The Early Detection of Hepatocellular liver cancer (DeLIVER)

University of Oxford requires access to NHS England data for the purpose of the following research project:

The Early Detection of Hepatocellular liver cancer (DeLIVER)

The DeLIVER study focuses specifically on hepatocellular carcinoma (HCC), the most common type of primary liver cancer in the UK. The DeLIVER programme is investigating new approaches for earlier liver cancer detection.

Hepatocellular cancer (HCC) is one of the fastest rising and 4th commonest cause of cancer death world-wide, associated with viral infection, alcohol and obesity. Currently, 80% of HCCs are diagnosed at late stage with a 5-year survival less than 5%. HCC is usually associated with liver inflammation, advanced fibrosis and field cancerisation, as evidenced by multiple HCC that arise contemporaneously irrespective of aetiology. Strategies for the early detection (EDx) of HCC are urgently required so that curative therapies may be applied. To date, little effort has been made to characterise the pre-cancerous liver landscape, and current imaging techniques and biomarkers that seek to identify HCC.

Enrolment into the Pearl study began in February 2022. To date, 2271 participants have been enrolled from 44 different liver clinics.

Enrolment into Selina study began in May 2022. To date, 254 participants have been enrolled into this study.

Recruitment for both cohorts ceased at the end of 2025.

The DeLIVER study team will submit both studies as 1 cohort to NHS England which will total ~2525 participants.

The following is a summary of the aims of the research project provided by the University of Oxford.

To undertake research to evaluate HCC surveillance and how it could be more efficiently targeted at a higher risk subgroup, to improve early HCC detection. Primarily to:

- To evaluate the predictors of HCC occurrence.

- To evaluate the predictors of HCC progression, treatment and prognosis.

- To develop and evaluate scores estimating individualised patient risk of HCC.

- Describing the natural history (i.e. clinical course) of cirrhosis and HCC.

- Evaluate the benefit and harms of existing HCC surveillance.

The research aims to understand the pre-cancer liver landscape and develop translatable early detection methods, risk prediction, and therapeutics.

The goal of DeLIVER is to reduce liver cancer mortality by increasing its detection at an early stage when it is most amenable to treatment.

The DeLIVER programme is made up of six work packages which each address a different aspect of the overall research aims.

Work package 1 - Development of HCC early detection patient cohorts and is made up of three studies, DELPHI, Selina and Pearl.

This data request is for the Selina and Pearl studies delivered under The Early Detection of Hepatocellular liver cancer (DeLIVER).

Selina cohort (Small early liver cancer with natural history follow-up). The Selina cohort follows participants with early-stage HCC over time. All participants attend an enrolment visit and then a follow-up visit 12 months later.

Pearl cohort (Prospective Cohort for Early Detection of Liver Cancer). Pearl is a cohort study including people with a diagnosis of cirrhosis without liver cancer who are attending specialist liver centres in the UK.

Relationship between Pearl and Selina:

Selina and Pearl are sibling studies exploring the same disease process from different angles/starting points (i.e. Pearl from the point of cirrhosis, and Selina from the point of early HCC diagnosis). Although separate studies, they run in parallel and are overseen by the same team and data controller (University of Oxford).

This data request is relating to the Selina and Pearl studies only. The Pearl study runs alongside Selina study to provide a comparator group assessment of diagnostic test performance.

The following NHS England Data will be accessed: Hospital Episode Statistics (HES)

• Admitted Patient Care (APC) and Outpatients (OP) – necessary to quantify non-liver related comorbidities and instances of cirrhosis decompensation, which affect prognosis and suitability for HCC treatments.

• Diagnostic Imaging Dataset (DID's) – necessary to quantify uptake of surveillance and diagnostic tests relating to HCC diagnosis and management).

• Civil Registration Mortality – necessary to quantify survival and prognosis. Full date of death data is required to quantifying survival (i.e. mortality risk) of the cohort and how this is modified by liver cancer surveillance and relevant risk factors. To make these analyses as reliable, reproducible and precise as possible, precise information on the date of death is required. Information on the month and year of death alone would not be an adequate proxy.

• NDRS Consolidated Cancer Data (package 9) – necessary to quantify the incidence of cancer, particularly liver cancer.

The level of the Data will be:

• Identifiable – necessary because although the applicant will pseudonymise the data at the University of Glasgow Robertson Centre of Biostatistics (RCB) Trusted Research Environment (TRE), there could be a means to identify individuals by comparing identifiers at held at the University of Oxford.

The Data will be minimised as follows:

- Limited to a study cohort identified by the University of Oxford for patients of all genders, age >18 years showing evidence of cirrhosis with an underlying aetiology of at least one of the following: chronic HBV infection, chronic HCV infection, alcoholic liver disease, non-alcoholic fatty liver disease or haemochromatosis.

- Limited to data between 2010/11- latest annual data. Historical data (i.e. data preceding enrolment in Pearl/Selina) are required in order to characterise patients in terms of risk factors and comorbidity burden.

