Methodology articles & events
Methodological articles
Characteristics, consent patterns, and challenges of randomized trials using the Trials within Cohorts (TwiCs) design: A scoping review. Amstutz A et al, JCE 2024
Randomised trials conducted using cohorts: A scoping review. Nickolls BJ et al, BMJ Open 2024.
​
Hyperbaric Oxygen Therapy and Late Local Toxic Effects in Patients with Irradiated Breast Cancer: A randomised clinical trial. Mink van der Molen et al, 2024
​
Hyperbaric Oxygen Therapy for Management of Late Radiation Toxicity - A Honey of a trial. Editorial Hahn et al, 2024
​
The Trial within Cohorts (TwiCs) study design in oncology: experience and methodological reflections. Kessels et al, 2023
​
SYMPOSIUM: Staged and tailored informed consent, 13th September 2023. An international one day online symposium bringing together trialists, clinicians, members of the public, and bioethicists to share perspectives and experiences of staged-and-tailored approaches to informed consent for individually randomised pragmatic trials.
​
Most patients reported positively or neutrally of having served as controls in the TwiCs design. Verweij et al, 2022. The first study of patient experiences of a staged and tailored informed consent approach as used in the TwiCs design.
​
The first completed full trial using the cmRCT design testing an intervention for self-reported depression was associated with a number of important benefits. Further research is required to compare the acceptability and cost effectiveness of standard pragmatic RCT design with the cmRCT design.
Viksveen P, Relton C and Nicholl J Trials (2017) 18:308 doi: 10.1186/s13063-017-2059-4.
Cohort Multiple Randomised Controlled Trials (cmRCT) design: efficient but biased? A simulation study to evaluate the feasibility of the Cluster cmRCT design
This article reports a number of simple simulations evaluating a hypothetical cluster RCT in patients at risk of CVD. The authors conclude that based on these simulation studies the ITT effect in routine practice is likely to lie somewhere between the ITT and IV estimates from the trial – depending on refusal rates.
Pate A, Candlish J, Sperrin M and Van Staa TP on behalf of GetReal Work Package BMC Medical Research Methodology (2016) 16:109. doi: 10.1186/s12874-016-0208-1.
​
This article describes the rationale for and design of the Prospective Dutch ColoRectal Cancer cohort - a large observational cohort study, serving as a multiple trial and biobanking facility. Seven months after initiation 650 patients have been recruited and 9 embedded cohort or cmRCT designed studies are currently recruiting patients.
Burbach JP, Kurk SA, Coebergh van den Braak RR, Dik VK, May AM, Meijer GA, Punt C, Vink GR, Los M, Hoogerbrugge N, Huijgens PC,Ijzermans JN, Kuipers EJ de Noo ME, Pennings JP, van der Velden AM, Verhoef C, Siersema PD, van Oijen MG, Verkooijen HM and Koopman M Acta Oncologica (2016) 25:1-8.
This article evaluates the methodological challenges of conducing RCTS within a cohort. The authors conclude that equally valid results can be obtained from trials conducted within cohorts as from standard stand alone pragmatic RCTs. However, the efficiency of the design compared to the standard pragmatic RCT depends on the amount and nature of non-compliance in the intervention arm.
van der Velden JM, Verkooijen HM, Young-Afat DA, Burbach JPM, van Vulpen M, Relton C, van Gils CH, May AM and Groenwold RHH International Journal of Epidemiology (2016) 1–7 doi: 10.1093/ije/dyw050.
Staged-informed consent in the cohort multiple randomized controlled trial design
A key feature of the cmRCT design is that informed consent is 'patient centred' i.e. the process of obtaining patient consent replicates that in real world routine health care, where patients are not told that their treatment will be decided by chance, nor are they told about treatments that they cannot then receive. However, there is disagreement as to whether control groups should be informed that they have been randomised to not receive an new intervention being trialled/ tested for their condition. The authors have adapted the cmRCT design where in the first stage, at entry into the cohort, all potential participants are asked for consent to be randomly selected to be approached for experimental interventions or to serve as controls without further notice. This staged-informed consent procedures allows triallists to use the TwiCs approach but avoids pre-randomisation.
Young-Afat DA, Verkooijen HM, Van Gils CH, Van der Velden JM, Burbach J, Elias SG, Van Delden J, Relton C, Van Vulpen M and Van der Graaf R Epidemiology (2016).
​
Reporting guidelines
​
Reporting guidelines have now been published for reporting RCTs using cohorts and routinely collected data (CONSORT-ROUTINE) Kwakkenbos et al 2021. The Consolidated Standards of Reporting Trials (CONSORT) extension for randomised controlled trials conducted using cohorts and routinely collected data (CONSORT-ROUTINE) was developed to look at the unique characteristics of trials conducted with these types of data with the goal of improving reporting quality in the long term by setting standards early in the process of uptake of these trial designs.
​
Methods and results used in the development of CONSORT-ROUTINE Imran et al 2021. This article describes the methods used to develop CONSORT-ROUTINE reporting guidelines. The final checklist includes five new items and eight modified items. The extension Explanation & Elaboration document further clarifies aspects that are important to report.
​
Learning Health Systems and TwiCs
​
Learning health care systems: Highly needed but challenging Wouters et al (2020). This article describes how the TwiCs approach encompasses strategies that contribute to a health care system in which “the process of generating and applying the best evidence will be natural and seamless components of the process of care itself.”
They argue that implementing innovative study designs such as TwiCs may promote scientific research in a way that is more congruous with daily care delivery, while key ethical and legal distinctions between care and research (eg, informed consent, independent ethics review) continue to exist.
​
Reviews
​
Scoping review of randomised controlled trials conducted using cohorts Nickolls, et al. 2021. This scoping review will examine the extent, range and nature of research activity for trials conducted using cohorts between 2007 and January 2021 and seek to clarify working definitions and conceptual boundaries for trials using cohorts.
​
​
Ethics
The Ethics of TwiCs symposium (Relton et al, 2016) brought together both bioethicists and regulators with triallists using (or planning to use) the TwiCs approach. The objectives of the two day symposium were to share experiences of the design and good practice, discuss how TwiCs relate to the current ethical framework, provide a forum for debating ethical issues, explore the potential of the TwiCs approach to create learning healthcare environments, and to identify future directions for conceptual and empirical research. The videos, slides and posters from the event can all be viewed here.
​
Ethics articles
Proposals to conduct Randomized Controlled Trials Without Informed Consent: a narrative review
This article reviews all randomised controlled trial designs without informed consent for randomisation including those which are routinely used such as cluster randomised designs and emergency medicine research. Ten different approaches are identified - including the cmRCT approach are discussed, and the relationship between learning healthcare environments and the cmRCT approach is discussed.
​Flory JH, Mushlin AI and Goodman ZI Journal of general Internal Medicine (2016) doi:10.1007/s11606-016-3780-5.
A novel randomised controlled trial design in prostate cancer
The authors describe the conduct and results of a small focus group to guage the attitudes of patients to the cmRCT design. Six men aged between 60 and 80 yers all had varying stages of prostate cancer. The consensus was that the 'basic idea was good', they could retain choice over their treatment and clinician. The group felt that they would agree to being approached in the future if a new intervention became available in a clinical trial, but that the consent process should be clear on this at the outset. This small preliminary research is the first step in assessing how paitnets may react if approached to partcipate in a cmRCT.
Anastasiadis E, Ahmed HU, Relton C and Emberton M BJU International (2015) doi:10.1111/bju.12735.