title: Observations on Three Endpoint Properties and Their Relationship to Regulatory Outcomes of European Oncology Marketing Applications.
abstract: BACKGROUND
  Guidance and exploratory evidence indicate that the type of endpoints and the magnitude of their outcome can define a therapy's clinical activity; however, little empirical evidence relates specific endpoint properties with regulatory outcomes.
  
  
  METHODS
  We explored the relationship of 3 endpoint properties to regulatory outcomes by assessing 50 oncology marketing authorization applications (MAAs; reviewed from 2009 to 2013).
  
  
  RESULTS
  Overall, 16 (32%) had a negative outcome. The most commonly used hard endpoints were overall survival (OS) and the duration of response or stable disease. OS was a component of 91% approved and 63% failed MAAs. The most commonly used surrogate endpoints were progression-free survival (PFS), response rate, and health-related quality of life assessments. There was no difference (p = .3801) between the approved and failed MAA cohorts in the proportion of hard endpoints used. A mean of slightly more than four surrogate endpoints were used per approved MAA compared with slightly more than two for failed MAAs. Longer OS and PFS duration outcomes were generally associated with approvals, often when not statistically significant. The approved cohort was associated with a preponderance of statistically significant (p < .05) improvements in primary endpoints (p < .0001 difference between the approved and failed groups).
  
  
  CONCLUSIONS
  Three key endpoint properties (type of endpoint [hard/surrogate], magnitude of an endpoint outcome, and its statistical significance) are consistent with the European Medicines Agency guidance and, notwithstanding the contribution of unique disease-specific circumstances, are associated with a predictable positive outcome for oncology MAAs.
  
  
  CONCLUSIONS
  Regulatory decisions made by the European Medicines Agency determine which new medicines will be available to European prescribers and for which therapeutic indications. Regulatory success or failure can be influenced by many factors. This study assessed three key properties of endpoints used in preauthorization trials (type of endpoint [hard/surrogate], magnitude of endpoint outcome, and its statistical significance) and whether they are associated with a positive regulatory outcome. Clinicians can use these properties, which are described in the publicly available European public assessment reports, to help guide their understanding of the clinical effect of new oncologic therapies.
authors.affiliation: Centre for Innovation in Regulatory Science, London, United Kingdom; Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands; Division of Clinical Pharmacology, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Pharmacology, School of Life Sciences, University of Liverpool, Liverpool, United Kingdom LLiberti@cirsci.org.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Liberti
authors.affiliation: Centre for Innovation in Regulatory Science, London, United Kingdom; Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands; Division of Clinical Pharmacology, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Pharmacology, School of Life Sciences, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Pieter
authors.initials: P
authors.lastname: Stolk
authors.affiliation: Centre for Innovation in Regulatory Science, London, United Kingdom; Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands; Division of Clinical Pharmacology, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Pharmacology, School of Life Sciences, University of Liverpool, Liverpool, United Kingdom.
authors.forename: James Neil
authors.initials: JN
authors.lastname: McAuslane
authors.affiliation: Centre for Innovation in Regulatory Science, London, United Kingdom; Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands; Division of Clinical Pharmacology, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Pharmacology, School of Life Sciences, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Jan
authors.initials: J
authors.lastname: Schellens
authors.affiliation: Centre for Innovation in Regulatory Science, London, United Kingdom; Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands; Division of Clinical Pharmacology, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Pharmacology, School of Life Sciences, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Alasdair M
authors.initials: AM
authors.lastname: Breckenridge
authors.affiliation: Centre for Innovation in Regulatory Science, London, United Kingdom; Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands; Division of Clinical Pharmacology, Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Pharmacology, School of Life Sciences, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Hubert
authors.initials: H
authors.lastname: Leufkens
mesh_terms: D018572:Disease-Free Survival; D017277:Drug Approval; D023381:Endpoint Determination; D005060:Europe; D006801:Humans; D040541:Marketing; D009369:Neoplasms / Q000188:drug therapy / Q000453:epidemiology* / Q000473:pathology
keywords: Accelerated approvals; Endpoints; Marketing authorization application; Oncology; Overall survival; Progression-free survival