HPS-4/TIMI 65/ORION-4: A double-blind randomized placebo-controlled trial assessing the effects of inclisiran on clinical outcomes among people with atherosclerotic cardiovascular disease. Application for data for invitation.

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Objective for processing

The University of Oxford requires demographic, mortality and Hospital Episode Statistics (HES) data to recruit participants into the ORION-4 study. University of Oxford requires access to NHS England data for the purpose of the following research project: Investigators at The University of Oxford have instigated this work to achieve benefits for patients by obtaining reliable evidence about the safety and effectiveness of a new cholesterol lowering medication called Inclisiran. Inclisiran is given as an injection 2-3 times a year and reduces bad (low-density lipoproteins (LDL)) cholesterol. The ORION-4 study will find out whether inclisiran safely reduces heart attacks, strokes and cardiovascular deaths in people who already have cardiovascular disease. 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. HPS-4/TIMI 65/ORION-4: A double-blind randomized placebo-controlled trial assessing the effects of inclisiran on clinical outcomes among people with atherosclerotic cardiovascular disease. Application for data for invitation The ORION-4 study is co-sponsored by The University of Oxford and The Medicines Company (now acquired by Novartis). The protocol and procedures have been developed by the Chief Investigator at the Clinical Trial Service Unit, University of Oxford in an academic collaboration with the TIMI Group - an academic research group within Harvard University - and The Medicines Company (now acquired by Novartis) which are part of the Steering Committee for the trial. The Steering Committee would determine the scientific objectives of the trial, ensure adequate progress towards those objectives and review any papers prior to publication. As is usual with this type of trial, the Steering Committee also has other international experts from other institutions to advise the trial management team. The following is a summary of the aims of the research project provided by / on behalf of University of Oxford In respect of the data under this Agreement, the University of Oxford is the sole data controller and also processes the data for this study. Under the direction of the University of Oxford, Paragon Customer Communications (London) Ltd will also process personal data (name, address) in order to produce, print and mail the invitation letter. Paragon Customer Communications (London) Ltd has a proven track record of securely processing personal data for research (this company mailed 9 million participant communications for the UK Biobank study) and for the NHS. While the Steering Committee signs off the high level plan, the University has full autonomy to determine what personal data is obtained and how it will be processed. The University of Oxford would determine how, when and by whom personal data is processed and is responsible for the security of those data. • Investigate the safety and effectiveness of Inclisiran, a cholesterol-lowering drug, in reducing heart attacks, strokes, and cardiovascular deaths in individuals with existing cardiovascular disease. The data will be stored and processed at the University of Oxford. Patient’s NHS and Hospital Numbers may be shared with the NHS Trusts that treated them so that the Trust can confirm patient’s eligibility by checking local laboratory results for cholesterol levels. Other than sharing these data items with NHS Trusts, and with Paragon Customer Communications (London) Ltd (see above), data supplied by NHS Digital would not be released to any other organisation or used for any other purpose. No Harvard University employees will have access to record level data under this Agreement. The Medicines Company (now acquired by Novartis) will not access data under this Agreement. • ORION-4 is a randomized clinical trial involving inclisiran versus placebo to assess cardiovascular outcomes in participants. The University of Oxford established the Clinical Trial Service Unit (CTSU), now within the Nuffield Department of Population Health, in the 1980s to conduct large trials such as the International Study of Infarct Survival (ISIS) trials. Since then CTSU has successfully completed a number of landmark studies including the 20,000 participant Heart Protection Study, the 9500 participant SHARP study, the 26,000 participant HPS-2/THRIVE study and the 30,000 participant HPS-3/REVEAL study. • Develop streamlined clinical trial methods to benefit future research. The aim of processing the data is to recruit consenting participants for a randomized trial. At the beginning of the trial, half of the participants will be put in the group to be given active inclisiran and the other half will be put in the group to be given placebo injections. This will be done by chance, in a similar way to tossing a coin, called “randomization”. The participants will be followed to find out whether the active inclisiran group experienced fewer heart attacks, strokes and cardiovascular disease outcomes than the placebo group thereby demonstrating the effects of the treatments. The trial will also seek to establish whether the treatment is safe by looking to see whether the active inclisiran group evidenced increased risk of any other health conditions/outcomes. • To recruit 12,000 participants for a randomized clinical trial, comparing the effects of Inclisiran against a placebo The demographic (including name, address and GP practice details), mortality and HES data are required to assist the University of Oxford in identifying and recruiting eligible participants. Since patients who have had one of the qualifying clinical conditions (heart attack, stroke, peripheral arterial revascularisation procedure or aortic aneurysm repair) at any time are potentially eligible for the study, the HES records requested include data from historic HES records. For convenience, data from 1997 onwards are requested. The ORION-4 team will inform NHS Digital of the NHS Hospital Trusts where an ORION-4 site is to be based so that only patients who have been admitted to that Hospital Trust are included in the data. Potentially eligible participants will be invited on behalf of the Local Investigator using local NHS headed paper to attend a Screening Appointment at the ORION-4 clinic (usually in their local NHS Hospital). If they choose to attend, they will be invited to consent to participate in the clinical trial. • Demographic, mortality, and Hospital Episode Statistics (HES) data are used to recruit participants with cardiovascular conditions for the study. Historical HES records from 1997 onwards will be utilized for comprehensive participant identification. Since the aim of the processing is to make contact with the potentially eligible patients directly, less intrusive methods such as use of pseudonymised or anonymised methods are not possible. Given the large number of invitations which are likely to be required in order to recruit 12,000 participants into the study in the UK (it is anticipated that around 0.5M invitation letters will be sent), it would not be practical for the patients’ usual health care team to seek consent prior to invitation. • Establish the safety profile of Inclisiran by monitoring potential health outcomes in the treatment group. This objective of undertaking the ORION-4 research study aiming to improve future patients’ health is the justification for processing under GDPR Article 6(1)(e) and Article 9(2)(j). The processing of data outlined in this application occurs without the consent of the data subjects. Any risk to individual data subjects from loss of data is minimized by a number of robust security processes. Inconvenience to data subjects is minimized by sending only a single invitation letter in which it is clear that they do not need to take part in the study. These issues have been considered by both the Confidentiality Advisory Group and the Research Ethics Committee. • The study is a collaboration between the University