title: Statistical controversies in clinical research: building the bridge to phase II-efficacy estimation in dose-expansion cohorts.
abstract: BACKGROUND
  Regulatory agencies and others have expressed concern about the uncritical use of dose expansion cohorts (DECs) in phase I oncology trials. Nonetheless, by several metrics-prevalence, size, and number-their popularity is increasing. Although early efficacy estimation in defined populations is a common primary endpoint of DECs, the types of designs best equipped to identify efficacy signals have not been established.
  
  
  METHODS
  We conducted a simulation study of six phase I design templates with multiple DECs: three dose-assignment/adjustment mechanisms multiplied by two analytic approaches for estimating efficacy after the trial is complete. We also investigated the effect of sample size and interim futility analysis on trial performance. Identifying populations in which the treatment is efficacious (true positives) and weeding out inefficacious treatment/populations (true negatives) are competing goals in these trials. Thus, we estimated true and false positive rates for each design.
  
  
  RESULTS
  Adaptively updating the MTD during the DEC improved true positive rates by 8-43% compared with fixing the dose during the DEC phase while maintaining false positive rates. Inclusion of an interim futility analysis decreased the number of patients treated under inefficacious DECs without hurting performance.
  
  
  CONCLUSIONS
  A substantial gain in efficiency is obtainable using a design template that statistically models toxicity and efficacy against dose level during expansion. Design choices for dose expansion should be motivated by and based upon expected performance. Similar to the common practice in single-arm phase II trials, cohort sample sizes should be justified with respect to their primary aim and include interim analyses to allow for early stopping.
authors.affiliation: Departments of Biostatistics.
authors.forename: P S
authors.initials: PS
authors.lastname: Boonstra
authors.affiliation: Departments of Biostatistics.
authors.forename: T M
authors.initials: TM
authors.lastname: Braun
authors.affiliation: Departments of Biostatistics.|Radiation Oncology.
authors.forename: J M G
authors.initials: JMG
authors.lastname: Taylor
authors.affiliation: Departments of Biostatistics.
authors.forename: K M
authors.initials: KM
authors.lastname: Kidwell
authors.affiliation: Departments of Biostatistics.
authors.forename: E L
authors.initials: EL
authors.lastname: Bellile
authors.affiliation: Departments of Biostatistics.
authors.forename: S
authors.initials: S
authors.lastname: Daignault
authors.affiliation: Departments of Biostatistics.
authors.forename: L
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Departments of Biostatistics.
authors.forename: K A
authors.initials: KA
authors.lastname: Griffith
authors.affiliation: Radiation Oncology.
authors.forename: T S
authors.initials: TS
authors.lastname: Lawrence
authors.affiliation: Internal Medicine, University of Michigan, Ann Arbor, USA.
authors.forename: G P
authors.initials: GP
authors.lastname: Kalemkerian
authors.affiliation: Departments of Biostatistics.|Radiation Oncology.
authors.forename: M J
authors.initials: MJ
authors.lastname: Schipper
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D017321:Clinical Trials, Phase I as Topic / Q000706:statistics & numerical data*; D003198:Computer Simulation; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D054796:Drug Dosage Calculations; D023381:Endpoint Determination / Q000706:statistics & numerical data; D006801:Humans; D020714:Maximum Tolerated Dose; D008495:Medical Oncology / Q000706:statistics & numerical data*; D015233:Models, Statistical; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy*; D012107:Research Design / Q000706:statistics & numerical data*; D018401:Sample Size; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents
keywords: 3 + 3; continual reassessment method; interim analysis; maximum tolerated dose; phase I design; sample size