Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP2)

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

Processing activities

[11 paragraphs unchanged] 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). [8 paragraphs unchanged]

Benefits reported

While mortality was collected at certain points in the study, the use of NHS England data allowed more complete data to be gathered at the follow up stage than would have been available from other sources. All anticipated data processing was carried out and outputs were produced as below. The results of the trial showed that simvastatin is not effective in improving clinical outcomes in patients with ARDS, although the use of simvastatin in critically ill patients does not appear to be associated with serious adverse effects. These results do not provide support for the use of simvastatin in the management of ARDS. However, these data indicate that simvastatin may be used in critically ill patients with a coexisting condition in which a statin is normally indicated (e.g. coronary heart disease). 1. Study Report, which has been uploaded onto the EudraCT System. The production of the study report for EudraCT is a regulatory requirement for a clinical trial of an Investigational Medicinal Product. The wider research community have access to the results of this study and should therefore be aware that simvastatin is not effective in improving clinical outcomes in patients with ARDS. This is expected to ensure that no undue risk and burden is put upon additional patients through a similar study to get the same results. 2. The final study data was published in peer reviewed journal ‘The New England Journal of Medicine’. 3. A Final Report for funder Efficacy and Mechanism Evaluation Programme was produced. The success of the trial depended on the collaboration of doctors, nurses and researchers from across the study sites. Therefore, the results of the trial were reported first to trial collaborators. The trial was reported in accordance with the Consolidated Standards of Reporting Trials (CONSORT) guidelines (www.consortstatement.org). The findings were presented at national and international meetings with open access abstracts on-line and in accordance with the open access policies proposed by the leading research funding bodies. The findings were published in the New England Journal of Medicine. The results were therefore readily accessible to the public, health care professionals and scientists. A layperson’s summary of the principal findings of the results was sent to all patients involved in the study on their request. In addition, a layperson’s summary was sent to local and national patient support and liaison groups (e.g. CritPaL, hospital patient groups). An ongoing update of the trial was provided on the HARP-2 trial website. The outputs do not contain NHS England data and 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. This study has informed guidance in the Scandinavian clinical practice guideline on fluid and drug therapy in adults with ARDS, which recommended that statins are not used in the treatment of ARDS. Furthermore, this work has been included in two systematic reviews of randomised clinical trials in critically ill patients with severe sepsis, which concluded that statin therapy should not be recommended in the management of ARDS or severe sepsis in critically ill patients. The study outputs should generate new information to inform policy-makers and individual care practitioners as to how best to manage patients with ARDS; and generate new research hypotheses to be tested to improve patient care. While mortality was collected at certain points in the study, the use of NHS England data allowed more complete data to be gathered at the follow up stage than would have been available from other sources. The results of the trial showed that simvastatin is not effective in improving clinical outcomes in patients with ARDS, although the use of simvastatin in critically ill patients does not appear to be associated with serious adverse effects. These results do not provide support for the use of simvastatin in the management of ARDS. However, these data indicate that simvastatin may be used in critically ill patients with a coexisting condition in which a statin is normally indicated (e.g. coronary heart disease). The wider research community have access to the results of this study and should therefore be aware that simvastatin is not effective in improving clinical outcomes in patients with ARDS. This is expected to ensure that no undue risk and burden is put upon additional patients through a similar study to get the same results.

Unchanged: Objective for processing, Expected output, Expected measurable benefits.

