Data-driven treatment selection for seamless phase II/III trials incorporating early-outcome data.
Seamless phase II/III clinical trials are conducted in two stages with treatment selection at the first stage. In the first stage, patients are randomized to a control or one of k > 1 experimental treatments. At the end of this stage, interim data are analysed, and a decision is made concerning which experimental treatment should continue to the second stage. If the primary endpoint is observable only after some period of follow-up, at the interim analysis data may be available on some early outcome on a larger number of patients than those for whom the primary endpoint is available. These early endpoint data can thus be used for treatment selection. For two previously proposed approaches, the power has been shown to be greater for one or other method depending on the true treatment effects and correlations. We propose a new approach that builds on the previously proposed approaches and uses data available at the interim analysis to estimate these parameters and then, on the basis of these estimates, chooses the treatment selection method with the highest probability of correctly selecting the most effective treatment. This method is shown to perform well compared with the two previously described methods for a wide range of true parameter values. In most cases, the performance of the new method is either similar to or, in some cases, better than either of the two previously proposed methods.
Warwick Medical School, The University of Warwick, Coventry CV4 7AL, UK.
Cornelia Ursula
CU
Kunz
Tim
T
Friede
Nick
N
Parsons
Susan
S
Todd
Nigel
N
Stallard
D017322:Clinical Trials, Phase II as Topic / Q000379:methods*; D017326:Clinical Trials, Phase III as Topic / Q000379:methods*; D003198:Computer Simulation; D003627:Data Interpretation, Statistical; D003657:Decision Making; D006801:Humans; D016032:Randomized Controlled Trials as Topic / Q000379:methods; D016896:Treatment Outcome
adaptive seamless design; multi-arm multi-stage trial; surrogate endpoint