Academic Commons

Theses Doctoral

The Limb-Leaf Design: A New Way to Explore the Dose Response Curve in Adaptive Seamless Phase II/III Trials

Spivack, John Henry

This dissertation proposes a method to explore a dose response curve adaptively, allowing new doses to be inserted into the trial after initial results have been observed. The context of our work is adaptive seamless Phase II/III trials and a systematic Limb-Leaf Design is developed. In a case of a nonmonotonic dose response curve where the desired level of effect exists in only a narrow dose range, a simulated comparison between a Limb-Leaf Design and a standard (Thall, Simon, and Ellenberg or TSE-type) adaptive seamless design shows a savings in risk adjusted expected sample size of up to 25%. Chapter 1 is a review of concepts and particular adaptive seamless designs of interest. Chapter 2 proposes dose addition in adaptive seamless designs and identifes ALS research as an area of application. Chapter 3 develops dose addition as an application of existing methodology. Chapter 4 identifies shortcomings of this approach and proposes a new Horizontal Test as the basis for the Limb-Leaf Design. Chapter 5 supports the development of the Limb-Leaf Design with several theoretical observations. The Limb-Leaf Design is developed in Chapters 6 and 7. Chapter 8 shows a comparison of the Limb-Leaf Design with a TSE-type adaptive seamless design by simulation. Future work is suggested in Chapter 9.

Subjects

Files

  • thumnail for Spivack_columbia_0054D_10481.pdf Spivack_columbia_0054D_10481.pdf application/pdf 657 KB Download File

More About This Work

Academic Units
Biostatistics
Thesis Advisors
Cheng, Bin
Degree
Ph.D., Columbia University
Published Here
December 20, 2011
Academic Commons provides global access to research and scholarship produced at Columbia University, Barnard College, Teachers College, Union Theological Seminary and Jewish Theological Seminary. Academic Commons is managed by the Columbia University Libraries.