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

Objective for processing

Belfast Health and Social Care Trust (BHSCT) requires require access to NHS Digital England data for the purpose of the following clinical trial: Hydroxymethylglutaryl-CoA “Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury Lung Injury (ALI) to Reduce Pulmonary dysfunction (HARP2). (HARP2)” clinical trial. Background: 'Simvastatin' is a drug which is used to lower cholesterol. 'Hydroxymethylglutaryl-CoA reductase' is an enzyme in the body which is involved in the production of cholesterol. 'Pulmonary dysfunction' refers to diseases of the lungs. [1 paragraph unchanged] ALI has significant resource implications, prolonging intensive care unit (ICU) and hospital stay, and requiring rehabilitation in the community. The cost per ICU bed-day exceeds £1800 and delivery of critical care to patients with ALI accounts for a significant proportion of ICU capacity. Based on available data, in the UK and Ireland it is estimated that up to 45,000 cases of ALI occur, with an estimated 13,000-22,000 deaths per year in patients with ALI. Only 54% of survivors are able to return to work 12 months after hospital discharge. The high incidence, mortality, long-term consequences and high economic costs mean that ALI is an extremely important problem. The following is a summary of the aims of the HARP2 trial provided by BHSCT: The Belfast Health and Social Care Trust (BHSCT) hosts the Northern Ireland Clinical Trials Unit (NICTU) and the two organisations are the same legal entity. The NICTU provides services for a selection of Sponsors and Sponsor’s delegates. The BHSCT in their role as Sponsor delegated trial activities for this study to the NICTU. 1) To conduct a randomised, double-blind, placebo-controlled phase 2 trial of simvastatin for the treatment of ALI / ARDS. The Chief Investigator (CI) for the HARP2 study is an employee of the BHSCT. The CI came up with the original research question and the NICTU was on board from the beginning of the project and involved in supporting the CI through the grant application stage. 2) To understand the biological mechanisms by which simvastatin treatment might work in patients with ARDS. Aims & Objectives: Patients were consented into the trial with the condition that “The data from this study will be kept for at least fifteen years after its conclusion and may be used in other research studies.” The HARP2 study was a clinical trial which ran from 06/12/2010 to 20/06/2016. The aim of the HARP2 study was to test the hypothesis that treatment with enteral simvastatin 80mg once, daily for a maximum of 28 days will be of therapeutic value in patients with ALI. The study had two distinct objectives: The HARP2 trial is now complete. BHSCT require continued access to NHS England data for archiving in the public interest, with the potential for future re-use of the data in related research studies which would be subject to separate approved Data Sharing Agreements with NHS England. Objective 1 This Agreement only permits processing of the data for the purpose of secure storage and back up. To conduct a randomised, double-blind, placebo-controlled phase 2 trial of simvastatin for the treatment of ALI/ARDS. This Agreement does not permit any onward sharing of the data with the exception that the data may be viewed for the purpose of an audit by a regulator. A sponsoring organisation and/or the Controller itself may also exercise the right to audit. Objective 2 This Agreement permits the necessary processing of the data for the purposes of permanently destroying, deleting or erasing the data once it is no longer required for the purpose for which it was collected. Once destroyed/deleted or erased, BHSCT must confirm destruction to NHS England. To understand the biological mechanisms by which simvastatin treatment might work in patients with ARDS. If any further data processing is required in addition to the above purposes or if the data needs to be moved to a different organisation, BHSCT must submit an amendment request to NHS England before data is accessed. The trial is now complete. BHSCT originally needed to retain NHS Digital data as part of the Medicines for Human Use (Clinical Trials) legislation which mandates retention of study data for 5 years after the HARP2 study has ended for inspection purposes. The following NHS England data will be accessed: BHSCT now wish to retain the data beyond the 5 year minimum requirement under the UK Data Protection Act 2018 - to archive