The aim of WS3 is to design innovative stratified clinical trial models for AILDs, with a focus on the new mechanistic taxonomy. It will take biological markers of disease process and drive diagnostics with Industry and Patient support, as well as design and seek acceptance for the unique trials models, using those markers that will be needed to evaluate new therapy approaches. Close working with WS1 & 2 will allow us to identify relevant biological pathways in patients with AILD which are relevant to the new disease taxonomy. We will develop and adopt novel biological response markers into clinical trial design. This will allow us to develop pathway-specific as well as disease-specific trials of new or re-purposed therapies, with our industry partners. Trials will be sponsored principally by industrial partners in the Industrial Programme. There will also be opportunity around re-purposing of existing drugs in investigator initiated studies.

To deliver this WS we will develop innovative trial designs and delivery models. We have a Diagnostics, Drugs, Devices and Biomarkers clinical trials team (D3B) in the Institute of Translational Medicine at the University of Birmingham that will ensure robust processes of trial development by providing specialist clinical trials design/development expertise and regulatory knowledge. Additionally, Birmingham hosts a dedicated BRC funded ‘Devices and evaluation of tests’ research theme relevant to the exploitation of data arising from WS1/2. Critical aspects of phase 1b studies include assessment of safety/tolerability of new therapies, yet standard designs (e.g. 3+3 or more advanced continual reassessment method [CRM]) assume a monotonic dose-activity relationship, whose main aim is to obtain the maximum tolerated dose. To allow for possible non-monotonic dose-activity relationship with new therapies, we will develop dose-finding designs that utilise a 2-stage CRM with modifications for the first phase, to obtain tolerable doses. This method provides a robust framework to more swiftly explore the safety of multiple doses of new therapies in patients. For early phase 2 studies we will continue the development of Bayesian adaptive designs to maximise the chances of identifying the dose at which a particular intervention is biologically effective, allowing for assessments of efficacy from much smaller patient cohorts. For later phase studies we have the UKCRC registered Birmingham Clinical Trials Unit (led by Brocklehurst) which has an extensive portfolio of trials across a wide range of disease areas, with experience of novel trial design (e.g. multi-factorial designs, adaptive designs and cluster trials). For rare conditions with stratification, Bayesian methods will also be needed to explore sub-group effects within strata to look for differential responses. WS1 & 2 will generate data on potential trial end-points and WS3 will implement the novel statistical methodologies needed to use these in trial settings.

To ensure rapid recruitment to future trials we will adopt the principles of the successful Trials Acceleration Programme developed in Birmingham which has allowed rapid set-up of new trials by having established agreements with extensive networks of recruiting sites able to recruit to a portfolio of trials co-ordinated by the Birmingham Hub. In UK-AILD, the network will be focused around the UK-AILD recruiting centres and will utilise the UK-PBC, UK-AIH and UK-PSC cohorts for recruitment supported by the Industry Programme-funded trials platform manager.

Given the proposed radical change in the model for trials delivery in AILD it will be essential that the proposed models; the markers likely to inform them, and the relevant trials endpoints are acceptable to potential users of the models (i.e. industry, patients and regulators). To facilitate this process we will organise and deliver an Industry Forum with all stakeholders to facilitate the necessary agreements. This approach has proved highly successful in other rapidly emerging liver disease areas such as NAFLD.