Continuing Education Courses

Chairpersons: Lorrene Buckley, Eli Lilly and Company, Indianapolis, IN; Hanan Ghantous, US FDA/CDER, Silver Spring, MD; and Caitlin Murphy, Smithers Avanza, Gaithersburg, MD

Drug development is a term used to define the entire process of bringing a new drug or device to the market. It is an integrated, multidisciplinary endeavor which includes drug discovery, chemistry and pharmacology, nonclinical safety testing, manufacturing, clinical trials, and regulatory submissions. This workshop will overview the contributions of each area, with a focus on safety assessment, and some of the challenges that can arise. The role of CMC will be discussed in the context of early and late stage product development and approaches to assess, control and limit impurities. The importance of toxicological assessment will be discussed from selection of a candidate drug through determination of a FIH start dose. Clinical trial development and progress will be discussed in the context of regulatory requirements. Lastly, we will discuss the different types of nonclinical FDA submissions, issues and considerations in the review process of these submissions and case examples of what not to do, as well as advice on how to write a good IND/NDA.

Introduction
Hanan Ghantous, US FDA/CDER, Silver Spring, MD

Chemistry, Manufacturing, and Controls (CMC): What Goes In, What Goes On, and What Comes Out
Eric Jensen, Consultant, Indianapolis, IN

The Role of Toxicology in Drug Development
Paul Cornwell, Eli Lilly and Company, Indianapolis, IN

Introduction to Clinical Trials
Aimee Hodowanec, US FDA/CDER, Silver Spring, MD

Regulatory Submissions and the Review Process
Ilona Bebenek, US FDA/CDER, Silver Spring, MD

Chairpersons: Jay Tibbitts, AbbVie, San Francisco, CA; and Andrew Vick, Charles River, Ashland, OH

The process of advancing potentially therapeutic molecules from discovery to early clinical trials can be costly, time consuming, and be associated with considerable uncertainty and risk. There are three key areas where uncertainty and risk need to be evaluated, and important decisions made regarding the future of a candidate molecule: transition to first-in-human development, predicting the human efficacious dose, and selecting the maximum recommended starting dose and dosing scheme for the first in human trial. In this session we will discuss how PKPD and other quantitative pharmacology approaches can be applied to provide a more quantitative assessment of feasibility and risk, and inform better decision making for drug candidates.

The Therapeutic Index: A Tool for Informing Molecule Selection and Advancement–Potential
Jay Tibbitts, AbbVie, San Francisco, CA

Translating PK/PD from Animals to Humans, and Predicting the Human Efficacious Dose–Potential
Brian Stoll, AbbVie, Worcester, MA

Predicting the Optimal Dose and Dose Regimen in Early Clinical Trials
Jessica Hawes, US FDA/CDER, Silver Spring, MD

Chairpersons: David Jones, MHRA, London, United Kingdom; and Martin Green, US FDA/CBER, Silver Spring, MD

The World Health Organization (WHO) has played a key role for over 50 years in establishing the international biological reference preparations necessary to standardize vaccines and other biological substances as well as developing WHO guidelines and recommendations (written standards) on the production, control, nonclinical and clinical evaluation of biological products. However, nonclinical requirements have changes, especially with the need to rapidly progress new products into the clinic (e.g., for Ebola and Zika). The session will discuss how regulatory requirements for vaccines has evolved and will present case examples of novel nonclinical approaches.