data in the public interest; and because patients consented to their data being retained for 15 years and shared for future research. • Medical Research Information Service (mortality data) – necessary because the primary trial outcome (ventilator free days) is derived from date of death; mortality status at different time points are secondary trial outcomes; and BHSCT did not want to write to study participants who had already died. No additional data will be requested from NHS Digital. The level of the data is pseudonymised. BHSCT have destroyed all identifiable data relating to the HARP-2 trial. This Agreement permits processing of the data for the purpose of secure storage and back up. The data will be minimised as follows: This Agreement does not permit any onward sharing of the data with the exception that the data may be viewed for the purpose of an audit by a regulator. A sponsoring organisation and/or the data controller itself may also exercise the right to audit. • Limited to a study cohort identified by BHSCT as individuals with ALI, recruited into the HARP2 clinical trial between 2010 and 2014 This Agreement permits the necessary processing of the data for the purposes of permanently destroying, deleting or erasing the data once it is no longer required for the purpose for which it was collected. Once destroyed/deleted or erased, BHSCT must confirm destruction to NHS Digital. • Limited to mortality data between 2010 and 2016 If any further data processing is required in addition to the above purposes or if the data needs to be moved to a different location/organisation, BHSCT must submit an amendment request to NHS Digital before data is accessed. BHSCT 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. Cohort: The lawful basis for processing personal data under the UK GDPR is: Trial participants were selected from participating ICUs. Adult general ICUs were selected on the basis of the following criteria: 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. 1. Willingness to participate in the trial The lawful basis for processing special category data under the UK GDPR is: 2. Evidence that they have access to the patient population 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. 3. Evidence of suitable facilities and resources to participate This processing is in the public interest because it aims to produce generalisable and publicly available information to inform future decisions over patients’ treatments or care. 4. Documented willingness to comply with the protocol, standard operating procedures, the principles of good clinical practice and regulatory requirements The funding for the HARP2 trial was provided by the Efficacy and Mechanism Evaluation (EME) – a partnership between the Medical Research Council (MRC) and the National Institute for Health Research (NIHR). The funding was specifically for the trial described. Funding for related research will be sought on an ongoing basis. Patients treated within the participating ICUs were eligible if they fulfilled particular inclusion and exclusion criteria. Key factors from these criteria include: The funder(s) will have no ability to suppress or otherwise limit the publication of findings. • Patients receiving invasive mechanical ventilation HSC Business Services Organisation (BSO) is a processor acting under the instructions of BHSCT. HSC BSO’s role is limited to providing servers for BHSCT. HSC BSO do not access the data. • Patient must have ALI British Telecommunications (BT) house the BSO servers. BT do not process the data. • Age over 16 years • Less than 48 hours from the onset of ALI • Patient must not be pregnant Other criteria included exclusion of potential participants due to patients currently receiving particular treatments or being diagnosed with particular disease (such as liver disease). Potential patients were identified at study sites (Adult intensive care units (ICUs)) and were individually randomised after informed consent had been obtained and eligibility confirmed. The trial intervention was Simvastatin 80mg once daily administered eternally via a feeding tube or orally for up to 28 days. The control group was a placebo once daily administered eternally via a feeding tube or orally for up to 28 days. A total number of 540 patients were recruited to the trial. Of this total cohort, 259 patients were allocated to simvastatin and 281 patients to placebo. Recruitment began on 21 December 2010 and ran until 13 March 2014. Trial Procedures: For the purpose of the