The application of adaptive designs in phase III randomised controlled trials in cancer

Abstract

The research conducted within this thesis investigated the application of adaptive designs within phase III cancer trials, in particular, the use of multi-arm multi-stage designs (MAMS) were investigated. The application of adaptive designs in phase III randomised controlled trials are becoming common. These designs have the ability to reduce the number of patients required, be efficient in reducing the time needed and effective in having the ability to answer many questions within one trial. A literature review found that adaptive designs were regularly implemented but the reporting of these methods were poor. I proposed there should be an adaptive design extension to the CONSORT 2010 guidelines and subsequently this has been published. A scoping exercise of cancer trials conducted within the Warwick Clinical Trials Unit found that adaptive methods were regularly implemented without classifying them as adaptive designs. This scoping exercise was extended to identify exemplar trials that have implemented adaptive design methodology and to understand the design, conduct and reporting of these trials. MAMS designs within three common cancer sites (breast, colon and lung) were investigated using a superiority hypothesis, primarily focusing on the longer term outcome of overall survival. Simulations were used to demonstrate how MAMS designs can be extended for use with a non-inferiority (NI) hypothesis. A MAMS design was then applied to a trial investigating the optimal duration of Herceptin therapy for patients diagnosed with early breast cancer. A MAMS design with a NI hypothesis appeared feasible from a statistical viewpoint however the operational aspects must be considered to ensure the trials’ success. My research showed that implementing a MAMS design within cancer trials can be more efficient and effective. It is anticipated that the use of adaptive designs within phase III randomised trials will continue to increase and are now required to be fully reported