Title: Developing novel trial design and analysis methods for dose-response models in complex interventions
Funder: Department of Health and Social Care

Abstract: Research Question This project aims to address two questions within dose-response modelling literature: how can we develop a causally valid, non-linear dose-modelling method for psychotherapy and how can we integrate dose optimization in the early stages of a psychotherapy clinical trial? Background In psychotherapy clinical trials, dose is defined as the frequency and number of sessions. A method does not currently exist that appropriately models the relationship between dose and effect. Existing methods are not able to make causal interpretations, ignore the bias created by non-adherence and assume linearity of dose-response. This simplification of trajectories allows for broad and bias conclusions about new psychotherapies, which leads to anecdotal prescription of therapy dose. This anecdotal approach is also used in the design of psychotherapy interventions. There is a gap in the literature for complex designs that optimize dose in the early intervention stages, leading to possibly insufficient doses being administered that are not empirically compared to different doses. Aims & Objectives To develop a statistical method for dose-response modelling, that is applicable to psychotherapy trials and addresses limitations identified within the existing literature. To develop a clinical trial design that incorporates an optimal dose-finding mechanism into the early stages of the design, allowing for empirical decisions regarding dosage of psychotherapy to be made during the trial. Methods I will review current dose-response methods used for both psychotherapy and pharmaceutical interventions (WP1). This will provide a starting point to expand on existing methods and develop new methods that are applicable to the nuances of psychotherapy. The precision and assumptions of the methods will be compared using simulated data and further applied to existing trial data (WP2). The second focus of the project will involve developing a novel clinical trial design. I will review the current dose-finding designs in pharmaceutical trials (WP3). I will build on and translate these methods into a design for psychotherapy interventions, that is practical, efficient and allows for empirical identification of optimal dose in psychotherapy (WP4). I will work with stakeholder and PPI groups to disseminate the findings (WP5).Timelines for delivery I will review current dose-response methods until month 5, where I will begin development of a new method between months 5 and 15. In months 16 to 22, I will review trial designs for dose-finding and simultaneously begin to develop new trial designs between month 20 and 30. I will allow for 6 months to complete writing my thesis at the end of the fellowship. PPI engagement is embedded throughout the fellowship. Regular supervision meetings and stakeholder meetings will be held and ensure the delivery of the proposed timeline. Anticipated impact and dissemination I will actively disseminate my findings within KCL and the King's Clinical Trials Unit to use my findings to inform the analysis and design of future trials. The outputs of this research will be disseminated at international and local conferences and produce four publications leading to a wider impact in clinical trials.

Lay abstract: Aims Talking therapies are a well-recognised mental health intervention, but it is often not clear how much of the therapy (the 'dose') a person needs in order to achieve a good outcome. In this research I aim to address two major gaps in clinical trials of talking therapies. The first aim is to develop a statistical method for analysing the relationship between dose and the effect of the intervention, that considers differences between individual patients and allows for complicated associations. The second aim is to propose a new clinical trial design that allows researchers to build into the design of the trial how to find out the best dose of different psychotherapy interventions. BackgroundIn talking therapies, we can consider dose-response as the relationship between the frequency or number of sessions and the effect on a person's symptoms. Typically, it is assumed that people respond identically to psychotherapy, and that each additional session is equally as beneficial to everyone. This is a flawed assumption for a number of reasons. Many people experience sudden gains, where they make rapid improvements and then plateau. Furthermore, we include people who choose not to attend their allocated sessions, ignoring the differences between those who do and do not take up their offer of treatment. Ignoring these differences leads to incorrect conclusions about the effectiveness of treatments, and providing unsuitable or demanding doses of talking therapies in clinical practice. For all these reasons, current statistical methods for dose-response modelling are too simplistic. There is also a stark contrast between how dose is chosen for drugs and talking therapies. In drug trials, the guidelines suggest that dose finding is built into trial designs to find the optimal dose, and there are different forms of trial designs that do this. In talking therapy trials, this is not usual practice and the number and frequency of sessions is chosen by expertise rather than from data. There is a need to adapt the designs from drug trials to use with talking therapies. Design & Methods Focus 1: I will review the statistical methods used to explore dose-response relationships. This will include both drug and talking therapy trials. Once I have reviewed the existing methods, I will have the foundation to propose a new, less biased method of analysis. I will compare my new method with the current methods using both simulated data where I know the true results, and application to existing clinical trial data testing talking therapies in people with psychosis. Focus 2: I will propose a new trial design to find the best dose when creating new talking therapies in mental health. I will review current clinical trial designs that do this in drug trials and expand these so they are applicable to talking therapies. Existing and proposed designs will be evaluated using statistical approaches. Patient & Public InvolvementPatient and public involvement is key to this project and will be embedded throughout. I will work with patients to explore how to improve communication of findings from trials so that future patients can make an informed choice regarding talking therapies. The definition of dose intensity will be informed by patients' views. My trial designs must be acceptable to patients so that they would consent to participate in future studies. DisseminationI will publish at least four scientific publications and disseminate the findings at international conferences in the fields of biostatistics, clinical trials, and mental health. I will form new collaborations, nationally and internationally, as well as work within the King's Clinical Trials Unit to inform the design and analysis of future trials.

Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: MENTAL HEALTH