of Oxford, Novartis, and the TIMI group from Harvard, with a Steering Committee overseeing scientific objectives and progress. For those who provide informed consent, the University of Oxford will apply to NHS Digital for subsequent follow up data under a separate Data Sharing Agreement. • If effective, Inclisiran could significantly reduce premature death and disability related to cardiovascular conditions, contributing to public health improvements. Notwithstanding their role as a co-sponsor, The Medicines Company (now acquired by Novartis) are not considered joint Data Controllers for this application, and will not attempt to influence the design of the study, nor suppress any aspect of publication of the findings. The following NHS England Data will be accessed: The data requested under this application are used to invite potentially eligible patients to join the ORION-4 trial. Although Novartis (and previously The Medicines Company) are co-sponsors of the trial, the division of responsibilities within the co-sponsorship arrangement means that the University of Oxford is responsible for; • Hospital Episode Statistics(Admitted Patient Care) • deciding what personal data are collected, necessary to investigate the safety and effectiveness of Inclisiran, a cholesterol-lowering drug, in reducing heart attacks, strokes, and cardiovascular deaths in individuals with existing cardiovascular disease who have attended the Orion-4 clinic. • how those data are processed, • Demographics necessary to list clean the cohort already identified as potentially eligible for invitation to the ORION-4 trial prior to mailing invitations • engaging relevant data processors, and The level of the Data will be : Identifiable – necessary to investigate whether inclisiran safely reduces heart attacks, strokes and cardiovascular deaths in people who already have cardiovascular disease. The ORION-4 team will supply NHS England with a list of ICD and OPCS codes which indicate that an individual has had one of the vascular conditions listed in the trial inclusion criteria. The HES data will then be searched so that only people with one or more of these conditions recorded in their HES record are included in the data transfer. Further filters are applied to exclude individuals aged under 55, deceased individuals and individuals not currently registered with an NHS GP. • ensuring that the data is processed securely and in line with data protection legislation. The Data will be minimised as follows : Novartis are responsible for other parts of the clinical trial which do not involve data under this application. • The ORION-4 team will supply NHS England with a list of ICD and OPCS codes which indicate that an individual has had one of the vascular conditions listed in the trial inclusion criteria. The HES data will then be searched so that only people with one or more of these conditions recorded in their HES record are included in the data transfer. Further filters are applied to exclude individuals aged under 55, deceased individuals and individuals not currently registered with an NHS GP. This an investigator initiated trial with a purpose of improving the health of people with vascular disease. If inclisiran turns out to be safe and effective this will result in financial benefit for Novartis, as the manufacturer of the drug, but the purpose of ORION-4 is public health.” The data is limited to people who are likely to be able to be able to attend an ORION-4 clinic. The ORION-4 team will inform NHS England of the NHS Hospital Trusts where an ORION-4 site is to be based so that only patients who have been admitted to that Hospital Trust are included in the data-set. ********** Records for individuals who have expressed an opt-out will be removed prior to data transfer. This amendment (May 2020) is requested to allow the use of both formal and informal fact of death in the list cleaning process. All of the other data processing activities are unchanged. An updated protocol is provided for completeness but there are no changes which affect the recruitment process or the activities undertaken by the trial participants. • Limited to a study cohort identified by University of Oxford as people who are likely to be able to attend an ORION-4 clinic. ********** The University of Oxford is the research sponsor and the controller as the organisation responsible for ensuring that the data will only be processed for the purpose described above. Although Novartis (previously The Medicines Company) are co-sponsors of the trial, Novartis are responsible for other parts of the clinical trial which do not involve data under this agreement. This further amendment (May 2021) is to include a second invitation letter to individuals who have not responded to the first invitation. Prior to the coronavirus outbreak, the ORION-4 senior management team had reviewed the response to participant invitation for this study. Although around one in 20 potentially eligible people invited to join the study do express interest in taking part, less than 1.2% of those invited end up being randomised. This is mainly because many people do not meet the requirement of having a point-of-care total cholesterol of at least 4 mmol/l at the Screening visit. As a consequence it is anticipated that sites may exhaust their pool of potentially eligible patients and, indeed, some have already done so. Furthermore, the coronavirus pandemic has caused a substantial delay to recruitment and the likely impact of this on future response to invitations is not known. In previous studies using similar invitation methods, a significant number of potentially eligible patients who did not reply to an initial mailed invitation, did volunteer to take part after receiving a second invitation. The lawful basis for processing personal data under the UK GDPR is: This amendment seeks approval for second ORION-4 invitation letter to be sent to potentially eligible patients who have not responded to the initial invitation letter. This process and template letter have been approved by Research Ethics Committee (REC) and Confidential Advisory Group (CAG). 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 In addition, this amendment has updated the processing location and contact details for Paragon Customer Communications (now Paragon Customer Communications (London) Limited) and includes changes to the objective for processing in light of the acquisition of The Medicines Company by Novartis, who are now co-sponsor of the trial. The lawful basis for processing special category data under the UK GDPR is: Note that all staff at Paragon Customer Communications (London) Ltd who access the data provided to them by University of Oxford are substantive employees of Paragon Customer Communications (London) Ltd who have been appropriately trained in data protection and confidentiality. 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 The Medicines Company (now acquired by Novartis) The funding is specifically for the study described. The Novartis is the co-sponsor of the trial. Novartis will not attempt to influence the design of the study, nor supress any aspect of publication of the findings. Novartis are responsible for other parts of the clinical trial which do not involve data under this application. The data received from NHS England will only be accessed by individuals within the Clinical Trial Service Unit who have authorisation to access the data for the purpose(s) described, all of whom are substantive employees of the University of Oxford and have been appropriately trained in data protection and confidentiality. The potential exception to this is that identifying NHS and Hospital Numbers may be shared with the NHS Trusts that have previously treated the potential participants. This would not involve giving those NHS Trusts new information about the participants, since they recorded the data in the first place. It would simply be a practical step to enable the Trusts to identify the individuals in their own patient records in order to undertake a further eligibility check based on local laboratory blood cholesterol results. No other data linkages will be made.

