MR1474 - UK-PBC Project - cohort datasets

Text removed is struck through; text added is underlined. Unchanged paragraphs are summarised rather than repeated.

Datasets: + Civil Registrations of Death; + Emergency Care Data Set (ECDS); + Medicines dispensed in Primary Care (NHSBSA data)

Objective for processing

Primary biliary cholangitis (PBC, formerly primary biliary cirrhosis) is a rare, chronic liver disease characterised by autoimmune destruction of the small, intrahepatic bile ducts. PBC eventually leads to end-stage liver disease in a substantial proportion of cases. The disease affects up to 20,000 people in the UK, where it remains a leading indication for liver transplantation (LT). Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge requires access to NHS England data to verify data collected for following research project: UK-PBC is a UK-wide precision medicine initiative that is aimed at improving understanding of PBC and developing precision medicine for PBC. It was established with a Stratified Medicine Award from the Medical Research Council (MRC). UK-PBC is led by Newcastle University, Imperial College, London, the University of Birmingham and the University of Cambridge. More than 150 NHS Trusts or Health Boards across the UK are collaborating in the project. UK-PBC is divided into 3 Work Strands (WS): The UK-PBC (United Kingdom - Primary Biliary Cholangitis) Genetics Study. WS1 is led from the Academic Department of Medical Genetics at the University of Cambridge. The focus of WS1 is to recruit and characterise a large, prospective PBC cohort (the UK-PBC Research Cohort). This involves the collection of detailed clinical information including results of medical investigations, important clinical events and life events (date of death, cause of death and date of birth) from participants and collaborating centres. These data are stored in the UK-PBC Database, located on an NHS server behind the N3 firewall at Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust (CUH); they are used for statistical modelling of disease. For avoidance of doubt, data from NHS Digital will never be uploaded into the UK-PBC Database; these data will be stored separately on NHS CUH servers behind N3 firewall for the agreed duration; they will be used to identify discrepancies or missing data in the clinical data already collected by UK-PBC for the purpose of statistical modelling of disease. The following is a summary of the aims of the research project provided by Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge: WS2 of UK-PBC is focused on the mechanistic basis of PBC. This work is informed by the statistical models of disease derived by WS1. For the avoidance of doubt, WS2 has NO access to clinical data collected and curated by WS1. WS2 will have NO access to NHS Digital data. "Primary biliary cholangitis (PBC, formerly primary biliary cirrhosis) is a rare, chronic liver disease characterised by immune-mediated destruction of small bile ducts inside the liver, leading in many cases to liver cirrhosis and its associated complications, including chronic liver failure, liver cancer and death. WS3 is focussed on clinical trial design and patient education. Clinical trial design by WS3 is informed by the statistical models of disease derived by WS1. For the avoidance of doubt, WS3 has NO access to clinical data collected and curated by WS1. There will be NO sharing of NHS Digital data with WS3. This data sharing agreement (DSA) is with the University of Cambridge, which is the Joint Data Controller for WS1 of UK-PBC, together with CUHFT. As stated above, there will be NO linkage of NHS Digital data to other UK-PBC datasets, and there will be NO sharing of NHS Digital data to any other work strands in UK-PBC. The cause of PBC is unknown, however, there is evidence that genetic factors are important. By studying DNA and information obtained from people with PBC, the study team hope to achieve a better understanding of how genetic factors contribute to this disease. WS1 of UK-PBC is now funded via Immune-Mediated Inflammatory Disease Biobanks – UK (IMIDBio-UK). IMIDBio-UK is a multi-centre collaboration between academia, the NHS, industry and patient groups that is aimed at cross-disease meta-analysis of existing and future research datasets across diverse autoimmune and auto-inflammatory disease to identify shared and unique mechanisms for autoimmunity. IMIDBio-UK is funded by the MRC. The lead research organisation is the University of Glasgow. Cambridge, representing WS1 of UK-PBC, is a named collaborator in IMIDBio-UK, one of five key academic partners who will receive funding under the IMIDBio-UK MRC Award (ref MR/R014191/1). Only two medications are licensed to treat PBC. Ursodeoxycholic acid is used as first-line therapy. It is inexpensive (£1,000 per patient per year) and well tolerated, but only has moderate efficacy. Obeticholic acid is used as second-line therapy. It is significantly more expensive (£28,000 per patient, per year) and less well tolerated by patients due to side effects. For avoidance of doubt: UK-PBC is a UK-wide precision medicine initiative that is aimed at improving knowledge and understanding of PBC. UK-PBC is divided into 3 Work Strands (WS). Work strand 1 (WS1) is led by the University of Cambridge and Cambridge University Hospitals NHS Foundation Trust. 