Stratified Medicine in Primary Biliary Cirrhosis (PBC): Understanding Disease Mechanisms and Targeting Therapies (UK-PBC)

Lead Research Organisation: Newcastle University
Department Name: Institute of Cellular Medicine

Abstract

Primary Biliary Cirrhosis (PBC) is a chronic liver disease affecting 20,000 patients in the UK. The aim of our project is to transform our capacity to treat it. The problem is that whereas many PBC patients respond well to treatment with a drug called ursodeoxycholic acid ("urso") around 30% do not. We now know that when people don't respond to urso they run a real risk of their liver disease getting worse over time, leading ultimately to cirrhosis with all its complications and for which the only treatment is liver transplantation. The goal of the UK-PBC project, which is supported by academic centres, doctors, patient groups and industry throughout the UK, is to understand why it is that some people don't respond to urso, to find better ways of predicting who will and won't respond, and to identify the best way to treat people who don't respond (a number of drugs have been suggested as sensible treatments for people who don't respond to urso but at present we don't know how and in whom to use them). We are working with patient groups to recruit over half of all urso non-responding PBC patients in Britain (we have already recruited a third) making this a truly unique study. Our preparatory studies have already shed light on why people are at risk of PBC, and have shown that PBC is less likely to respond to treatment in young patients and in men. We now need to know why and to know what we can do about it.

The UK-PBC study will be in 3 sections. In the 1st section we will work with the PBC Foundation to recruit patients and to organise to collect important clinical information, together with a blood sample. The clinical information will allow us to identify whether someone has responded to urso or not (as well as how bad their symptoms are). The blood samples will allow us to understand key aspects of people's make up, including their genes and the way their immune system works, and the differences in make up between people who do and don't respond to urso. In addition to the main group of patients we will invite a smaller group of patients who are at very high risk of not responding to urso (those in whom PBC was diagnosed below the age of 50), or who have already not responded, to take part in a more detailed study in which we explore the actual damage to their liver in the 2nd section of the study.

In the 2nd section of our study we will explore what is different about PBC in people who do and don't respond to urso. This will allow us to identity the processes that cause non-response and to identify the best possible treatments for people who don't respond. It is thought that PBC is caused by the immune system mis-identifying the cells that line the bile duct and trying to reject them. This leads to damage to the bile ducts which impairs bile flow. Bile, which is toxic, then builds up in the liver causing more damage to the bile ducts and thus further bile duct injury. Injury eventually leads to scarring, and ultimately cirrhosis. In the second study section we will explore whether people who don't respond to urso have a more aggressive immune response than responders, have more toxic bile, have bile duct cells that react differently to injury (coping less well) or are more susceptible to liver scarring. Critically, all of these potential causes match up to existing potential treatments, or areas where new treatments can be developed rapidly.

In the 3rd section we will work with patient groups and industry partners to develop a national approach to studying new drugs in PBC to make it easier and more cost-effective to explore new drugs; a step which will encourage companies to want to develop new treatments which will ultimately benefit patients. We also begin to develop a national approach to treatment of PBC so that all patients benefit from the best possible treatments.

Our goal is nothing less than a transformation in our understanding of how to treat this significant disease

Technical Summary

Primary biliary cirrhosis (PBC) is the commonest autoimmune liver disease and a significant cause of morbidity and mortality. Ursodeoxycholic acid (UDCA), the only licensed therapy, slows progression to cirrhosis, but response is inadequate or absent in around 30% of patients, with non-responders facing a 5-fold increased risk of death or need for liver transplant. There is substantial industry interest in novel approaches to treating UDCA non-responders, but little information is available regarding mechanisms underpinning failure to respond to UDCA precluding informed decision making about which agents to take to clinical trial as second-line therapies. We will further develop the 5000 person UK-PBC patient cohort, the largest and best characterised in the world, by targetting recruitment of existing UDCA non-responding patients, and those at high risk of future non-response (for reasons of age), and will utilise it to explore the mechanisms of UDCA non-response. We will work with our industrial and patient-group partners to develop and deliver innovative clinical trials of stratified therapy, and will explore structured approaches to the future delivery of care nationally in PBC. The multi-disciplinary UK-PBC research consortium (www.UK-PBC.com) is fully established and has published landmark clinical and mechanistic studies. A multi-strand approach will be used in which patients will be recruited, pheno-, sero- and genotyped and stratified for UDCA response. A nested cohort of highly informative high-risk/non-responding patients will undergo more detailed cell- & tissue-based study with correlation of biological and clinical outcomes. Mechanistic themes addressing the core pathological processes in PBC will be able to access informative patients to undertake studies aimed at addressing the mechanisms and markers of non-response and identifying optimal therapeutic approaches. Our goal is to move to targeted clinical intervention by the end of the funding period.

