Informatics and Computational Safety Analysis Staff (ICSAS) Programs and Activities

Note: Mention of commercial products in the descriptions below does not imply endorsement by the U.S. Food and Drug Administration.

Database Projects: Creating an FDA Knowledge Base and Institutional Memory

FDA Center for Drug Evaluation and Research (CDER) records are a unique repository of the results of clinical and non-clinical studies and post-marketing clinical adverse events. With major advances in computers and information technology, this unique scientific and regulatory information resource can now be more effectively used to address pre- and post-marketing issues. These issues include improving the scientific basis of regulatory actions, supporting guidance development, and contributing to the general advancement of science and product development.

• The Informatics and Computational Safety Analysis Staff (ICSAS) Toxicology Database Project was initiated to develop an electronic database for pharmaceutical toxicology studies stored in Agency archives. This database also provides information needed to develop computational toxicology (ComTox) software program modules and serves as a resource for FDA research and regulatory decisions.
   
• The ICSAS Toxicology Database permits chemical sub-structure searches using ISIS™/Base [external link] or CACTVS [external link] software programs. The goal is to be able to identify clusters of compounds that share common sub-structure components, including structural alerts, and then to link these clusters of compounds with toxicology studies at multiple endpoints. Ultimately, the Toxicology Database will provide an electronic summary of archival files of non-clinical acute, sub-chronic, reproductive and developmental, carcinogenicity, genetic toxicology, and metabolism studies submitted to the FDA.
   
• The ICSAS Pre-Clinical Toxicology Database is being used to build an FDA-wide Toxicology Database. Toxicology studies from all FDA centers will become accessible and eligible for inclusion in FDA ComTox software program modules. Progress in this direction has already been made and FDA's Center for Food Safety and Applied Nutrition (CFSAN) has furnished ICSAS access to CFSAN archive toxicology study data [external link] to be included in the database.
   
• The ICSAS Databases: Maximum Recommended Therapeutic Dose (MRTD) of Pharmaceuticals in Humans,^(6,15) Human Liver Adverse Effects,⁽¹⁸⁾ Genetic Toxicity, Reproductive and Developmental Toxicity, and Carcinogenicity,^(16,17) and Salmonella Mutagenicity E-State Descriptors⁽⁷⁾ are the bases for published research. These databases contain non-proprietary information. The first of these is also available through the Distributed Structure-Searchable Toxicity (DSSTox) Public Database Network [external link] Website.

CDER's Division of Information Disclosure Policy (formerly the Freedom of Information (FOI) Office) New Drug Application (NDA) microfiche records of pharmacology/toxicology reviews were converted into an electronic format. Similarly, CFSAN has engaged contractors to support their data transfer and collection efforts.⁽¹⁾ Data collection projects are envisioned at other FDA Centers (i.e., the Center for Biologics Evaluation and Research (CBER), the Center for Devices and Radiological Health (CDRH), the Center for Veterinary Medicine (CVM), and the National Center for Toxicological Research (NCTR)).

Through a Cooperative Research and Development Agreement (CRADA) with Leadscope, Inc., some ICSAS databases are now publicly available in ToxML format [external link].

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Chemical Structure Similarity Searching

The ICSAS relational toxicology databases include three types of information:

• Chemical structures;
• Critical administrative and toxicological data elements extracted from FDA and non-FDA toxicology studies; and
• Text files linked to internal pharmacology/toxicology reviews, freedom of information (FOI) documents, literature references, and summary data.

Under a cooperative research and development agreement (CRADA) with MDL® Information Systems, Inc., the ISIS™/Host [external link] software program has been provided to CDER to evaluate the capability to integrate all three types of information. ICSAS has conducted a successful pilot study to evaluate the ability of ISIS™/Host to identify and retrieve information from CDER Toxicology Databases based on chemical structural similarity. A new project has also begun under which CACTVS [external link] chemoinformatics software will also be used for this purpose. When fully implemented, for example, CDER reviewers will be able to quickly receive a list of drugs in FDA files that are structurally related to a compound in an Investigational New Drug (IND) application, including links to background resource material. This information will be of value for anticipating potential issues and interpreting study results. This capacity will contribute to a more thorough, efficient, and consistent regulatory review by facilitating ready access to FDA institutional memory.