1) IMID-Bio UK does not itself generate research data. The aim of IMIDBio-UK is to provide a platform for the sharing of research data generated by fully- independent, ethically approved research projects, each having its own ethics approval and study documentation (e.g. participant information sheet and informed consent form). There is no requirement for the ethics approvals and study documentation of the respective, independent research projects to be aligned - there is only a requirement for the participants in the respective projects to have consented to the sharing of pseudonymised research data (for the avoidance of doubt, however, it is re-iterated that there is NO onward access to NHS Digital Data from UK-PBC to IMIDBio-UK or any other organisation. There is only sharing of research data generated by UK-PBC [e.g. transcriptional datasets]). People with PBC are recruited to the UK-PBC Genetics Study via the UK-PBC Consortium, a research network consisting of 182 NHS acute trusts or health boards (“collaborating centres”) across the UK. Any adult (≥ 18 years of age) with PBC who can provide informed consent is eligible to join the Research Cohort, PBC being defined according to the British Society of Gastroenterology (BSG) guidelines. Clinical data are collected directly from electronic patient records at collaborating centres using electronic case record forms. These clinical data are used for statistical analyses. 2) The respective research projects generating research data that will be shared with IMIDBio- UK are completely independent of one another. Thus, Cambridge/UK-PBC is not influenced by any of the other academic partners collaborating in IMIDBio-UK. These other academic partners have no say in how UK-PBC-related research data are collected, generated, organised or stored by Cambridge. They have no special access to research data collected and curated by UK-PBC. Likewise, Cambridge/UK-PBC does not influence the research projects of these other academic partners. Furthermore, as stated above, there is NO onward access of NHS Digital Data from UK-PBC to IMIDBio-UK; other academic centres collaborating in IMIDBio-UK, or any other organisation. Thus, because Cambridge/UK-PBC is completely independent of the other academic partners collaborating in IMIDBio-UK and because no onward access of NHS Digital Data is granted to any other organisation, there is no need for a data controller in the other academic centres listed in the funding award letter. The goals: IMIDBio-UK was awarded £1,707,539 by the MRC. Of this, £221,276 was allocated to Cambridge to support UK-PBC-related research activities (see page 1, paragraph 2 of the funding award letter). The remainder (~£1.5M) was divided between the other academic centres to support their respective research activities. As stated above, the respective research projects supported by the IMIDBio-UK award are completely independent of one another. Thus, the research activities undertaken by one academic partner are not influenced by any other academic partners. The implication is that the other academic partners collaborating in IMIDBio-UK have nothing to do with this application. The role of UK-PBC in IMIDBio-UK is to share existing and future research datasets (for example, genetic or transcriptional data) for cross-disease meta-analysis, as described above. To reiterate, however, and for the avoidance of doubt, data derived from NHS Digital will NOT be shared with IMIDBio-UK; there will be NO onward access to data derived from NHS Digital. 1) Establishment of the stratified therapy model in PBC. Whereby patients with the greatest need receive the most appropriate treatment at the point of diagnosis. 3) The applicant apologises for the confusing and similar terms. IMIDBio-UK has two Work Streams, Work Stream 1 and Work Stream 2. Work Stream 1 of IMIDBio-UK is completely separate to Work Strand 1 of UK-PBC. 2) Increase understanding of the mechanism(s) of UDCA (ursodeoxycholic acid, normally present in the bile) non-response through a systematic programme of innovative research. 