Adding experimental treatment arms to Multi-Arm Multi-Stage platform trials in progress

Thomas Burnett, Franz Koenig, Thomas Jaki

Research output: Contribution to journalArticlepeer-review

1 Citation (SciVal)

Abstract

Multi-arm multi-stage (MAMS) platform trials efficiently compare several treatments with a common control arm. Crucially MAMS designs allow for adjustment for multiplicity if required. If for example, the active treatment arms in a clinical trial relate to different dose levels or different routes of administration of a drug, the strict control of the family-wise error rate (FWER) is paramount. Suppose a further treatment becomes available, it is desirable to add this to the trial already in progress; to access both the practical and statistical benefits of the MAMS design. In any setting where control of the error rate is required, we must add corresponding hypotheses without compromising the validity of the testing procedure.To strongly control the FWER, MAMS designs use pre-planned decision rules that determine the recruitment of the next stage of the trial based on the available data. The addition of a treatment arm presents an unplanned change to the design that we must account for in the testing procedure. We demonstrate the use of the conditional error approach to add hypotheses to any testing procedure that strongly controls the FWER. We use this framework to add treatments to a MAMS trial in progress. Simulations illustrate the possible characteristics of such procedures.

Original languageEnglish
Pages (from-to)3447-3462
Number of pages16
JournalBiometrics
Volume43
Issue number18
Early online date9 Jun 2024
DOIs
Publication statusPublished - 15 Aug 2024

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

Funding

This research was supported by the NIHR Biomedical Research Centre (BRC\u20101215\u201020014). This report is independent research supported by the National Institute for Health Research (Prof Jaki's Senior Research Fellowship, NIHR\u2010SRF\u20102015\u201008\u2010001). T Jaki received funding from the UK Medical Research Council (MC_UU_00002/14, MC_UU_00040/03 and MR/V038419/1). Franz K\u00F6nig is a member of the EU Patient\u2010Centric Clinical Trial Platform (EU\u2010PEARL) which has received funding from the Innovative Medicines Initiative 2 Joint Undertaking, grant no 853966. This Joint Undertaking receives support from the EU Horizon 2020 Research and Innovation Programme, EFPIA, Children's Tumor Foundation, Global Alliance for TB Drug Development, and SpringWorks Therapeutics. The views expressed in this publication are those of the authors. They are not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and Social Care (DHSC). The funders and associated partners are not responsible for any use that may be made of the information contained herein.

FundersFunder number
European Federation of Pharmaceutical Industries and Associations
Springworks Therapeutics
Children's Tumor Foundation
Horizon 2020
Medical Research CouncilMR/V038419/1, MC_UU_00002/14, MC_UU_00040/03
Medical Research Council
Manchester Biomedical Research CentreBRC‐1215‐20014
Manchester Biomedical Research Centre
Innovative Medicines Initiative853966
Innovative Medicines Initiative
National Institute for Health and Care ResearchNIHR‐SRF‐2015‐08‐001
National Institute for Health and Care Research

Keywords

  • adaptive designs
  • conditional error
  • design modification
  • multi-arm multi-stage

ASJC Scopus subject areas

  • Epidemiology
  • Statistics and Probability

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