title: How were new medicines discovered?
abstract: Preclinical strategies that are used to identify potential drug candidates include target-based screening, phenotypic screening, modification of natural substances and biologic-based approaches. To investigate whether some strategies have been more successful than others in the discovery of new drugs, we analysed the discovery strategies and the molecular mechanism of action (MMOA) for new molecular entities and new biologics that were approved by the US Food and Drug Administration between 1999 and 2008. Out of the 259 agents that were approved, 75 were first-in-class drugs with new MMOAs, and out of these, 50 (67%) were small molecules and 25 (33%) were biologics. The results also show that the contribution of phenotypic screening to the discovery of first-in-class small-molecule drugs exceeded that of target-based approaches - with 28 and 17 of these drugs coming from the two approaches, respectively - in an era in which the major focus was on target-based approaches. We postulate that a target-centric approach for first-in-class drugs, without consideration of an optimal MMOA, may contribute to the current high attrition rates and low productivity in pharmaceutical research and development.
authors.affiliation: Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, California 94304, USA. david.swinney@irnd3.org
authors.forename: David C
authors.initials: DC
authors.lastname: Swinney
authors.forename: Jason
authors.initials: J
authors.lastname: Anthony
mesh_terms: D017277:Drug Approval; D015195:Drug Design; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004345:Drug Industry; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D058990:Molecular Targeted Therapy; D000069437:Pharmacological Phenomena; D014481:United States; D014486:United States Food and Drug Administration