4) Several Pharmaceutical companies are also named collaborators in IMIDBio-UK. This is because Pharma are interested in finding new indications for existing immune-modulatory agents, as well as the identification of new therapeutic targets in autoimmune conditions. The MRC, which funds IMIDBio-UK, actively encourages collaboration with Industry to ensure that research findings are rapidly translated into clinical practice. For the avoidance of doubt, however, Cambridge (representing WS1 of UK-PBC) does NOT receive funding from the Pharmaceutical companies collaborating in IMIDBio-UK. These companies have no influence on UK-PBC and no special access to research data collected and curated by UK-PBC. 3) To develop markers to identify patients likely to respond poorly or not at all to treatment, allowing these poor-responders and non-responders to be followed-up closely." NHS Digital datasets offer important information corresponding to the clinical data already captured from participants and collaborating centres in this study. The important clinical events and investigations to be collected exist within: Hospital Episodes Statistics (HES); Inpatient episodes, Outpatient appointments, Accident and Emergency attendances, Diagnostic Imaging Dataset, Cancer data and Mortality data. These products are listing all the specific variables that would help link PBC medical information with important health events, part of the purpose of the project, as outlined above. The following NHS England data will be accessed: • Hospital Episode Statistics (HES) Admitted Patient Care (APC), Accident & Emergency (A&E), Outpatients and Emergency Care Data Set (ECDS) – necessary to verify: 1. Comorbidities 2. Date of PBC diagnosis 3. Date of development of chronic liver failure 4. Date of development of liver cancer 5. Date of liver transplantation • Diagnostic Imaging Dataset (DIDs) – necessary to verify liver cirrhosis in participants undergoing 6-monthly liver ultrasound scans • Civil Registration Mortality – necessary to verify date and cause of death • Medicines dispensed in Primary Care (NHSBSA data) – necessary to verify: 1. Date first-line treatment with ursodeoxycholic acid is commenced 2. Date second-line treatment with obeticholic acid, bezafibrate or fenofibrate is commenced. The use of NHS England data to verify the date of PBC diagnosis and the date of clinical outcomes (chronic liver failure, liver cancer or liver transplantation) is key to conducting accurate statistical analyses for risk prediction and treatment stratification, including in particular time-to-event survival analyses, which measures the time taken for patients to reach a clinical outcome from the point of diagnosis (e.g. time from PBC diagnosis to liver transplantation or time from PBC diagnosis to death). The use of NHS England data to verify the date and duration of medication used in PBC will be vital in comparing patient outcomes on these drugs. The UK-PBC Genetic Study will be analysing the impact of the medicines dispensed in primary care to establish the safety and effectiveness on patient care. Ultimately, do patients who receive one drug respond better than patients who receive another? The level of data will be identifiable, necessary because although the Cambridge University Hospitals NHS Foundation Trust will receive pseudonymised data (along with their study ID) from NHS England, the Cambridge University Hospitals NHS Foundation Trust hold the cohort identifiers. The data will be minimised as follows: • Limited to a study cohort of approx. 5,543 identified by Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge and sent to NHS England • Limited to data between 1997/98 and 2022/23 years. The UK-PBC Genetics Study is jointly sponsored by the University of Cambridge and Cambridge University Hospitals NHS Foundation Trust. As joint sponsors, both the University of Cambridge and Cambridge University Hospitals NHS Foundation Trust are responsible for the management and delivery of the UK-PBC Genetics Study and are therefore Joint Controllers for the purpose of this agreement. The lawful basis for processing personal data under the UK GDPR is: Article 6(1)(e) - processing is necessary for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller; The lawful basis for processing special category data under the UK GDPR is: Article 9(2)(j) - processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject. This processing is in the public interest because it adheres to the UK Policy Framework for Health and Social Care Research, which protects and promotes the interests of patients, service users and the public, and aims to produce generalisable and publicly available information to inform future decisions over patients’ treatments or care. The funding comes from multiple sources. Current funders include: • the Medical Research Council (MRC) – The funding award from the MRC ended in December 2022, however a proportion of the funds remain and will be used for ongoing funding of the study • a research award from the National Institute for Health Care Research (Efficacy and Mechanism Evaluation Award) – Funding is in place until 30/06/2026. Funding to continue the work described will be sought on an ongoing basis. The funders will have no ability to suppress or otherwise limit the publication of findings. There has been no direct patient and public involvement and engagement (PPIE) for this study.

