TY - JOUR

T1 - An overview of methodological considerations regarding adaptive stopping, arm dropping and randomisation in clinical trials

AU - Granholm, Anders

AU - Kaas-Hansen, Benjamin Skov

AU - Lange, Theis

AU - Schjørring, Olav Lilleholt

AU - Andersen, Lars W.

AU - Perner, Anders

AU - Jensen, Aksel Karl Georg

AU - Møller, Morten Hylander

N1 - Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

PY - 2023

Y1 - 2023

N2 - OBJECTIVE: Adaptive features may increase flexibility and efficiency of clinical trials, and improve participants' chances of being allocated to better interventions. Our objective is to provide thorough guidance on key methodological considerations for adaptive clinical trials.STUDY DESIGN AND SETTING: We provide an overview of key methodological considerations for clinical trials employing adaptive stopping, adaptive arm dropping, and response-adaptive randomisation. We cover pros and cons of different decisions and provide guidance on using simulation to compare different adaptive trial designs. We focus on Bayesian multi-arm adaptive trials, although the same general considerations apply to frequentist adaptive trials.RESULTS: We provide guidance on: 1) interventions and possible common control, 2) outcome selection, follow-up duration and model choice, 3) timing of adaptive analyses, 4) decision rules for adaptive stopping and arm dropping, 5) randomisation strategies, 6) performance metrics, their prioritisation, and arm selection strategies, and 7) simulations, assessment of performance under different scenarios, and reporting. Finally, we provide an example using a newly developed R simulation engine that may be used to evaluate and compare different adaptive trial designs.CONCLUSION: This overview may help trialists design better and more transparent adaptive clinical trials and to adequately compare them before initiation.

AB - OBJECTIVE: Adaptive features may increase flexibility and efficiency of clinical trials, and improve participants' chances of being allocated to better interventions. Our objective is to provide thorough guidance on key methodological considerations for adaptive clinical trials.STUDY DESIGN AND SETTING: We provide an overview of key methodological considerations for clinical trials employing adaptive stopping, adaptive arm dropping, and response-adaptive randomisation. We cover pros and cons of different decisions and provide guidance on using simulation to compare different adaptive trial designs. We focus on Bayesian multi-arm adaptive trials, although the same general considerations apply to frequentist adaptive trials.RESULTS: We provide guidance on: 1) interventions and possible common control, 2) outcome selection, follow-up duration and model choice, 3) timing of adaptive analyses, 4) decision rules for adaptive stopping and arm dropping, 5) randomisation strategies, 6) performance metrics, their prioritisation, and arm selection strategies, and 7) simulations, assessment of performance under different scenarios, and reporting. Finally, we provide an example using a newly developed R simulation engine that may be used to evaluate and compare different adaptive trial designs.CONCLUSION: This overview may help trialists design better and more transparent adaptive clinical trials and to adequately compare them before initiation.

U2 - 10.1016/j.jclinepi.2022.11.002

DO - 10.1016/j.jclinepi.2022.11.002

M3 - Journal article

C2 - 36400262

VL - 153

SP - 45

EP - 54

JO - Journal of Clinical Epidemiology

JF - Journal of Clinical Epidemiology

SN - 0895-4356

ER -