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 is provided by Cancer Research UK. The funding is specifically for the The Early Detection of Hepatocellular Liver Cancer DeLIVER study described. Funding is in place until 31/12/2026.

The funder will have no ability to suppress or otherwise limit the publication of findings.

Robertson Centre for Biostatistics (RCB), University of Glasgow is a processor acting under the instructions of the University of Oxford.

The Pearl Management Group comprises the Chief Investigator, the DeLIVER programme manager and the

Principal Investigator responsible for the Pearl cohort and the Pearl project manager. The Pearl Management Group meets on a regular basis and report to the DeLIVER steering committee.

The DeLIVER Steering Committee includes 1 member from Roche Ltd, which discusses the management of all studies under the umbrella of the DeLIVER consortium; including the Pearl and Selina studies. The member of Roche Ltd will have no influence on the NHS England data or will gain any commercial benefit from their involvement.

Data will be accessed by:

• researchers who have access the data and who will be affiliated to the University of Oxford. Access to NHS England data at the RCB will be by authorised researchers which will take place within the RCB Trusted Research Environment (TRE).

Data will be accessed by:

• Individuals holding an honorary contract under the supervision of a substantive employee of the University of Oxford for the purposes described in this DSA only. [Organisation] must maintain records in a single location that cover the following details of each individual given access under an honorary contract:

o Their substantive employer;

o Their role in respect of the purpose for the processing specified in the DSA;

o The start date and end date of the duration in which the Data will be accessed by the individual under an honorary contract;

o The necessity for the Data to be accessed by the person(s) holding an honorary contract, instead of a substantive employee of an organisation named as controller or a processor in this DSA;

o Confirmation that an appropriate contract is in place which follows the relevant guidance and is countersigned by the substantive employer of the honorary contract holder.

A Public and Patient Involvement and Engagement group helped refine the purpose of the research. The group strongly supported the collection of the data for the purposes described above.

Input into the study design as well as the generation of protocol and participant information sheet was sought from patient groups (as part of the British Liver Trust and the Hepatitis C Trust) and patient representatives form part of the DeLIVER Steering Committee.

The University of Oxford will transfer data to NHS England. The data will consist of identifying details (specifically NHS Number, Date of Birth, Gender and a unique person ID) for the cohort to be linked with NHS England data.

NHS England will provide the relevant records from the HES APC, OP, DID's, NDRS Consolidated, Deaths and Cancer Registration datasets to the University of Glasgow. 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.

The University of Glasgow will download the Data and securely transfer to the Robertson Centre of Biostatistics (RCB) Trusted Research Environment (TRE) within the University of Glasgow.

The data supplied by NHS England will be linked to data collected by DeLIVER to enable DeLIVER to meet the objectives of our project. For example, to determine how laboratory tests (collected via DeLIVER) are associated with incidence of HCC (determined via data from the NDRS cancer register). Integration of these data will only be possible within the confines of RCB Trusted Research Environment (TRE).

The Data will be stored on servers at the University of Oxford and University of Glasgow within the confines of RCB Trusted Research Environment (TRE).

The University of Glasgow RCB uses offsite back-up services provided by Iron Mountain.

The Data will be accessed by authorised personnel via remote access.

The Controller(s) must confirm and provide evidence upon audit by NHS England that access via any remote device complies with the data security obligations within this DSA and the Data Sharing Framework Contract.

For remote access:

- Remote access will only be from secure locations situated within the territory of use (as further restricted elsewhere within the DSA if so done) stated within this DSA;

- Access controls granting users the minimum level of access required are in place;

- Remote access is only via secure connections (e.g., VPNs or secure protocols) to protect data;

- Multifactor authentication (MFA) is required for remote access;

- Device security, including up-to-date software and operating systems, antivirus software, and enabled firewalls are utilised for the remote access;

- All remote access is undertaken within the scope of the organisation’s DSPT (or other security arrangements as per this DSA) and complies with the organisation’s remote access policy.

The above applies in addition to any condition set out elsewhere within the DSA (e.g. who may carry out processing, and for what purpose).

Remote processing will be from secure locations with the UK. The data will not leave the UK at any time.

Data will be accessed by individuals with an honorary contract with the University of Oxford. The individuals will act as an agent of the University of Oxford at all times under supervision from employees of the University of Oxford. Aside from this/these individuals, access is restricted to employees of the University of Oxford who have authorisation from the Principal Investigator.

All personnel accessing the Data have been appropriately trained in data protection and confidentiality.

There will be no requirement and no attempt to reidentify individuals when using the 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.

Researchers from the the University of Oxford will analyse the Data for the purposes described above.