Processing activities

The University of Oxford will establish ORION-4 sites (generally in NHS Trusts which treated high numbers of individuals for heart attacks, strokes or cardiovascular conditions). Once a local NHS Trust has completed the study feasibility assessment, the University of Oxford will inform NHS Digital that that NHS Trust is now a confirmed site. The University of Oxford will transfer data to NHS England. The data will consist of identifying details specifically NHS Number; Surname; Forename; Date of Birth; Postcode; Gender and a unique person ID) for the cohort to be linked with NHS England data. Using a combination of the Hospital Episodes Statistics (HES) and Personal Demographics Service (PDS) databases, NHS Digital will extract the details of patients aged 55 and over for whom a previous hospital episode with an ICD 10 code or other diagnostic code indicating eligibility for the trial has been recorded by one or more of those NHS Trusts. Patients who are deceased or who are not current registered with an NHS GP would be excluded. NHS England will provide the relevant records from the Hospital Episode Statistics(Admitted Patient Care and Demographics datasets to University of Oxford. The Data will contain directly identifying data items including Name, Latest address and postcode , Date of Birth, Sex , ICD 10 or other diagnostic or procedure codes to indicate eligibility, NHS Trust, NHS Number , Hospital Number , GP practice code, Admission date of most recent episode with an ICD 10 code or other diagnostic code meeting the inclusion criteria and Postcode which are required to extracts, identifying and contact details about potentially eligible participants plus their ICD 10 or other diagnostic or procedure codes to indicate eligibility, NHS Numbers, Hospital Numbers and GP Practice Codes. The latter 4 items are required for liaison with the NHS Trusts where possible to further determine eligibility prior to the mail out. NHS Digital will provide to the University of Oxford a file containing the following identifying data items for potentially eligible participants: The Data will not be transferred to any other location. • Name The Data will be stored on servers at Clinical Trial Service Unit within the University of Oxford. • Latest address and postcode The Data will be accessed onsite at the premises of University of Oxford only. • Date of Birth The Data will not leave England/Wales at any time. • Sex Access is restricted to individuals within the Clinical Trial Service Unit who have authorisation to access the data for the purpose(s) described, all of whom are substantive employees of the University of Oxford. • ICD 10 or other diagnostic or procedure codes to indicate eligibility All personnel accessing the Data have been appropriately trained in data protection and confidentiality. • NHS Trust The Data will not be linked with any other data. • NHS Number There will be no requirement and no attempt to reidentify individuals when using the Data. • Hospital Number Analysts from the Clinical Trial Service Unit will process/analyse the Data for the purposes described above. • GP practice code • Admission date of most recent episode with an ICD 10 code or other diagnostic code meeting the inclusion criteria The University of Oxford will undertake further work to ascertain eligibility. This may include sending a list of NHS and Hospital Numbers securely to the local NHS Trust so that they can undertake further eligibility checks based on the blood cholesterol levels as recorded in the Trust laboratory system. During the study recruitment period, the University of Oxford will regularly submit batched lists of potentially eligible individuals back to NHS Digital who will provide a ‘List Cleaning’ service and report back the individuals’ current vital status, current address and current GP practice code. The following data items will be returned to NHS Digital as part of the list cleaning process; NHS Number; Surname; Forename; Date of Birth; and Postcode. This information is required to minimise the risk of writing to recently deceased individuals or writing to incorrect addresses. The GP practice code is required so that a letter can be sent to the GP immediately after a participant’s screening appointment in order to inform the GP of the participants planned enrolment into the trial and allow the GP to opt that participant out of randomization if they feel appropriate. The University of Oxford will write to the potential participants identified in the List Cleaning reports inviting them to an ORION-4 Screening Appointment at the ORION-4 clinic within the relevant NHS Trust. Should they choose to attend, at the appointment they will be invited to participate in the trial and give informed consent if they wish. In order to efficiently print and mail invitation letters, batches of personal data (name, address) will be sent securely to Paragon Customer Communications (London) Ltd who will process these data in order to produce, print and mail the invitation letters. Once mailing is complete, personal data held by Paragon Customer Communications (London) Ltd will be destroyed. The data received from NHS Digital will only be accessed by individuals within the Clinical Trial Service Unit who have authorisation to access the data for the purpose(s) described, all of whom are substantive employees of the University of Oxford and have been appropriately trained in data protection and confidentiality. The potential exception to this is that identifying NHS and Hospital Numbers may be shared with the NHS Trusts that have previously treated the potential participants. This would not involve giving those NHS Trusts new information about the participants, since they recorded the data in the first place. It would simply be a practical step to enable the Trusts to identify the individuals in their own patient records in order to undertake a further eligibility check based on local laboratory blood cholesterol results. No other data linkages will be made. The raw data will be securely held at the CTSU within The University of Oxford in a separate restricted area of the database (with access limited to a very small