title: Statistical controversies in clinical research: futility analyses in oncology-lessons on potential pitfalls from a randomized controlled trial.
abstract: BACKGROUND
  Pre-planned futility analyses are commonly used in oncology studies. The LUME-Lung 2 study (NCT00806819; 1199.14) was stopped early based on a pre-planned, non-binding futility analysis of investigator-assessed progression-free survival (PFS), although subsequent analysis showed that the primary endpoint of improvement in centrally reviewed PFS was met. Retrospective analyses were conducted to understand the discrepancy between interim futility and final analyses.
  
  
  METHODS
  LUME-Lung 2 investigated nintedanib in combination with pemetrexed versus placebo‒pemetrexed for the treatment of patients with advanced or recurrent non-squamous non-small cell lung cancer who had relapsed or failed one prior line of chemotherapy. Pre-planned futility analysis was carried out by the Data Monitoring Committee (DMC) after 50% of the events for the primary PFS analysis (713 events) had occurred; the threshold for futility was a conditional power of < 20%. Conditional/predictive powers and hazard ratios were calculated retrospectively after varying percentages of events had occurred for both investigator- and centrally reviewed PFS.
  
  
  RESULTS
  At the time of the pre-planned futility analysis, the conditional power was 10.3% and the predictive power was 18.5%; no safety issues were identified. Retrospective analysis showed that the conditional and predictive powers fluctuated considerably over time for both investigator- and centrally reviewed PFS and that the power only dropped by a notable amount, and below the futility threshold, at the time of the futility analysis.
  
  
  CONCLUSIONS
  Retrospective investigations suggest that, had the DMC analysis been carried out at another time point, or had centrally reviewed PFS data been used, the futility outcome may have been different and the trial may have been continued. The design of futility analyses requires careful consideration and confirming negative futility outcomes by second analysis may be appropriate.
  
  
  BACKGROUND
  NCT00806819.
authors.affiliation: L-Biostat, KU Leuven, Leuven, Belgium.|Department of Biostatistics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Lesaffre
authors.affiliation: University of Maryland Greenebaum Cancer Center, Baltimore.
authors.forename: M J
authors.initials: MJ
authors.lastname: Edelman
authors.affiliation: Indiana University, Melvin and Bren Simon Cancer Center, Indianapolis, USA.
authors.forename: N H
authors.initials: NH
authors.lastname: Hanna
authors.affiliation: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: K
authors.initials: K
authors.lastname: Park
authors.affiliation: The Christie NHS Foundation Trust, Manchester, UK.
authors.forename: N
authors.initials: N
authors.lastname: Thatcher
authors.affiliation: Department of Biostatistics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Willemsen
authors.affiliation: Boehringer Ingelheim Pharmaceuticals GmbH & Co. KG, Biberach.
authors.forename: B
authors.initials: B
authors.lastname: Gaschler-Markefski
authors.affiliation: Boehringer Ingelheim Pharmaceuticals GmbH & Co. KG, Biberach.|Institute of Clinical Pharmacology, University Göttingen, Göttingen.
authors.forename: R
authors.initials: R
authors.lastname: Kaiser
authors.affiliation: Department of Surgery, Interdisciplinary Thoracic Oncology, University Medical Center Mannheim, University of Heidelberg, Heidelberg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Manegold
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D056808:Biostatistics; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D017326:Clinical Trials, Phase III as Topic / Q000706:statistics & numerical data*; D003627:Data Interpretation, Statistical; D018572:Disease-Free Survival; D057239:Early Termination of Clinical Trials / Q000706:statistics & numerical data; D023381:Endpoint Determination / Q000706:statistics & numerical data*; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D008175:Lung Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D018447:Medical Futility; D015233:Models, Statistical; D000068437:Pemetrexed / Q000008:administration & dosage; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data*; D012107:Research Design / Q000706:statistics & numerical data*; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D007211:Indoles; D000068437:Pemetrexed; C530716:nintedanib
keywords: futility analysis; methodology; modelling, biostatistics; non-small cell lung cancer