ORION-4: Data linkage to support outcome and other clinical data collection for consented participants

The University of Oxford requests access to the Medicines Dispensed in Primary Care dataset, and fact of death (referred to as 'Vital Status'), current address and GP surgery details from the Personal Demographics Service dataset, for a randomised controlled trial entitled ORION-4 (“A Randomized Trial Assessing the Effects of Inclisiran on Clinical Outcomes Among People With Cardiovascular Disease”).

ORION-4 is registered in clinicaltrials.gov (NCT03705234) and has approval from the Health Research Authority (IRAS 240684).

ORION-4 is an ongoing trial of a new cholesterol lowering drug called inclisiran, and is co- sponsored by the University of Oxford and Novartis. Inclisiran is administered as an injection 2-3 times per year and reduces low-density lipoprotein (LDL) cholesterol. The ORION-4 trial will determine if this drug is helpful in reducing cardiovascular events such as strokes and heart attacks in people with a previous history of such conditions, and who have high cholesterol levels despite available treatment with established cholesterol-lowering medications. The main purpose of the medicines data research project is to enable the assessment of the efficacy and safety of inclisiran in relation to non-study medications. The trial recruited 13,190 participants in the UK. If shown to be effective, this treatment could substantially reduce premature death and disability from these conditions. A secondary objective is developing streamlined trial methods that would benefit future research.

This study was initiated by independent scientists at the Clinical Trial Service Unit (CTSU) based at the University of Oxford. It is sponsored by the University of Oxford, and the Medicines Company (MDCO), which was acquired by Novartis - a Swiss-American multinational pharmaceutical corporation - in January 2020, in collaboration with the TIMI Study Group - an academic research organisation - based at Brigham and Women’s Hospital, Harvard Medical School, Boston.

It is noted that Novartis is named as a study sponsor in the study protocol, however, The University of Oxford are the sole controller for this Agreement. The University of Oxford determines which personal data should be collected (in line with the protocol) and how, when and by whom personal data is processed. The University of Oxford is responsible for the security of those data.

The University of Oxford and Novartis will act as co-sponsors of the trial and will share sponsorship responsibilities: the University will be the academic lead and sole Controller for the trial and Novartis will be the regulatory lead (e.g. managing regulatory submissions and interactions). Novartis will also provide packaged study medication (Inclisiran and matching placebo) for the study.

The aim of ORION-4 is to improve the health of patients with cardiovascular disease. However, if proven safe and effective, Novartis will benefit from the increased use of inclisiran. This an investigator initiated trial with a purpose of improving the health of people with vascular disease. If the results show that inclisiran is safe and effective this could also increase revenue for the manufacturer, funder and co-sponsor Novartis, as the manufacturer of the drug.

Most aspects of the ORION-4 study design have been closely modelled on previous successful studies undertaken by the Clinical Trial Service Unit. In particular, the patient population, eligibility criteria, recruitment strategies and follow-up methods are very similar to those of the HPS-2THRIVE study and the REVEAL study, both of which successfully recruited over 8000 UK participants. Participant feedback from these studies has informed the design of ORION-4. Furthermore, the ORION-4 study design, methods and participant information has been reviewed by the Nuffield Department of Population Health participant panel which includes previous trial participants. This panel will be involved in developing future participant facing materials, including participant newsletters and eventually, the communication of study results.

No data obtained as part of this Agreement will be shared with Novartis. However, as part of the trial Steering Committee, Novartis may be presented with results from analysis of data provided as part of this Agreement in the form of aggregated outputs with small numbers suppressed, and will have the opportunity to review any papers prior to publication. The Steering Committee determines the scientific objectives of the trial, ensures adequate progress towards those objectives and reviews any papers prior to publication. As is usual with this type of trial, the Steering Committee has representatives from the funder/co-sponsor Novartis and also has other experts from other institutions to advise the trial management team. Neither the Steering Group nor Novartis will have access to or process any NHS England record-level Data. The funders have no ability to supress any findings or control any of the outputs.

