induced cutaneous and systemic damage by co-exposure to HOCl-based swimming pool disinfectants, examined in cell culture, skin tissue models, and mouse models of UV-induced skin damage and cancer. The public health relevance of human exposure to chlorination stress (mediated by HOCl) and solar radiation in the context of recreational swimming pool use creates an urgent need for detailed molecular investigations. The ultimate goal of this research is to substantiate occurrence and molecular nature of adverse health effects that result from this relevant environmental co-exposure.


18-4

A vision for a return to the moon means providing an environment aboard manned spacecraft capable of supporting astronaut health and safety. Experts within the Toxicology and Environmental Chemistry (TEC) group at Johnson Space Center establish safe spacecraft environmental limits and assess air and water quality aboard current spacecraft (International Space Station (ISS) and Commercial Cargo). Safety assessment of travel to and from the moon will be compared and contrasted to traditional risk assessments and development of allowable exposures.

Session Chairs: Eric Harstad, Theravance Biopharma, South San Francisco, CA; and
Matthew Whittaker, US FDA/CDER, Silver Spring, MD

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 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.


19-1
2:00 PM–2:15 PM
Introduction: SEND Workshop
Joseph Horvath, Bristol-Myers Squibb Company, New Brunswick, NJ
19-2
2:15 PM–2:35 PM
Successes and Challenges with SEND: Sponsor Perspective on Outsourcing SEND Generation
Mark Carfagna, Eli Lilly and Company, Indianapolis, IN
19-3
2:35 PM–2:55 PM
SENDsationally Complex Dataset Generation Approaches in the Biotech World: Sponsor Perspective on In-House SEND Generation
Shameen Afif-Rider, AstraZeneca, Gaithersburg, MD
19-4
2:55 PM–3:15 PM
Blueprint for the Small Company/Consultant
Kenjie Amemiya, Aclairo Pharmaceutical Development Group, Inc., Pleasanton, CA
3:15 PM–3:45 PM
Break
19-5
3:45 PM–4:05 PM
Computer-Aided Toxicology Study Interpretation
Mandie Rhodes, Bristol-Myers Squibb Company, Princeton, NJ
19-6
4:05 PM–4:25 PM
The Impact of SEND Data on US FDA Review of Nonclinical Studies
Matthew Whittaker, US FDA/CDER, Silver Spring, MD
19-7
4:25 PM–4:45 PM
Improving SEND Submissions to the US FDA
Patricia Brundage, US FDA/CDER, Silver Spring, MD
4:45 PM–5:00 PM
Panel Discussion

 


19-1

This introduction will set the stage for this Workshop on SEND and will describe in brief (1) the basis of the SEND model, (2) the timeline of SEND development, (3) considerations for implementing SEND, and (4) the future direction of SEND.


19-2

This is the first in a series of presentations that will cover sponsor experiences with SEND from three different perspectives. Pharmaceutical companies have taken various approaches to prepare SEND datasets for regulatory review. Examples of SEND data strategies that include outsourced, in-house, and small company viewpoints will be covered. This presentation will focus on outsourcing of SEND preparation. Additionally, quality and timing of SEND datasets, internal interpretation and warehousing, and challenges associated with implementation of SEND will be discussed.


19-3

This is the second in a series of presentations that will cover sponsor experiences with SEND from three different perspectives. This presentation will focus on in-house SEND creation; challenges with interim submissions, as well as data warehousing and QC of datasets.


19-4

This is the third in a series of presentations that will cover sponsor experiences with SEND from three different perspectives. This presentation will discuss approaches used by small companies, start-ups, and consultants, with a specific focus on unique challenges and strategies for SEND with limited resources.


19-5

Through study data standardization brought by CDISC SEND, data visualization tools are now being used to facilitate study interpretation. We will explore some of the advantages of interactive data visualizations, some of the specific views that are enabling faster high-quality study interpretations, and how extending these capabilities to cross-study analysis may unlock even greater value.


19-6

The US FDA Center for Drug Evaluation and Research (CDER) is implementing the use of software tools that allow nonclinical reviewers to take advantage of the availability of SEND datasets. Reviewers will be able to analyze study results from multiple perspectives, as they will no longer be limited by the single perspective presented by the static tables and figures in PDF study reports. The use of SEND datasets is expected to increase the efficiency of nonclinical review processes and lead to more informed regulatory decision-making.


19-7

Submission of quality SEND datasets to the US FDA is necessary for reviewers to effectively review the data. Awareness of frequent data standard implementation issues identified by the US FDA, which impact the usability of the data, will improve the quality of future submissions. A better understanding of the Technical Rejection Criteria and the Technical Conformance Guide is also expected to improve the submission of SEND datasets to the US FDA and ultimately improve the regulatory review process.