number of individuals) and de-encrypted on a per-participant basis once the patient confirms that they are interested in taking part in the trial. Data is stored encrypted to AES-256 or equivalent in storage and transit with access is limited to a small number of individuals. Access is via the UK invitations IT applications controlled by requiring a unique user name and password. After invitation, individuals who have not responded, may be sent a single further invitation to participate. If they do not respond to this second invitation, they will not be invited again. Data about those participants who declined to participate, or have been considered to have declined to participate through non-response, will be held initially in order to avoid inviting those individuals again. Once recruitment is complete, reports will be generated using these data in order to describe the recruitment procedures for the trial (for example establishing the number of individuals invited to participate by age and sex). Such reports will not contain any identifying information (including small groups which could potentially be identified). Once these reports have been completed, the data provided by NHS Digital for those individuals will be irrevocably deleted. This will be undertaken as soon as possible after the end of the recruitment period in 2022 and before the analysis of the main study results is complete in 2025. The data provided under this Agreement will only be used for the purposes of recruitment and recruitment analysis and will not be used for any subsequent purposes within the clinical trial. The lawful basis for processing data under GDPR has been reviewed against the guidance provided by IGARD and been assessed as acceptable. The details are: Article 6(1)(e) (processing is necessary for the performance of a task in the public interest or in the exercise of official authority vested in the controller) Public Authority - The Data Protection Act 2018 s7(1)(a) defines ‘public bodies’ for the purpose of the GDPR as “a public authority as defined by the Freedom of Information Act 2000”. The FOI Act 2000 Part 1, section 3 (1)(a)(i) specifies that a public authority means any body which is listed in Schedule 1. Schedule 1 of the FOI Act 2000 lists “Maintained schools and further and higher education institutions” as public authorities. Public Task - The University of Oxford has a queen in counsel statute which states: “The principal objects of the University are the advancement of learning by teaching and research and its dissemination by every means”. See: https://www.ox.ac.uk/sites/files/oxford/field/field_document/University%20Statutes%20August%202012%20-%20July%202013.pdf] In addition, the Higher Education and Research Act 2017 Part 3 sets out the establishment of United Kingdom Research and Innovation. The Higher Education Funding Council for England (HEFCE) maintained a register of higher education providers until the end of 2017/18 and this listed [Organisation] (http://webarchive.nationalarchives.gov.uk/20180319125824/http://www.hefce.ac.uk/reg/register). Since April 2018 the Office for Students has replaced HEFCE and launched a new registration process; the Office for Students register lists the University of Oxford, which is available on their website https://www.officeforstudents.org.uk/advice-and-guidance/the-register/the-ofs-register/. The Higher Education and Research Act 2017 Section 93 (1) sets out the functions that include (a) carry out research into science, technology, humanities and new ideas. Necessity - Throughout the application process, the necessity of the processing for the performance of the task has been assessed. This included but was not limited to ensuring appropriate minimisation of the data to ensure that only the minimum amount of data required are processed. During the application process it has been considered whether the information that the processing aims to determine is already available from other sources or whether the task could be performed using publicly available data or data from alternative sources than NHS Digital. Consideration has been given to whether the volume of data being requested is proportionate to the expected benefit and, through examination of the expected benefits consideration has been given to whether the task is itself necessary. The applicants have been involved in this process and participated in teleconference with our data production team to agree which data products and fields were appropriate for use for the purpose of processing. Therefore, we are satisfied that this request is appropriate, necessary and proportionate for the performance of the task described in the Purpose statement and that there is no other reasonable means for the data processor to achieve their purpose that is less intrusive to the data subjects. 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) - 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 ways in which the processing of data will be of benefit to the public – thereby demonstrating that the processing is in the public interest – are described in section ‘5d. ii. Expected Measurable Benefits to Health and/or Social Care Including Target Date’. - In accordance with GDPR Article 89(1) processing is subject to appropriate safeguards. These include: i. The data recipient’s technical and organisational measures to safeguard the data have been assessed and meet NHS Digital’s acceptance criteria (see sections 2 and 5b of this application for further details); ii. The requested data has been assessed as proportionate to the aim pursued (see section 5a of this application for further details); iii. Controls, data retention and processing activities have been assessed to ensure respect to the essence of the right to data protection (see sections 5a, 5b and 8a of this application for further details); iv. Measures to protect the rights and freedoms of data subjects have been assessed including transparency (fair processing) publishing subject’s rights to withdraw consent and/or have their data erased or rectified, etc. (further information on fair processing is provided within this Abstract below and in section 4 of this application).

