Decompensated Liver Cirrhosis Research Network (UK-CLIF): Building consensus for hepatology trials in the UK

Introduction

Liver disease is now the most common cause of premature death amongst non-communicable diseases in the UK (Figure 1). The burden of liver disease has increased substantially since the Covid-19 pandemic, with mortality rates around ~25% higher in 2024 than 2019¹. Moreover, it has been widely documented that there are grave inequities in the provision of liver care and clinical outcomes from cirrhosis. Inpatient mortality from cirrhosis varies widely between non-specialist hospitals in England, and mortality rates within 60-days of admission are several times higher than comparable admissions for stroke or ischaemic heart disease².

Figure 1. Liver disease deaths are now the commonest cause of working years of life lost amongst non-communicable diseases (Data: Office for National Statistics, 2022).

In parallel, clinical trial performance in the UK, including within liver disease, has tailed off. As noted in the recent review of clinical trials by Lord O’Shaughnessy, within the last five years our relative performance in initiation and recruitment to phase 3 clinical trials has fallen with our relative ranking to other countries decreasing from 4^th to 10^th globally³. Within the area of liver cirrhosis a number of large clinical trials have been undertaken in the UK in recent years; however, new therapies for decompensated cirrhosis remain lacking and some large studies have closed early (e.g. NIHR award 16/99/02).

Novel therapeutic approaches to the management of liver cirrhosis and urgently needed, and to achieve this several aspects of clinical trial design and delivery may be innovated in the post-pandemic era. The overarching aim of the UK-CLIF project is to establish a nationwide, multi-stakeholder network to address shortfalls in, and improve delivery and impact of, clinical research in decompensated cirrhosis.

The specific objectives of UK-CLIF were to: (a) establish a prototype multi-stakeholder network to advance cirrhosis research, with emphasis on geographical areas of high disease prevalence or limited research activity; (b) co-develop consensus positions on fundamental aspects of cirrhosis research in the UK, such as research infrastructure for cirrhosis clinical trials and clinical factors affecting research delivery; (c) identify research priorities for future trials and collaborative research.

Methods

Results

The development of network connections as measured by network mapping are shown in Figure 2. The findings of the facilitated workshops are outlined below.

Figure 2. Network evolution from baseline (left panel), after 1^st online meeting (centre panel), and after 2^nd online meeting (right panel).

Geographic locations are approximated.

Results of the World Café workshops are summarised in Table 1. Thematic findings addressing (i) research infrastructure and recruitment, and (ii) clinical factors, affecting research delivery in cirrhosis are listed. Some issues were raised by participants at both meetings (left column); the issues that were only raised in one meeting are also listed (centre and right columns). Common themes were: the need for patient-centric trial designs, protocol and strategies for engagement, the lack of resource for clinicians to participate in research, and variability in the standard of inpatient care for cirrhosis which may impact the ‘control’ arm for interventional studies in this group.

Table 1. Summary of findings from World Café workshops.

Common issues (Bristol and Liverpool)	Additional issues from Bristol workshop	Additional issues from Liverpool workshop
1. Research infrastructure and recruitment ☐   Better information needed for patients on research trials and benefits of participating in ☐   Trials are not well designed to engage a wide range of patients ☐   Need to approach patients to join research at an appropriate point in their care journey ☐   The importance of involving families and carers in discussions about research participation ☐   There is generally low health literacy in the population so hard to engage patients 2a. Clinical factors affecting research delivery ☐   Lack of priority for research in NHS - focus on care delivery ☐   Low numbers of specialist nurses – both liver nurses and research nurses ☐   Lack of clinic space and physical resources for research ☐   Clinicians need information and encouragement to get involved e.g. research as regular item on 2b. Consistent standards of care ☐   Need for agreed liver disease care standards ☐   Better linking of care across primary, secondary and tertiary care ☐   Set up national registers of cirrhosis patients and trials	1. Research infrastructure and recruitment ☐   Research to focus on what would most improve patients’ quality of life ☐   Research into prescribing and compliance with medication regimes ☐   The importance of psychological support to patients ☐   Engage more patients to advise on research ☐   Remote monitoring of patients as a key research area 2a. Clinical factors affecting research delivery ☐   Time and trust to facilitate collaboration with industry is lacking ☐   Research does not easily feed into practice changes even when successful ☐   Researchers to make more use of a wide range of channels, including social media to disseminate research	1. Research infrastructure and recruitment ☐   Perceived stigma of liver disease ☐   Research focus on early diagnosis and prognosis ☐   Need for research on precision/ personalised medicine ☐   Therapies needed to prevent cirrhosis complications ☐   Research into new ascites treatments 2a. Clinical factors affecting research delivery ☐   Lack of protected clinician time for research ☐   Lack of research training for professionals ☐   More network and collaboration between centres, regional networks and funding create 2b. Consistent standards of care ☐   Lack of national data on prevalence, patient numbers and outcomes

