title: Factors associated with failure of oncology drugs in late-stage clinical development: A systematic review.
abstract: BACKGROUND
  We aimed to describe the reasons for failure of experimental anticancer drugs in late-stage clinical development.
  
  
  METHODS
  We searched the PharmaProjects database (https://citeline.com/products/pharmaprojects/) for anticancer drugs discontinued between 01/01/2009 and 06/30/2014. Drug programs that reached phase III trials, but never gained Food and Drug Administration (FDA) approval were compared to 37 anti-cancer drugs achieving FDA approval in this time period.
  
  
  RESULTS
  Forty-two drugs fit our criteria for development failures. These failed drugs (49% targeted, 23% cytotoxics, and 28% other) were tested in 43 cancer indications (drug programs). Only 16% (7/43) of failed drug programs adopted a biomarker-driven rationale for patient selection versus 57% (21/37) of successful drug programs (P<0.001). Phase II trial information was available in 32 of 43 failed drug programs and in 32 of 37 successful programs. Nine of the 32 trials (28%) of failed drugs versus 28 of 32 trials (87%) of successful drugs (P<0.001) achieved proof of concept (single agent response rate (RR) ⩾20% or combination therapy showing a ⩾20% RR increase above the median historical RR without the experimental agent (with a minimal absolute increase of 5%) or a randomized phase II trial showing significance (P⩽0.05) for its primary outcome). No pattern of study sites, trial design or funding characteristics emerged from the failed drug analysis.
  
  
  CONCLUSIONS
  For drugs that reached Phase III, lack of a biomarker-driven strategy and failure to attain proof of concept in phase II are potential risk factors for later discontinuation, especially for targeted agents.
authors.affiliation: Department of Clinical Oncology, Hospital Sirio Libanes, Sao Paulo, Brazil. Electronic address: jardimde@gmail.com.
authors.forename: Denis L
authors.initials: DL
authors.lastname: Jardim
authors.affiliation: Quintiles Pharmaceuticals, Durham, NC, USA.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Groves
authors.affiliation: Breitfeld Group, LLC, Chapel Hill, NC, USA.
authors.forename: Philip P
authors.initials: PP
authors.lastname: Breitfeld
authors.affiliation: Center for Personalized Cancer Therapy and Division of Hematology and Oncology, University of California, San Diego, CA, USA.
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D004341:Drug Evaluation / Q000379:methods* / Q000592:standards; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D000970:Antineoplastic Agents
keywords: Biomarker; Drug development; FDA; Phase III trials; Precision medicine