Expected output

[3 paragraphs unchanged] From experience with previous trials it is anticipated that between 20 and [43 words unchanged] Section 251 support. Obtaining the list of potentially eligible individuals from NHS Digital England leads to the following benefits for the study; First, any delay in [67 words unchanged] invitation would be out of date. Thirdly, obtaining data directly from NHS Digital England allows individual preferences about opt-outs to use of their data be upheld. Obtaining GP practice information for each potentially eligible participant will help to [132 words unchanged] be more efficient and accurate to use up-to-date GP information through NHS Digital’s England’s List Cleaning service. [2 paragraphs unchanged] ************************ Amendment Oct 2024 - Recruitment to ORION-4 is now complete with 16,124 participant recruited globally (including 13,190 in the UK) (see https://www.ndph.ox.ac.uk/news/cholesterol-lowering-drug-trial-completes-recruitment-with-16-124-participants). Due to delays in completing recruitment because of COVID-19, the trial follow-up will continue through 2026 and therefore the main trial results will be available in 2027. The impact of these results (see original application text above) will not be affected by this delay. An initial evaluation of the invitation process was presented at the International Clinical Trial Methodology Conference (ICTMC) in early October 2024. We now plan to complete these analyses and publish a paper evaluating the process which will inform future trials. Outputs will be disseminated through the Health Data Research UK Trials Programme, the NIHR / MRC Trials Methodology Partnership and the UK Clinical Research Collaboration.

Expected measurable benefits

[2 paragraphs unchanged] The data from NHS Digital England is extremely beneficial in recruiting the large numbers of participants needed for [50 words unchanged] details were obtained direct from NHS Hospital Trusts rather than from NHS Digital. England. Many people invited to take part in research choose not to for [64 words unchanged] considerably more difficult to achieve this without the data requested from NHS Digital. England. Beyond the ORION-4 study, the recruitment methods using data from NHS Digital England would inform trial design and produce benefits to future research. To reliably [71 words unchanged] reliable knowledge about which treatments work and which are harmful. Using NHS Digital England data to mail invitation letters to large numbers of potentially eligible people [94 words unchanged] CTSU and shared with other researchers using initiatives such as the CTTi. ************* Amendment Oct 2024 – Recruitment to ORION-4 is completed with follow-up continuing. The expected benefits of the trial are unchanged from the original application. We are requesting an extension for 12 months in order to complete analyses to evaluate the invitation process to inform future trials. This will help researchers to recruit more effectively in future trials.

Benefits reported

By 2020, the trial has established around 100 research sites across the UK and recruitment is progressing well. Because of the requirement of the trial to include people with higher cholesterol values a substantial proportion of people volunteering are not able to take part which has meant that recruitment has been slower than expected. However, because of the large-scale central invitation process using the data requested in this application, additional patients can be invited without substantial extra cost. This DSA is to support recruitment to the ORION-4 trial by providing details of potentially eligible patients to the University of Oxford so they could be invited to join the trial. Recruitment was delayed due to the impact of COVID-19 on the NHS but despite this, ORION-4 exceeded its recuitment target recruiting 13,190 participants in the UK. This means that the study is on track to deliver important, practice changing results, once the follow-up period completes in 2026. The method developed for recruitment into this study in the UK will be shared with other researchers. A preliminary analysis evaluating the invitation process was presented at the International Clinical Trials Methodology Conference in October 2024.

