Title: Design and analysis of efficient randomised trials in mental health
Funder: Department of Health and Social Care

Abstract: Background: Patients, clinicians and funders need efficient randomised trials. This applies across all clinical disciplines, in both academia and industry, and both nationally and internationally. Some disciplines, notably oncology, have pioneered more efficient trial designs to address this issue. However these trial designs are not yet fully used in mental health or for complex or psychosocial interventions. Psychosis is an area where implementing them would bring large patient benefit.Aims: To improve the health of patients by introducing efficient trials, with applications in mental health. This programme includes seven objectives: 1. Review the literature on efficient trials and identify barriers to their use and uptake in mental health 2. Adapt existing and develop novel efficient trial designs for patient stratification, multiple treatments and patient-care pathways 3. Incorporate causal modelling into the analysis of efficient trials 4. Produce a unified approach for the statistical analysis of post-randomisation variables in trials 5. Develop a new framework and guidelines for performing efficient trials in mental health 6. Form two new national groups to engage with clinical and methodological communities 7. Undertake a bespoke leadership programme and build research capacity to deliver world-leading clinical trials methodology Methods: There are two methodological work-streams, targeting complementary elements of trials WS1: Improving trial designsWe will define efficient trials, and systemically review the current literature. This will include (but is not limited to): adaptive designs for dose-finding, multi-arm multi-stage designs, umbrella trials and sequential multiple assignment randomized trials. We will perform a Delphi survey with patients, clinicians, academics, funders and other stakeholders to identify barriers to implementing these in mental health and for complex interventions. We will use the results to propose extensions to existing designs or create novel designs, on which we will seek further feedback. We will develop a platform for the implementation of these designs. WS2: Improving trial analysis We will review and unify the currently separate analytic approaches for post-randomisation variables, including missing data, non-compliance, mediation and surrogate outcomes. We will consider how analysis of non-compliance and mediation can be performed in efficient trials, in which analysis currently focuses on the intention-to-treat question. We will consider how to develop weighted combinations of multiple outcomes as a primary outcome, assess which methods for interim analysis are appropriate for use with complex interventions, and extend these for intermediate outcomes including neuroimaging and intensive longitudinal data. Methodological advances will be made using statistical theory, Monte Carlo simulation studies, and by application to existing trial datasets. Anticipated impact and dissemination: We will produce guidance documents and online training materials for performing efficient trials in mental health, drawing on the MRC Complex Interventions guidance, but updating it to reflect new methodology. The applicant will have a highly visible leadership role, forming and leading two national groups to work together to implement the research in this proposal and building research capacity. This work addresses the translational gap from developing methodology to implementation of methods for evaluating new treatments, in order to deliver them more expeditiously and effectively.

Lay abstract: Background: Patients, clinicians and funders need better randomised trials. Trials are considered the 'gold standard' way of testing if a new treatment works or not. Since 2008, over three million volunteers have taken part in trials in the UK, and the NIHR spends over 100m on them each year. However, they take too long to provide answers, cost considerable time and money, and half of trials fail to show that the new treatment is better than comparator suggesting the new treatment might not be being targeted to the right people. In disease areas like cancer, researchers use 'efficient trial' designs. These test several new drug treatments simultaneously and find answers to more questions more quickly. Such trials recruit patients at a faster rate and improve the chances of patients receiving treatments that work. In other areas, for instance, mental health, the toolbox of trial designs is not being used. There may be valid reasons for this, for example if the designs are better suited to testing drugs than psychological therapies, but sometimes it is simply that researchers are unaware of them. Aim: To improve the health of patients and the public by conducting better trials. We will produce new ideas for designing and analysing trials, consult widely with clinicians, patients and the public, and work out how they can best be used in the future. These are important issues across the world in all areas of medicine. Initially we will focus on new treatments for psychosis and other areas of mental health: these have major impacts on large numbers of people but research is under-resourced and could be carried out more efficiently. Methods: We will focus on two complementary elements of trials: 1. The design: We will review all aspects of 'efficient trial' designs and establish why they are not being used effectively. We will do this by surveying the literature and by asking patients and clinicians in mental health their views. We will propose solutions for removing barriers to their use, and ask patients and clinicians about the acceptability of these improved designs. We will form a research group with the skills to deliver efficient trials. 2. The analysis: We will make better use of the data already collected in trials and improve its interpretation, particularly in situations where patients are unable to follow their allocated treatment or provide outcome data. We will seek to understand how to deliver treatments at the right intensity to the right patients. Answers to these analysis questions will also be needed for the designs considered in section 1 above. Patient and public involvement: These ideas have been developed in cooperation with patient and clinical groups. These flagged making trials quicker, testing multiple treatments simultaneously, and focusing on outcomes important to patients as crucial issues in mental health trials. We will meet regularly with a broad clientele of service users and clinicians to obtain feedback and input, and to ensure we continue to research the issues most important to them. Dissemination: The applicant will establish a highly visible leadership role in order to persuade the clinical and patient communities to adopt the ideas and findings from this research programme. We will form an expert group to advise clinicians and researchers about the most efficient trial designs. We will write articles explaining the concepts, give presentations to patients, clinicians and funders, and place training materials and practical resources online. The promise of this work is the major improvement in patient's outcomes obtainable from using better trials to test treatments that patients want, in ways they support, and which clinical researchers have the confidence to use.

Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: MENTAL HEALTH