Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Trials
Published in: Trials 1/2019

Open Access 01-12-2019 | Methodology

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

Authors: Francesca Schiavone, Riya Bathia, Krishna Letchemanan, Lindsey Masters, Claire Amos, Anna Bara, Louise Brown, Clare Gilson, Cheryl Pugh, Nafisah Atako, Fleur Hudson, Mahesh Parmar, Ruth Langley, Richard S. Kaplan, Chris Parker, Gert Attard, Noel W. Clarke, Silke Gillessen, Nicholas D. James, Tim Maughan, Matthew R. Sydes, On behalf of past and present members of the STAMPEDE and FOCUS4 Trial Management Group

Published in: Trials | Issue 1/2019

Login to get access

Abstract

Background

There 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.

Methods

We 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.

Results

Specific 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.

Conclusions

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.

Trial registration

FOCUS4: ISRCTN Registry, ISRCTN90061546. Registered on 16 October 2013. STAMPEDE: ISRCTN Registry, ISRCTN78818544. Registered on 2 February 2004.
Footnotes
1
Our lessons learnt from a central data management perspective are reported in our companion paper ‘Operational aspects of adaptive platform protocols’.
 
Literature
1.
Saville BR, Berry SM. Efficiencies of platform clinical trials: A vision of the future. Clin Trials. 2016;13(3):358–66.CrossRef
2.
Hatfield I, Allison A, Flight L, Julious SA, Dimairo M. Adaptive designs undertaken in clinical research: a review of registered clinical trials. Trials. 2016;17(1):150.CrossRef
3.
Wason J, Magirr D, Law M, Jaki T. Some recommendations for multi-arm multi-stage trials. Stat Methods Med Res. 2016;25(2):716–27.CrossRef
4.
Sydes MR, Parmar MK, Mason MD, Clarke NW, Amos C, Anderson J, et al. Flexible trial design in practice - stopping arms for lack-of-benefit and adding research arms mid-trial in STAMPEDE: a multi-arm multi-stage randomized controlled trial. Trials. 2012;13:168.CrossRef
5.
Parmar MK, Sydes MR, Cafferty FH, Choodari-Oskooei B, Langley RE, Brown L, et al. Testing many treatments within a single protocol over 10 years at MRC Clinical Trials Unit at UCL: Multi-arm, multi-stage platform, umbrella and basket protocols. Clin Trials. 2017;14(5):451–61.CrossRef
6.
Parmar MK, Carpenter J, Sydes MR. More multiarm randomised trials of superiority are needed. Lancet. 2014;384(9940):283–4.CrossRef
7.
Woodcock J, LaVange LM. Master protocols to study multiple therapies, multiple diseases, or both. N Engl J Med. 2017;377(1):62–70.CrossRef
8.
Mawocha SC, Fetters MD, Legocki LJ, Guetterman TC, Frederiksen S, Barsan WG, et al. A conceptual model for the development process of confirmatory adaptive clinical trials within an emergency research network. Clin Trials. 2017;14(3):246–54.CrossRef
9.
Adams R, Brown E, Brown L, Butler R, Falk S, Fisher D, et al. Inhibition of EGFR, HER2, and HER3 signalling in patients with colorectal cancer wild-type for BRAF, PIK3CA, KRAS, and NRAS (FOCUS4-D): a phase 2–3 randomised trial. Lancet Gastroenterol Hepatol. 2018;3(3):162–71.CrossRef
10.
A proposed charter for clinical trial data monitoring committees: helping them to do their job well. Lancet. 2005;365(9460):711–22.
11.
Brueton VC, Vale CL, Choodari-Oskooei B, Jinks R, Tierney JF. Measuring the impact of methodological research: a framework and methods to identify evidence of impact. Trials. 2014;15:464.CrossRef
12.
Hearn J, Keat N, Law K, Sharpe R. How Cancer Research UK is adapting to adaptive designs. Trials. 2011;12(1):A6.CrossRef
