On the estimation of the binomial probability in multistage clinical trials.

Journal Article (Journal Article)

Due to the optional sampling effect in a sequential design, the maximum likelihood estimator (MLE) following sequential tests is generally biased. In a typical two-stage design employed in a phase II clinical trial in cancer drug screening, a fixed number of patients are enrolled initially. The trial may be terminated for lack of clinical efficacy of treatment if the observed number of treatment responses after the first stage is too small. Otherwise, an additional fixed number of patients are enrolled to accumulate additional information on efficacy as well as on safety. There have been numerous suggestions for design of such two-stage studies. Here we establish that under the two-stage design the sufficient statistic, i.e. stopping stage and the number of treatment responses, for the parameter of the binomial distribution is also complete. Then, based on the Rao-Blackwell theorem, we derive the uniformly minimum variance unbiased estimator (UMVUE) as the conditional expectation of an unbiased estimator, which in this case is simply the maximum likelihood estimator based only on the first stage data, given the complete sufficient statistic. Our results generalize to a multistage design. We will illustrate features of the UMVUE based on two-stage phase II clinical trial design examples and present results of numerical studies on the properties of the UMVUE in comparison to the usual MLE.

Full Text

Duke Authors

Cited Authors

  • Jung, S-H; Kim, KM

Published Date

  • March 30, 2004

Published In

Volume / Issue

  • 23 / 6

Start / End Page

  • 881 - 896

PubMed ID

  • 15027078

International Standard Serial Number (ISSN)

  • 0277-6715

Digital Object Identifier (DOI)

  • 10.1002/sim.1653


  • eng

Conference Location

  • England