Optimal sequential enrichment designs for phase II clinical trials

Yong Zang, Ying Yuan

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)54-66
Number of pages13
JournalStatistics in Medicine
Volume36
Issue number1
DOIs
StatePublished - Jan 15 2017

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Phase II Clinical Trials
Clinical Trials
Sample Size
Subgroup
Endometrial Neoplasms
Design
Biomarkers
Treatment Effects
Therapeutics
Decision Rules
Null hypothesis
Optimization Algorithm
Efficient Algorithms
Simulation Study
Minimise
Evaluate

Keywords

  • molecularly targeted agents
  • optimal design
  • personalized medicine
  • phase II trials
  • subgroups

ASJC Scopus subject areas

  • Epidemiology
  • Statistics and Probability

Cite this

Optimal sequential enrichment designs for phase II clinical trials. / Zang, Yong; Yuan, Ying.

In: Statistics in Medicine, Vol. 36, No. 1, 15.01.2017, p. 54-66.

Research output: Contribution to journalArticle

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