Potentially eligible trial participants were identified on an ongoing basis via centralised electronic health record screening, in collaboration with NHS England (under data sharing agreement DARS-NIC-172240-R4R0L). If willing to take part, eligible trial participants were invited to attend a screening visit where eligibility is confirmed and consent is collected, and then entered a placebo run-in after a first injection (enables exclusion of patients who respond well to the placebo intervention). Approximately 2 months later, consented participants attended a randomisation visit and started receiving either active or placebo injections. Follow-up visits with treatment administration are then performed after 3 months, and then every 6 months onwards until the scheduled treatment period is complete (estimated to be about 5 years).

Randomized controlled trials (RCTs) are the gold-standard for the assessment of efficacy and safety of medical interventions. Data used in RCTs is usually collected specifically for research during long time periods and with a high level of detail, making the conduct of high-quality RCTs both a complex and costly endeavour. With regards to concomitant medications, these data are usually collected by research staff based on patient-reported information, making this process the de facto standard in trials. However, data routinely collected for health care purposes is considerably similar to that collected for medical research (including on medications), sparking an interest in the use of routinely collected data (RCD) to inform the design and conduct of RCTs. Moreover, RCD is usually gathered via electronic systems and may prove to be more accurate than manually-recorded data. Harnessing RCD might therefore provide enhanced data integrity and completeness for planning, recruitment and follow-up purposes, bearing the promise of reduced costs and improved external validity of results.

Validating the use of routinely collected data on medications for randomised trials:

Under this Agreement, The University of Oxford request access to the Medicines Dispensed in Primary Care dataset (also referred to as "BSA Medicines data") to conduct methodological research on the use of routinely-collected data on medications for the purpose of large-scale randomized trials. This will provide direct benefit to the ORION-4 study by enabling the study team to understand the accuracy of the data entered by the local research staff. After the development of preliminary methodological work to assess the agreement between BSA Medicines data and that entered by trial staff, the BSA Medicines dataset will be used to further characterise the cohort at baseline, allowing analysis of the effects of the treatments in different types of patients, and may help to identify new diagnoses (e.g. diabetes). This will help the team identify long-term outcomes in the cohort and assess the effects of the treatments on these outcomes. The processing of this data and use of the BSA Medicines dataset for ORION-4 is in line with the Direction covering that dataset where the purpose is to drive the linkage of medicines data with other data sets to provide intelligence about the safety and effectives of medicines.

The Medicines Dispensed in Primary Care dataset contains all records of medications prescribed or dispensed in the community setting in England and submitted for reimbursement to the NHS Business Services Authority (BSA), starting from April 2018. Given its wide scope and broad coverage, these data hold significant potential for use in medical research and clinical trials in particular.

Under this Agreement, the University of Oxford propose to compare self-reported medication data collected by local research staff during trial visits with the data collected from the Medicines Dispensed in Primary Care dataset.

The main aim will be comparing capture of specific drugs of interest to the ORION-4 trial at the time of each individual participant study visit. Drug groups of interest will include:

- cholesterol-lowering drugs

- antithrombotic drugs

- antihypertensive / heart failure drugs

- antidiabetic drugs

Secondary aims will be:

1) to calculate the total number of individual drugs identified at each time point, and highlight drug groups that may be missed by each of the two sources,

2) to derive measures of medication adherence using the Medicines Dispensed in Primary Care dataset for lipid-lowering drugs (namely for statins) and assess how they relate to total cholesterol levels measured at randomisation, and

3) to assess the feasibility of aligning this RCD source with CDISC standards for medications data collection in trials.

The ultimate goal of all the aims described is to develop the methodology needed to use the Medicines Dispensed in Primary Care dataset to look at the safety, efficacy, and management of drugs, in this trial and other future settings, as specified by the dataset directions.