cost-effectiveness analysis, all survivors were followed up at 3, 6, and 12 months after randomisation. Health related quality of life was measured using the EQ-5D administered at discharge and at 3, 6 and 12 months. Resource utilisation data was collected via questionnaires administered at 6 and 12 months. When on study patients had the following study events and data collection points: • Examination Points: Daily up to day 28, at discharge, 3, 6 and 12 months • Primary Outcome: Ventilator free days (VFDs) • Secondary Outcomes including: (a) Change in oxygenation index (OI) from baseline to day, 3, 7, 14 and 28 (b) Change in sequential organ failure assessment (SOFA) score from baseline to day 3, 7, 14 and 28 (c) All cause mortality 28 days post randomisation (d) Mortality at (first) discharge from ICU (e) Mortality at (first) discharge from hospital (f) Mortality at 12 months post randomisation (g) Safety (h) Biological mechanisms (i) Health-related quality of life (j) Cost effectiveness. BHSCT did not want to send follow-up questionnaires out to patients until their mortality status was established. BHSCT requested mortality status information from NHS Digital’s Medical Research Information Service (MRIS) to ensure that questionnaires were not sent out to deceased patients. BHSCT previously received Death Registration and demographic data including the following fields: • Status Alive or Dead • Date of Death • NHS Number • Date of Birth BHSCT did not receive any NHS numbers/ Dates of Birth from NHS Digital that were not already held by the Trust. For time points where it was not possible to collect date of death by other means, the date of death provided by NHS Digital allowed for the key study endpoints (which were made up of data derived from the date of death) to be produced and the final report to be generated. BHSCT are the Data Controller for this Data Sharing Agreement who managed the trial and in turn, the processing of NHS Digital data previously conducted. BHSCT also process NHS Digital data. The legal bases for the processing of the data and processing of special category personal data are: 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 the controller, and 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. NICTU have identified the above legal bases for the processing of this data as the study aimed to address some of the key issues presented to healthcare providers & patients suffering from ALI. The outputs of this study generated new information to inform patient care and new research hypotheses to be tested to improve patient care. The high incidence, mortality, long-term consequences and high economic costs mean that ALI is an extremely important problem presented to healthcare providers and the public. Benefits from this study’s processes aimed to identify viable solutions for addressing these problems. HSC Business Services Organisation (BSO) is an additional data processor of NHS Digital, as described further in ‘Processing Activities’. This Organisation provides IT infrastructure for BHSCT and are therefore listed as data processors. They supply support to the system, but do not access data. Therefore, any access to the data held under this agreement would be considered a breach of the agreement. This includes granting of access to the database[s] containing the data. BT are subcontracted to house the BSO servers and they are a storage location / Organisation which is classed as “Bricks and Mortar” storage that houses the BSO IT infrastructure and cannot access the data. BT do not access data held under this agreement as they only supply the building. Therefore, any access to the data held under this agreement would be considered a breach of the agreement. This includes granting of access to the database[s] containing the data. The study was funded by Efficacy and Mechanism Evaluation (EME). EME supports research in the mechanisms of diseases and treatments. EME is a partnership between the Medical Research Council (MRC) and the National Institute for Health Research (NIHR). These organisations are not data controllers as they do not have any control of the processing of the data. The data is processed in line with the processes dictated by the sponsor and not the funder. As per Health Research Authority (HRA), it is the sponsor who determines what data is collected for the research study through the protocol, case report form and/or structured data fields in a database. The sponsor therefore acts as the controller in relation to the research data.

