Continuing Education Courses

Continuing Educations (CE) courses are 3.5 hours each and are held either Sunday morning (AM) or Sunday afternoon (PM). Preregistration is required and seating is limited.

Sunday, November 6

(AM Courses) 8:00 AM–11:30 AM

(CE1) Exposure, Routes/Frequency of Administration and Nonclinical Formulations—The Toxicity Conundrum

SESSION CHAIRS: Holly D. Dursema, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT and Shayne C. Gad, Gad Consulting Service, LLC, Raleigh, NC

In nonclinical studies we attempt to achieve sufficient multiples of exposure by the planned clinical route of administration so that we can adequately explore on- and off-target toxicities. However, this may come at a price if the characteristics of the compound require novel excipients triggering additional investigations or require excipients with subtle, but very real, toxicities that could confound study interpretation. This course will discuss the rules around exposure and modifications to achieve increased exposure by being flexible and/or thinking outside of the box.

Introduction of Rules and Regulations around Dose Levels and Exposure—What Do They All Mean?
Matthew Bogdanffy, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT
All Is Good—Use of Nonclinical Formulations Containing Excipients With Well-Characterized Toxicities
Debie Hoivik, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT
When You Need to Bridge—Changing Formulations during Nonclinical Development
Evan A. Thackaberry, Genentech Inc., South San Francisco, CA
New Excipient(s) and the Safety Assessment of New Drug Candidates
R. Christian Moreton, FinnBrit Consulting, Waltham, MA
Achieving Adequate Drug Exposure in Nonclinical Studies—An FDA Perspective
Carol Galvis, US FDA, CDER, Silver Spring, MD

(CE2) The Role of the Toxicologist Post-IND Submission: What Comes Next?

SESSION CHAIRS: Mary Ellen Cosenza, MEC Regulatory & Toxicology Consulting, LLC, Moorpark, CA and Kristina DeSmet, United Therapeutics, Durham, NC

This course, developed by the Early Career Professional Outreach Subcommittee, will provide an overview of the role of the Toxicologist after an IND is submitted through the filing of an NDA, or BLA, and into the post-approval phase. A discussion of regulatory guidelines and timing of pivotal studies, developmental and reproductive toxicology studies, and carcinogenicity studies for small molecules and biologics will be discussed. An interactive session with case studies for small molecules and biologics will be conducted where participants are provided background information and the clinical development plan. Working in groups, participants will identify toxicology studies required to support the development plan. The final session will cover activities for registration and the role of the toxicologist following NDA/BLA submission including mandatory regulatory updates, post-approval changes, secondary indications, new formulations, and line extensions.

ICH M3 and the Timing of Toxicology Studies
Mary Ellen Cosenza, MEC Regulatory & Toxicology Consulting, Moorpark, CA
Developmental and Reproductive Toxicology Studies
Dinesh Stanislaus, GlaxoSmithKline, King of Prussia, PA
Carcinogenicity Study Planning and Timing
Ronald W. Steigerwalt, Takeda California, Inc., San Diego, CA
Registration, Postapproval, and Overarching Regulatory Responsibilities
Laura Dill Morton, Aclairo Pharmaceutical Development Group, Vienna, VA
Case Studies Aligning Toxicology and Clinical Development Plans
Robert F. Stachlewitz III, Charles River, Reno, NV

(CE3) The Breakthrough of Oligonucleotide Therapeutics: What Is Happening in between Small and Large Molecules?

SESSION CHAIRS: Sven Korte, Covance Preclinical Services GmbH, Münster, Germany and Brian Vuillemenot, Genentech Inc., South San Francisco, CA

This course is aimed for toxicologists, but equally provides a great summary for pharmaceutical and regulatory experts; a rare chance to get guided through this field by a variety of world leading experts. This course will define different classes of oligonucleotide-based drugs on the basis of mechanism of action and summarize the history of this compound class; characterize pharmacokinetics and toxicology properties of antisense oligonucleotide (ASO) drugs; describe how toxicology testing strategies might differ from typical small molecules; make you benefit from in depth knowledge when conducting intrathecal screening and chronic lumbar or port catheter studies in juvenile and mature cynomolgus monkeys (n=500); the course will help you to understand the clinical relevance of toxicity findings; and inform participants of the recent advancement in the antisense field and look to the future of the technology.

