The Importance of Reverse Translation for Preclinical Off-Target Mitigation: Quantification and Mitigation of Biases in the FDA Adverse Event Reporting System
Brian K Shoichet,
Posted 10 Aug 2016
bioRxiv DOI: 10.1101/068692 (published DOI: 10.7554/eLife.25818)
Posted 10 Aug 2016
The Food and Drug Administration Adverse Event Reporting System (FAERS) is the primary source for postmarketing pharmacovigilance. Though potentially highly useful, the database reflects reporting biases, stimulated reporting, and suffers from lack of standardization and the use of multiple drug synonyms. These biases can suggest adverse drug reactions (ADRs) where none exist, and can obscure others that do exist. To decrease the noise in FAERS, and to reinforce important associations, we mapped over 750,000 drug identifiers in FAERS to the normalized chemical structures of their ingredients. This illuminated associations that would not otherwise be apparent, and also allowed a time-resolved analysis of ADR reporting. It also revealed similarities between drugs and adverse events across therapeutic classes, enabling unbiased classification of adverse events, indications, and drugs with similar clinical profiles. For instance, comparison of two selective cyclooxygenase-2 inhibitors, celecoxib and rofecoxib finds distinctive FAERS profiles after time-resolved analysis. We also investigated key idiosyncrasies, such as confusion between drug indications and drug ADRs, which can tar a drug treating a life-threatening disease, like thalidomide's use against myeloma, with a deadly ADR that is likely the result of the disease itself, multiplications of the same report, which unjustifiably increases its apparent importance, and the correlation of reported ADRs with public events, regulatory announcements, and with publications. Comparing the pharmacological, pharmacokinetic, and clinical ADR profiles of methylphenidate, aripiprazole and risperidone, and of kinase drugs targeting the VEGF receptor (VEGF-R2), demonstrates how underlying molecular mechanisms can emerge from ADR co-analysis. The precautions and methods we describe may enable investigators to avoid confounding chemistry-based associations and reporting biases in FAERS, and illustrate how comparative analysis of ADRs can reveal underlaying mechanisms.
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