This is a platform alteration: a trial management perspective on the operational aspects of adaptive and platform and umbrella protocols

Matthew R Sydes,Lindsey Masters,Fleur Hudson,Krishna Letchemanan,Riya Bathia,Nafisah B Atako ,Cheryl Pugh,Past ,Clare Gilson,Tim Maughan,Francesca Schiavone,Silke Gillessen,Mahesh Parmar,Ruth E Langley ,Claire Amos,Louise Brown,Anna Bara,G Attard ,Chris Parker,Nicholas D James,Noel W Clarke,Richard Kaplan

doi:10.1186/s13063-019-3216-8

Abstract

BackgroundThere are limited research and literature on the trial management challenges encountered in running adaptive platform trials. This trial design allows both (1) the seamless addition of new research comparisons when compelling clinical and scientific research questions emerge, and (2) early stopping of accrual to individual comparisons that do not show sufficient activity without affecting other active comparisons. Adaptive platform design trials also offer many potential benefits over traditional trials, from faster time to accrual to contemporaneously recruiting multiple research comparisons, added flexibility to focus on more promising research comparisons via pre-planned interim analyses and potentially shorter time to primary results. We share here our experiences from a trial management perspective, highlighting the challenges and successes.MethodsWe evaluated the operational aspects of making changes to these adaptive platform trials and identified both common and trial-specific challenges. The operational steps and challenges linked to both the addition of new research comparisons and stopping recruitment following pre-planned interim analysis were considered in our evaluation.ResultsSpecific operational challenges in these adaptive platform protocols, additional to those in traditional two-arm trials, were identified. Key lessons are presented describing some of the solutions and considerations over conducting these trials.Careful consideration on the practicality of the protocol structure (modular versus single protocol), the longevity and continuity of trial oversight committees, and having clear clinical and scientific criteria for the addition of new research comparisons were identified as some of the most common challenges.ConclusionsUnderstanding the operational complexities associated with running adaptive platform protocols is paramount for their conduct, adaptive platform trials offer an efficient model to run randomised controlled trials and we are continuing to work to reduce further the effort required from an operational perspective.Trial registrationFOCUS4: ISRCTN Registry, ISRCTN90061546. Registered on 16 October 2013. STAMPEDE: ISRCTN Registry, ISRCTN78818544. Registered on 2 February 2004.

Highlights

There are limited research and literature on the trial management challenges encountered in running adaptive platform trials
Understanding the operational complexities associated with running adaptive platform protocols is paramount for their conduct, adaptive platform trials offer an efficient model to run randomised controlled trials and we are continuing to work to reduce further the effort required from an operational perspective
Molecular selection of therapy in colorectal cancer (FOCUS4) (ISRCTN90061546) and STAMPEDE (ISRCTN78818544) are key examples of implementing adaptive and platform designs; both trials are sponsored by the Medical Research Council (MRC), designed and coordinated from MRC Clinical Trials Unit (CTU) at University College London (UCL); both trial designs are presented in Fig. 1a and b

Summary

Introduction

There are limited research and literature on the trial management challenges encountered in running adaptive platform trials. Multi-Arm Multi-Stage (MAMS) trials are one practicable design which can contemporaneously assess multiple research treatments, often with a shared control arm, and selectively focus on more promising research comparisons via pre-planned interim analyses with in-built stopping guidelines [4, 5]. This novel design can intuitively couple with the assessment of other promising treatments in a platform protocol (sometimes known as ‘master protocol’ or ‘living protocol’), initially or later [6, 7].

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Results

Conclusion