Processing activities

This study is now completed and closed. This Agreement permits processing only for the purposes given in 'Objectives 'Objective for Processing'. If any further data processing is required, BHSCT must submit an amendment request to NHS Digital England before data is accessed. [3 paragraphs unchanged] (3) Clinical trial data needs to be retained and accessible for 15 years after trial completion this completion. This requirement would be subject to further data extension requests – - no data will be retained without an Agreement being in place. An approved Data Sharing Agreement (DARS-NIC-155413-MSPHM / MR1294) was created between the Northern Ireland Clinical Trials Unit (NICTU - part of the Belfast Health and Social Care Trust) and NHS Digital. Under this Data Sharing Agreement, data was uploaded to NHS Digital for each patient as below: BHSCT transferred data to NHS England. The data consisted of identifying details (specifically NHS Number, Date of Birth, Postcode, and a unique person ID) for the cohort to be linked with NHS England data. • NHS Number NHS England provided the relevant records from the Medical Research Information Service (MRIS) dataset (precursor to Civil Registrations (Deaths) dataset) to BHSCT. The data contained directly identifying data items including NHS Number and Date of Birth. • Date of Birth BHSCT have destroyed all patient identifiable information following closure of the HARP-2 trial. The only NHS England data retained is date of death. 'Fact of death' and 'ventilator free days' have been generated as further data fields based fully/ partially off the supplied date of death. • Post Code The data will be stored on servers at BHSCT. • NICTU ID Number BHSCT uses offsite back-up services provided by HSC BSO. Data was then downloaded from NHS Digital as below: The data will be accessed onsite at the premises of BHSCT or by authorised personnel via remote access. The data will remain on the servers BHSCT and HSC BSO at all times. • Status Alive or Dead The data will not be transferred to any other location. • Date of Death Personnel are not technically capable of downloading or copying data to local devices. • NHS Number The data will not leave Northern Ireland at any time. • Date of Birth Access is restricted to employees of BHSCT who have authorisation from. The Chief Investigator, Sponsor and Quality Assurance Team of the BHSCT’s Clinical Trials Unit have authorisation to access this data. • NICTU ID Number All personnel accessing the data have been appropriately trained in data protection and confidentiality. BHSCT did not receive any NHS numbers/ Dates of Birth from NHS Digital that were not already held by the Trust. The data is linked at person record level with other trial data obtained via Case Report Forms and study Questionnaires. No onward sharing of NHS Digital data is permitted except in the form of aggregated data with small number suppression applied. Identifying details were linked to mortality data to ensure that BHSCT only conducted follow-up questionnaires with known survivors. Identifying details were stored in a separate database to the main linked dataset which was used for analysis. There is no longer a requirement, and there will be no attempt, to re-identify individuals when using the data. The data processing was carried out in accordance with the aims of the trial described in ‘Objectives for Processing’ and all the outputs were produced (see ‘Expected Outputs’ and ‘Yielded Benefits’). This all took place prior to the change of the Data Protection Act and introduction of the General Data Protection Regulations. Analysts from BHSCT processed the data for the purposes of the HARP2 clinical trial described in ‘Objective for Processing’. The trial received ethical approval from the Office for Research Ethics Committees Northern Ireland (ORECNI) on 08/09/2010. Data processing is only carried out by substantive employees of the data processor(s) and or data controller(s) who have been appropriately trained in data protection and confidentiality. The ethical approval allowed the NICTU to hold patient names and addresses to allow them to be contacted before questionnaires were sent out. This was to prevent the NICTU sending out questionnaires to patients who had passed away. The key to identify the patients from their NICTU ID number was held electronically at the NICTU. This key was stored electronically (by the HARP-2 NICTU study team) within the NICTU Trial Master File, which is hosted on the BHSCT ICT servers. The access to this data is restricted to the HARP-2 study team only (for use on the study). No one else at the NICTU has access to this key and so the data was unidentifiable to everyone outside the study team. The data from NHS Digital was received via secure file transfer from the Medical Research Information Service (MRIS) within NHS Digital. The data was stored electronically (by the HARP-2 NICTU study team) within the NICTU Trial Master File (TMF), which is hosted on the BHSCT ICT servers. The access to this data is restricted to the HARP-2 study team (for use on the study) and the Quality Assurance Manager (who has access to the Trial Master File to allow internal audits). No hard copy of this data exists. The NICTU TMF has all the documentation required under Good Clinical Practice (GCP) to be maintained for a clinical trials (e.g. contracts, communication, meeting minutes, regulatory approvals, database validations and approvals). This is on paper and in electronic format for most of the documentation but data received from the MRIS from NHS digital was only held in electronic form. A version of this data with all identifiers (except the NICTU ID Number) removed was also placed on the MACRO database, which is hosted on the HSC Business Services Organisation (BSO) servers. The only data moved to this environment persistent from what was disseminated by NHS Digital is data derived from Date of Death field covered under this agreement. Date of death was converted into 28 day mortality status (alive/dead) which was used as part of the derivation for Ventilator Free days (VFDs) until day 28 which was the primary outcome on the HARP-2 trial. Data is being stored by both BHSCT and BSO but no longer being processed. This data was entered onto the MACRO database by the HARP-2 study team. The MACRO system has password-protected access. BSO hosts the MACRO clinical study databases on their servers. BSO supply IT infrastructure for BHSCT and are therefore listed as data processors. They supply support to the system, but do not access data. Therefore, any access to the data held under this agreement would be considered a breach of the agreement. This includes granting of access to the database[s] containing the data. BT are subcontracted to house the BSO servers and they are a storage location / Organisation which is classed as “Bricks and Mortar” storage that houses the BSO IT infrastructure and cannot access the data. BT do not access data held under this agreement as they only supply the building. Therefore, any access to the data held under this agreement would be considered a breach of the agreement. This includes granting of access to the database[s] containing the data. BSO was established on 1 April 2009 to provide a wide range of business and specialist professional services to the wider Health and Social Care (HSC) environment. BSO is an integral part of the HSC regional infrastructure in Northern Ireland. Data in the MACRO system was moved from this system into the statistical software which is hosted on the BHSCT ICT servers. The software is held on files restricted to the statistical department. The data was analysed as per the Statistical Analysis Plan (SAP) and put into final reports in the form of aggregated data with small numbers suppressed.

