title: Role of chronic toxicology studies in revealing new toxicities.
abstract: Chronic (>3 months) preclinical toxicology studies are conducted to support the safe conduct of clinical trials exceeding 3 months in duration. We have conducted a review of 32 chronic toxicology studies in non-rodents (22 studies in dogs and 10 in non-human primates) and 27 chronic toxicology studies in rats dosed with Merck compounds to determine the frequency at which additional target organ toxicities are observed in chronic toxicology studies as compared to subchronic studies of 3 months in duration. Our review shows that majority of the findings are observed in the subchronic studies since additional target organs were not observed in 24 chronic non rodent studies and in 21 chronic rodent studies. However, 6 studies in non rodents and 6 studies in rodents yielded new findings that were not seen in studies of 3-month or shorter duration. For 3 compounds the new safety findings did contribute to termination of clinical development plans. Although the incidence of compound termination associated with chronic toxicology study observations is low (∼10%), the observations made in these studies can be important for evaluating human safety risk.
authors: Merck and Co., Inc., West Point, PA, USA. Electronic address: alema_galijatovic@merck.com.
authors: Alema
authors: A
authors: Galijatovic-Idrizbegovic
authors: Merck and Co., Inc., West Point, PA, USA.
authors: Judith E
authors: JE
authors: Miller
authors: Merck and Co., Inc., Rahway, NJ, USA.
authors: Wendy D
authors: WD
authors: Cornell
authors: Linguamatics Solutions, USA.
authors: James A
authors: JA
authors: Butler
authors: Merck and Co., Inc., West Point, PA, USA.
authors: Gordon K
authors: GK
authors: Wollenberg
authors: Merck and Co., Inc., West Point, PA, USA.
authors: Frank D
authors: FD
authors: Sistare
authors: Merck and Co., Inc., West Point, PA, USA.
authors: Joseph J
authors: JJ
authors: DeGeorge
mesh_terms: D000818:Animals; D016208:Databases, Factual; D004305:Dose-Response Relationship, Drug; D004345:Drug Industry; D006801:Humans; D023421:Models, Animal; D015203:Reproducibility of Results; D018570:Risk Assessment; D013045:Species Specificity; D013997:Time Factors; D036401:Toxicity Tests, Chronic / Q000379:methods*; D059550:Toxicity Tests, Subchronic / Q000379:methods*
keywords: Chronic; Human safety risk; Preclinical species; Toxicology studies