Targeting Long Noncoding RNAs: A New Therapeutic Paradigm
Balkrishen Bhat, RaNA Therapeutics Inc., Cambridge, MA
Approach to Nonclinical Safety Assessment for 2'-MOE Modified ASO: Attributes of a Platform Technology
Tae-Won Kim, Ionis Pharmaceuticals, Inc., Carlsbad, CA
US Regulatory Experience with Oligonucleotide-Based Therapeutics
Ronald L. Wange, US FDA, Silver Spring, MD
Conduct and Design of NHP Studies for First In-Man Studies
Sven Korte, Covance Inc. Preclinical Services GmbH, Münster, Germany
When Your Cup Runneth Over: Advances in Antisense Chemistry, Targeting, and Mechanisms
Scott Henry, Ionis Pharmaceuticals, Inc., Carlsbad, CA

(CE4) Analysis and Visualization of Nonclinical eData (SEND)

SESSION CHAIRS: Timothy McGovern, US FDA, CDER, OND, Silver Spring, MD and Lorrene Buckley, Eli Lilly and Company, Inc., Indianapolis, IN

The CDISC Standard for Exchange of Nonclinical Data (SEND) provides a standard for the interchange of nonclinical tabulation datasets between organizations such as pharmaceutical sponsors and CROs and for submission to a regulatory authority. The adoption of SEND by CDER/FDA is intended to facilitate timely and accurate review of nonclinical data submitted in support of human pharmaceutical applications. The submission of individual animal data as electronic line listings will allow easier storage and handling of the data and will permit reviewers (industry and regulatory) to more easily analyze and visualize the data.

Efforts to date have focused on how to develop SEND data packages (dataset, DEFINE file, and SDRG) of a quality that is fit for use. This session will provide a perspective on the handling and utility of SEND data from the perspectives of Pharmacology/Toxicology Reviewers in CDER and nonclinical safety assessment scientists in the pharmaceutical industry. Presentations will focus on the value of SEND analyses as well as the challenges faced by regulatory scientists, drug developers, and supporting industry partners.

Introduction: The SEND Parts of a Submission
Timothy McGovern, US FDA, CDER, OND, Silver Spring, MD
KickStart: A Primer for Analysis and Visualization of SEND Datasets at FDA
John Ho, US FDA, CDER, Silver Spring, MD
How an FDA Reviewer May View and Analyze Electronic Data Submitted in SEND
Imran Khan, US FDA, CDER, OND, Silver Spring, MD
Intra-Study Data Visualization and Analysis—Value of SEND to Toxicologists in Industry
Junguo (Joe) Zhou, Janssen Research and Development, LLC, Raritan, NJ
Applications of SEND Data in the Pharmaceutical Industry
Jeffrey Foy, Celgene, Summit, NJ and Kimberly Connelly, Celgene, Summit, NJ

(PM Courses) 1:00 PM–4:30 PM

(CE5) Biomarkers of Endocrine Effects and Reproductive Toxicity

SESSION CHAIRS: Adam Aulbach, MPI Research, Mattawan, MI and David Honor, AbbVie Laboratories, Worcester, MA

The evaluation of endocrine and reproductive clinical pathology endpoints in nonclinical safety studies presents a unique set of preanalytical, analytical, and interpretative challenges to the regulatory scientist. Regulatory guidance does not require the inclusion of these endpoints in traditional safety studies; however, they are sometimes incorporated without appropriate consideration for their use. These sessions will provide an overview of the current principles and approaches to assessing toxicity of the endocrine and reproductive systems with an emphasis on the appropriate selection and utility of endocrine biomarkers. Discussions will also focus on regulatory requirements for the inclusion of these markers and future directions for their use in the pharmaceutical industry and within drug development. These sessions will be of interest to both industry and regulatory pathologists and scientists.

Introductions
Adam Aulbach, MPI Research, Mattawan, MI
Overview of Reproductive Toxicology and DART Studies
Alan Hoberman, Charles River Laboratories, Horsham, PA
Reproductive Endocrinology and Toxicology in Female Nonhuman Primates
J. Mark Cline, Wake Forest School of Medicine, Winston-Salem, NC
Male Reproductive Toxicology, Evaluation of Inhibin B, and Future Directions
Robert E. Chapin, Pfizer, Inc., Groton, CT
The Use of Hormone Measurements in Preclinical Studies: Study Design, Analysis, and Interpretation
John O’Connor, DuPont, Newark, DE

(CE6) Carcinogenicity Studies: Perspectives on Design and Execution for Successful Product Registration

SESSION CHAIRS: Suzanne R.T. Wolford, Covance Inc., Madison, WI and Owen McMaster, US FDA, Silver Spring, MD

The guidelines for carcinogenicity testing of drugs and environmental chemicals have undergone recent revisions. In addition, the practical aspects of running these large studies create challenges even for those with experience. As the body of knowledge increases, so does the variability in study design and execution of these studies, raising many questions. This course will explore aspects of the study design, interpretation of data, and reporting. It will also include an interactive forum on the reporting and approval process.