Processing activities

The Academic Department of Medical Genetics at the University of Cambridge, Work strand 1 of UK-PBC, will securely transfer the list of NHS numbers and study IDs to the NHS Digital team (these are the only identifiers allowed to be shared by the project's consent materials) for all participants (currently 4,448) who have signed the Consent Form version 5. The NHS numbers will be collected by the UK-PBC research nurses at the English Trusts and Welsh Health Boards, as part of the study. Cambridge University Hospitals NHS Foundation Trust will transfer data to NHS England. The data will consist of identifying details (specifically NHS number, date of birth and study ID) for all participants (currently 5,543) for the cohort to be linked with NHS England data. With regard to the list cleaning purpose Work Strand 1 of UK-PBC within the University of Cambridge will supply NHS number and Study ID. This information will be reviewed by NHS Digital for participants in UK-PBC. This list will be cleaned for the purpose of updating and filling in information not provided by cohort when they signed up to the study. This will allow updating of information so linkage to other data sets will be possible for the whole participant cohort. NHS England will provide the relevant records from the HES, ECDS, DIDs, Mortality and NHSBSA datasets to Cambridge University Hospitals NHS Foundation Trust. The data will contain no direct identifying data items but will contain a unique person ID which can be used to link the data with other record level data already held by the recipient in order to verify clinical information already held in the UK-PBC Genetic Study database. Once the data has been extracted by NHS Digital team, data with only the study id and date of birth and no other direct patient identifiers will be returned to University of Cambridge. Work Strand 1 of UK-PBC within the University of Cambridge will then receive a dataset with the Health Data, while the Study ID and date of birth will be the only identifiers, and the NHS number omitted. The data will not be transferred to any other location. The transfer, to NHS Digital and back, will take place using a secure system, SEFT. The traffic will be directly between the Data Manager of the study and NHS Digital. The data will be stored on servers at Cambridge University Hospitals NHS Foundation Trust. This will be in a separate location to the UK-PBC Genetic study database. The only individuals accessing the NHS Digital data are the lead investigators and their teams who are substantive employees of the University of Cambridge and who have honorary contracts with the Cambridge University Hospitals NHS Trust. NHS Digital Data will be accessed from NHS Trust computers located within the Academic Department of Medical Genetics at the University of Cambridge. As per completed Security Questions Section, there will be no data storage on laptops or mobile devices; data will only be accessed from NHS Trust computers located within the Academic Department of Medical Genetics at the University of Cambridge. The data will be accessed onsite at the premises of Cambridge University Hospitals NHS Foundation Trust only. For the avoidance of doubt, data from NHS Digital will be stored on CUHFT servers behind N3 but it will never be uploaded into the UK-PBC Database, nor will it be used to correct information already contained in the UK-PBC Database. This is to ensure that there is no onward access to NHS Digital datasets, in any form. Personnel are prohibited from downloading or copying data to local devices. Data from NHS Digital will be used solely by the UK-PBC research team within Work Strand 1 at the University of Cambridge for prognostic modelling and will subsequently be electronically shredded. The data will not leave England at any time. The findings will be presented in aggregated format with small numbers suppressed at medical or scientific conferences, and meetings of the PBC Foundation (the leading PBC support group in the UK). Furthermore, findings will be published in medical and scientific journals, and the newsletters of the PBC Foundation and the UK-PBC project. Please note that participant