Planned Impact

The proposed project is predicated on delivery of impact to both patients and industry. The potential beneficiaries of this project include patients with PBC, the NHS, and Industrial partners.

PBC PATIENTS: It is now clear (and the outline data from UK-PBC confirm this) that there is significant unmet need in PBC, with an important sub-group of patients failing to respond to current licensed therapy. The goal of the UK-PBC project is to understand the biology of non-response and to improve therapy by targetting, evaluating, and, where needed, developing second-line therapies. UK-PBC will also provide a platform for future studies of therapy for the important and life altering symptoms of PBC, although this is not the primary focus of the current application. Benefit to patients will therefore come through improved therapy for, typically young, high-risk patients. Successful applications of second line therapy will both lengthen survival and, we would anticipate, improve the quality of life of patients. The patient groups are strong advocates for UK-PBC and have played a critical role in developing the project to its current form. They will be the major beneficiaries of project impact.

THE NHS: PBC represents an important cause of end-stage liver disease with up to 10% of liver transplants in the UK still being for end-stage PBC. The development and application of effective second-line therapy would benefit the NHS through reducing the need for liver transplantation in end-stage disease (an extremely costly treatment) and by reducing the costs associated with its clinical manifestations (variceal bleeding, management in intensive care units etc). Clearly, should effective second-line therapy reduce the need for transplant in PBC there will be additional beneficiaries, namely patients with other forms of chronic liver disease for whom transplant is necessary and whose chances of receiving an organ will be increased if the need for organ use in PBC is reduced. Depending on the nature of effective second-line therapy there is also significant potential for a fundamental change in delivery of care in PBC, with a move away from specialist clinics for the majority of patients, who are in fact low risk, to targeted therapy delivered in a primary care setting. This aspect is addressed in more detail in the pathways to impact document. UK-PBC is fully engaged with exploring pathways to enhance care delivery in PBC as well as undertaking the mechanistic studies outlined in this proposal.

INDUSTRY: There is considerable industrial interest in PBC. There are, however, key questions we need to answer regarding identification of the most appropriate second-line therapies, how to identify potential recipients, and how to deliver effective trials. There is also a need for more robust biomarkers to identify high risk disease allowing a change in treatment paradigm to more effective therapy given earlier in the disease course. The UK-PBC platform will provide a unique opportunity to explore the mechanistic basis of failure to respond to primary therapy, allowing informed decision making regarding second-line agents. The infrastructure and patient cohorts of UK-PBC will also provide a unique platform to undertake focussed second-line therapy trials in PBC. The potential offered here is reflected in the interest shown by industry in the UK-PBC initiative, with companies investing in the programme as well as offering support. In addition to pharmaceutical company interest the opportunities around enhanced sero-diagnosis and biomarker development to enable better characterisation of risk in this disease have proved to be of significant interest to biomarker and serology companies who are also partners in the project.

The UK-PBC consortium members have a strong track record of delivering impact in PBC and the infrastructure provided by a stratified medicine programme would transform our capacity to benefit patients.

Publications

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Brain JG (2013) Biliary epithelial senescence and plasticity in acute cellular rejection. in American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons

 
Description Authorship Guidelines
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
Impact IMproved reach in clinical care
 
Description British (BSG/UK-PBC) Clinical Guidelines
Geographic Reach Asia 
Policy Influence Type Membership of a guideline committee
Impact UK treatment guidelines jointly developed between UK-PBC and the British Society of Gastroenterologists. Standardises the implementation of stratified medicine in practice in the UK. Fully incorporates UK-PBC data into practice
URL https://www.bsg.org.uk/resource/bsg-and-ukpbc-primary-biliary-cholangitis-treatment-and-management-g...
 
Description European (EASL) Clinical Practice Guidelines
Geographic Reach Europe 
Policy Influence Type Membership of a guideline committee
Impact Updated European treatment guidelines for PBC. Led by UK-PBC academics these guidelines fully incorporate stratified medicine into clinical practice across Europe
URL https://easl.eu/publication/the-diagnosis-and-management-of-patients-with-primary-biliary-cholangiti...
 
