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Research Methods & Reporting

Key design considerations for adaptive clinical trials: a primer for clinicians

BMJ 2018; 360 doi: https://doi.org/10.1136/bmj.k698 (Published 08 March 2018) Cite this as: BMJ 2018;360:k698
  1. Kristian Thorlund, professor12,
  2. Jonas Haggstrom, team lead, data sciences2,
  3. Jay JH Park, research scholar1,
  4. Edward J Mills, professor12
  1. 1Department of Health Research Methods, Evidence, and Impact (HEI), McMaster University, Ontario, Canada
  2. 2The Bill and Melinda Gates Foundation, Seattle, Washington, USA
  1. Correspondence to: EJ Mills millsej{at}mcmaster.ca
  • Accepted 20 December 2017

This article reviews important considerations for researchers who are designing adaptive clinical trials. These differ from conventional clinical trials because they allow and even enforce continual modifications to key components of trial design while data are being collected. This innovative approach has the potential to reduce resource use, decrease time to trial completion, limit allocation of participants to inferior interventions, and improve the likelihood that trial results will be scientifically or clinically relevant. Adaptive designs have mostly been used in trials evaluating drugs, but their use is spreading. The US Food and Drug Administration recently issued guidance on adaptive trial designs, which highlighted general principles and different types of adaptive clinical trials but did not provide concrete guidance about important considerations in designing such trials. Decisions to adapt a trial are not arbitrary; they are based on decision rules that have been rigorously examined via statistical simulations before the first trial participant is enrolled. The authors review important characteristics of adaptive trials and common types of study modifications and provide a practical guide, illustrated with a case study, to aid investigators who are planning an adaptive clinical trial

Summary points

  • Adaptive trials enable continual modification to the trial design based on interim data. They can reduce use of resources and time or improve the likelihood of success of the trial

  • Common adaptive designs allow for interim sample size reassessment to ensure sufficient power, adaptation of the allocation ratio to ensure more patients receive the superior treatment, dropping of inferior treatments, addition of new treatment arms to save time and resources, population “enrichment” to narrow scope of the clinical trial, or transition directly from one trial phase to another

  • Planning adaptive trials is rooted in comprehensive simulations to understand the likely consequences and gains of all possible adaptations and the appropriateness of the …

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