Vital Status and updated contact details for trial participants:

Also under this Agreement, The ORION-4 Coordinating Centre at the University of Oxford is requesting use of the Personal Demographics Service (PDS) to undertake a 'vital status' check on current study participants. The study team needs to mail letters to UK trial participants who have provided informed consent at their screening visit (for example to confirm inclusion in the study, further study appointment bookings, general correspondence with the study team about participation in the study, or newsletters). In order to avoid causing distress to family members, the Coordinating Centre team would like to undertake a vital status check before any central participant mailings to remove those participants who have since sadly passed away. In addition, the University of Oxford request the participant's current address and GP surgery code. These details are checked by the local research coordinator at each study visit. However, some participants have moved and not updated the study team with their new address and GP surgery especially during the clinic disruption due to COVID-19. Having their latest address and GP surgery code from the Personal Demographics Service (PDS) would enable the University of Oxford to get in contact with study participants to offer them a further study appointment if possible in their new area and ensure that any communication is sent to their correct GP. Vital status and updated contact details are requested at monthly intervals for the duration of this DSA to allow rolling updates to the data already held by the study during this period.

Data will only be used for the purpose of this research project. Name and address may be shared securely with Paragon Customer Communications, a mailing house, in order to send letters to participants or their doctors. Paragon Customer Communications are acting as a Processor on the instructions of the University of Oxford.

Atos IT Services UK Limited are a sub-Processor. Atos IT services UK Limited has been appointed to provide various services under the Managed IT services contract from Paragon Customer Communications. These are listed below. Under each service banner Atos IT services UK Limited pre-vetted resources will have access to Paragon's IT estate in order to deliver the required support and services. In some cases, Atos IT services UK Limited resources will have direct or indirect access to client data.

1. Service desk and IT service management

2. Hosting and networks infrastructure

3. End user compute

4. Application development, support and maintenance

5. Information security services

Whilst the data will remain resident onshore in UK data centres only, there may be instances where data may be viewed by authorised Atos IT services UK Limited employees from outside the UK and EU, but this is on a read-only basis and there are processes in place so files/data cannot be downloaded to the employee’s location.

The University of Oxford is the sole Controller and will process Personal Data under GDPR 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. As a higher education establishment, the University of Oxford conducts research to improve health care and services, and the data requested is necessary for the performance of a task carried out in the public interest.

Additionally, under GDPR Article 9(2)(j) processing of Special Category Personal Data (of which Health data is one) is necessary for archiving for research purposes. Data minimisation processes are being followed and only data that is specifically required for the purposes of this study have been requested, to protect the rights of the data subjects. The data are required for research purposes in the public interest – meeting the conditions in the DPA 2018 Schedule 1 Part 1 (4) – which GDPR Recital 52(2) determines is an appropriate derogation from the prohibition on processing special categories of personal data.

The duty of confidentiality is met as all study participants have provided written informed consent.

This research project will also contribute to an ongoing DPhil (Philosophy Doctorate) thesis, by a student who is a substantive employee of the University of Oxford. Funding is provided by the Medical Research Council through a studentship awarded to the project lead by the Population Health Research Unit at the Nuffield Department of Population Health, University of Oxford. Funding for the ORION-4 trial was provided by a research grant from The Medicines Company to the University of Oxford for the trial. Novartis acquired The Medicines Company in 2020 and took over the funding of the study.

In the interests of transparency, it is noted here that this an investigator-initiated trial with a purpose of improving the health of people with vascular disease. Novartis will provide study funding and packaged study medication (inclisiran and matching placebo) for the study and are co-sponsor of the trial. Novartis holds the UK marketing authorisation for inclisiran, and inclisiran is from a class of drugs called siRNAs. As the sole manufacturer of an siRNA for use in lipid management, Novartis could hold a unique competitive position to gain financially if inclisiran is widely prescribed within the NHS. However this is not the primary purpose or outcome of ORION-4. Inclisiran was selected for study in ORION-4 because it has a number of features which make it a potentially useful population health intervention: infrequent 6-monthly injections, storage at room temperature (no cold-chain requirements) and a 50% reduction in LDL-cholesterol. If the results of ORION-4 show that inclisiran is safe and effective this will also increase revenue for the Novartis but this is not the primary purpose of ORION-4.

