Continuing Education Courses
Carcinogenicity Studies: Perspectives on Design and Execution for Successful Product Registration
Owen McMaster 1, Hanan Ghantous1, Scott Boley2, Thomas Larsen3, John Vahle4
1FDA. 2MPI Research, 3Covance Laboratories, Inc. 4Lilly
The guidelines for carcinogenicity testing of drugs, biologics, and environmental chemicals have undergone recent revisions. Evaluation of the carcinogenic potential of therapeutic agents is now a very complex, multi-step process which is conducted only for chemicals which meet certain criteria. The practical aspects of running these large studies create challenges even for those with experience. This course will begin by exploring the history of carcinogenicity testing followed by an overview of the current international guidelines. The design and execution of carcinogenicity studies will then be discussed in detail, with topics including dose justification, strain differences, routes of administration, diet, the choice of negative controls, positive controls, sentinel animals, biomarkers, and formulations. The collection, evaluation and categorization of histopathology data will be detailed including topics such as background lesions, historical control data, toxicity vs neoplastic findings, toxicity vs exaggerated pharmacology, peer reviews, Pathology Working Groups and various statistical approaches. The procedures for evaluating data from carcinogenicity studies differ in the various regulatory and environmental agencies. The interpretation of carcinogenicity data will be discussed, including considerations of the context of use of the test compound. This will be followed by an examination of the future of the ICH S1 regulatory paradigm and an update to the status of the proposed changes to the S1 Guidelines by ICH’s Expert Working Group. In the final presentation, there will be analysis of the impact of positive carcinogenicity results on ongoing trials, approvals, prescribing information and post marketing events, with 2 or 3 case studies.
List of topics:
- Introduction and overview of guidelines.
- Practical aspects of design and testing.
- Pathology, statistics and presentation of data.
- Evaluating carcinogenicity studies including status update on proposed changes to the ICH S1 Guidelines.
- Carcinogenicity Study Outcomes: Impact on biopharmaceutical safety assessment, product approvals, labeling, and post marketing surveillance.
For whom the course is intended:
This course is intended for those working in academia, pharmacology, toxicology, regulatory affairs and drug development who are interested in obtaining the latest information regarding the carcinogenicity testing of drugs and environmental chemicals.
Carcinogenicity, ICH, Regulatory, Nonclinical, Drug.
Health-Based Limits for Toxicological Risk Assessment: Setting Acceptable Daily Limits for Pharmaceutical and Chemical Safety
Patricia Weideman1, Andrew Maier2, Brad Stanard3, and Robert Sussman4
1 Sakari Consultants LLC, Stratham NH USA, 2University of Cincinnati, Cincinnati OH USA, 3Medimmune, Gaithersburg MD USA, 4SafeBridge Consultants Inc., New York, NY USA
Health-based exposure limits (HBELs) have been used for many years to assure safety or assess risks from potential adverse health-related effects arising from exposures to xenobiotics. Acceptable Daily Exposure (ADE) and Permitted Daily Exposure (PDE) are terms referencing assessments that can be considered as the bases for a variety of health-based assessments associated with the development and manufacture of industrial chemicals and pharmaceuticals. ADEs/PDEs have similar overall intent and definition as other HBELs and have increasing regulatory implications. As an example, the transition to the use of HBELs (i.e. ADEs) to protect product quality of pharmaceuticals has gained industry and regulatory interest. HBELs rely on robust hazard assessments that can be used as the basis for subsequent risk assessments, such as occupational exposure limits (OELs) and the derivation of limits for cleaning validation processes and control of cross-contamination. Default approaches for limit-setting (e.g. 10 ppm) have not been based on current health-based risk assessment methods. In contrast to the default approaches, derivation of ADEs and subsequent limits includes the use of robust datasets. Although the datasets for pharmaceuticals are generally more complete than those for chemical manufacturing, many aspects of the evolving methods in deriving HBELs for either industrial chemicals or pharmaceuticals are the same with application of appropriate adjustment factors to better inform hazard and risk decisions. The use of ADEs is a step toward better informed science- and health risk-based decisions. Methods used to derive ADEs are complex and are not harmonized among various regulatory constituencies and practitioners.
List of topics:
- Regulatory and Industry Trends in Deriving Health-Based Exposure Limits
- Application of Data-Derived Health Limits Versus Default Limits
- Point of Departure As a Central Aspect of ADE Derivation
- Fine-Tuning Health-Based Assessments: Applying Adjustment Factors and Use of Pharmacokinetic Data
For whom the course is intended:
This session will provide background and tools for toxicologists and regulators to better understand the basis, derivation, and application of ADE/PDE assessments for protection of human safety as an attempt to provide more consistency in approach and outcomes.
Keywords: ADE, PDE, hazard assessment, risk assessment
RISK21: A Practical Framework for Risk Assessment in the 21st Century
Michelle Embry1, Alan Boobis2, Angelo Moretto3
1 ILSI Health and Environmental Sciences Institute, 2 Imperial College London, 3University of Milan
In 2007, a report on Toxicity Testing in the 21st Century (“TT21C”) by the United States National Research Council laid out a vision to leverage scientific advances to make toxicity testing faster, less expensive, more relevant to human exposures, and less reliant on animal testing.
To complement the global effort to fulfill this vision, in 2009, the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI), launched its multi-partite, Risk Assessment in the 21st Century (RISK21) Project. RISK21 is a tiered evaluation strategy which emphasizes a problem formulation-based, exposure-driven approach to risk assessment. A key component is the RISK21 Matrix, a freely available electronic tool, which enables the visualization of the intersection of exposure and toxicity data, and facilitates risk communication beyond those with technical expertise. The end result is a systematic and transparent approach to risk-based decision making.
The objective of this course is to teach the risk assessment approach developed by the RISK21 to emerging and established scientists. The specific goals are 1) Communicate the overarching principles of the RISK21 approach; 2) Provide an introduction to the roadmap and visualization matrix; and 3) Conduct hands-on case studies using the visualization matrix.
List of topics:
- Problem formulation
- Risk assessment
- Risk communication
- Tiered evaluation strategies
- Cumulative risk
For whom the course is intended: The course is intended for toxicologists, exposure scientists, and risk assessors involved in evaluation of chemicals for prioritization, screening, product development, alternatives assessment, risk assessment, etc., as well as those interested in/engaged in risk communication. The course is applicable to all chemical sectors and exposure scenarios.
Keywords: RISK21, risk assessment, problem formulation, tiered evaluation strategy, risk communication
Water Security: Integrating Lessons Learned for Water Quality and Sustainability
The purpose of the course is to provide a common risk based framework for issues of water pollution and water quality. It uses WHO documents to present the issues from the global problems of ensuring water quality. Risk management examples are presented by the course faculty and are linked to the basic toxicology and illustrations of how toxicology informs this topic. We will also choose a set of abstracts from those submitted to the CTDC to have regional fellows and junior scientists from around the world share their experiences on water quality. These case studies are discussed by the group during the one-day course workshop. This course framework provides a context for issues of water security but illustrates issues faced by the local and international developing countries and communities. This course will follow the successful approach used in Brazil and Mexico at other IUTOX-ICSU sponsored congresses and will have the recently published book chapter (Cambridge Press series) for context for these discussions.