Recommendations for Biostatistics of Repeated Toxicity Studies
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Drug Information Joumal, Vol. 31, pp. 327-334, 1997 Printed in the USA. All rights reserved.
Copyright 0 1997 Drug Information Association Inc.
RECOMMENDATIONS FOR BIOSTATISTICS OF REPEATED TOXICITY STUDIES* LUDWIGA. HOTHORN,PHD University of Hannover, Hannover, Germany
K. K. LIN, PHD Food and Drug Administration, Center for Drug Evaluation and Research, Rockville, Maryland
C . HAMADA,MS University of Tokyo, Tokyo, Japan
W. REBEL,MD Boehringer Mannheim GmbH, Mannheim, Germany
The Drug Information Association “3rd Annual Biostatistical Meeting” was held on August 27 and 28, 1996 in Tokyo. The purpose of this meeting was to discuss biostatistical recommendationsfor repeated toxicity studies. The purpose, objective, design, conduct, analysis, and interpretation are described. Key Words: Repeated toxicity studies; Biostatistics;Recommendations
combined carcinogenicitylchronic toxicity study can be analyzed in an analogous way]). THE PURPOSE OF repeated toxicity studies The administration route also depends on the is to determine the dose levels (or treatments) clinical administration. Normally two spethat cause toxic effects upon repeated admin- cies, selected from rodents and nonrodents, istration of substance to mammals andor are used. Details for conduct, design, perfordose levels at which no toxic effects occur. mance, and analysis are described in several The duration varies from one week to two guidelines, for example, those of the United years depending on the objective and the ex- States, Organisation for Economic Co-operapected period of clinical use (short term: one tion and Development, European Union, Jamonth or shorter; subchronic: 3 -12 months pan, and others. and chronic: 12 months and longer [The nonOn the one hand, repeated toxicity studies neoplastic findings of a carcinogenicity or are “screening” or pilot studies because of their toxicological objective (general safety/ risk assessment), their decision making based *The views expressed are those of the authors and not on numerous endpoints, and repeated meanecessarily those of their employers. sures. On the other hand, repeated toxicity Presented at the DIA “3rd Annual Biostatistical studies can also be designed in a directional Meeting,” August 27-28, 1996, Toyko, Japan. manner, for example, for a specific toxicoReprint address: Prof. Dr. Ludwig A. Hothorn, University of Hannover, LG Bioinformatics, Herrenhauser logical mechanism based on an a p i o n assumption (eg, the substance under investigaStr.2, D-30419 Hannover, Germany.
PURPOSE
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Ludwig A. Hothorn, K. K. Lin, C.Humada, and W.Rebel
tion belongs to a class of chemical substances with a known toxic mechanism) or results from earlier studies. Usually, repeated toxicity studies are performed as a battery of tests, for example, four-week, three-month and six-month studies in rats and 6112-month studies in dogs. Sometimes the information of no observed effect level and other findings such as toxic effects, target organs, and reversibility obtained from intermediate repeated tox
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