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The Computational Toxicology Program and ComTox Consulting Service

Effectively retrieving and applying the vast quantity of information contained in electronic databases is critical. Computational toxicology (ComTox) incorporates information from toxicology databases and applies advances in computer technology and quantitative structure activity relationship (QSAR) methods to screen compounds for potential toxicity. One mission of ICSAS is to provide validated ComTox programs for regulatory and scientific decision support.  ICSAS evaluated the predictive performance of commercial ComTox software (MCASE[external link], OncoLogic[external link], and TOPKAT[external link]) in the mid-1990s and demonstrated that none of these programs at that time provided reliable estimates of the carcinogenic potential of pharmaceuticals in rodents.

To overcome this lack of effective commercial programs, ICSAS and MultiCASE, Inc. established a Cooperative Research and Development Agreement (CRADA) and together developed human expert rules to enhance the performance of the MC4PC quantitative structure activity relationship software program which reduces chemicals to 2 - 10 atom fragments and sorts the fragments in relation to biological activity or toxicity (structural alerts), lists the structural alerts linked to a query compound, and lists the structures, names, and activity of compounds in the database that are related to the query substance.

More recently, ICSAS and MDL Informations Systems, Inc. signed a CRADA to improve the precision of MDL QSAR's predictions that are based on the statistical correlation between a molecule's toxicity and its electrotopological descriptor values.

Both these approaches can contribute new scientific insights into the relationship of molecular structure to toxicity. The MC4PC and MDL QSAR analyses developed by ICSAS provide highly specific predictions of rodent carcinogenicity,^(14),(5) and are now commercially available from MultiCASE, Inc[external link] and MDL Information System, Inc.[external link], respectively. A MC4PC program for estimating teratogenic potential (i.e., Segment II Assay) has also been developed with support, in part, by funding from the FDA Office of Women's Health. In 2005, MC4PC modules for predicting many different genetic toxicity endpoints^(16),(17) were released through MultiCASE, Inc. and modules for predicting bacterial mutagenesis in Salmonella⁽⁷⁾ were provided to MDL Information Systems, Inc. for distribution. Ultimately, ICSAS intends to develop a complete set of computational toxicology software for all the major types of toxicology studies submitted to the FDA in support of pharmaceutical and food additive marketing applications.

ICSAS has also developed MC4PC and MDL QSAR modules to predict adverse effects of chemical substances to humans. Recently published papers ^(15),(6) show how the maximum recommended therapeutic dose (MRTD) of pharmaceuticals (also known as the maximum recommended daily dose (MRDD)) and the no effect level (NOEL) of many organic chemicals can be predicted with considerable precision.

At CDER, MC4PC and MDL QSAR toxicology and human adverse effect prediction modules are now used to supply information to support regulatory decisions on the nature and extent of testing needed for excipients or contaminants and degradents identified late in the development of a new product which were not present in the material used in toxicity studies (Sample report ). CDER reviewers send the chemical structure of the material in question to the Computational Toxicology Consulting Service at ICSAS, and a MC4PC/MDL QSAR report is generated and returned to the review division.

ICSAS MC4PC and MDL QSAR software modules will also be of great value to the pharmaceutical industry as an aid for compound selection in drug discovery and development. Commercial distribution of the ICSAS MC4PC modules under the CRADA with MultiCASE, Inc. and MDL QSAR modules under the CRADA with MDL Information Systems, Inc. are generating resources that will be used to support the maintenance, improvement, and development of computational toxicology prediction software at ICSAS.

ICSAS is also working with other QSAR products, including Bioreason ClassPharmer[external link], Lhasa Derek for Windows[external link], Prous Institute for Medical Research BioEpisteme[external link], and Leadscope Prediction Modeler[external link], which have different logical approaches to toxicological predictions. ICSAS anticipates that a careful synthesis of predictions from a number of QSAR software packages will, in the end, produce the most accurate analysis of chemical substances of interest to FDA.

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ComTox Regulatory Application of ICSAS MC4PC by the Center for Food Safety and Applied Nutrition (CFSAN)

The Food and Drug Administration Modernization Act of 1997 (FDAMA) established a premarket notification system[external link] for Food Contact Substances (FCS) that is largely replacing the food additive petition process for such substances. This premarket notification process places the burden on FDA to object to a notification within 120 days or an FCS may be legally marketed on the 121^st day. Estimates for the number of industry FCS submissions under this program ranged as high as 6000 annually as compared to less than 50 per year considered before FDAMA's implementation. Although the use of FCS in food packaging and processing equipment typically results in very low exposure, FCS are industrial chemicals that may have high potential toxicity. In addition, many FCS contain minor amounts of impurities, some of which may be known carcinogens.