Introduction and Overview of Guidelines
Suzanne R.T. Wolford, Covance Inc., Madison, WI
Practical Aspects of Design and Testing
Scott E. Boley, MPI Research, Mattawan, MI
Pathologic Evaluation and Interpretation of Data from Standard Carcinogenicity Models
Thomas Larsen, Covance Inc., Chantilly, VA
FDA Review of Carcinogenicity Studies and Status of ICH S1 and Implications
Todd Bourcier, US FDA, Silver Spring, MD
Carcinogenicity Study Outcomes: Impact on Biopharmaceutical Safety Assessment, Product Approvals, Labeling, and Postmarketing Surveillance
John Vahle, Eli Lilly and Company, Inc., Indianapolis, IN

(CE7) Derivation and Implementation of Health-Based Exposure Limits for the Pharmaceutical Industry

SESSION CHAIRS: Patricia Weideman, Sakari Consultants, LLC, Stratham, NH and Andrew Maier, University of Cincinnati, Cincinnati, OH

Health-based exposure limits have been used in pharmaceutical development and manufacturing to protect against potential adverse health effects. For many years, the most common application of health-based exposure limits has been for occupational exposure limits (OELs) which, as derivatives of acceptable daily exposures (ADEs), have been used to protect workers who manufacture or process pharmaceuticals. However, a transition to the use of ADEs to protect product quality has gained industry and regulatory interest. Recent regulatory scrutiny and international guidance have focused attention on prevention of cross-contamination in equipment or facilities, including residues of active pharmaceutical ingredients (APIs) that may be present in medicinal products produced subsequently in the same equipment or facility. Various empirical approaches have been used historically to manage cross-contamination issues and good manufacturing procedures (GMPs). In contrast to ADEs, these empirical approaches have not been based on current health-based risk assessment methods. Although ADEs are a step toward health risk-based decisions, the methods used to derive ADEs are complex and are not harmonized among various constituencies. This session will provide background and tools for toxicologists and regulators to better understand the basis, derivation, and application of these unique assessments for protection of patients and product quality.

Introduction
Patricia Weideman, Sakari Consultants, LLC, Stratham, NH
Why ADEs, Why Now?
Patricia Weideman, Sakari Consultants, LLC, Stratham, NH
Implementing Acceptable Daily Exposure Limits: Operational Considerations
Robert Sussman, SafeBridge Consultants, Inc., New York, NY
Application of Data-Derived Health Limits Versus Default Limits for Product Quality
Andrew Maier, University of Cincinnati, Cincinnati, OH
The Point of Departure as a Central Aspect of ADE Derivation
Joel Bercu, Gilead Sciences Inc., Foster City, CA
Fine-Tuning the Health-Based Assessment: Applying Adjustment Factors and Use of Pharmacokinetic Data
Bruce Naumann, Merck & Co., Inc., Kenilworth, NJ

(CE8) The Use and Misuse of Statistics in Toxicology

SESSION CHAIRS: Heidi Hsieh, Covance Inc., Madison, WI and Kenneth Olivier Jr., Merrimack Pharmaceuticals, Inc., Cambridge, MA

Participants are encouraged to bring their laptops in order to utilize the hands-on portion of this course. Google Chrome and MS Excel should be preloaded on laptop for optimal participation in the course.

Toxicology is a borrowing, complex, and highly integrated discipline, describing biological events resulting from exposure of organisms to chemical/biological entities. Mathematics, in the form of statistics, is applied to these events to evaluate any differences between test and control groups and to help predict “What’s the worst that can happen?”, usually to humans. This course will provide two presentations followed by hands-on work through examples, assisted by experienced mentors/toxicologists. Main topic: avoiding indiscriminate use of statistics in toxicology studies with small group sizes (n=3), with a focus on significance (i.e., toxicological > biological > statistical). Concepts to be covered and demonstrated include: statistical power versus group size; type of statistics that can be used sensibly with group sizes of less than five; continuous data analysis; overview of summary statistics; ANOVA; Fischer’s Exact; overview of carcinogenicity statistics; assessing significance and integrating statistical data with other data to evaluate trends, dose-response relationships, and support from other parameters; alternative methods (e.g., control chart analyses); and finally, approaches that can be used to increase statistical power (e.g., combining males and females). This course is applicable to all fields of toxicology that require regulatory toxicity studies to support registration of chemicals, medical devices and/or drugs.

Misuse of Statistics in Toxicology Studies
Adam Woolley, ForthTox Limited, Linlithgow, Scotland
Appropriate Use of Statistics in Toxicology
Shayne C. Gad, Gad Consulting Services, Raleigh, NC