TY - JOUR

T1 - Optimising the data combination rule for seamless phase II/III clinical trials

AU - Hampson, Lisa

AU - Jennison, Chris

N1 - Copyright © 2014 © 2014 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

PY - 2015/1

Y1 - 2015/1

N2 - We consider seamless Phase II/III clinical trials which compare K treatments with a common control in Phase II, then test the most promising treatment against control in Phase III. The final hypothesis test for the selected treatment can use data from both Phases, subject to controlling the familywise type I error rate. We show that the choice of method for conducting the final hypothesis test has a substantial impact on the power to demonstrate that an effective treatment is superior to control. To understand these differences in power we derive optimaldecision rules, maximising power for particular configurations of treatment effects. Rules with optimal frequentist properties are found as solutions to multivariate Bayes decision problems. Although the optimal rule depends onthe configuration of treatment means considered, we are able to identify two decision rules with robust efficiency: a rule using a weighted average of the Phase II and Phase III data on the selected treatment and control, and a closed testing procedure using an inverse normal combination rule and a Dunnett test for intersection hypotheses. For the first of these rules, we find the optimal division of a given total sample size between Phase II and Phase III.We also assess the value of using Phase II data in the final analysis and find that for many plausible scenarios, between 50% and 70% of the Phase II numbers on the selected treatment and control would need to be added to the Phase III sample size in order to achieve the same increase in power.

AB - We consider seamless Phase II/III clinical trials which compare K treatments with a common control in Phase II, then test the most promising treatment against control in Phase III. The final hypothesis test for the selected treatment can use data from both Phases, subject to controlling the familywise type I error rate. We show that the choice of method for conducting the final hypothesis test has a substantial impact on the power to demonstrate that an effective treatment is superior to control. To understand these differences in power we derive optimaldecision rules, maximising power for particular configurations of treatment effects. Rules with optimal frequentist properties are found as solutions to multivariate Bayes decision problems. Although the optimal rule depends onthe configuration of treatment means considered, we are able to identify two decision rules with robust efficiency: a rule using a weighted average of the Phase II and Phase III data on the selected treatment and control, and a closed testing procedure using an inverse normal combination rule and a Dunnett test for intersection hypotheses. For the first of these rules, we find the optimal division of a given total sample size between Phase II and Phase III.We also assess the value of using Phase II data in the final analysis and find that for many plausible scenarios, between 50% and 70% of the Phase II numbers on the selected treatment and control would need to be added to the Phase III sample size in order to achieve the same increase in power.

KW - Bayes decision problem

KW - combination test

KW - closed testing procedure

KW - multiple hypothesis testing

KW - seamless phase II/III trial

KW - treatment selection

U2 - 10.1002/sim.6316

DO - 10.1002/sim.6316

M3 - Journal article

VL - 34

SP - 39

EP - 58

JO - Statistics in Medicine

JF - Statistics in Medicine

SN - 0277-6715

IS - 1

ER -