In order to meet FDAMA due dates, the CFSAN Office of Food Additive Safety developed risk management methods to prioritize the use of limited review resources on premarket applications that present the greatest potential risk to the public health. CFSAN had earlier applied such a strategy in developing its Threshold of Regulation (TOR) process and Special Project Team to deal with food additive reviews of relatively low potential risk. However, because of the large number of FCS submissions predicted under the premarket notification process, CFSAN developed a knowledge base and infrastructure in the area of structure activity relationship (SAR) analyses in order to be able to rapidly make scientifically informed and sound decisions regarding review priorities.

With partial funding by the Office of the FDA Commissioner, ICSAS has assisted CFSAN in developing and applying appropriate MC4PC toxicology and clinical effects modules to meet their needs and in training personnel in the use of MC4PC. Further investigations will also be conducted to evaluate ComTox programs to estimate potential FCS reproductive toxicity and other endpoints of interest to CFSAN.

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Application of Computational Toxicology to Assess Clinical Adverse Drug Reactions

ICSAS has developed a chemical structure (".mol"-file) based indexing system for the CDER drug dictionary to facilitate the analysis of information in the clinical Spontaneous Reporting System (SRS) database. This approach may alleviate many of the difficulties related to the multitude of drug trade names associated with a single drug product in the SRS database. The development of an indexing system based on the chemical structure of the active chemical moiety of a drug product facilitates data analysis and enables the linking of animal and clinical databases. With the help of CDER's Office of Post Marketing Drug Risk Assessment, we have evaluated the application of MC4PC [external link] to predict post-marketing adverse events using the SRS database and the more recently developed Adverse Event Reporting System (AERS) database.