Description Substantial contribution to the data set and process around FDA and EMA approval for, and NICE assessment (positive) of OCALIVA, a new drug for PBC
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
 
Description Clinical Research Training Fellowship
Amount £262,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 08/2014 
End 07/2017
 
Description Cohort Development
Amount £50,000 (GBP)
Organisation Intercept Pharmaceuticals 
Sector Private
Country United States
Start 01/2012 
End 12/2013
 
Description Data Input support
Amount £27,820 (GBP)
Organisation Lumena Pharmaceuticals 
Sector Private
Country United States
Start 11/2013 
End 12/2017
 
Description HPRU: Toxicology of Chronic Disease
Amount £500,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 04/2014 
End 03/2019
 
Description Meeting Organisation
Amount £60,000 (GBP)
Organisation Intercept Pharmaceuticals 
Sector Private
Country United States
Start 12/2013 
End 06/2014
 
Description OCA on cognitive Symptoms
Amount £22,169 (GBP)
Organisation Intercept Pharmaceuticals 
Sector Private
Country United States
Start 12/2014 
End 11/2017
 
Description Sheila Sherlock Fellowship
Amount € 30,000 (EUR)
Organisation European Association for the Study of the Liver (EASL) 
Sector Learned Society
Country European Union (EU)
Start 05/2014 
End 04/2015
 
Description TRC Doctoral and Postdoctoral Fellowships (G Mells and J Dyson)
Amount £560,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 08/2014 
End 07/2018
 
Description Wellcome Trust Senior Research Fellowship (H Cordell)
Amount £1,052,135 (GBP)
Funding ID 102858/Z/13/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2014 
End 09/2019
 
Title UDCA Responnse Score 
Description This is the second UK-PBC risk score and allows prediction, at presentation with the disease, of the likely future response to UDCA. Newly developed and validated it will pave the way to stratification early in PBC, with early introduction of more effective treatment early in the disease course in patients at high risk of future treatment non-response. This represents the future of the stratified model in PBC 
Type Of Material Computer model/algorithm 
Year Produced 2018 
Provided To Others? Yes  
Impact Will be integral to future base-line stratified clinical trials 
 
Title UK-PBC Database 
Description The new UK-PBC Database had been developed by Dr Tony Bennett from Illuminaries Ltd®. This database allows research staff in collaborating centres to log into it from any NHS computer to view information about participants recruited from their own centres and to complete Case Record Forms (CRFs) online and upload the results of medical investigations directly into the database. The database went live towards the end of 2015 and research teams in most collaborating centres have started to use it. 
Type Of Material Database/Collection of data 
Provided To Others? No  
Impact Research teams have found the database easy to use - and better than the previous, paper-based system. 
URL http://www.uk-pbc.com/newsevents/UKPBC%20Newsletter.pdf
 
Title UK-PBC Risk Score 
Description A fully validated clinical risk score using readily available clinical data that allows accurate prediction of the likely outcome for patients established on first line therapy with UDCA. Recommended in all guidelines and in widespread clinical use this tool has been integral in bringing stratified medicine into normal clinical practice in PBC 
Type Of Material Computer model/algorithm 
Year Produced 2016 
Provided To Others? No  
Impact Incoporated into clinical practice and recommended in key guidelines 
URL http://www.uk-pbc.com/resources/tools/riskcalculator/
 
Description Development Programme with Intercept Pharmaceuticals 
Organisation Intercept Pharmaceuticals
Country United States 
Sector Private 
PI Contribution Knowledge and scientific opportunity building on our track record in the field.
Collaborator Contribution Research funding support along with reagents to explore novel potential uses for Intercept drugs. A substantial further investment (c£2m) is currently in discussion.
Impact Publications in press
Start Year 2010
 
Description IMID-BIO Research Consortium 
Organisation University of Glasgow
Department School of Medicine Glasgow
Country United Kingdom 
Sector Academic/University 
PI Contribution The IMID BIO programme is cross-linking research consortia in the immune-mediated diseases. The programme is led by the University of Glasgow. Both UK-PBC and UK-AIH are partner structures. We have contributed data from the UK-PBC and UK-AIH consortia
Collaborator Contribution Contributions of data sets from other immune diseases which can be integrated along with PBC and AIH data sets
Impact Still in devlelopment
Start Year 2017
 
