A Phase II/III Randomized Clinical Trial Design with Sequential Decision Rule Based on Multiple Primary Endpoints

• Activity Number: 423
• Type: Contributed
• Date/Time: Tuesday, August 2, 2011 : 2:00 PM to 3:50 PM
• Sponsor: Biopharmaceutical Section
• Author(s): Qian Shi*+ and Daniel J. Sargent
• Companies: Mayo Clinic and Mayo Clinic
• Keywords: clinical trial design ; multiple endpoints ; sequential hypothesis testing

Abstract

Early efficacy screening before definitive phase III study is necessary to prevent sub-optimal regimens being tested further. A seamless phase II/III study design provides the opportunity to improve efficiency and provide early efficacy screening. In many practical scenarios, co-primary endpoints are needed to be considered to capture the unique nature of a disease. We proposed and applied a phase II/III randomized design with sequential final decision rule to a clinical trial comparing combined modality neo-adjuvant therapy to the selective use of radiation in intermediate risk rectal cancer. The co-primary endpoints of disease-free survival (DFS) and time to local recurrence (TLR) were assessed jointly by the sequential hypothesis testing procedure. DFS was tested for noninferiority first and then the superiority if the noninferiority was established. Then if the superiority test was inconclusive, the TLR was tested for noninferiority. This design can also incorporate different endpoints in phase II stage. The decision rules and study characteristics were optimized based on simulation studies.