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U.S. Department of Health and Human Services

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Human Liver Adverse Effects Database

FDA's Center for Drug Evaluation and Research, Office of Pharmaceutical Science, Informatics and Computational Safety Analysis Staff's Adverse Effects Database contains data for 631 unique pharmaceuticals listed in FDA/CDER's Spontaneous Reporting System Database. The ICSAS Adverse Effects Database includes adverse drug reaction (ADR) reports described using a standardized vocabulary of 1191 COSTAR terms linked to 22 organ systems which are based upon the anatomical COSTAR term nomenclature. For each of the 631 drugs in our database, we extracted the counts of ADR reports for all populated COSTAR terms for the time periods described below.

Pharmaceutical shipping unit data were used to estimate pharmaceutical usage and human exposure and were selected to match the time period of the ADR data. The data were obtained as “units” which refer to package shipping units. When available, we manually extracted and summed these data for the first five years of marketing, and integrated the information into our database for each pharmaceutical.

The adverse event data were obtained in three groups. Group 1 contained 356 pharmaceuticals that were approved as New Molecular Entities between January 1, 1978 and December 31, 1996. The shipping unit data for this group were summed for each pharmaceutical for the first five years after approval, except for pharmaceuticals approved after December 31, 1991 where shipping data were summed until December, 1996. In those cases where marketing of the pharmaceutical was delayed for several years after its approval, data for the first five years of marketing were used. Group 2 contained 253 pharmaceuticals that were approved prior to January 1, 1978. Since shipping unit data were not available to us prior to this date, shipping data were summed for the five year period from January 1, 1992 to December 31, 1996. Group 3 contained 22 pharmaceuticals from an additional set of drugs for which no shipping data were obtained. These 22 drugs were selected because they have 30 or more ADR reports associated with a single COSTAR term. These chemicals were classified as having a significant adverse effect and were included in the database only for modeling these specific endpoints.

The ADR report data and the pharmaceutical shipping values were used to estimate pharmaceutical usage and human exposure by calculating a Reporting Index (RI) for up to a five year period for each pharmaceutical in the study. The RI = (# ADR reports / # shipping units) × 1,000,000. Index values were calculated for all 631 generic pharmaceuticals in the database with available shipping data. Where less than five years of data were available, ADR and shipping data are from matching time periods.

Of the 631 compounds in the database, 490 have ADR data available for one or more of the 47 liver effects COSTAR term endpoints. The liver adverse effect data from the five liver enzyme increase endpoints, were used to optimize the database for identification of a significant adverse effect, as described in the following research article: Matthews, E.J., Kruhlak, N.L., Weaver, J.L., Benz, R.D., and Contrera, J.F. Assessment of the Health Effects of Chemicals in Humans: II. Construction of an Adverse Effects Database for QSAR Modeling, Current Drug Discovery Technologies, 2005, 1:243-254. The abstract for this article is as follows:

The FDA's Spontaneous Reporting System (SRS) database contains over 1.5 million adverse drug reaction (ADR) reports for 8620 drugs/biologics that are listed for 1191 COSTAR (Coding Symbols for Thesaurus of Adverse Reaction) terms of adverse effects. We have linked the trade names of the drugs to 1861 generic names and retrieved molecular structures for each chemical to obtain a set of 1515 organic chemicals that are suitable for modeling with commercially available QSAR software packages. ADR report data for 631 of these compounds were extracted and pooled for the first five years that each drug was marketed. Patient exposure was estimated during this period using pharmaceutical shipping units obtained from IMS Health. Significant drug effects were identified using a Reporting Index (RI), where RI = (# ADR reports / # shipping units) × 1,000,000. MCASE/MC4PC software was used to identify the optimal conditions for defining a significant adverse effect finding. Results suggest that a significant effect in our database is characterized by ≥4 ADR reports and ≥20,000 shipping units during five years of marketing, and a RI ≥4.0. Furthermore, for a test chemical to be evaluated as active it must contain a statistically significant molecular structural alert, called a decision alert, in two or more toxicologically related endpoints. We also report the use of a composite module, which pools observations from two or more toxicologically related COSTAR term endpoints to provide signal enhancement for detecting adverse effects.

The data presented here are for five liver enzyme COSTAR endpoints and a composite module which pools data from the five individual endpoints.

The database contains the following fields:

  1. The generic name of each chemical
  2. The chemical structure in Simplified Molecular Input Line Entry System (SMILES) code format (generated using MultiCASE Inc.'s MC4PC program)
  3. For module A10 (liver enzyme composite module):
    1. Overall activity category for each compound (A for active, M for marginally active, or I for inactive) based on the number of active and marginally active scores for each compound at the five individual endpoints (see research article for full description of method)
    2. Number of endpoints at which each compound is marginally active (M)
    3. Number of endpoints at which each compound is active (A)
  4. For modules A11 to A15 (alkaline phosphatase increased, SGOT increased, SGPT increased, LDH increased, and GGT increased, respectively):
    1. Overall activity category for each compound (A for active, M for marginally active, or I for inactive) based on the RI and ADR values (see the research article for full description of method)
    2. Number of ADR reports for each compound, given as <4 or ≥4
    3. Reporting Index value for each compound, except where no shipping units were available (NSU)

Group 1 comprises of compounds for which ADR data were available for the first five years of marketing, so when no ADR reports were listed during this period the compounds were evaluated as inactive. Group 2 comprises of compounds for which a "steady state" period of ADR data were available (1992-1996). In cases where no ADR reports were filed during this period, the compounds were scored as "NA" (data not available) since they may have had one or more ADR reports during their first five years of marketing which should not be negated by a lack of ADR reports during the steady-state period.

All data contained in this file are non-proprietary.

Comments or corrections of these data should be sent to: R.Daniel.Benz@fda.hhs.gov.

Human Liver Adverse Effects Database (490 pharmaceuticals)

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