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 121st
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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