Leveraging Human Genetics to Identify Safety Signals Prior to Drug Marketing Approval and Clinical Use

Drug Saf. 2020 Jun;43(6):567-582. doi: 10.1007/s40264-020-00915-6.

Abstract

Introduction: When a new drug or biologic product enters the market, its full spectrum of side effects is not yet fully understood, as use in the real world often uncovers nuances not suggested within the relatively narrow confines of preapproval preclinical and trial work.

Objective: We describe a new, phenome-wide association study (PheWAS)- and evidence-based approach for detection of potential adverse drug effects.

Methods: We leveraged our established platform, which integrates human genetic data with associated phenotypes in electronic health records from 29,722 patients of European ancestry, to identify gene-phenotype associations that may represent known safety issues. We examined PheWAS data and the published literature for 16 genes, each of which encodes a protein targeted by at least one drug or biologic product.

Results: Initial data demonstrated that our novel approach (safety ascertainment using PheWAS [SA-PheWAS]) can replicate published safety information across multiple drug classes, with validated findings for 13 of 16 gene-drug class pairs.

Conclusions: By connecting and integrating in vivo and in silico data, SA-PheWAS offers an opportunity to supplement current methods for predicting or confirming safety signals associated with therapeutic agents.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Drug Approval*
  • Drug-Related Side Effects and Adverse Reactions / epidemiology*
  • Drug-Related Side Effects and Adverse Reactions / genetics
  • Electronic Health Records
  • Genome-Wide Association Study
  • Humans
  • Phenotype
  • White People