We list here details on the many collaborative projects which are led by the Hubs, and funded by the Network. Details on current funding opportunities can be found here.
Network-funded projects have included workshops, primary research, development of guidance and training events. The summary below captures the projects by year of funding and as projects are completed supporting documents and outputs will be added for more information on this research.
We have also funded a cohort of PhD studentships in trials methodology research, and support eight Working Groups.
Aims: This project aims to 1) identify the key elements leading to successful trials conducted by surgical TRCs and 2) synthesise these findings to develop strategies to enhance clinician engagement in trials across other clinical specialties, including clinician training.
Methods: A qualitative research study to inform a one day trialist stakeholders workshop. The research will include: 1) non-participant observation of TRC-linked surgical trials and TRC meetings, and 2) in-depth semi-structured interviews with key clinicians and trials units staff. Trials and linked personnel will be purposefully sampled across three geographical locations to include a variety of surgical specialties, clinicians and TRCs. Meetings and interviews will be audio-recorded and transcribed. Thematic analysis of transcripts will use the constant comparative method.
Outputs: Results will be synthesised and reviewed by co-applicants. These will inform a meeting with key trialists and clinical stakeholders to develop strategies to enhance clinicians’ engagement in trials which could subsequently be tested in other specialties and inform post-graduate clinician training. Peer-review publications and presentations.
We plan a piece of literature work (analyses of NIHR HTA funded main trials with an internal pilot study to explore their decision making in relation to progression criteria) and a two-day event. The combined activities will build on our individual expertise and lead to guidance documents to be published, material to be made available on the web and further meetings with clinical trialists and funding bodies to widely implement the recommendations for when to conduct each type of pilot and/or feasibility study design.
In the 2013 World Health Report, there was an unequivocal statement that unless low- and middle-income countries (LMICs) become the generators and not the recipients of research data, there will never be any real improvements in public health outcomes in these most underserved regions of the world. This lack of data is the result of too few studies being conducted in low-income settings. Therefore undertaking methodology research is required to identify the gaps and issues in order to optimise design, ease and quality with the aim of making research relevant and accessible to health care workers in these regions.
The MRC HTMR Network has established a portfolio of methodology research of relevance to the UK trials community. It is important, and timely, to establish the relevance of this work to LMIC settings, but also to identify gaps where further research would benefit clinical trials in LMICs. The aim of this project is to identify trials methodology research priorities in LMICs. We predict each region can gain valuable lessons from the other.
The MRC/NIHR EME Programme funds clinical studies testing both if an intervention works in a defined population of patients, and providing opportunity to understand disease or treatment mechanisms. However, there remain significant methodological challenges in performing mechanistic evaluations and accounting for departures from randomised allocations in order to assess efficacy (rather than effectiveness). Uptake of the available methods has been limited, though increasing in popularity.
Our aim is to organise a workshop and training day centred on how to use causal methods to understand mechanisms of action for treatments. The workshop will invite experts in the area to identify important topics and challenges and to discuss ways in which these methods might be utilised more in clinical research studies. A representative from the EME board will give an overview of the scheme, and how they consider mechanisms evaluation when evaluating applications. The results of this workshop will inform a training day approximately six months later for researchers who are interested in incorporating mechanistic methods into their clinical studies.
We will hold a one-day workshop in Lancaster in 2016. We will invite key stakeholders from the area, including representatives from the EME board, and discuss issues and suitable methods for different types of intervention: pharmaceutical, psychotherapy, behaviour change, and surgery. The outcomes of the workshop will be used to develop a training day for researchers in clinical studies.
Six months after the one day workshop we will hold a one day training workshop, also provisionally in Lancaster. This workshop will be aimed at clinicians and methodologists new to the area and who are in the process of designing mechanistic studies, and intending to apply for EME funding. We plan to use organisations such as the NIHR Clinical Research Network, the RDS, and EME to advertise to find applicants.