Description Pfizer biomarkers funding 
Organisation Pfizer Inc
Country United States 
Sector Private 
PI Contribution The research team is performing a cohort based assessment of risk biomarkers in PBC and providing Pfizer with data and reports.
Collaborator Contribution Pfizer have provided funding to allow the assessment to be carried out.
Impact No outcomes so far.
Start Year 2015
 
Title GSK2330672 
Description A Study to Evaluate the Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of Repeat Doses of GSK2330672 Administration in Subjects With Primary Biliary Cirrhosis (PBC) and Symptoms of Pruritus 
Type Therapeutic Intervention - Drug
Current Stage Of Development Initial development
Year Development Stage Completed 2017
Development Status Under active development/distribution
Clinical Trial? Yes
Impact A Study to Evaluate the Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of Repeat Doses of GSK2330672 Administration in Subjects With Primary Biliary Cirrhosis (PBC) and Symptoms of Pruritus 
URL https://clinicaltrials.gov/show/NCT01899703
 
Title Safety, Tolerability, and Efficacy of GS 9674 in Adults With Primary Biliary Cholangitis Without Cirrhosis (PBC-Phase 2) 
Description Safety, Tolerability, and Efficacy of GS 9674 in Adults With Primary Biliary Cholangitis Without Cirrhosis (PBC-Phase 2) Sponsor: Gilead Sciences 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2018
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Safety, Tolerability, and Efficacy of GS 9674 in Adults With Primary Biliary Cholangitis Without Cirrhosis (PBC-Phase 2) Sponsor: Gilead Sciences 
URL https://clinicaltrials.gov/show/NCT02943447
 
Title Seladelpar (MBX-8025) in Subjects With Primary Biliary Cholangitis (PBC) 
Description Seladelpar (MBX-8025) in Subjects With Primary Biliary Cholangitis (PBC) Sponsor: CymaBay 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2018
Development Status Under active development/distribution
Clinical Trial? Yes
UKCRN/ISCTN Identifier CB8025-21629
Impact Seladelpar (MBX-8025) in Subjects With Primary Biliary Cholangitis (PBC) Sponsor: CymaBay 
URL https://clinicaltrials.gov/show/NCT02955602
 
Title Study to Evaluate the Effects of Two Doses of MBX-8025 in Subjects With Primary Biliary Cirrhosis (PBC) 
Description Study to Evaluate the Effects of Two Doses of MBX-8025 in Subjects With Primary Biliary Cirrhosis (PBC) Sponsor: CymaBay 
Type Therapeutic Intervention - Drug
Current Stage Of Development Initial development
Year Development Stage Completed 2017
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Study to Evaluate the Effects of Two Doses of MBX-8025 in Subjects With Primary Biliary Cirrhosis (PBC) Sponsor: CymaBay 
URL https://clinicaltrials.gov/show/NCT02609048
 
Title Study to Evaluate the Efficacy and Safety of Elafibranor in Patients With Primary Biliary Cholangitis (PBC) and Inadequate Response to Ursodeoxycholic Acid 
Description Study to Evaluate the Efficacy and Safety of Elafibranor in Patients With Primary Biliary Cholangitis (PBC) and Inadequate Response to Ursodeoxycholic Acid Sponsor: Genfit 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2018
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Study to Evaluate the Efficacy and Safety of Elafibranor in Patients With Primary Biliary Cholangitis (PBC) and Inadequate Response to Ursodeoxycholic Acid Sponsor: Genfit 
URL https://clinicaltrials.gov/show/NCT03124108
 
Title UK-PBC Risk Calculator 
Description The calculator uses information from the UK-PBC Research Cohort to estimate the risk (expressed in percentage) that a PBC patient established on treatment with Ursodeoxycholic acid (UDCA) will develop liver failure requiring liver transplantation within 5, 10 or 15 years from diagnosis. The calculator is in the format of an Excel spreadsheet. 
Type Of Technology Software 
Year Produced 2016 
Impact Provision of UK-PBC Risk Calculator for patients, practitioners and public to download for information. 
URL http://www.uk-pbc.com/resources/tools/riskcalculator/
 
Title UK-PBC Risk Score iPhone App 
Description The app estimates the risk (expressed in percentage) that a PBC patient established on treatment with Ursodeoxycholic acid (UDCA) will develop liver failure requiring liver transplantation within 5, 10 or 15 years from diagnosis. The score may be used to identify high-risk patients for closer monitoring and second-line therapies, as well as low-risk patients who could potentially be followed-up in primary care. 
Type Of Technology Webtool/Application 
Year Produced 2015 
Impact Too early for impact to have been realised. 
URL http://www.uk-pbc.com/newsevents/uk-pbcriskscoreiphoneappnowavailable.html
 