Under this Agreement, one extract of the Medicines Dispensed in Primary Care data linked to the ORION-4 cohort of participants will be requested from NHS England. The Demographics dataset will be returned separately linked to the ORION-4 cohort. The cohort will include all participants randomised in England/Wales.

The details for linkage purposes will include ORION-4 study number (Study ID), NHS Number, name, date-of-birth and postcode. After receipt of the cohort details and respective linkage, NHS England will provide a linked copy of the Medicines Dispensed in Primary Care dataset on a one-off basis as soon as possible. NHS England will also provide a report to the University of Oxford on any NHS Numbers that are not found.

The data will be transferred via NHS England's Secure Electronic File Transfer System (SEFT).

Data processing will be carried out by substantive employees of the University of Oxford who have received appropriate training in data protection and confidentiality.

Record-level data will be stored, accessed and backed up at back-up storage sites on campus at University of Oxford.

All data received will be kept, accessed, and processed within the University’s systems using a secure password-protected environment, with access granted on a need-to-know basis. Personally-identifiable data will be kept in a highly secure specific data store with access restricted to a small number of employees. The pseudonymised data is stored in a separate secure location with separate controls on whom can access these data for analysis.

Statistical data analysis will be carried out via devices owned and managed by the University of Oxford, either onsite or 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).

Access will be provided only to individuals directly involved in processing these data for the purpose outlined in this Agreement.

No data received under this Agreement will be shared with any parties other than the University of Oxford except for:

1) Paragon Customer Communications who receive name and address of ORION-4 participants in order to mail letters to them or their doctors as instructed by the University of Oxford, and

2) Atos IT Services UK Limited who provide various services under the Managed IT services contract from Paragon Customer Communications, and therefore act as its contracted sub-processor.

In particular, no record-level data provided by NHS England as part of this agreement will be provided to Novartis.

Paragon Customer Communications will destroy all data received from the University of Oxford 30 days after each mailing.

Except the data shared with Paragon Customer Communications, the data will not be onwardly shared in any way other than in the form of aggregated outputs with small numbers suppressed (as per the HES analysis guide), which may be presented to other investigators in the ORION-4 study, Novartis, and the broader scientific community via research publications and presentations.

Data will be retained for a period of 25 years to allow internal monitoring by the University of Oxford and for academic archiving purposes, in line with the information given to consenting participants in the study Patient Information Leaflet.

The data requested will be restricted to that required for the analyses proposed here, namely details on drug prescribed and drug paid/dispensed, as well as prescription and dispensing setting. NHS Number and Date of Birth will be requested to confirm correct linkage, although these are already known to the study and will be provided by the University of Oxford to NHS England upon provision of the cohort details. NHS number and date of birth are requested from NHS England so that these can be cross-checked with the ones already held by the study.

NHS England data provided under the Data Sharing Agreement will not be combined with data from the US or used in joint analyses. The data requested in the DSA will be used to check and validate the existing data collection method in the UK and as such improve the quality of the research data collected as part of the trial.

Data obtained about vital status of the cohort will be used to avoid mailing letters to individuals who have sadly passed away since being recruited to the study. Monthly extracts will be requested to ensure that vital status is up-to-date. Data about updated address and GP surgery details will be used to ensure that letters to participants and their GPs are correctly addressed. This data will be stored securely within NDPH servers and accessed only by members of the team developing the IT applications required for the mailings and by senior members of the ORION-4 team who may need to resolve queries. Paragon Customer Communications will also receive name and address of ORION-4 participants in order to mail letters to them or their doctors as instructed by the University of Oxford.

The data from NHS England will not be used for any other purpose other than that outlined in this Agreement. The data will be collected, analysed, and published independently of any sources of funding. The funders will have no ability to suppress any findings should they lead to any negative outcomes on their products.

All organisations party to this agreement must 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 i.e.: employees, agents and contractors of the Data Recipient who may have access to that data).

