title: Testing paradigm for prediction of development-limiting barriers and human drug toxicity.
abstract: The financial investment grows exponentially as a new chemical entity advances through each stage of discovery and development. The opportunity exists for the modern toxicologist to significantly impact expenditures by the early prediction of potential toxicity/side effect barriers to development by aggressive evaluation of development-limiting liabilities early in drug discovery. Improved efficiency in pharmaceutical research and development lies both in leveraging "best in class" technology and integration with pharmacologic activities during hit-to-lead and early lead optimization stages. To meet this challenge, a discovery assay by stage (DABS) paradigm should be adopted. The DABS clearly delineates to discovery project teams the timing and type of assay required for advancement of compounds to each subsequent level of discovery and development. An integrative core pathology function unifying Drug Safety Evaluation, Molecular Technologies and Clinical Research groups that effectively spans all phases of drug discovery and development is encouraged to drive the DABS. The ultimate goal of such improved efficiency being the accurate prediction of toxicity and side effects that would occur in development before commitment of the large prerequisite resource. Good justification of this approach is that every reduction of development attrition by 10% results in an estimated increase in net present value by $100 million.
authors.affiliation: Drug Safety and Disposition, Millennium Pharmaceuticals, Inc., 45 Sidney Street, Cambridge, MA 02139, USA. sassevil@mpi.com
authors.forename: V G
authors.initials: VG
authors.lastname: Sasseville
authors.forename: J H
authors.initials: JH
authors.lastname: Lane
authors.forename: V J
authors.initials: VJ
authors.lastname: Kadambi
authors.forename: P
authors.initials: P
authors.lastname: Bouchard
authors.forename: F W
authors.initials: FW
authors.lastname: Lee
authors.forename: S K
authors.initials: SK
authors.lastname: Balani
authors.forename: G T
authors.initials: GT
authors.lastname: Miwa
authors.forename: P F
authors.initials: PF
authors.lastname: Smith
authors.forename: C L
authors.initials: CL
authors.lastname: Alden
mesh_terms: D000818:Animals; D002626:Chemistry, Pharmaceutical; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008099:Liver / Q000473:pathology; D023421:Models, Animal; D015203:Reproducibility of Results; D012107:Research Design; D014116:Toxicology / Q000379:methods*