What’s New in the EU Regulatory Arena for Vaccines?
David Jones, MHRA, London, United Kingdom

Risk Assessment of Vaccines Relative to the FDA’s Predictive Toxicology Roadmap
Martin (David) Green, US FDA/CBER, Silver Spring, MD

Dose Site-Related Study Findings following Administration of Vaccines
Paul Baldrick, Covance, Inc., North Yorkshire, United Kingdom

Case Studies on Regulatory Toxicology for Prophylactic Vaccines for the Developing and Developed World—Challenges and Approaches
Judith Baumeister, GlaxoSmithKline, Wavre, Belgium

Chairpersons: Nicholas Macri, Envigo, Albuquerque, NM; and K. Kumar Chanagi, Cambridge, United Kingdom

Safety assessment of inhaled therapeutics and chemicals, both industrial and environmental, requires detailed evaluation of the upper respiratory tract along with other standard protocol tissues. Regulatory agencies require the assessment of specific areas of the nasal cavity, larynx, trachea, and lungs in rodent and non-rodent animal models. Although histopathological changes in these organs are well-characterized in the literature, interpretation of their adversity and relevance to man are less clear-cut. The first half of this session will focus on methodologies used to deliver drugs by inhalation and the deposition patterns of inhaled drugs. Presentations on common background and test article-associated changes in different species, and comparative sensitivities of the upper respiratory tract, will cover the histopathological aspects of inhalation studies and their relevance to man. During the second half of the session, the importance of pulmonary macrophages in respiratory health and disease and models used in inhalation studies will be addressed. The final talk will focus on the use of imaging strategies for lung function. This will include MRI, CT, SPECT, PET, and optical modalities, which are being used in the pharmaceutical industry to understand disease in a longitudinal fashion. These modalities increase our understanding of drug delivery and allow discrimination of different aspects of lung pathology, including ventilation deficits, lung perfusion, pulmonary edema, cell migration, and fibrotic lesions.

An Introduction to the Inhalation Study: Methods of Exposure and Tissue Processing
Alison Rowles, GlaxoSmithKline, Herts, United Kingdom

Evaluation of Common Background and Test Item-Associated Microscopic Changes in the Upper Respiratory Tract of Rodents and Dogs in Inhalation Studies
Nicholas P. Macri, Envigo, Albuquerque, NM

Comparative Sensitivities of the Upper Respiratory Tract in Laboratory Animals
Vasanthi Mowat, Envigo, Cambridgeshire, United Kingdom

An Overview of Pulmonary Macrophages in Health, Disease and Medicines Development
Kristen J. Nikula, Seventh Wave Laboratories, Maryland Heights, MO

Strategy and Methodologies for Assessing and Interpreting Respiratory Function Endpoints in Toxicology Studies
Ronald Wolff, RK Wolff Safety Consulting Inc, Fort Myers, FL

Imaging Strategies to Discriminate and Characterize Lung Pathology and Function
K. Kumar Changani, Cambridge, United Kingdom

Chairperson: Patricia C. Ryan, MedImmune, LLC
AAAS Facilitator: Mary Catherine Longshore

Join your colleagues for an American Association for the Advancement of Science Communicating Science workshop specifically designed to help you plan and participate in a wide variety of public engagement activities. During this 3-hour workshop designed for scientists and engineers, you will develop your public engagement and science communication skills through discussion, self-reflection, small-group work* and practice sessions. The workshop focuses on the importance of effective, two-way communication and is designed to enable you to engage in meaningful, reciprocal dialogue with diverse audiences. When the session is complete, you will be able to clearly identify a public engagement goal, define a relevant audience, and craft and rehearse messages tailored to that audience.

*This course will not use the standard CE booklet format but will supply participants with handouts and workshop material. Upon completion of the course, an optional survey will be provided for those who choose to opt-in for additional resources provided by AAAS.

Chairpersons: Douglas Ball, D&B ChemTox, LLC, Southbury, CT; and Elizabeth Martin, AstraZeneca, Cambridge, United Kingdom

Leachables from pharmaceutical container closure systems can present potential safety risks to patients. Extractables studies may be performed as a risk mitigation activity to identify potential leachables for dosage forms with a high degree of concern associated with the route of administration. To address safety concerns, approaches to toxicological safety evaluation of extractables and leachables have been developed and applied by pharmaceutical manufacturers. This CE course provides a perspective on approaches to safety evaluations by reviewing and applying general concepts and integrating key steps in the toxicological evaluation of individual extractables or leachables.