identifiable details will never be presented or published. All personnel accessing the data have been appropriately trained in data protection and confidentiality. All outputs will be restricted to aggregate data with small numbers suppressed in line with the HES Analysis Guide. NHS England data is used to verify the study data held in the UK-PBC Genetic study database. Although NHS England data will be linked at person record level with the UK-PBC Genetic study data for the consented cohort for the purposes of verification, the UK-PBC Genetic study data and NHS England data will never be combined. The UK-PBC Genetic study data and NHS England data are kept on separate servers. At no time is NHS England data added to the UK-PBC Genetic study database. The verification process is to compare the study data held in the UK-PBC database against the NHS England data disseminated under this Agreement, specifically asking the questions did the event happen? and was the date the event happened correct? Where the data do not match the study team will query the discrepancy with the recruiting site, who will access the original source of hospital records and obtain the correct value. NHS England data will not be used to amend the data contained in the UK-PBC database. The NHS England data from NHS Digital will not be used for any other purpose other than that outlined further processing or used in this Agreement. the outcomes of the study. NHS Digital reminds all organisations party to this agreement of the need to comply with the Data Sharing Framework Contract requirements, including those regarding the use (and purposes of that use) by “Personnel” (as defined within the Data Sharing Framework Contract ie: employees, agents and contractors of the Data Recipient who may have access to that data) The identifying details will be stored in a separate database to the linked dataset used for analysis. All analyses will use the pseudonymised dataset. There will be no requirement and no attempt to reidentify individuals when using the pseudonymised dataset. The participant’s title, full name and address (including post-code) are details collected by the research team upon enrolment (only NHS number is allowed to be transferred to NHS Digital by the consent materials). As a result, there is no requirement for NHS Digital to provide them. Also, UK-PBC researchers have selected the fewest possible variables that focus on diagnoses, investigations, procedures and treatments. Dates requested are very specific and essential to prognostic modelling, in terms of identifying inter-correlations between such important events and the point in time they happened. Researchers from Cambridge University Hospitals NHS Foundation Trust will process the data for the purposes described above. Access is restricted to two employees. One is substantively employed by both Cambridge University Hospitals NHS Foundation Trust and University of Cambridge, the second is substantively employed by Cambridge University Hospitals NHS Foundation Trust and holds an honorary contract with University of Cambridge. However, the UK-PBC project intends to collect data only from the date of diagnosis (PBC) until the date of data linkage. The date of diagnosis is sometimes known to be several decades back for some participants, therefore, all data product periods have been selected, in an attempt to collect data as close to the date of diagnosis as possible. Data updates for the cohort would ideally be provided on an annual basis, after the first data extract by NHS Digital. The medicines data is not deemed disclosive and information on a GP level is available in the public domain. However, should the published information pose a risk of re-identification, the following suppression methodology should be applied: Please note that record level data will not be onwardly shared. Only aggregated data will get published with small numbers suppressed in line with the HES Analysis Guide. · Zeros should be shown. · 1-7 to be rounded to 5. · Any other numbers rounded to nearest 5. · Rounding unnecessary for averages etc. · Percentages calculated from rounded values. · If zeros need to be suppressed, round to 5.