Cost-effectiveness models are used in health economic decision making to compare the costs and effects of competing strategies for the management of disease. These decision recommendations are uncertain due to limitations in the available evidence. Value of information calculations measure the expected improvement in our decision recommendations, on the monetary scale, if we reduce (EVSI) or eliminate (EVPPI) uncertainty by gathering further evidence. EVPPI and EVSI can therefore be used to guide research funding decisions, and inform trial design. However, as EVPPI and EVSI involve the expectation of a maximum of a conditional expectation, 2-level nested Monte Carlo simulation and sometimes additional Markov chain Monte Carlo simulation is necessary. This is very computationally intensive and often impractical.
This project aims to assess the potential of efficient sampling techniques to reduce the computational burden of EVPPI and EVSI. Simulations where the decision doesn’t change contribute nothing to EVPPI and EVSI. One approach is therefore to use importance sampling and stratified sampling schemes to sample more frequently in the space where decisions change, with appropriate re-weighting.
We will develop importance sampling methods for use in the computation of EVPPI and EVSI, and explore their performance on a range of examples. Another approach is to use a method from pricing financial derivatives, such as simple call and put options, which also rely on the estimation a maximum of several processes. We will explore whether numerical techniques developed in this area of mathematical finance, in particular for non-Normal underlying stocks, can be applied to the estimation of the EVPPI and EVSI. We will meet with technical experts in simulation methodology and pricing financial derivatives, to explore how these techniques can be applied to EVPPI and EVSI.
We will then apply the methodology to some illustrative examples, and present the work in a focused meeting.
Phase I dose-escalation studies are essential to determine the safe dosing range of a novel compound. Despite the poor operating characteristics of algorithmic methods such as the 3+3 design, superior model-based strategies are still rarely used. One of the main reasons why these Bayesian adaptive designs are not implemented is the lack of easy-to-use and accessible software. This project seeks to develop software for model-based dose-escalation studies. A standalone, fully documented system will be developed that allows investigators to plan, explore and conduct such studies without the need for technical expertise in the underlying methods. To ensure that the software is fit for purpose, it will be rigorously tested by different user groups (clinical experts, principal investigators, trial managers, statisticians) and training workshops will be held to facilitate uptake.
Stratified medicine has the potential to significantly improve the benefit-risk ratio in the treatment of many diseases. A randomised controlled trial (RCT) design is perceived as the gold standard for demonstrating the clinical utility of a biomarker-guided approach to treatment. To this end, a large number of biomarker-guided trial designs have been proposed in the literature, but navigating through this literature can be challenging and there is little guidance on which design is optimal in a given setting.A systematic review of biomarker-guided trial designs has recently been undertaken by Antoniou, Jorgensen and Kolamunnage-Dona (co-applicants on this proposal), which identified over 200 relevant papers. The review identified that there is significant variability between authors in terms of the terminology used and descriptions of the different designs, which has resulted in significant ambiguity and confusion regarding biomarker-guided trial designs. To address this problem, in this project, we propose to develop a website using interactive visualisation to provide a user-friendly and easily accessible resource for informing those embarking on a biomarker-guided trial on the most optimal design. The website will initially mirror the findings of the systematic review, but in a much more accessible format, and will subsequently be extended to provide a truly interactive tool allowing searches for the optimal design in a given setting as well as sample size estimates. The idea for the project has stemmed from feedback from attendees of conferences and meetings where the systematic review work was presented, which suggested a real need for information on the different trial designs to be available in an easily accessible and user-friendly format.
Slow recruitment and poor retention are common challenges to the successful delivery of clinical trials. Patient and public involvement (PPI) in research has the potential to enhance recruitment and retention in clinical trials, but there have been few attempts to investigate this experimentally. The aim of this project is to develop a PPI intervention aimed at improving recruitment and/or retention in surgical trials.