Overview of Practices for Extractables and Leachables Studies
Cheryl Stults, C&M Technical Consulting, San Mateo, CA

Toxicological Safety Assessment for Extractable and Leachable Studies (E&L): Case Study 1
Uma Bruen, Merck & Co., Kenilworth, NJ

Toxicological Safety Assessment for Extractable and Leachable (E&L) Studies: Case Study 2
Brad Stanard, AstraZeneca, Gaithersburg, MD

PQRI PDP Best Practices: Use of a Classification Strategy to Develop Analytical and Safety Thresholds for Parenteral Drug Products
Douglas Ball, D&B ChemTox, LLC, Southbury, CT

Nonclinical Review of Extractable Leachable Studies: Practical Advice from an FDA Reviewer
R. Daniel Mellon, US FDA/CDER, Silver Spring, MD

Chairpersons: Matthew Abernathy, Eli Lilly, Indianapolis, IN; and Elizabeth Hausner, US FDA/CDER, Silver Spring, MD

The cardiovascular system is an intricate meshwork of organ structures regulated by multiple feedback loops to maintain organ perfusion, deliver fuel, and remove cellular waste. Due to the range of CV targets that are dispersed throughout our many tissues, it should be of no surprise that a high percentage of drug attrition falls at the feet of cardiovascular findings both pre-clinically and clinically. Given the high exposures achieved and techniques used to assess CV safety in preclinical models, the number of preclinical observations of CV effects generally exceeds the prevalence of effects observed clinically. Findings may range from cardiomyopathy to arrhythmia, and not all CV safety signals carry the same weight when deciding to continue to develop a compound. Thus, safety margin and target patient population heavily influence judgment-based development decisions beginning early on in compound discovery. This course will focus on mechanisms for both histological and functional cardiac effects encountered during drug development. Additionally, decision-making strategies for unexpected CV effects and use of in silico models to predict the mechanism and translation of cardiac effects to the clinic will be covered in depth.

Cardiac Toxicity: Options from a Regulatory Perspective
Elizabeth Hausner, US FDA/CDER, Silver Spring, MD

Integrative Cardiovascular Toxicologic Pathology- Building Translational Bridges
Brian Berridge, NIEHS/NTP, Durham, NC

Measuring, Interpreting, and Decision Making Based on Drug-Induced Hemodynamic Effects, Case Studies in Diabetes and Oncology
Derek Leishman, Eli Lilly and Company, Indianapolis, IN

Safe QTc Prolongation? How the Comprehensive In Vitro Proarrhythmia Assessment Will Spare Nontorsadogenic Molecules that Prolong Cardiac Repolarization (QTc Interval)
Wendy Wu, US FDA/CDER, Silver Spring, MD

In Silico Modeling in Cardiorenal Safety Assessment
Melissa Hallow, University of Georgia, Athens, GA

Chairpersons: Debra Kirchner, Covance, Madison, WI; and William Brock, Brock Scientific Consulting, Montgomery Village, MD

Assembly of quality, safety and efficacy information as an electronic common technical document (CTD) is described in the ICH M4. The CTD format supports regulatory review processes and a globally harmonized electronic submission. The electronic CTD format is required at the time of submission for a new drug application (e.g., IND, NDA, MAA, etc.). A great deal of time is expended to prepare the eCTD to ensure that all data required for submission are adequately described, key messages of the clinical drug development plan are thoroughly and accurately explained, and the format is consistent with the Sponsor’s style guide and requirements. Similarly, review of the drug application by the regulatory reviewer takes considerable time which may need to be compressed depending on the timeframe required for approval such as the case with break-through therapies. This session will explore the development of the CTD, covering all aspects of preparation and review. Although the focus of this course is on the nonclinical modules, the presentations will also include the relationship of the nonclinical modules to other modules of the CTD (e.g., clinical).

