An investigation of time effect in Bayesian Adaptive Multi-arm Multi-stage Design and Platform Trial

Abstract

Platform trials continuously evaluate multiple treatments by allowing new arms to join at different stages. The control data collected before a new arm joins is often used to enhance statistical power. However, this approach relies heavily on the exchangeability assumption, frequently violated by systematic response changes over time (time trends). Such trends can bias treatment effect estimates and inflate type I errors, especially under BRAR.

This thesis investigates the impact of time trends in adaptive multi-arm multi-stage (MAMS) and platform trial designs, proposing robust analytical methods. I explore scenarios with both equal and unequal strength of time trends across trial arms. Results show equal-strength trends exacerbate bias in BRAR with early stopping rules, motivating the use of flexible models robust to various time patterns.

For unequal-strength time trends, existing methods yield biased estimates. Thus, I extend these methods to handle unequal trends, achieving unbiased estimates, albeit with reduced power. Additionally, I generalise estimands to align explicitly with clinical research objectives, emphasising their importance for valid inference. Among evaluated approaches, flexible mixed-effects models consistently provide unbiased treatment effect estimates and maintain statistical power.

Finally, I expand adaptive MAMS designs to fully accommodate platform trial complexities, demonstrating robustness through extensive simulation studies. This thesis extends our knowledge of platform trials by addressing the time trend problem via advanced analytical methodologies for managing time trend challenges in platform trials in practice.

More information

Identifiers

ORCID for Ziyan Wang: orcid.org/0009-0000-9482-9538

ORCID for Dave Woods: orcid.org/0000-0001-7648-429X

ORCID for Dankmar Böhning: orcid.org/0000-0003-0638-7106

ORCID for Sean Ewings: orcid.org/0000-0001-7214-4917

Catalogue record

Export record