A hybrid phase I‐II/III clinical trial design allowing dose re‐optimization in phase III. Issue 2 (3rd April 2019)

• Record Type: Journal Article
• Authors: Chapple, Andrew G.; Thall, Peter F.
• Is Part Of: Biometrics. Volume 75:Issue 2(2019)
• Page Start: 371
• Page End: 381
• Publication Date: 2019-04-03
• Subjects: Bayesian design -- Clinical trial -- dose finding -- phase I‐II clinical trial -- phase III clinical trial; Biometry -- Periodicals; 570.15195
• DOI: 10.1111/biom.12994
• Languages: English
• ISSNs: 0006-341X

Abstract

Abstract: Conventionally, evaluation of a new drug, A, is done in three phases. Phase I is based on toxicity to determine a "maximum tolerable dose" (MTD) of A, phase II is conducted to decide whether A at the MTD is promising in terms of response probability, and if so a large randomized phase III trial is conducted to compare A to a control treatment, C, usually based on survival time or progression free survival time. It is widely recognized that this paradigm has many flaws. A recent approach combines the first two phases by conducting a phase I‐II trial, which chooses an optimal dose based on both efficacy and toxicity, and evaluation of A at the selected optimal phase I‐II dose then is done in a phase III trial. This paper proposes a new design paradigm, motivated by the possibility that the optimal phase I‐II dose may not maximize mean survival time with A . We propose a hybridized design, which we call phase I‐II/III, that combines phase I‐II and phase III by allowing the chosen optimal phase I‐II dose of A to be re‐optimized based on survival time data from phase I‐II patients and the first portion of phase III. The phase I‐II/III design uses adaptive randomization in phase I‐II, and relies on a mixture model for the survival time distribution as a function of efficacy, toxicity, and dose. A simulation study is presented to evaluate the phase I‐II/III design and compare it to the usual approach that does not re‐optimize the dose of A in phase III.