The project will consist of 4 stages:
The use of statistical analysis plans (SAPs), drawn up in advance of the analysis phase of a trial, is an accepted means of reducing bias in reporting the results of randomised controlled trials (RCTs). However, while health economic analysis plans (HEAPs) to guide trialists in conducting economic evaluations alongside RCTs are becoming more widespread, they lag behind SAPs in terms of standardisation and acceptance, and there is a fundamental question over whether they add value to the trial process at all. In the collective experience of members of the Health Economic Resource Use and Costs Working Group, there is currently substantial variation in the structure, format and content of HEAPs, and no real agreement on either their purpose or appropriate methods of oversight. Clarity on the need for, and appropriate usage of, HEAPs would be advantageous.
We therefore propose to hold a workshop on HEAPs for about 50 attendees in Bristol, with three key aims. First, we plan to review the limited number of currently available guidelines addressing aspects of HEAPs. We also intend to collate information about the current usage of HEAPs in terms of their structure, content and purpose. Finally, we aim to provide a forum in which health economists and other interested parties engaged in applied economic evaluations can open a dialogue on appropriate methods of standardisation with a view to creating guidance in future work.
Resource-use measurement in economic evaluations conducted alongside randomised controlled trials (RCTs) is commonly carried out by asking patients to provide information via a questionnaire or diary. However, there is no well validated instrument available that is flexible enough to work across different health conditions and care settings. Health economists tend to use unvalidated bespoke instruments for each trial, which results in unnecessary repetition of work, and hinders comparisons between trials.
To identify a core set of economically important resource-use items that are suitable for future inclusion in a modular patient-reported resource-use measure.
Instruments currently lodged in DIRUM (the Database of Instruments for Resource-Use Measurement, www.dirum.org), and additional instruments sourced from health economists, will be examined to determine the items of resource use that are commonly collected in RCTs. A comprehensive list of care items encountered will be compiled; items will then be categorised into ‘domains’ describing different types of healthcare (e.g. inpatient care, community care or medication). The item list will be systematically reduced to 10-20 key items per domain to form the basis for the Delphi survey.
A Delphi panel comprising patients, health economists and trialists from varying backgrounds will be engaged. In round 1 of the Delphi process, professional participants will be asked to rate the items according to their economic importance in a trial context, while patients will be asked to assign ratings based on the item’s relevance. Participants will also be asked to suggest additional items of healthcare resource use for consideration.
Items deemed insufficiently important according to predefined criteria encompassing both professional and patient responses will be dropped. A second Delphi round will be undertaken in which feedback from the first round will be presented to participants. A third Delphi round may be conducted if significant differences of opinion remain.
People doing clinical trials and other types of health research often struggle when trying to choose the outcomes to measure which would be of most use to the patients, practitioners and policy makers who will use their research to help them make decisions. These difficulties for trialists are passed on to those producing and reading systematic reviews of trials, many of whom have experienced the frustration of finding that the original researchers either did not measure certain outcomes or measured them in such different ways that it is difficult or impossible to compare, contrast or combine the studies. Much could be gained if there was an agreed minimum set of core outcomes for each medical condition, which were measured and reported in all clinical trials in that area. The COMET Initiative, launched in 2010, has brought together an international network of individuals and organisations interested in the development, application and promotion of such core outcome sets (COS).
A review of the literature has identified core outcome sets in nearly 200 medical conditions, and we are also aware of over 30 ongoing projects. COMET has put this information together in a publically available, searchable database. To date there has been no formal quality assessment of these studies and there is a pressing need to do so using internationally recognised criteria, both for COS developers and for trialists using COS.
This proposal requests funds to host a consensus meeting which is part of a larger study to develop the quality assessment instrument for studies developing COS. The outputs could impact immediately on the increasing number of ongoing and planned COS studies.
The HTMR Network has provided funding to support a workshop focussed on new Chief Investigators. The workshop is likely to be run again in 2016. Dates are to be confirmed. To add your name to our mailing list please email us.The workshop is targeted to recently funded Chief Investigators on RCTs.