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Available FDA QSAR Modules

Carcinogenicity (MC4PC)(14)[external link]
Description	#Chems	ID
FDA Rodent Carcinogenicity Male Mouse (Non-proprietary)	1002	AF1
FDA Rodent Carcinogenicity Female Mouse (Non-proprietary)	991	AF2
FDA Rodent Carcinogenicity Male Rat (Non-proprietary)	889	AF3
FDA Rodent Carcinogenicity Female Rat (Non-proprietary)	902	AF4
FDA Male/Female Rat and Mouse	1239	AFU
FDA Male/Female Rat	1108	AFV
FDA Male/Female Mouse	1000	AFW
Carcinogenicity (MDL QSAR)(5)[external link]
Description	#Chems	ID
Male Rat	1285	QMR
Female Rat	1285	QFR
Male Mouse	1285	QMM
Female Mouse	1285	QFM
Genetic Toxicity (MC4PC)(16,17)[external link]
Description	#Chems	ID
FDA Microbial Composite	1485	A7A
FDA Salmonella Composite	1444	A7B
FDA Escherichia Composite	212	A7C, A7D
FDA Fungal Composite	243	A7E, A7F
FDA Drosophila Composite	238	A7G, A7H, A7I
FDA Rodent Mutation In Vivo Composite	87	A7J, A7K
FDA Hgprt Composite	260	A7O
FDA Micronucleus In Vivo Composite	333	A7S, A7T, A7L
FDA Unscheduled DNA Synthesis (UDS) Composite	152	A8A, A8B, A8C
FDA Mouse Lymphoma Composite	328	A7N
FDA Chromosome Aberrations In Vitro Composite	556	A7U, A7V, A7W, A7X
FDA Transformation Composite	256	A8D, A8E, A8F, A8G
FDA Chromosome Aberrations In Vivo Composite	112	A7P
Bacterial Mutagenicity (MDL QSAR)(7)[external link]
Description	#Chems	ID
Salmonella Composite	3228	QST
E. coli Composite	472	QEC
Microbial Mutagenicity Composite	3338	QBM
Salmonella Mutagenicity (MC4PC)[external link]
Description	#Chems	ID
FDA Salmonella typhimurium (TA100) Mutation in Absence of S9	1407	AN1
FDA Salmonella typhimurium (TA1535) Mutation in Absence of S9	1213	AN2
FDA Salmonella typhimurium (TA1537) Mutation in Absence of S9	889	AN3
FDA Salmonella typhimurium (TA97) Mutation in Absence of S9	475	AN4
FDA Salmonella typhimurium (TA98) Mutation in Absence of S9	1409	AN5
FDA Salmonella typhimurium (TA100) Mutation in Presence of Rat S9	1410	AR1
FDA Salmonella typhimurium (TA1535) Mutation in Presence of Rat S9	1201	AR2
FDA Salmonella typhimurium (TA1537) Mutation in Presence of Rat S9	885	AR3
FDA Salmonella typhimurium (TA97) Mutation in Presence of Rat S9	469	AR4
FDA Salmonella typhimurium (TA98) Mutation in Presence of Rat S9	1377	AR5
FDA Salmonella typhimurium (TA100) Mutation in Presence of Hamster S9	1410	AR1
FDA Salmonella typhimurium (TA1535) Mutation in Presence of Hamster S9	1195	AH2
FDA Salmonella typhimurium (TA1537) Mutation in Presence of Hamster S9	821	AH3
FDA Salmonella typhimurium (TA97) Mutation in Presence of Hamster S9	438	AH4
FDA Salmonella typhimurium (TA98) Mutation in Presence of Hamster S9	1181	AH5
FDA Salmonella typhimurium Composite of All Strains and S9 Conditions	1733	A66
Developmental and Reproductive Toxicity (MC4PC)[external link]
Description	#Chems	ID
FDA Teratogenicity Rabbit	812	AFA
FDA Teratogenicity Rat	1286	AFB
FDA Teratogenicity Mouse	794	AFC
FDA Teratogenicity Miscellaneous Mammal	1409	AFD
Adverse Human Liver Effects (MC4PC)(18)[external link]
Description	#Chems	ID
FDA Liver Enzyme Combined	397	AB0
FDA Alkaline Phosphatase Increased	399	AB1
FDA SGOT Increased	401	AB2
FDA SGPT Increased	402	AB3
FDA GGT Increased	382	AB4
FDA Liver Obstruction Combined	391	AB5
FDA Bilirubinemia	414	AB6
FDA Jaundice	396	AB7
FDA Jaundice Cholestatic	391	AB8
FDA Liver Pathology Combined	385	AB9
FDA Liver Failure	390	ABA
FDA Liver Damage	385	ABB
FDA Liver Function Abnormal	476	ABC
FDA Hepatitis	420	ABD
Maximum Recommended Daily Human Dose (MC4PC)(15)[external link]
Description	#Chems	ID
FDA MRTD Humans	1169	A8D
Maximum Recommended Daily Human Dose (MDL QSAR)(6)[external link]
Description	#Chems	ID
Maximum Recommended Daily Dose	1309	QMD
Maximum Tolerated Dose (MC4PC)[external link]
Description	#Chems	ID
FDA Maximum Tolerated Dose Male Rat - Lethal Dose	957	AFE
FDA Maximum Tolerated Dose Female Rat - Lethal Dose	967	AFF
FDA Maximum Tolerated Dose Male Mouse - Lethal Dose	892	AFG
FDA Maximum Tolerated Dose Female Mouse - Lethal Dose	905	AFH
FDA Maximum Tolerated Dose Male Rat - Nontoxic Dose	957	AFI
FDA Maximum Tolerated Dose Female Rat - Nontoxic Dose	967	AFJ
FDA Maximum Tolerated Dose Male Mouse - Nontoxic Dose	892	AFK
FDA Maximum Tolerated Dose Female Mouse - Nontoxic Dose	905	AFL

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Publications

(1) Benz, R.D. and Irausquin, H. (1991) Priority-based Assessment of Food Additives Database of the U.S. Food and Drug Administration Center for Food Safety and Applied Nutrition. Environmental Health Perspectives 96:85-89.

(2) Contrera, J.F. (1998) Transgenic Animals: Refining the Two Year Rodent Carcinogenicity Study. Laboratory Animals 27:30-34.

(3) Contrera, J.F. and DeGeorge, J.J. (1998) In Vivo Transgenic Bioassays and the Assessment of the Carcinogenic Potential of Pharmaceuticals. Environmental Health Perspectives 106(Sup1):71-80.

(4) Contrera, J.F., Jacobs, A.C., DeGeorge, J.J., Chen, C.H., Choudary, J.B., DeFelice, A.F., Fairweather, W.R., Farrelly, J.G., Fitzgerald, G.G., Goheer, A.M., Jordan, A.W., Kelly, R.E., Lin, D., Lin, K.K., Meyers, L.L., Osterberg, R.E., Prasanna, H.R., Resnick, C.A., Sheevers, H.V. and Sun, J. (1997) Carcinogenicity Testing and the Evaluation of Regulatory Requirements for Pharmaceuticals. Regulatory Toxicology and Pharmacology 25:130-145.

(5) Contrera, J.F., Matthews, E.J., and Benz, R.D. (2003) Predicting the Carcinogenic Potential of Pharmaceuticals in Rodents Using Molecular Structural Similarity and E-State Indices. Regulatory Toxicology and Pharmacology 38:243-259.