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

Objective for processing

The University of Oxford requires demographic, mortality and HES Hospital Episode Statistics (HES) data to recruit participants into the ORION-4 study. Investigators at The University of Oxford have instigated this work to achieve [21 words unchanged] is given as an injection 2-3 times a year and reduces bad (LDL ) (low-density lipoproteins (LDL)) cholesterol. The ORION-4 study will find out whether inclisiran safely reduces heart [30 words unchanged] secondary objective is developing streamlined trial methods that would benefit future research. The ORION-4 study is co-sponsored by The University of Oxford and The Medicines Company. Company (now acquired by Novartis). The protocol and procedures have been developed by the Chief Investigator at [17 words unchanged] an academic research group within Harvard University - and The Medicines Company (now acquired by Novartis) which comprise are part of the Steering Committee for the trial. The Steering Committee would determine the [31 words unchanged] other international experts from other institutions to advise the trial management team. In respect of the data under this Agreement, the University of Oxford [12 words unchanged] study. Under the direction of the University of Oxford, Paragon Customer Communications (London) Ltd will also process personal data (name, address, sex) address) in order to produce, print and mail the invitation letter. Paragon Customer Communications (London) Ltd has a proven track record of securely processing personal data for [57 words unchanged] data is processed and is responsible for the security of those data. The data will be stored and processed at the University of Oxford. [28 words unchanged] for cholesterol levels. Other than sharing these data items with NHS Trusts, and with Paragon Customer Communications (London) Ltd (see above), data supplied by NHS Digital would not be released to any other [12 words unchanged] have access to record level data under this Agreement. The Medicines Company (now acquired by Novartis) will not access data under this Agreement. [6 paragraphs unchanged] Notwithstanding their role as a co-sponsor, The Medicines Company (now acquired by Novartis) are not considered joint Data Controllers for this application, and will not attempt to influence the design of the study, nor suppress any aspect of publication of the findings. The data requested under this application are used to invite potentially eligible patients to join the ORION-4 trial. Although Novartis (and previously The Medicines Company) are co-sponsors of the trial, the division of responsibilities within the co-sponsorship arrangement means that the University of Oxford is responsible for; • deciding what personal data are collected, • how those data are processed, • engaging relevant data processors, and • ensuring that the data is processed securely and in line with data protection legislation. Novartis are responsible for other parts of the clinical trial which do not involve data under this application. This an investigator initiated trial with a purpose of improving the health of people with vascular disease. If inclisiran turns out to be safe and effective this will result in financial benefit for Novartis, as the manufacturer of the drug, but the purpose of ORION-4 is public health.” ********** This amendment (May 2020) is requested to allow the use of both formal and informal fact of death in the list cleaning process. All of the other data processing activities are unchanged. An updated protocol is provided for completeness but there are no changes which affect the recruitment process or the activities undertaken by the trial participants. ********** This further amendment (May 2021) is to include a second invitation letter to individuals who have not responded to the first invitation. Prior to the coronavirus outbreak, the ORION-4 senior management team had reviewed the response to participant invitation for this study. Although around one in 20 potentially eligible people invited to join the study do express interest in taking part, less than 1.2% of those invited end up being randomised. This is mainly because many people do not meet the requirement of having a point-of-care total cholesterol of at least 4 mmol/l at the Screening visit. As a consequence it is anticipated that sites may exhaust their pool of potentially eligible patients and, indeed, some have already done so. Furthermore, the coronavirus pandemic has caused a substantial delay to recruitment and the likely impact of this on future response to invitations is not known. In previous studies using similar invitation methods, a significant number of potentially eligible patients who did not reply to an initial mailed invitation, did volunteer to take part after receiving a second invitation. This amendment seeks approval for second ORION-4 invitation letter to be sent to potentially eligible patients who have not responded to the initial invitation letter. This process and template letter have been approved by Research Ethics Committee (REC) and Confidential Advisory Group (CAG). In addition, this amendment has updated the processing location and contact details for Paragon Customer Communications (now Paragon Customer Communications (London) Limited) and includes changes to the objective for processing in light of the acquisition of The Medicines Company by Novartis, who are now co-sponsor of the trial. Note that all staff at Paragon Customer Communications (London) Ltd who access the data provided to them by University of Oxford are substantive employees of Paragon Customer Communications (London) Ltd who have been appropriately trained in data protection and confidentiality.

