Edwin J. Matthews & Joseph F. Contrera

Construction of Toxicology Databases and SAR Software at FDA/CDER

Food and Drug Administration, Center for Drug Evaluation and Research, Office of Testing and Research (HFD-900), 5600 Fishers Lane, Rockville, Maryland 20857, USA.

FDA's Center for Drug Evaluation and Research (CDER), Office of Testing and Research (OTR), Regulatory Research and Analysis Program has two missions: (1) construction of electronic databases for pre-clinical toxicology studies for pharmaceuticals and (2) development of structure activity relationship (SAR) software programs which can provide reliable estimates of the potential toxicities of FDA-regulated chemicals. OTR's toxicology databases serve as a resource for Center research and regulatory decisions, and they provide data needed to develop SAR software database modules. OTR has constructed comprehensive databases for carcinogenicity and reproductive and developmental studies; additional databases for acute, sub-chronic, genetox and metabolism studies are planned. The OTR database architecture includes short field, complete text, and chemical structure records organized in a relational and chemical, sub-structure searchable formats using ISIS/BASE and ACCESS software.

OTR's SAR project aspires to provide rapid and reliable decision support information in situations in which toxicology data is either un-available or inadequate. The software is needed to estimate and to prioritize the potential toxicities of contaminants of FDA regulated compounds. In response to a recent Congressional directive for a 120-day review of indirect food additives, FDA's Center for Food Safety and Applied Nutrition (CFSAN) will employ SAR software to evaluate and regulate indirect food additives. The software is also needed to estimate the potential reproductive toxicities of drugs in Phase I clinical trials that include women of child bearing potential. These trials now include women volunteers, and are often conducted before the results of animal reproductive and developmental toxicity studies are available.

To meet Agency SAR needs, OTR has established Material Transfer Agreements (MTAs) or Cooperative Research and Development Agreements (CRADA) with SAR-Industry experts. Under a CRADA, OTR and Multicase, Inc. are co-developing a human expert version of MULTI-CASE which emulates the Center's weight of evidence regulatory procedures to evaluate results of toxicology studies. OTR Multicase modules have incorporated a scaling factor based upon the potency of each chemical's toxicologic response and reproducibility of its positive findings. To ensure good coverage for FDA-regulated compounds, OTR has constructed expanded control MULTI-CASE modules with extensive data-sets of compounds including food additives, pharmaceutical and industrial chemicals tested for specific toxicities. Furthermore, OTR databases for internal use contain both non-proprietary and proprietary data, because the program's resolving power for biophores associated with toxicity were enhanced as the control databases were expanded. In a ongoing beta-test, rodent carcinogenicity modules exhibited ~90% coverage for Agency-regulated organic compounds, and positive and negative predictivities exceed 85%.

OTR is dedicated to making its Agency SAR software and toxicology databases available to FDA-regulated industry and the public. OTR and Multicase, Inc. now offer TYPE I, read and write, database modules which contain only non-proprietary data. TYPE I modules AF1-AF4 are available which estimate the potential carcinogenicity of organic compounds in male and female rats and mice. Later this year modules should be available to estimate reproductive and developmental toxicities.

The inclusion of proprietary data in SAR software for public distribution presents a major challenge. As a possible solution to this problem, subject to Agency approval, OTR and Multicase, Inc. could offer TYPE II, read only, modules that include both non-proprietary and proprietary data. In TYPE II modules the identity and the structure of proprietary compounds is encrypted and un-accessible to the user! This policy would be analogous to the accepted practice of publishing the results of toxicity studies in which the identity of proprietary compounds are encoded. TYPE II modules would be identical to those used within the Agency in all other aspects and would be periodically updated to improve their performance.

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