title: The genetics of drug efficacy: opportunities and challenges.
abstract: Lack of sufficient efficacy is the most common cause of attrition in late-phase drug development. It has long been envisioned that genetics could drive stratified drug development by identifying those patient subgroups that are most likely to respond. However, this vision has not been realized as only a small proportion of drugs have been found to have germline genetic predictors of efficacy with clinically meaningful effects, and so far all but one were found after drug approval. With the exception of oncology, systematic application of efficacy pharmacogenetics has not been integrated into drug discovery and development across the industry. Here, we argue for routine, early and cumulative screening for genetic predictors of efficacy, as an integrated component of clinical trial analysis. Such a strategy would identify clinically relevant predictors that may exist at the earliest possible opportunity, allow these predictors to be integrated into subsequent clinical development and provide mechanistic insights into drug disposition and patient-specific factors that influence response, therefore paving the way towards more personalized medicine.
authors.affiliation: Target Sciences, GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Nelson
authors.affiliation: Target Sciences, GlaxoSmithKline, Stevenage SG1 2NY, UK.
authors.forename: Toby
authors.initials: T
authors.lastname: Johnson
authors.affiliation: GlaxoSmithKline, Durham, North Carolina 27713, USA.|Acclarogen, Cambridge CB4 0WS, UK.
authors.forename: Liling
authors.initials: L
authors.lastname: Warren
authors.affiliation: PAREXEL International, Research Triangle Park, North Carolina 27713, USA.
authors.forename: Arlene R
authors.initials: AR
authors.lastname: Hughes
authors.affiliation: Target Sciences, GlaxoSmithKline, Seattle, Washington 98107, USA.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Chissoe
authors.affiliation: Target Sciences, GlaxoSmithKline, Stevenage SG1 2NY, UK.
authors.forename: Chun-Fang
authors.initials: CF
authors.lastname: Xu
authors.affiliation: Target Sciences, GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA.
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Waterworth
mesh_terms: D054316:Biomarkers, Pharmacological / Q000032:analysis; D055808:Drug Discovery / Q000639:trends; D005838:Genotype; D006801:Humans; D010597:Pharmacogenetics / Q000639:trends; D057285:Precision Medicine / Q000639:trends; D016896:Treatment Outcome
chemical_list: D054316:Biomarkers, Pharmacological