Expected output

The verified clinical characteristic data will be presented in an aggregated format with small numbers suppressed in line with the HES Analysis Guide, within scientific journals dependent on research submission and acceptance for publication. Research will be presented at conferences and meetings such as; British Association for the Study of Liver Disease (BASL) this is an annual conference within the UK for the study of liver disease, European Association for the Study of Liver Disease (EASL) this is an annual conference within Europe for the study of liver disease and American Association for the Study of Liver Disease (AASLD) this is an annual conference within America for the study of liver disease. The findings will also be presented at meetings of the PBC Foundation (the leading PBC support group in the UK), and the newsletters of the PBC Foundation and the UK-PBC project. The output of the dissemination of NHS England data is a verified source of data to ensure high quality data is available for use in the analysis and reporting. The following general principles apply: The outputs of the UK-PBC Genetic Study are as follows: - All outputs and publications contain only aggregated data with small numbers suppressed in line with the HES Analysis Guide. The output of the preliminary study was: - Within summary tables, numbers will be rounded to the nearest 10 observations. • Paper reference: Murillo Perez et al. Greater Transplant-Free Survival in Patients Receiving Obeticholic Acid for Primary Biliary Cholangitis in a Clinical Trial Setting Compared to Real-World External Controls. Gastroenterology (https://pubmed.ncbi.nlm.nih.gov/36150526/) - All outputs will be checked by the UK-PBC Data Management Committee to ensure that no subject is identifiable from the information presented. The expected outputs of the processing of the larger ongoing study will be: - Individual level data will never be presented or published. Only summary data will be presented or published. • clinical information held in the UK-PBC Database (obtained from local research teams) is verified. - Data from NHS Digital will be used as part of the work with Work Strand 1 within Cambridge to complete missing data and resolve discrepancies between participant and clinician completed questionnaires. • Submissions to peer reviewed journals (e.g. Journal of Hepatology, Gut, Gastroenterology and Lancet Gastroenterology and Hepatology) expected August 2024 - List of fields of data already collected have been supplied to NHS Digital. All data requested from NHS Digital is already captured as part of the data capture. The data already captured will be downloaded from the UK-PBC Database on NHS computers behind the N3 firewall. • Presentations at meetings of the PBC Foundation (the leading PBC support group in the UK) - Any discrepancies or missing data in the project's data capture will be verified and completed using NHS Digital data. • Presentations at the British Association for the Study of Liver Disease annual conference, the European Association for the Study of Liver Disease annual conference and the American Association for the Study of Liver Disease annual conference. Outputs: Publication of the research is dependent on the timeline it takes for the data to be sent. The project envisages approximately 16-18 months from the date the data is received; however it is dependent on the data being received. • Updating study participants via the newsletters of the PBC Foundation and the UK-PBC Genetics Study of new findings • Publication of dashboards on UK-PBC website The outputs will be communicated to relevant recipients through the following dissemination channels: • Journals • Webinars open to clinicians and specialist nurses • Social media via Twitter • Posters displayed at medical conferences • Participant newsletters • Reports aimed at participants It is anticipated that outputs will be produced and disseminated by January 2025.

Expected measurable benefits

UK-PBC is aimed at developing a precision medicine approach to PBC treatment; delivering the right treatment to the right patient at the right time. This will be achieved by identification of patient groups within the PBC patient cohort who are more likely to respond to one type of therapy or another and to identify groups of patients at the point of diagnosis who are likely to have more aggressive disease and need closer monitoring and surveillance. Identification of patient sub-groups promptly at the point of diagnosis will allow patients at highest risk of progressive liver disease to be promptly treated with second line therapy, or newer agents and/or to be included into medical trials. This will also enable these high-risk groups to be included in closer surveillance and clinical follow-up within the healthcare setting. The findings of the UK-PBC Genetic Study are expected to contribute to evidence-based decision-making for policy-makers, local decision-makers such as doctors, and patients to inform best practice to improve the care, treatment and experience of health care users relevant to the subject matter of the study. The goals: The use of the data could: 1) Establishment of the stratified therapy model in PBC. Whereby patients with the greatest need receive the most appropriate treatment at the point of diagnosis. • lead to the identification or improvement of treatments or interventions, or health and care system design to improve health and care outcomes or experience. 2) Increase understanding of the mechanism(s) of UDCA (ursodeoxycholic acid, normally present in the bile) non-response through a systematic programme of innovative research. • inform planning health services and programmes, for example to improve equity of access, experience and outcomes. 