Findings regarding (iii) research priorities in cirrhosis, were not analysed thematically as there was little cross-over between workshops; these data are presented in supplemental material. The top voted research priorities in the Bristol workshop were: greater use of quality of life as a trial endpoint, and de-prescription of medications as an intervention. The top priorities in the Liverpool workshop were: precision/personalised approaches to therapy (e.g. using -omics) and therapies preventing the first complication of cirrhosis. Individual voting scores for each workshop, and categorical data on participant type, are also presented in the underlying data⁵.

Discussion

This robust process described above has demonstrated stakeholder engagement, network development and facilitated discussion of consensus positions regarding fundamental aspects of liver cirrhosis research in England. The initial steps of network expansion let to coverage across most areas of England, with representatives including patients, carers, hepatologists, nurses, allied healthcare professionals, translational researchers, and representatives from industry and the third sector. Importantly, this diverse network was used to invite participants for the detailed, World Café workshops.

The independently facilitated workshops highlighted three themes, developed by consensus, affecting translational research delivery for liver cirrhosis: patient-centric trial design, research-focussed career pathways and standardisation of inpatient care. These will be discussed in turn below.

Patient-centric materials and trial design were raised, and voted for, at both the Bristol and Liverpool workshops. In particular, patient-centric processes were thought important to involve participants from underserved and hard to reach communities. Liver disease frequently affects groups that are underserved, predominantly through socio-economic factors. The median age of death from liver disease in the five most deprived areas of England and Wales is 62 years, compared with 71 years in the least deprived⁶. In other clinical areas, such as cardiovascular disease, when clinical trial recruitment was not representative of real-world practice translational benefits were not realised⁷. Therefore, there is a strong case to facilitate inclusion of hard to reach participants in cirrhosis trials, including co-design of trial protocols and patient-facing materials.

In particular, the need to adapt recruitment strategies for patients with alcohol-related liver disease (ARLD) was discussed. The challenges of recruitment and retention of patients in this group has been described by investigators in the Unites States, although there are few UK trials targeting this group. A specific trial discussed was the AlcoChange study (ISRCTN 10911773), investigating a digital therapeutic in ARLD. Examples of patient-centric processes from this trial include remote consent, remote data collection and amenable visit schedules. The ongoing learning from this trial will priced valuable information for future studies in this patient group.

A perceived lack of prioritisation of clinical research within NHS trusts was also raised as a barrier. This ranged from lack of infrastructure and physical resources, research staff and protected clinician time. Of note, the recent O’Shaughnessy report on UK clinical trials⁸, and the response from the UK government⁹, recommends a ‘Clinical Trials Career Path’ to be integrated into the NHS Long Term Workforce Plan. Additionally, the National Institute for Health and Care Research (NIHR) has launched competitive funding streams for infrastructure bids, such as the Commercial Research Delivery Centres bid, which are aligned with the aims to improve NHS research infrastructure articulated in our workshops as well as the O’Shaughnessy review. Nevertheless, this barrier to translational hepatology research merits ongoing attention.

The third aspect discussed, and voted for, was the variation in cirrhosis care between secondary and tertiary centres, the consequent need for agreed national care standards and, ideally, a prospectively maintained registry of cirrhosis patients. In particular, this variation impacts the delivery of trials where ‘standard care’ is the control – increasingly so as interventions become more complex. This variation in standard care leads to heterogeneity of outcomes and decreased statistical power to demonstrate the efficacy of potentially useful treatments. Importantly, to address this, the UK-CLIF network has partnered with the British Society for Gastroenterology Liver Committee to develop quality standards for inpatient care of decompensated cirrhosis – this project is in progress.

Finally, potential research priorities for the coming years were raised at both workshops (supplemental data). The highest-ranking topics were chosen by robust qualitative prioritisation methodology. However, it is clear for such a broad area as research questions a larger sample size is required. To achieve this, UK-CLIF has partnered with the James Lind Alliance to conduct a nationwide priority-setting process for liver cirrhosis (https://www.jla.nihr.ac.uk/priority-setting-partnerships/liver-cirrhosis/). This is an externally facilitated, transparent qualitative process, with balanced inclusion of patient, carer and clinician interests and perspectives. This process has commenced and will report in early 2025.

Ethics & consent

This project was not classified as research according to HRA criteria (https://www.hra-decisiontools.org.uk/research/) or by local R&D colleagues, hence formal ethical approval and informed consent was not required.