Processing activities

[16 paragraphs unchanged] In order to efficiently print and mail invitation letters, batches of personal data (name, address, sex) address) will be sent securely to Paragon Customer Communications (London) Ltd who will process these data in order to produce, print and mail the invitation letters. Once mailing is complete, personal data held by Paragon Customer Communications (London) Ltd will be destroyed. [2 paragraphs unchanged] After invitation, individuals who have not responded will responded, may be considered to have declined sent a single further invitation to participate. These individuals If they do not respond to this second invitation, they will not be invited again. Data about those participants who declined to participate, or have been considered [93 words unchanged] as soon as possible after the end of the recruitment period in 2020 2022 and before the analysis of the main study results is complete in 2025. [1 paragraph unchanged] This amendment (May 2020) is requested to allow the use of both formal and informal fact of death in the list cleaning process. All of the other data processing activities are unchanged. An updated protocol is provided for completeness but there are no changes which affect the recruitment process or the activities undertaken by the trial participants. The lawful basis for processing data under GDPR has been reviewed against the guidance provided by IGARD and been assessed as acceptable. The details are: Article 6(1)(e) (processing is necessary for the performance of a task in the public interest or in the exercise of official authority vested in the controller) Public Authority - The Data Protection Act 2018 s7(1)(a) defines ‘public bodies’ for the purpose of the GDPR as “a public authority as defined by the Freedom of Information Act 2000”. The FOI Act 2000 Part 1, section 3 (1)(a)(i) specifies that a public authority means any body which is listed in Schedule 1. Schedule 1 of the FOI Act 2000 lists “Maintained schools and further and higher education institutions” as public authorities. Public Task - The University of Oxford has a queen in counsel statute which states: “The principal objects of the University are the advancement of learning by teaching and research and its dissemination by every means”. See: https://www.ox.ac.uk/sites/files/oxford/field/field_document/University%20Statutes%20August%202012%20-%20July%202013.pdf] In addition, the Higher Education and Research Act 2017 Part 3 sets out the establishment of United Kingdom Research and Innovation. The Higher Education Funding Council for England (HEFCE) maintained a register of higher education providers until the end of 2017/18 and this listed [Organisation] (http://webarchive.nationalarchives.gov.uk/20180319125824/http://www.hefce.ac.uk/reg/register). Since April 2018 the Office for Students has replaced HEFCE and launched a new registration process; the Office for Students register lists the University of Oxford, which is available on their website https://www.officeforstudents.org.uk/advice-and-guidance/the-register/the-ofs-register/. The Higher Education and Research Act 2017 Section 93 (1) sets out the functions that include (a) carry out research into science, technology, humanities and new ideas. Necessity - Throughout the application process, the necessity of the processing for the performance of the task has been assessed. This included but was not limited to ensuring appropriate minimisation of the data to ensure that only the minimum amount of data required are processed. During the application process it has been considered whether the information that the processing aims to determine is already available from other sources or whether the task could be performed using publicly available data or data from alternative sources than NHS Digital. Consideration has been given to whether the volume of data being requested is proportionate to the expected benefit and, through examination of the expected benefits consideration has been given to whether the task is itself necessary. The applicants have been involved in this process and participated in teleconference with our data production team to agree which data products and fields were appropriate for use for the purpose of processing. Therefore, we are satisfied that this request is appropriate, necessary and proportionate for the performance of the task described in the Purpose statement and that there is no other reasonable means for the data processor to achieve their purpose that is less intrusive to the data subjects. 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) - 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 ways in which the processing of data will be of benefit to the public – thereby demonstrating that the processing is in the public interest – are described in section ‘5d. ii. Expected Measurable Benefits to Health and/or Social Care Including Target Date’. - In accordance with GDPR Article 89(1) processing is subject to appropriate safeguards. These include: i. The data recipient’s technical and organisational measures to safeguard the data have been assessed and meet NHS Digital’s acceptance criteria (see sections 2 and 5b of this application for further details); ii. The requested data has been assessed as proportionate to the aim pursued (see section 5a of this application for further details); iii. Controls, data retention and processing activities have been assessed to ensure respect to the essence of the right to data protection (see sections 5a, 5b and 8a of this application for further details); iv. Measures to protect the rights and freedoms of data subjects have been assessed including transparency (fair processing) publishing subject’s rights to withdraw consent and/or have their data erased or rectified, etc. (further information on fair processing is provided within this Abstract below and in section 4 of this application).

Unchanged: Expected output, Expected measurable benefits, Benefits reported.

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

Datasets: + Demographics

Processing activities

[22 paragraphs unchanged] This amendment (May 2020) is requested to allow the use of both formal and informal fact of death in the list cleaning process. All of the other data processing activities are unchanged. An updated protocol is provided for completeness but there are no changes which affect the recruitment process or the activities undertaken by the trial participants.

Expected output

[2 paragraphs unchanged] This study will use streamlined recruitment methods to identify and recruit 15,000 [76 words unchanged] be used to identify and recruit most of the 12,000 eligible UK participants by the end of 2019. participants. [2 paragraphs unchanged] The List Cleaning outputs will reduce the risk of attempting to contact recently deceased individuals and potentially causing distress to living relatives. Furthermore Furthermore, the regular list cleaning will help to ensure that addresses are accurate. [38 words unchanged] it is important to minimise this risk by undertaking regular list cleaning. [1 paragraph unchanged]

Expected measurable benefits

The results of ORION-4 will be relevant to the 7 million people [19 words unchanged] reversible risk factor for cardiovascular disease. Evidence from large, randomized trials have lead led to the widespread use of statins in individuals with and at risk [83 words unchanged] 0.15M deaths from cardiovascular disease which occur each year in the UK. It is expected that the results of ORION-4 in 2025 will be [68 words unchanged] but require 4 weekly injections and are expensive to produce. As a result result, they are not widely available for patients in the UK. Since inclisiran [26 words unchanged] safe and effective in reducing the risk of heart attacks and strokes. Furthermore Furthermore, this treatment may overcome problems with medication adherence which are particularly problematic [40 words unchanged] the numbers of heart attacks, strokes and deaths from cardiovascular disease globally. [2 paragraphs unchanged]

Benefits reported

Not stated in the previous version; added here.