Description Cholestasis Past Present and Future 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Launched in 2014, a science meeting bringing together the field leaders in cholestasis to discuss cutting edge science. Hosted by UK-PBC this has played an important role in building the "brand" of UK-PBC. Run again in 2015 and will henceforth be bi-annual
Year(s) Of Engagement Activity 2014,2015
URL http://www.profbriefings.co.uk/ppfcholestasis2015/
 
Description Industrial strength research Interview with MRC 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact In an interview with the MRC, Professor Jones explained why it is vitally important for academic and industry researchers to collaborate, and how UK-PBC is at the forefront of this.
Year(s) Of Engagement Activity 2015
URL http://www.mrc.ac.uk/news/browse/industrial-strength-research/
 
Description Leading Edge - School workshops 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact The day gave students an increased understanding of liver disease and information about a career in academia

Students visited the Fibrosis lab at Newcastle University
Year(s) Of Engagement Activity 2010,2011,2012,2014
URL http://research.ncl.ac.uk/fibrosislab/newsevents/publicengagement/leadingedge/
 
Description National Teaching Sessions on Stratified care in PBC 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact National teaching sessions carried out in conjunction with Falk and Pharma. Additional teaching sessions at DDF and AASLD.
Year(s) Of Engagement Activity 2015
 
Description New model for consultation around clinical guidelines 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact We have worked with patient organisations to develop a new model for involving patients in new or updated clinical guidelines
Year(s) Of Engagement Activity 2017
 
Description Patient Group Meetings 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact PBC patient research update meetings. These are held around the region 6 times per year to explain our research, the rationale behind it, the key findings and what this means and may mean for the future improvements in treatment

In addition to their intrinsic worth these meetings hold substantial benefits in terms of recruitment rates for our studies.
Year(s) Of Engagement Activity 2006,2007,2009,2012,2013
 
Description Precision Medicine Collaboration Nation event 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact The strength of UK-PBC partnerships (academic, industry, patient and funders) featured as an illustration of how vital partnerships are in research. UK-PBC achievements relating to this featured in the opening section at the Precision Medicine Collaboration Nation event 9th December 2015
Year(s) Of Engagement Activity 2015
URL http://www.uk-pbc.com/newsevents/uk-pbcfeaturesatmajornationalevent.html
 
Description Press Releases Presented at 50th European Association for the Study of the Liver (EASL) by Industry Partners Intercept 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Industry partner Intercept presented new data to inform EASL attendees and journalists of UK-PBC related research.
Year(s) Of Engagement Activity 2015
URL http://globenewswire.com/news-release/2015/04/13/723692/10128520/en/Intercept-Announces-New-Data-in-...
 
Description Regional PBC updates 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Six regional "teach-ins" and case discussions for local GI consultants around the UK to educate on current PBC management.
Year(s) Of Engagement Activity 2015
 
Description Science on a plate - Local School Engagement 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact The workshops gave students a better understanding of liver disease physiology

unknown
Year(s) Of Engagement Activity 2014
URL http://research.ncl.ac.uk/fibrosislab/newsevents/publicengagement/scienceonaplatesoap/
 
Description Table at Genetics Matters Event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Table at the Genetics Matters event in Newcastle Upon Tyne with a selection of print outs showing:

- differences between healthy and ill liver and bile duct
- some of the concurrent symptoms that individuals get (e.g. xanthoma)
- some visual stats about epidemiology and genetic overlap with other conditions
- manhattan plots from most recent GWAS
Year(s) Of Engagement Activity 2016
URL https://blogs.ncl.ac.uk/igmengagement/27th-february-2016-genetics-matters/
 
Description Treatment Landscape of PBC Video 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Gideon Hirschfield, UK-PBC member talks to Medpage about the Treatment Landscape of PBC
Year(s) Of Engagement Activity 2015
URL http://www.medpagetoday.com/PBCandNASHRapidResponseVideo/Gastroenterology/GeneralHepatology-Videos/1...
 
Description UK-PBC Symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact An educational session at DDF in June 2015 emphasising the importance of PBC and other autoimmune liver diseases and the clinical challenges. Aimed at clinical trainees.
Year(s) Of Engagement Activity 2015
URL http://www.ddf2015.org.uk/docs/default-source/default-document-library/liver-at-ddf201595759eb19f8d6...