Scientific Content of the CTD and Organization: The Mechanics of the CTD
Debra Kirchner, Covance, Inc., Madison, WI

The Nonclinical Narratives: The Message, Scientific Review and Association with Other Modules
William Brock, Brock Scientific Consulting, LLC, Montgomery Village, MD

The CTD Maze: FDA Reviewers’ Quest for the Message
John Dubinion, US FDA/CDER, Silver Spring, MD

Regulatory Review of the CTD—A View from EMA
David Jones, MHRA, London, United Kingdom

Panel Discussion

Chairpersons: Mary Ellen Cosenza, MEC Regulatory & Toxicology Consulting LLC, Moorpark, CA; and Marque Todd, Pfizer, San Deigo, CA

Immunogenicity continues to be a challenge for preclinical studies of biologics. ICH S6 notes that biologics intended for humans are immunogenic in animals. This immmunogenicity can impact the conduct and interpretation of these studies both from a PK perspective (e.g., clearance of the product), a pharmacology perspective (e.g., neutralization of activity) or from a toxicology perspective (e.g., toxicity of immune complexes). This course will discuss the challenges of evaluating immunogenicity in preclinical studies including study conduct strategies, NOAEL interpretation and the relevance of this information for the planning and conduct of clinical trials.

Basics of Preclinical Immunogenicity: Assays and Data Interpretation
Jay Tibbitts, AbbVie, South San Francisco, CA

Immunogenicity-Related Toxicity
Michael W. Leach, Pfizer, Inc., Cambridge, MA

How to Manage Immunogenicity in a Toxicology Study
Jeanine Bussiere, Amgen, Inc., Thousand Oaks, CA

Regulatory Perspective on Nonclinical immunogenicity
Mary Ellen Cosenza, MEC Regulatory & Toxicology Consulting LLC, Moorpark, CA

Chairpersons: Joseph DeGeorge, Bianca Holdings, LLC, Lansdale, PA; and Timothy McGovern, US FDA/CDER, Silver Spring, MD

This session will review current practices for nonclinical safety evaluation of small molecules, which have been effective in supporting safe clinical trials, based on the experience of member companies from the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ)/DruSafe. Specific areas covered are based on a 2017 IQ/DruSafe publication on this topic (Butler et al, 2017), including target selection, computational/in silico evaluation, early discovery safety screening, exploratory and pivotal first-in-human (FIH)-enabling paradigms, and considerations impacting human risk assessment/mitigation strategies. Discussion of relevant regulatory guidelines and submission strategies will be covered, including perspectives from a health authority regulator, and industry experience with the EMA revised guideline on early clinical trials. Throughout, case study examples will illustrate the decision-making strategies used to assess and select the subset of molecules that eventually progress to FIH testing in humans. The culmination of the session will bring all the concepts together in a panel discussion with drug development experts representing industry and health authority(ies). Participants will gain a broader understanding of the approaches, concepts and decision-making strategies to design nonclinical safety programs and prepare successful submission dossiers, to enable safe clinical trial design and protect human safety.

Discovery Toxicology Screening
Dolores Diaz, Denali Therapeutics, San Francisco, CA

Exploratory In Vivo Safety Pharmacology and Toxicology Paradigms
James Hartke, Celgene Corporation, San Diego, CA

FIH-Enabling Nonclinical Packages, and the Decision Proceed to Clinical Trials—Non-Case Study Information (Part 1)
Alexandros Papanikolaou, Pfizer, Groton, CT

FIH-Enabling Nonclinical Packages, and the Decision to Proceed to Clinical Trials—Case Studies (Part 2)
Alexandros Papanikolaou, Pfizer, Groton, CT

Health Authority Perspectives on Nonclinical Program Design and Dossier Preparation
Timothy McGovern, US FDA/CDER, Silver Spring, MD

Panel Discussion