The Utility of Adaptive Designs in Publicly Funded Confirmatory Trials

Introduction: Adaptive designs (ADs) are underused, particularly in publicly funded confirmatory trials, despite their promising benefits and methodological prominence given in the statistical literature. Research Question: This thesis investigates why ADs are underused in the publicly funded setting, explores facilitators, and proposes recommendations to improve their appropriate use. Methods: Confirmatory ADs are reviewed from a statistical and practical perspective. Cross-disciplinary key stakeholders are then interviewed to explore roadblocks to the use of ADs. Based on the interview findings, follow-up quantitative surveys are undertaken to explore wider perceptions on barriers, concerns, and facilitators aimed to generalise the findings. The surveys targeted CTUs (Clinical Trials Units), private sector organisations, and Public Funders in the UK. In view of some of the findings, case studies of applied confirmatory ADs are reviewed to highlight their scope and characteristic, and to investigate the state of reporting of the most common AD. The design and implementation of selected ADs is demonstrated using retrospective and prospective planned case studies. Lessons learned are highlighted to enhance the design of future trials of similar characteristics. Results: The main barriers to the use of ADs include the lack of funding support accessible to UK CTUs to aid their design; limited practical knowledge; preference for traditional mainstream designs; difficulties in marketing ADs to key stakeholders; limited time to support ADs relative to other competing priorities; lack of applied training; and insufficient access to case studies of undertaken ADs, which would facilitate practical learning and successful implementation. Researchers’ inadequate description of AD-related aspects (such as rationale, scope, and decision-making criteria to guide the planned AD) in grant proposals was viewed among the major obstacles by Public Funders. Suboptimal reporting of the design and conduct of undertaken ADs appears to influence concerns about their robustness in decision-making and credibility to change practice. Conclusions: Most obstacles appear connected to a lack of practical implementation knowledge and applied training, and limited access to adequately reported case studies to facilitate practical learning. Assurance of scientific rigour through transparent adequate reporting is paramount to the credibility of findings from adaptive trials. There is a need for a consensus guidance document on ADs and an AD-tailored CONSORT statement to enhance their reporting and conduct. This thesis provides detailed recommendations to improve the appropriate use of ADs and areas for future related research