3) To develop markers to identify patients likely to respond poorly or not at all to treatment, allowing these poor-responders and non-responders to be followed-up closely. • support knowledge creation or exploratory research (and the innovations and developments that might result from that exploratory work). To achieve the goals, complete clinical characterisation of patients using detailed clinical information including medical investigations and important clinical events (including the date and cause of death) is key. Data from NHS Digital will allow the project to verify the existing collected clinical characteristic data for accurate identification of sub groups of patients within the PBC cohort and treatment stratification so that patients with the greatest need are started on the most appropriate treatment and receive the greatest benefit. This stratified treatment approach will lead to improved disease outcomes and a more cost- effective approach to patient care. This will have a major impact in PBC enabling accurate identification of patients with sub-phenotypes, who might then be prioritised for mechanistic studies and clinical trials. Second-line treatment for PBC is expensive, e.g. obeticholic acid (OCA) at a standard dose of 5- 10mg once daily costs ~£80 per day (£29,000 per year). A large prospective cohort that is well-characterised in terms of disease severity, healthcare utilization, symptoms and health utility is essential for accurate health economic modelling and informed health economic opinion. This will benefit patients within the UK with PBC which at present is estimated at 20,000. The focus of WS1 is to recruit and characterise a large, prospective PBC cohort (the UK-PBC Research Cohort) for statistical modelling of disease, to improve risk prediction, risk stratification and treatment stratification in PBC. Risk prediction is important because it tells clinicians which patients are more likely to develop complications from PBC, and may benefit from closer monitoring in secondary care, whereas patients who are less likely to develop complications are more suitable for management in primary care and can be spared unnecessary healthcare encounters. The stratification of patients according to predicted risk may allow for improved allocation of healthcare resources. Treatment stratification is important as it ensures that patients who are likely to benefit from a drug, receive it, whereas patients who are unlikely to benefit from a drug are spared its side effects. The statistical modelling performed by the UK-PBC Genetics Study aligns with the government’s ‘UK Rare Diseases Framework’, which was developed to improve the diagnosis and treatment of patients with rare diseases across the UK. The findings of this study are expected to help develop a precision medicine approach to PBC management, delivering the right treatment to the right patient, at the right time. It is hoped that this approach will improve patient outcomes. In addition, whilst first-line therapy with ursodeoxycholic acid is relatively inexpensive (approximately £1,000 per patient per year), second-line therapy with obeticholic acid is expensive (approximately £28,000 per patient per year). There is limited clinical trial evidence to confirm whether obeticholic acid confers a survival benefit in PBC and allocation of this drug is often based on blood tests results which fail to take into account a patient’s stage of liver disease or their life expectancy independent of PBC. This means some patients who would benefit from the drug do not receive it, whereas other patients who are unlikely to benefit are exposed to unnecessary side effects. Allocation of obeticholic acid using a statistical model may be much more cost-effective, which is important for the UK healthcare economy; and less wasteful which is important for sustainable healthcare. Therefore the impact of this project may reach beyond benefits to PBC patients alone. Once the statistical models had been derived and validated (estimated completion August 2024), further studies would be required to measure their impact on treatment allocation and prescribing patterns in the UK. The development of these statistical models and their incorporation into clinical practice forms part of a post graduate research study, due to complete in April 2025. It is hoped that through publication of findings in appropriate media, the findings of this research will add to the body of evidence that is considered by the bodies, organisations and individual care practitioners charged with making policy decisions for or within the NHS or treatment decisions in relation to specific patients. Should the results of the analyses show statistically significant findings then UK-PBC would: • Share the findings on social media via the UK-PBC Twitter account and the PBC Foundation Twitter account • Share the findings at PBC Foundation Webinars which are regularly conducted with patients with PBC throughout the year • Share the findings with PBC specialist nurses throughout the UK via UK-PBC newsletters, who can share the findings with patients they see in clinical practice.

Benefits reported

Yielded Benefits is not a requirement for new applications. The study team were able to identify discrepancies in the UK-PBC database leading to a more accurate source of data. In the preliminary study participants from the UK-PBC Research Cohort were used as a control cohort in the analysis of PBC patients receiving Obeticholic acid medication (cases) versus PBC patients eligible for, but not receiving, Obeticholic acid. The analysis revealed that patients receiving Obeticholic acid medication were much less likely to die or need a liver transplant compared to patients who were not receiving Obeticholic acid. The findings of this study were published in ‘Gastroenterology’ Journal in September 2022. The findings of this preliminary study have led to the development of a larger study, currently ongoing, comparing the clinical outcomes of patients receiving Obeticholic acid using a larger cohort of Obeticholic acid-treated patients and Obeticholic acid-non-treated patients from the UK-PBC Research Cohort.