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U.S. Department of Health and Human Services


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AASLD-FDA-NIH-PhRMA Hepatotoxicity Steering Group Meeting, 2006 Presentations: New developments in preclinical prediction of human hepatotoxicity

James E. Sanders, DVM, PhD, DABT 
Diplomate of the American Board of Toxicology, Preclinical Development Team Leader, CDDD, PRDUS
New developments in preclinical prediction of human hepatotoxicity [PDF]

The Health and Environmental Sciences Institute has organized a Non-Clinical / Clinical Safety Correlations Technical Committee to develop improved understanding of the extent to which various types of human toxicities manifested during clinical trials could be predicted from standard toxicology studies. Publicity has been given to those cases of drugs that are dropped from clinical trials or withdrawn from the market for reasons of toxicity that were not predicted from animal studies. However, little attention has been given to the successful predictions from animal data, and there has been no systematic and comprehensive valuation of the utility of the tests conducted. Furthermore, whether the range of preclinical tests performed produce data that are relevant in the design and/or interpretation of human studies has not been addressed. In the face of continuing public, regulatory, and industry, pressures to increase the efficiency of the drug development process, this is an opportune time to conduct an evaluation to examine the value of animal studies as surrogates for predicting toxicity of drugs to humans and to address how nonclinical tests can be optimized to improve drug safety.

The current project is a follow-up to the initial stage of the program. The first stage of the project has been extended into a second stage to broaden the scope of the data collected and to generate additional data in a prospective manner. To meet these goals, the Non-Clinical / Clinical Safety Correlations Technical Committee has developed an internet-accessible system to facilitate the entry of proprietary compounds into a database to evaluate the concordance of animal toxicity and safety pharmacology data with actual human toxicities for a number of pharmaceutical agents exhibiting clinical toxicity during Phase I, II or III clinical trials. Members gain access to the database through a secure server where compounds can be entered in a confidential manner.

The details of toxicity manifested in animals considered to be counterparts of the human clinical toxicity profile are being fully documented beyond the organ system level. The database includes detailed compound information including toxicokinetic and metabolic interspecies comparison data. The dataset currently includes information for approximately 150 compounds with over 85 separate human toxicities. Data entry for the project is expected to proceed through the 1Q 2006. The data will be comprehensively evaluated during the remainder of 2006, and a workshop will be planned for 1Q 2007 to critically review the data analysis.

Biographical Sketch

Dr. James. E. Sanders joined J&J PRD in 2005 as a Preclinical Development Team Leader. In addition to preclinical development, he represents his company externally in forums and working parties such as the ILSI, Toxicology Forum, and PhRMA. His career in nonclinical safety assessment of pharmaceuticals spans over 25 years. Previously he was employed at Rhône-Poulenc Rorer as Director of Toxicology in 1987 and had continued with the merged companies, Aventis and Sanofi-Aventis, as a Distinguished Scientist. He was previously employed from 1981 to 1987 as a pathologist at Merck, Sharp and Dohme and from 1978 to 1981 as a staff pathologist in the U.S. Army at Walter Reed Army Institute of Research. Jim attended Ohio State University where he gained a DVM, an MS in Pharmacology and a PhD in toxicology. He is certified by the American Board of Toxicology and is a member of the Society of Toxicology, Teratology Society, DIA, and AVMA.