By 2020, the trial has established around 100 research sites across the UK and recruitment is progressing well. Because of the requirement of the trial to include people with higher cholesterol values a substantial proportion of people volunteering are not able to take part which has meant that recruitment has been slower than expected. However, because of the large-scale central invitation process using the data requested in this application, additional patients can be invited without substantial extra cost.

Unchanged: Objective for processing.

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

Objective for processing

[3 paragraphs unchanged] In respect of the data under this Agreement, the University of Oxford is the sole data controller. controller and also processes the data for this study. Under the direction of the University of Oxford, Paragon Customer Communications Ltd will also process personal data (name, address, sex) in order to produce, print and mail the invitation letter. Paragon Customer Communications Ltd has a proven track record of securely processing personal data for research (this company mailed 9 million participant communications for the UK Biobank study) and for the NHS. While the Steering Committee signs off the high level plan, the University [28 words unchanged] data is processed and is responsible for the security of those data. [3 paragraphs unchanged] The demographic (including name, address and GP practice details), mortality and HES data are required to assist the University of Oxford in identifying and recruiting eligible participants. Since patients who have had one of the qualifying clinical conditions (heart attack, stroke, peripheral arterial revascularisation procedure or aortic aneurysm repair) at any time are potentially eligible for the study, the HES records requested include data from historic HES records. For convenience, data from 1997 onwards are requested. The ORION-4 team will inform NHS Digital of the NHS Hospital Trusts where an ORION-4 site is to be based so that only patients who have been admitted to that Hospital Trust are included in the data. Potentially eligible participants will be invited on behalf of the Local Investigator [25 words unchanged] they will be invited to consent to participate in the clinical trial. Since the aim of the processing is to make contact with the potentially eligible patients directly, less intrusive methods such as use of pseudonymised or anonymised methods are not possible. Given the large number of invitations which are likely to be required in order to recruit 12,000 participants into the study in the UK (it is anticipated that around 0.5M invitation letters will be sent), it would not be practical for the patients’ usual health care team to seek consent prior to invitation. This objective of undertaking the ORION-4 research study aiming to improve future patients’ health is the justification for processing under GDPR Article 6(1)(e) and Article 9(2)(j). The processing of data outlined in this application occurs without the consent of the data subjects. Any risk to individual data subjects from loss of data is minimized by a number of robust security processes. Inconvenience to data subjects is minimized by sending only a single invitation letter in which it is clear that they do not need to take part in the study. These issues have been considered by both the Confidentiality Advisory Group and the Research Ethics Committee. [1 paragraph unchanged]

Processing activities

[2 paragraphs unchanged] NHS Digital will provide to the University of Oxford a file containing the following identifying data items for potentially eligible participants: [11 paragraphs unchanged] During the study recruitment period, the University of Oxford will regularly submit [20 words unchanged] the individuals’ current vital status, current address and current GP practice code. The following data items will be returned to NHS Digital as part of the list cleaning process; NHS Number; Surname; Forename; Date of Birth; and Postcode. This information is required to minimise the risk of writing to recently [46 words unchanged] GP to opt that participant out of randomization if they feel appropriate. [1 paragraph unchanged] The data received from NHS Digital will only be accessed by individuals within the Clinical Trial Service Unit who have authorisation to access the data for the purpose(s) described, all of whom are substantive employees of the University of Oxford. The potential exception to this is that NHS and Hospital Numbers may be shared with the NHS Trusts that have previously treated the potential participants. This would not involve giving those NHS Trusts new information about the participants, since they recorded the data in the first place. It would simply be a practical step to enable the Trusts to identify the individuals in their own patient records in order to undertake a further eligibility check based on local laboratory blood cholesterol results. In order to efficiently print and mail invitation letters, batches of personal data (name, address, sex) will be sent securely to Paragon Customer Communications Ltd who will process these data in order to produce, print and mail the invitation letters. Once mailing is complete, personal data held by Paragon Customer Communications Ltd will be destroyed. The data received from NHS Digital will only be accessed by individuals within the Clinical Trial Service Unit who have authorisation to access the data for the purpose(s) described, all of whom are substantive employees of the University of Oxford and have been appropriately trained in data protection and confidentiality. The potential exception to this is that identifying NHS and Hospital Numbers may be shared with the NHS Trusts that have previously treated the potential participants. This would not involve giving those NHS Trusts new information about the participants, since they recorded the data in the first place. It would simply be a practical step to enable the Trusts to identify the individuals in their own patient records in order to undertake a further eligibility check based on local laboratory blood cholesterol results. No other data linkages will be made. The raw data will be securely held at the CTSU within The University of Oxford in a separate restricted area of the database (with access limited to a very small number of individuals) and de-encrypted on a per-participant basis once the patient confirms that they are interested in taking part in the trial. Data is stored encrypted to AES-256 or equivalent in storage and transit with access is limited to a small number of individuals. Access is via the UK invitations IT applications controlled by requiring a unique user name and password. [3 paragraphs unchanged]

Benefits reported

Stated in the previous version and removed here.

Yielded Benefits is not a requirement for new applications.

Unchanged: Expected output, Expected measurable benefits.