Design Issues in Randomized Phase II/III Trials

Abstract

Phase II trials are used to show sufficient preliminary activity of a new treatment (in single-arm designs or randomized screening designs) or to select among treatments with demonstrated activity (in randomized selection designs). The treatments prioritized in a phase II trial are then tested definitively against a control treatment in a randomized phase III trial. Randomized phase II/III trials use an adaptive trial design that combines these two types of trials in one, with potential gains in time and reduced numbers of patients required to be treated. Two key considerations in designing a phase II/III trial are whether to suspend accrual while the phase II data mature and the choice of phase II target treatment effect. We discuss these phase II/III design parameters, give examples of phase II/III trials, and provide recommendations concerning efficient phase II/III trial designs.

ESMO-ESGO-ESTRO Consensus Conference on Endometrial Cancer: Diagnosis, Treatment and Follow-up

“…Setting up individual trials is both costly and time-consuming, although adaptive phase II/III trials may offer some advantages 210. Alternative strategies such as the ‘basket’ approach, which includes all patients subdivided by specific histological or molecular cohorts under the umbrella of a single trial, may be the most efficient way forward 211.…”

“…210 Alternative strategies such as the 'basket' approach, which includes all patients subdivided by specific histological or molecular cohorts under the umbrella of a single trial, may be the most efficient way forward. 211 Such trials should also incorporate novel endpoints and the design would be strengthened by the inclusion of sequential and repeated assessments of biomarkers.…”

New challenges for comparative effectiveness in oncology: choice of primary end points for randomized clinical trials

“…To minimize sample size requirements, the patients who are used in a screening analysis (using the intermediate end point) can be used in the definitive analysis (along with newly accrued patients) if the screening decision is to go forward [70]. This Phase II/III trial design approach can also be used with a trial with multiple experimental treatments, in which some of the experimental treatments are dropped during the trial because of insufficient benefit over the standard treatment after evaluation of the Phase II intermediate end point.…”

Evaluating Many Treatments and Biomarkers in Oncology: A New Design

“…Such designs can be adapted for different end points at different stages and use different decision criteria for moving from one stage to another. 32 For all therapies that pass activity screening in stage 2, a number of paths are possible. If no major changes are to be made to the research arm (eg, in biomarker selection criteria or agent dosing), a seamless move to stage 3 is possible, with outcome data on all patients entered during stages 1 and 2 being used in stages 3 and 4.…”