Evolving Statistical Issues in Carcinogenicity Studies
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0092-8615/97 Copyright 0 1997 Drug Information Association Inc.
EVOLVING STATISTICAL ISSUES IN CARCINOGENICITY STUDIES M. J. GODDARD,PHD Senior Statistician, Environmental Health Directorate, Health Canada, Ontario, Canada
The classical chronic carcinogenicity bioassay has served researchers well over the last few decades. Recently, howevec several factors have prompted a reevaluation of this approach, including budget pressures, a growing list of agents for study, and a better understanding of carcinogenesis. Herein some emerging strategies for obtaining similar or better information are considered. Rather than basing hazard identification and risk estimation on chronic bioassays of two sexes in two species, the possibility of a “reduced protocol” using a subset of the four assays is considered. The possibility of supplementing reduced protocol results from maximum tolerated dose information is raised. The trend to biologically based dose response models is considered, especially with reference to statistical issues associated with the “two-stage birth-death” model and physiologicallybased pharmacokinetic models. Key Words: Statistical issues; Reduced protocol; Two-stage model; Physiologically-based pharmacokinetic models
INTRODUCTION RESEARCHERS’ SCIENTIFIC understanding of carcinogenesis has been growing rapidly along with their understanding of ways to assess and manage risks. Now researchers are starting to suspect that some of the traditional carcinogenicity tests may not meet evolving needs efficiently. Recent studies have attempted to pinpoint weaknesses in the current approach, to identify components which are not cost-efficient, and to develop tools which meet knowledge needs not met by the traditional long-term chronic carcinogen bioassay. This overview tries to capture a few recent
Presented at the DIA Workshop “Immunotoxicity and Carcinogenicity of Pharmaceuticals,” January 27th. 1995, Arlington, Virginia. Reprint address: Dr. M. J. Goddard, B9-Environmental Health Centre, Locator 0800B1,Tunney’s Pasture, Ottawa, Ontario, Canada, KIA OL2.
initiatives focused on carcinogenicity testing. The basis for this is primarily two-fold: 1. Current methods are expensive (up to 2-4 million dollars each [l]) and may not be yielding cost-efficient information, and 2. Current designs may not provide the detailed observations needed to improve scientific understanding of the underlying mechanisms. The traditional two-year chronic bioassay has been the work-horse of carcinogenicity testing. The information available from these bioassays is now appearing in large databases (2) which affords the opportunity to evaluate the collection of results. In order to conserve funds, one consideration is to avoid testing all four combinations of two sexes in two species. The “reduced protocol” suggestion that was the focus of a recent workshop (3) as well as several publications is discussed next. Another direction in carcinogenicity
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M.J. God
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