those reports that could be of value to researchers developing drugs, these data have not been leveraged. For example, adverse event reports may contain information that could help in discerning which chemical structures may and may not be associated with particular problems. Almenoff described one approach that GlaxoSmithKline (GSK) has taken to attempt to extract and utilize that unrevealed information.

Molecular Clinical Safety Program

GSK developed the Molecular Clinical Safety Program (MCSP) as a way of closing the knowledge gap among various disciplines and helping to minimize both safety risks and attrition in the drug pipeline. The program consists of a large data warehouse that will ultimately house information on about 21,000 compounds, plus a set of tools for working with those data. Each compound is anchored to a chemical structure that can be linked to all the information in the database: class and dose information, physical properties, toxicology, pharmacokinetics, and metabolism and bioassay data. Each compound is also linked to human safety data, including disproportionality analysis (DPA) scores calculated from data in the FDA’s Adverse Event Reporting System (AERS), drug labeling information, and literature submissions. Ideally, the warehouse will also contain data and results from clinical trials, but because those data are more difficult to include, the system does not yet contain them.

The tools for interrogating the data include various statistical tools, such as recursive partitioning, as well as molecular mapping, visualization, and query and search tools. Starting with a particular drug, for example, it is possible to obtain its structure and then ask the database for a list of all other compounds with a similar structure, or perhaps all other compounds containing a particular substructure that can be used to compare a drug of interest with a reference drug. After a list of compounds has been generated, bioassay data can be obtained on all of those compounds, or the evaluator can examine those compounds that are on the market and evaluate their safety data. It is also possible to query for all the compounds that bind a particular molecule and examine the safety data associated with those molecules.

Example: Nelarabine and Neurotoxicity

Almenoff offered an example of how GSK researchers used this query tool to answer a retrospective question about nelarabine (a chemotherapy drug marketed by GSK as Arranon) that had been shown to cause demyelination in primate studies. Researchers wanted to determine whether interrogating the MCSP database could have provided them with information that might have made them proceed differently.

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