13.
Richman SD, Adams R, Quirke P, Butler R, Hemmings G, Chambers P, et al. Pre-trial inter-laboratory analytical validation of the FOCUS4 personalised therapy trial. J Clin Pathol. 2016;69(1):35–41.CrossRef
14.
Chan AW, Tetzlaff JM, Altman DG, Laupacis A, Gotzsche PC, Krleza-Jeric K, et al. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med. 2013;158(3):200–7.CrossRef
15.
Parker CC, Sydes MR, Mason MD, Clarke NW, Aebersold D, de Bono JS, et al. Prostate radiotherapy for men with metastatic disease: a new comparison in the STAMPEDE Trial. Clin Oncol. 25(5):318–20.
16.
Attard G, Sydes MR, Mason MD, Clarke NW, Aebersold D, de Bono JS, et al. Combining enzalutamide with abiraterone, prednisone, and androgen deprivation therapy in the STAMPEDE Trial. Eur Urol. 2014;66(5):799–802.CrossRef
17.
Gillessen S, Gilson C, James N, Adler A, Sydes MR, Clarke N. Repurposing metformin as therapy for prostate cancer within the STAMPEDE Trial platform. Eur Urol. 70(6):906–8.
18.
Gilbert DC, Duong T, Sydes M, Bara A, Clarke N, Abel P, et al. Transdermal oestradiol as a method of androgen suppression for prostate cancer within the STAMPEDE trial platform. BJU Int. 2018.
19.
James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Spears MR, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016;387(10024):1163–77.CrossRef
20.
Vale CL, Burdett S, Rydzewska LHM, Albiges L, Clarke NW, Fisher D, et al. Addition of docetaxel or bisphosphonates to standard of care in men with localised or metastatic, hormone-sensitive prostate cancer: a systematic review and meta-analyses of aggregate data. Lancet Oncol. 2016;17(2):243–56.CrossRef
Metadata
Title
This is a platform alteration: a trial management perspective on the operational aspects of adaptive and platform and umbrella protocols
Authors
Francesca Schiavone
Riya Bathia
Krishna Letchemanan
Lindsey Masters
Claire Amos
Anna Bara
Louise Brown
Clare Gilson
Cheryl Pugh
Nafisah Atako
Fleur Hudson
Mahesh Parmar
Ruth Langley
Richard S. Kaplan
Chris Parker
Gert Attard
Noel W. Clarke
Silke Gillessen
Nicholas D. James
Tim Maughan
Matthew R. Sydes
On behalf of past and present members of the STAMPEDE and FOCUS4 Trial Management Group
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Trials / Issue 1/2019
Electronic ISSN: 1745-6215
DOI
https://doi.org/10.1186/s13063-019-3216-8

Other articles of this Issue 1/2019

Trials 1/2019 Go to the issue

Study protocol

Topical sirolimus 0.1% for treating cutaneous microcystic lymphatic malformations in children and adults (TOPICAL): protocol for a multicenter phase 2, within-person, randomized, double-blind, vehicle-controlled clinical trial

Correction

Correction to: AMBIsome Therapy Induction OptimisatioN (AMBITION): High Dose AmBisome for Cryptococcal Meningitis Induction Therapy in sub-Saharan Africa: Study Protocol for a Phase 3 Randomised Controlled Non-Inferiority Trial

Methodology

Involving people living with dementia in research: an accessible modified Delphi survey for core outcome set development

Study protocol

Sequential dual-site High-Definition transcranial Direct Current Stimulation (HD-tDCS) treatment in chronic subjective tinnitus: study protocol of a double-blind, randomized, placebo-controlled trial

Research

Stroke aetiological classification reliability and effect on trial sample size: systematic review, meta-analysis and statistical modelling

Research

Facilitating trial recruitment: A qualitative study of patient and staff experiences of an orthopaedic trauma trial