title: Potential of patient-reported outcomes as nonprimary endpoints in clinical trials.
abstract: BACKGROUND
  The purpose of this research was to fully explore the impact of endpoint type (primary vs. nonprimary) on decisions related to patient-reported outcome (PRO) labeling claims supported by PRO measures and to determine if nonprimary PRO endpoints are being fully optimized.This review examines the use of PROs as both primary and nonprimary endpoints in support of demonstration of treatment benefit of new molecular entities (NMEs) and biologic license applications (BLAs) in the United States in the years 2000 to 2012.
  
  
  METHODS
  All NMEs and BLAs approved by the Food and Drug Administration (FDA) between January 2000 and June 2012 were identified using the FDA Drug Approval Reports Web page. Generic products granted tentative approvals were excluded. For all identified products, medical review sections from publicly available drug approval packages were reviewed to identify PRO endpoint status. Product labels (indication, clinical trials sections) were reviewed to determine the number and type of PRO claim.
  
  
  RESULTS
  A total of 308 NMEs/BLAs were identified. Of these, 70 NMEs/BLAs (23%) were granted PRO claims. The majority of product claims were for disease- or condition-specific signs and symptoms. Of the 70 products with PRO claims, a PRO was a primary endpoint for the vast majority (57 [81%]). A total of 19 of the 70 products were granted a PRO claim based on a nonprimary endpoint. While nonprimary endpoints were used most often to support claims of improved signs or symptoms, nonprimary endpoints were much more likely to support claims of higher order impacts.
  
  
  CONCLUSIONS
  Successful PRO labeling claims are typically based on primary endpoints assessing signs and symptoms. Based on this research, studies with PROs as primary endpoints are far more likely to facilitate positive regulatory review and acceptance of PROs in support of labeling claims. Although inclusion of PROs as nonprimary endpoints in clinical trials has its challenges, recent PRO labels granted by the FDA show that they can indeed be candidates for PRO labeling claims as long as they are supported by evidence.
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. ari.gnanasakthy@novartis.com
authors.forename: Ari
authors.initials: A
authors.lastname: Gnanasakthy
authors.forename: Sandra
authors.initials: S
authors.lastname: Lewis
authors.forename: Marci
authors.initials: M
authors.lastname: Clark
authors.forename: Margaret
authors.initials: M
authors.lastname: Mordin
authors.forename: Carla
authors.initials: C
authors.lastname: DeMuro
mesh_terms: D002986:Clinical Trials as Topic / Q000592:standards; D004348:Drug Labeling; D006801:Humans; D017063:Outcome Assessment, Health Care; D004364:Pharmaceutical Preparations / Q000592:standards; D019984:Quality Indicators, Health Care; D011788:Quality of Life; D057566:Self Report; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D004364:Pharmaceutical Preparations