(6) Contrera, J.F., Matthews, E.J., Kruhlak, N.L., and Benz, R.D. (2004) Estimating the Safe Starting Dose in Phase I Clinical Trials and No Observed Effect Level Based on QSAR Modeling of the Human Maximum Recommended Daily Dose. Regulatory Toxicology and Pharmacology 40:185-206.

(7) Contrera, J.F., Matthews, E.J., Kruhlak, N.L., and Benz, R.D. (2005) In Silico Screening of Chemicals for Bacterial Mutagenicity Using electrotopological E-state Indices and MDL QSAR Software. Regulatory Toxicology and Pharmacology 43:313-323.

(8) Contrera, J.F., MacLaughlin, P., Hall, L.H., and Kier, L.B. (2005) QSAR Modeling of Carcinogenic Risk Using Discriminant Analysis and Topological Molecular Descriptors. Current Drug Discovery Technologies 2:55-67.

(9) Contrera, J.F. and Woodcock, J. (1996) Pilot Project for Electronic Submissions. The Regulatory Affairs Journal 7(3):256-257.

(10) Dearfield, K.L. and Benz, R.D. (1999) Can the New Genetic Toxicology Tests be Used for Regulatory Safety Decisions? Enviromental and Molecular Mutagenesis 33:91-93.

(11) DeGeorge, J.J. and Contrera, J.F. (1996) A Regulatory Perspective on the Utility of Two Rodent Species in Carcinogenicity Testing. In Proceeding, Third International Conference on Harmonization, Yokohama, 1995 (P.F. D'Arcy and D.W.G. Harron, Eds.), pp. 274-277, Greystone Books Ltd., N. Ireland.

(12) DeGeorge, J.J., Myers, L.L., Takahashi, M. and Contrera, J.F. (1999) The Duration of Non-rodent Toxicity Studies for Pharmaceuticals. Toxicology Science 49:143-155.

(13) Matthews, E.J., Benz, R.D., and Contrera, J.F. (2000) Use of Toxicological Information in Drug Design. Journal of Molecular Graphics and Modeling 18(December):605-614.

(14) Matthews, E.J. and Contrera, J.F., (1998) A New Highly Specific Method for Predicting the Carcinogenic Potential of Pharmaceuticals in Rodents Using Enhanced MCASE QSAR-ES Software. Regulatory Toxicology and Pharmacology 28:242-264.

(15) Matthews, E.J., Kruhlak, N.L., Benz, R.D., and Contrera, J.F. (2004) Assessment of the Health Effects of Chemicals in Humans: I. QSAR Estimation of the Maximum Recommended Therapeutic Dose (MRTD) and No Effect Level (NOEL) of Organic Chemicals Based on Clinical Trial Data. Current Drug Discovery Technologies 1:61-76.

(16) Matthews, E.J., Kruhlak, N.L., Cimino, M.C., Benz, R.D., and Contrera, J.F. (2006) An Analysis of Genetic Toxicity, Reproductive and Developmental Toxicity, and Carcinogenicity Data: I. Identification of Carcinogens Using Surrogate Endpoints. Regulatory Toxicology and Pharmacology 44:83-96.

(17) Matthews, E.J., Kruhlak, N.L., Cimino, M.C., Benz, R.D., and Contrera, J.F. (2006) An Analysis of Genetic Toxicity, Reproductive and Developmental Tixicity, and Carcinogenicity Data: II. Identification of Genotoxicants, Reprotoxicants, and Carcinogens Using In Silico Methods. Regulatory Toxicology and Pharmacology 44:97-110.

(18) Matthews, E.J., Kruhlak, N.L., Weaver, J.L., Benz, R.D., and Contrera, J.F. (2004) Assessment of the Health Effects of Chemicals in Humans: II. Construction of an Adverse Effects Database for QSAR Modeling. Current Drug Discovery Technologies 1:243-254.

(19) Seng, J.E., Allaben, W.T., Nichols, M.L., Bryant, C.U., Contrera, J.F. and Leaky, J.E. (1999) A. Putting Dietary Control to the Test: Increasing Bioassay Sensitivity by Reducing Variability. Laboratory Animals 27:40-44.

(20) Yang, C., Benz, R.D., and Cheeseman, M.A. (2006) Landscape of Current Toxicity Databases and Database Standards. Current Opinion in Drug Discovery & Development 9:124-133.

Contact Us

Please send questions or comments concerning the contents of this page to Dan Benz at R.Daniel.Benz@fda.hhs.gov

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