The expected outputs of the processing will be:

1) A report of findings to:

Assess the agreement/concordance between adverse events recorded in the DeLiver clinical database versus NHS England registries. In particular, quantify and compare the rate of HCC incidence, mortality, decompensation, and surveillance uptake derived from: a) clinical records (i.e. the DeLiver clinical database); versus b) NHS England national registries. (target date: March 2026)

2) Assess the predictors of HCC development among people with cirrhosis. Develop a risk score to estimate HCC risk at the individual patient level. (target date: October 2027)

3) Describe the natural history of liver cirrhosis – i.e. with respect to all-cause mortality, decompensation and HCC development, HCC treatment and post-HCC survival (target date: Dec 2027).

4) Identify the clinical, epidemiological, biological factors/predictors associated with HCC treatment response and prognosis. (target date: June 2028)

5) Evaluation of the benefits and harms of existing HCC surveillance, and how this could be modified using risk score developed in outcome #2 (target date: June 2028).

• Submissions to peer reviewed journals - (e.g. Journal of Hepatology, and the British Medical Journal

• Presentations to the public - issuing press releases, (i) social media channels; (iii) circulating to prominent third sector organisations with whom we have strong links (e.g. British Liver Trust).

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• Presentations at scientific conferences to disseminate our findings to clinicians and practitioners. These conferences will include the HCC-UK conference, BASL annual meeting and the EASL congress.

• Dissemination to study participants via our quarterly participant newsletter and website.

• The results will also be shared with key policy groups across the UK, including the NHS England HCC surveillance working group and the NHS England early diagnosis advisory group.

The outputs will not contain NHS England Data and will only contain aggregated information with small numbers suppressed as appropriate in line with the relevant disclosure rules for the dataset(s) from which the information was derived.

The outputs will be communicated to relevant recipients through the following dissemination channels:

a) Open access publication in high-impact academic journals (e.g. Journal of Hepatology, and the British Medical Journal) to communicate our findings to other scientists in the field.

b) Presentation at scientific conferences to disseminate our findings to clinicians and practitioners. These conferences will include the HCC-UK conference, BASL annual meeting and the EASL congress.

c) Dissemination to study participants via our quarterly participant newsletter and website.

d) Dissemination to public via: (i) issuing press releases, (i) social media channels; (iii) circulating to prominent third sector organisations with whom we have strong links (e.g. British Liver Trust).

e) The results will also be shared with key policy groups across the UK, including the NHS England HCC surveillance working group and the NHS England early diagnosis advisory group.

The findings of this research 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 use of the data could:

• lead to the identification or improvement of treatments or interventions, or health and care system design to improve health and care outcomes or experience.

• advance understanding of the need for, or effectiveness of, preventative health and care measures for particular populations or conditions such as HCC.

• inform planning health services and programmes, for example to improve equity of access, experience and outcomes.

• provide a mechanism for checking the quality of care. This could include identifying areas of good practice to learn from, or areas of poorer practice which need to be addressed.

• support knowledge creation or exploratory research (and the innovations and developments that might result from that exploratory work).

Hepatocellular carcinoma (HCC) is the most common type of primary cancer and is an issue of growing public health concern. Namely:

- HCC is the fastest rising causes of cancer mortality in the UK.

- HCC is one of the “least survivable” cancers in the UK with five-year life expectancy <20%. This means that less than one in five patients remain alive five years after being diagnosed with HCC.

- The primary reason why HCC prognosis is so poor is that it is normally diagnosed at a late stage, when it is refractory to treatment. Indeed, HCC has been highlighted as a key barrier to NHS England reaching their target of detecting 75% of cancers at early stage by 2028.

These challenges are drawing attention to both the importance and constraints of HCC surveillance (i.e. checking people with cirrhosis regularly for HCC even if they have no symptoms).

This request for data may enable DeLIVER to understand the benefits and harms of existing HCC surveillance, and how it could be optimised by using risk scores that identify the patients who are mostly likely to develop HCC. The outputs produced may enable rising HCC mortality rates to be curtailed, and will improve efficiency/cost effectiveness of HCC surveillance.

It is hoped that during the initial 3-year period of the proposed data sharing agreement the benefits will be to :

1) Assess the agreement/concordance between adverse events recorded in the DeLiver clinical database versus NHS England registries. In particular, quantify and compare the rate of HCC incidence, mortality, decompensation, and surveillance uptake derived from: a) clinical records (i.e. the DeLiver clinical database); versus b) NHS England national registries. (target date: March 2026)

2) Assess the predictors of HCC development among people with cirrhosis. Develop a risk score to estimate HCC risk at the individual patient level. (target date: October 2027)

3) Describe the natural history of liver cirrhosis – i.e. with respect to all-cause mortality, decompensation and HCC development, HCC treatment and post-HCC survival (target date: Dec 2027).

4) Identify the clinical, epidemiological, biological factors/predictors associated with HCC treatment response and prognosis. (target date: June 2028)

5) Evaluation of the benefits and harms of existing HCC surveillance, and how this could be modified using risk score developed in outcome #2 (target date: June 2028).

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.

Yielded Benefits is not a requirement for new applications.