The main direct outputs of the work relating to the prescribing data will be scientific research papers and presentations at scientific meetings. The University of Oxford will aim for publication in trial methodology journals such as Trials and Clinical Trials, although broad medical journals, such as JAMA Network Open (a monthly open access medical journal published by the American Medical Association) or BMJ Open (a peer-reviewed open access medical journal that is dedicated to publishing medical research from all disciplines and therapeutic areas), and those in the pharmacoepidemiology and cardiovascular fields may also be considered.

Scientific presentations hope to be aimed at trial methodology conferences such as the International Clinical Trials Methodology Conference, the Society for Clinical Trials meeting, and the Cardiovascular Clinical Trialists Forum, although cardiology conferences such as the European Society of Cardiology (ESC) conference or the ESC Digital Summit may also be considered.

The results are aimed to also be disseminated through collaboration with the Health Data Research UK clinical trials program and the MRC-NIHR Trials Methodology Research Partnership.

The focus of the results presented centre on how routinely-collected data compares with self-reported medication as collected during trial visits. This hope to provide valuable information to the ORION-4 trial team on the accuracy of the data held within the trial database and inform future trials. Secondary outputs of this work aims to also include the coding and processes developed to handle these data.

The methods and results spanning from this work are hoped to also be included in a DPhil thesis to be submitted to the University of Oxford.

The target date for all the planned outputs of the Medicines methodology development work will be early 2025.

The ability to centrally mail study participants across the UK will reduce pressure on local research staff at a time of scarce resource within the NHS. By checking vital status prior to any mailings the ORION-4 coordinating centre aims to avoid causing distress to family members of participants who have passed away. In addition, the updated address and GP details aim to ensure that important communications to trial participants are correctly addressed and that participants can be offered an ongoing trial follow-up visit appointment. Using Paragon customer communications to undertake large scale mailings on the instruction of the University of Oxford improves efficiency and security.

The main purpose of the medicines data research project is to enable the assessment of the efficacy and safety of inclisiran in relation to a matching placebo, including the potential impact of other (non-study) medications being taken by a participant. After the development of preliminary methodological work to assess the agreement between BSA Medicines data and that entered by trial staff, the BSA Medicines dataset will be used to further characterise the cohort at baseline, allowing analysis of the effects of the treatments in different types of patients, and may help to identify new diagnoses (e.g. diabetes). This will help the team identify long-term outcomes in the cohort and assess the effects of the treatments on these outcomes. The processing of this data and use of the BSA Medicines dataset for ORION-4 is in line with the Direction covering that dataset where the purpose is to drive the linkage of medicines data with other data sets to provide intelligence about the safety and effectives of medicines.

Use of these data for medical research purposes may help reduce the costs and burden of data collection for research purposes and enable the deployment of broader, faster, and cheaper trials, streamlining the deployment of new interventions that can benefit patients and the NHS, as well as increasing University of Oxfords understanding of health and disease. Similarly, making better use of available data leads to fewer burden of resources for GP practices and hospitals participating in research, as well as to patients volunteering their time and information. It can also facilitate easier access to NHS organisations and patients that want to take part in research.

The secondary outputs aim to help streamline the use of these data for medical research. The lessons learnt may also inform the development of new international standards for data reporting in clinical trials that are able to accommodate routinely collected data on medications, enhancing trial procedures on a global scale.

Finally, the validation work proposed here hopes to help to pave the way for more randomised trials to be performed in the UK, contributing to make the NHS the world-leader in data-enabled clinical trials and thus supporting the broader healthcare and science economy, as outlined in the UK Government Life Sciences Industrial Strategy.

The data about current address, GP surgery and vital status aims to help the trial successfully communicate with participants and their GPs. This is important for a high quality participant experience but also important to allow the study to achieve high levels of adherence to study treatment. This is critical in producing robust results and hopes to help the study to generate practice changing results which, if the treatment is safe and effective, may improve outcomes for people with cardiovascular disease within the UK and around the world. Using Paragon Customer Communications to undertake large-scale mailings on the instruction of the University of Oxford improves efficiency and security.

No yielded benefits as of April 2024. The Data are being used to support a long-term trial, and therefore it is not expected that benefits will have been realised at this point in the trial.