title: Reducing attrition in drug development: smart loading preclinical safety assessment.
abstract: Entry into the crucial preclinical good laboratory practice (GLP) stage of toxicology testing triggers significant R&D investment yet >20% of AstraZeneca's potential new medicines have been stopped for safety reasons in this GLP phase alone. How could we avoid at least some of these costly failures? An analysis of historical toxicities that caused stopping ('stopping toxicities') showed that >50% were attributable to target organ toxicities emerging within 2 weeks of repeat dosing or to acute cardiovascular risks. By frontloading 2-week repeat-dose toxicity studies and a comprehensive assessment of cardiovascular safety, we anticipate a potential 50% reduction in attrition in the GLP phase. This will reduce animal use overall, save significant R&D costs and improve drug pipeline quality.
authors.affiliation: Drug Safety and Metabolism, AstraZeneca, Alderley Park, Macclesfield, SK10 4TG, UK. Electronic address: ruth.roberts@astrazeneca.com.
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Roberts
authors.affiliation: Drug Safety and Metabolism, AstraZeneca, Alderley Park, Macclesfield, SK10 4TG, UK.
authors.forename: Stefan L
authors.initials: SL
authors.lastname: Kavanagh
authors.affiliation: Drug Safety and Metabolism, AstraZeneca, Alderley Park, Macclesfield, SK10 4TG, UK.
authors.forename: Howard R
authors.initials: HR
authors.lastname: Mellor
authors.affiliation: Drug Safety and Metabolism, AstraZeneca, Alderley Park, Macclesfield, SK10 4TG, UK.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Pollard
authors.affiliation: Drug Safety and Metabolism, AstraZeneca, Alderley Park, Macclesfield, SK10 4TG, UK.
authors.forename: Sally
authors.initials: S
authors.lastname: Robinson
authors.affiliation: Drug Safety and Metabolism, AstraZeneca, Alderley Park, Macclesfield, SK10 4TG, UK.
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Platz
mesh_terms: D000818:Animals; D066126:Cardiotoxicity / Q000517:prevention & control; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000191:economics / Q000379:methods*; D004345:Drug Industry / Q000191:economics / Q000706:statistics & numerical data; D006801:Humans; D012106:Research / Q000191:economics / Q000706:statistics & numerical data; D018675:Toxicity Tests / Q000191:economics / Q000379:methods*