AbstractsMedical & Health Science

This thesis deals with the application of group sequential and adaptive methodology in three-arm non-inferiority trials for the case of normally distributed outcomes. Whenever feasible, use of the three-arm design including a test treatment, an active control and a placebo, is recommended by the health authorities. Nevertheless, especially from an ethical point of view, it is desirable to keep the placebo group size as small as possible. After giving a short introduction to two-arm non-inferiority trials, we investigate a hierarchical single-stage testing procedure for three-arm trials which starts by assessing the superiority comparison between test and placebo and then proceeds to the test versus control non-inferiority comparison. Based on formulas for the overall power we derive optimal sample size allocations that minimise the overall sample size. Interestingly, the placebo group size turns out to be very low under the optimal allocation. The optimal fixed sample size designs will then serve both as a starting point and a benchmark for the designs determined later. Subsequently, a general group sequential design for three-arm non-inferiority trials is presented that aims at further minimising the required sample sizes. By choosing different rejection boundaries for the two comparisons we obtain designs with quite different properties. The influence of the boundaries on the operating characteristics such as the expected sample sizes is investigated by means of a comprehensive comparison to the optimal fixed design. Moreover, approximately optimal boundaries are derived for different optimisation criteria such as minimising the placebo group size. It turns out that the implementation of group sequential methodology can further improve the optimal fixed designs, where the potential early termination of the placebo arm is a key advantage that can make the trial more acceptable for patients. After this, the group sequential testing procedure is extended to adaptive designs that allow data-dependent design changes at the interim analysis. In this context, we discuss optimal mid-trial decision-making based on the observed interim data, with a special focus on sample size re-calculation. In doing so, we will make use of the conditional power and the Bayesian predictive power. Our investigations show the advantages of the proposed adaptive designs over the optimal fixed designs. In particular, the possibility to adapt the sample sizes at interim can help to deal with uncertainties regarding the treatment effects, that often exist in the planning stage of three-arm non-inferiority trials. We conclude with a discussion of the results and an outlook on possible future work.