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An Analysis of Pharmaceutical Experience with Decades of Rat Carcinogenicity Testing: Support for a Proposal to Modify Current Regulatory Guidelines

Turner, Oliver and Colman, Karyn and Potenta, Daniel and Sistare, F.D. and Morton, D. and Alden, C. and Christensen, J. and Keller, D. and Jonghe, S.D. and Storer, R.D. and Reddy, M.V. and Kraynak, A. and Trela, B. and Bienvenu, J.G. and Bjurström, S. and Bosmans, v. and Dominick, M. and Evans, J. and Hailey, J.R. and Kinter, L. and Liu, M. and Mahrt, C. and Marien, D and Myer, J. and Perry, R. and Roth, A. and Sherratt, P. and Singer, T. and Slim, r. and Soper, K. and Fransson-Stehn, R. and Stoltz, J. and Turnquist, S. and vanHeerden, M. and Woicke, J. and Degeorge, J.J. (2011) An Analysis of Pharmaceutical Experience with Decades of Rat Carcinogenicity Testing: Support for a Proposal to Modify Current Regulatory Guidelines. Toxicologic Pathology, 39 (4). pp. 716-744. ISSN 0192-6233

Abstract

Data collected from 182 marketed and nonmarketed pharmaceuticals demonstrate that there is little value gained in conducting a rat two-year carcinogenicity study for compounds that lack: (1) histopathologic risk factors for rat neoplasia in chronic toxicology studies, (2) evidence of hormonal perturbation, and (3) positive genetic toxicology results. Using a single positive result among these three criteria as a test for outcome in the two-year study, fifty-two of sixty-six rat tumorigens were correctly identified, yielding 79% test sensitivity. When all three criteria were negative, sixty-two of seventy-six pharmaceuticals (82%) were correctly predicted to be rat noncarcinogens. The fourteen rat false negatives had two-year study findings of questionable human relevance. Applying these criteria to eighty-six additional chemicals identified by the International Agency for Research on Cancer as likely human carcinogens and to drugs withdrawn from the market for carcinogenicity concerns confirmed their sensitivity for predicting rat carcinogenicity outcome. These analyses support a proposal to refine regulatory criteria for conducting a two-year rat study to be based on assessment of histopathologic findings from a rat six-month study, evidence of hormonal perturbation, genetic toxicology results, and the findings of a six-month transgenic mouse carcinogenicity study. This proposed decision paradigm has the potential to eliminate over 40% of rat two-year testing on new pharmaceuticals without compromise to patient safety

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords: Rat, Carcinogenicity testing, modify current practice
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15
URI: https://oak.novartis.com/id/eprint/3980

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