Estimation after subpopulation selection in adaptive seamless trials

Peter K. Kimani, Susan Todd, Nigel Stallard

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)

Abstract

During the development of new therapies, it is not uncommon to test whether a new treatment works better than the existing treatment for all patients who suffer from a condition (full population) or for a subset of the full population (subpopulation). One approach that may be used for this objective is to have two separate trials, where in the first trial, data are collected to determine if the new treatment benefits the full population or the subpopulation. The second trial is a confirmatory trial to test the new treatment in the population selected in the first trial. In this paper, we consider the more efficient two-stage adaptive seamless designs (ASDs), where in stage 1, data are collected to select the population to test in stage 2. In stage 2, additional data are collected to perform confirmatory analysis for the selected population. Unlike the approach that uses two separate trials, for ASDs, stage 1 data are also used in the confirmatory analysis. Although ASDs are efficient, using stage 1 data both for selection and confirmatory analysis introduces selection bias and consequently statistical challenges in making inference. We will focus on point estimation for such trials. In this paper, we describe the extent of bias for estimators that ignore multiple hypotheses and selecting the population that is most likely to give positive trial results based on observed stage 1 data. We then derive conditionally unbiased estimators and examine their mean squared errors for different scenarios.

Original languageEnglish
Pages (from-to)2581-2601
Number of pages21
JournalStatistics in Medicine
Volume34
Issue number18
DOIs
Publication statusPublished - 15 Aug 2015
Externally publishedYes

Keywords

  • Adaptive seamless designs
  • Multi-arm multi-stage trials
  • Phase II/III clinical trials
  • Subgroup analysis
  • Subpopulation

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