title: An analysis of pharmaceutical experience with decades of rat carcinogenicity testing: support for a proposal to modify current regulatory guidelines.
abstract: Data collected from 182 marketed and nonmarketed pharmaceuticals demonstrate that there is little value gained in conducting a rat two-year carcinogenicity study for compounds that lack: (1) histopathologic risk factors for rat neoplasia in chronic toxicology studies, (2) evidence of hormonal perturbation, and (3) positive genetic toxicology results. Using a single positive result among these three criteria as a test for outcome in the two-year study, fifty-two of sixty-six rat tumorigens were correctly identified, yielding 79% test sensitivity. When all three criteria were negative, sixty-two of seventy-six pharmaceuticals (82%) were correctly predicted to be rat noncarcinogens. The fourteen rat false negatives had two-year study findings of questionable human relevance. Applying these criteria to eighty-six additional chemicals identified by the International Agency for Research on Cancer as likely human carcinogens and to drugs withdrawn from the market for carcinogenicity concerns confirmed their sensitivity for predicting rat carcinogenicity outcome. These analyses support a proposal to refine regulatory criteria for conducting a two-year rat study to be based on assessment of histopathologic findings from a rat six-month study, evidence of hormonal perturbation, genetic toxicology results, and the findings of a six-month transgenic mouse carcinogenicity study. This proposed decision paradigm has the potential to eliminate over 40% of rat two-year testing on new pharmaceuticals without compromise to patient safety.
authors.affiliation: Merck and Co., Inc., West Point, Pennsylvania 19486-0004, USA. frank_sistare@merck.com
authors.forename: Frank D
authors.initials: FD
authors.lastname: Sistare
authors.forename: Daniel
authors.initials: D
authors.lastname: Morton
authors.forename: Carl
authors.initials: C
authors.lastname: Alden
authors.forename: Joel
authors.initials: J
authors.lastname: Christensen
authors.forename: Douglas
authors.initials: D
authors.lastname: Keller
authors.forename: Sandra De
authors.initials: SD
authors.lastname: Jonghe
authors.forename: Richard D
authors.initials: RD
authors.lastname: Storer
authors.forename: M Vijayaraj
authors.initials: MV
authors.lastname: Reddy
authors.forename: Andrew
authors.initials: A
authors.lastname: Kraynak
authors.forename: Bruce
authors.initials: B
authors.lastname: Trela
authors.forename: Jean-Guy
authors.initials: JG
authors.lastname: Bienvenu
authors.forename: Sivert
authors.initials: S
authors.lastname: Bjurström
authors.forename: Vanessa
authors.initials: V
authors.lastname: Bosmans
authors.forename: David
authors.initials: D
authors.lastname: Brewster
authors.forename: Karyn
authors.initials: K
authors.lastname: Colman
authors.forename: Mark
authors.initials: M
authors.lastname: Dominick
authors.forename: John
authors.initials: J
authors.lastname: Evans
authors.forename: James R
authors.initials: JR
authors.lastname: Hailey
authors.forename: Lewis
authors.initials: L
authors.lastname: Kinter
authors.forename: Matt
authors.initials: M
authors.lastname: Liu
authors.forename: Charles
authors.initials: C
authors.lastname: Mahrt
authors.forename: Dirk
authors.initials: D
authors.lastname: Marien
authors.forename: James
authors.initials: J
authors.lastname: Myer
authors.forename: Richard
authors.initials: R
authors.lastname: Perry
authors.forename: Daniel
authors.initials: D
authors.lastname: Potenta
authors.forename: Arthur
authors.initials: A
authors.lastname: Roth
authors.forename: Philip
authors.initials: P
authors.lastname: Sherratt
authors.forename: Thomas
authors.initials: T
authors.lastname: Singer
authors.forename: Rabih
authors.initials: R
authors.lastname: Slim
authors.forename: Keith
authors.initials: K
authors.lastname: Soper
authors.forename: Ronny
authors.initials: R
authors.lastname: Fransson-Steen
authors.forename: James
authors.initials: J
authors.lastname: Stoltz
authors.forename: Oliver
authors.initials: O
authors.lastname: Turner
authors.forename: Susan
authors.initials: S
authors.lastname: Turnquist
authors.forename: Marjolein
authors.initials: M
authors.lastname: van Heerden
authors.forename: Jochen
authors.initials: J
authors.lastname: Woicke
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: DeGeorge
mesh_terms: D000818:Animals; D015197:Carcinogenicity Tests / Q000379:methods* / Q000592:standards; D002273:Carcinogens / Q000592:standards / Q000633:toxicity*; D016208:Databases, Factual; D003663:Decision Trees; D004195:Disease Models, Animal; D005069:Evaluation Studies as Topic; D005260:Female; D017408:Guidelines as Topic; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009152:Mutagenicity Tests / Q000379:methods* / Q000592:standards; D009369:Neoplasms / Q000139:chemically induced; D051381:Rats; D011916:Rats, Inbred F344; D012307:Risk Factors; D013223:Statistics as Topic; D036401:Toxicity Tests, Chronic
chemical_list: D002273:Carcinogens; D007166:Immunosuppressive Agents