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Optimal sequential enrichment designs for phase II clinical trials.

In the early phase development of molecularly targeted agents (MTAs), a commonly encountered situation is that the MTA is expected to be more effective for a certain biomarker subgroup, say marker-positive patients, but there is no adequate evidence to show that the MTA does not work for the other s...

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Published in:Statistics in Medicine Vol. 36; no. 1; pp. 54 - 67
Main Authors: Zang, Yong, Yuan, Ying
Format: algorithm equations & formulas research tables/charts Journal Article
Published: Wiley-Blackwell 1/15/2017
Online Access:View this record in EBSCOhost
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      jtl: Statistics in Medicine
      issn: 02776715
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      dt: 1/15/2017
      vid: 36
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      pub: Wiley-Blackwell
      place: Malden, Massachusetts
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        119947063
        119947063
        NLM27640874
        119947063
        10.1002/sim.7128
        NLM27640874
        119947063
      ppf: 54
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        atl: Optimal sequential enrichment designs for phase II clinical trials.
      aug:
        au:
          Zang, Yong
          Yuan, Ying
        affil: Department of Biostatistics, School of Medicine, Indiana University, Indianapolis IN 46202, U.S.A.
      sug:
        subj:
          Drug Therapy
          Models, Statistical
          Clinical Trials
          Study Design
          Algorithms
          Female
          Computer Simulation
          Phosphotransferases Antagonists and Inhibitors
          Dose-Response Relationship, Drug
          Endometrial Neoplasms Drug Therapy
          Sample Size
          Funding Source
          Human
          Female
      ab: In the early phase development of molecularly targeted agents (MTAs), a commonly encountered situation is that the MTA is expected to be more effective for a certain biomarker subgroup, say marker-positive patients, but there is no adequate evidence to show that the MTA does not work for the other subgroup, that is, marker-negative patients. After establishing that marker-positive patients benefit from the treatment, it is often of great clinical interest to determine whether the treatment benefit extends to marker-negative patients. The authors propose optimal sequential enrichment (OSE) designs to address this practical issue in the context of phase II clinical trials. The OSE designs evaluate the treatment effect first in marker-positive patients and then in marker-negative patients if needed. The designs are optimal in the sense that they minimize the expected sample size or the maximum sample size under the null hypothesis that the MTA is futile. An efficient, accurate optimization algorithm is proposed to find the optimal design parameters. One important advantage of the OSE design is that the go/no-go interim decision rules are specified prior to the trial conduct, which makes the design particularly easy to use in practice. A simulation study shows that the OSE designs perform well and are ethically more desirable than the commonly used marker-stratified design. The OSE design is applied to an endometrial carcinoma trial. Copyright © 2016 John Wiley & Sons, Ltd.
      pubtype: Academic Journal
      doctype:
        algorithm
        equations & formulas
        research
        tables/charts
        Journal Article
      ougenre: Article
    language: English
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