Expected output

[1 paragraph unchanged] 1. Study Report, which has been uploaded onto the EudraCT System. The [8 words unchanged] a regulatory requirement for a clinical trial of an Investigational Medicinal Product. The funder expected the study to be run in line with regulatory requirements. The funder as with all public sector funders has an expectation that the research will be disseminated via publication and appropriate data sharing of anonymised data. [3 paragraphs unchanged] The findings were presented at national and international meetings with open access [16 words unchanged] bodies. The findings were published in the New England Journal of Medicine. This secured a searchable compendium of these publications and the The results were therefore readily accessible to the public, health care professionals and scientists. Due to limited resources, it was not possible to provide each surviving patient with a personal copy of the results of the trial. However, a A layperson’s summary of the principal findings of the results was sent to [18 words unchanged] and national patient support and liaison groups (e.g. CritPaL, hospital patient groups). A report of the study findings was sent to the INVOLVE registry. [1 paragraph unchanged] The outputs do not contain NHS England data and 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. This study has informed guidance in the Scandinavian clinical practice guideline on fluid and drug therapy in adults with ARDS, which recommended that statins are not used in the treatment of ARDS. [1] Furthermore, this work has been included in two systematic reviews of randomised clinical trials in critically ill patients with severe sepsis, which concluded that statin therapy should not be recommended in the management of ARDS or severe sepsis in critically ill patients.[2],[3]. 1. Claesson J, Freundlich M, Gunnarsson I, Laake JH, Møller MH, Vandvik PO, et al. Scandinavian clinical practice guideline on fluid and drug therapy in adults with acute respiratory distress syndrome. Acta Anaesthesiol Scand 2016;60:697–709. https://doi.org/10.1111/aas.12713 2. Thomas G, Hraiech S, Loundou A, Truwit J, Kruger P, Mcauley DF, et al. Statin therapy in critically-ill patients with severe sepsis: a review and meta-analysis of randomized clinical trials. Minerva Anestesiol 2015;81:921–30. 3. Nagendran M, McAuley DF, Kruger P, Papazian L, Truwit J, Thompson BT, et al. Statin therapy for acute respiratory distress syndrome: an individual patient data meta-analysis of randomised clinical trials. Intensive Care Med 2017;43:663–71. https://doi.org/10.1007/s00134-016-4649-0 The study outputs should generate new information to inform policy-makers and individual care practitioners as to how best to manage patients with ARDS; and generate new research hypotheses to be tested to improve patient care.

Expected measurable benefits

The expected benefit of the study was to show if simvastatin is effective in improving clinical outcomes in patients with ARDS. If this was not proven, there was still expected to be a benefit to publishing the results of the study, in that it should prevent similar research being carried out unnecessarily. The wider research community have access to the results of this study and should therefore be aware that simvastatin is not effective in improving clinical outcomes in patients with ARDS. This is expected to ensure that no undue risk and burden is put upon additional patients through a similar study to get the same results. ALI has significant resource implications, prolonging intensive care unit (ICU) and hospital stay, and requiring rehabilitation in the community. The cost per ICU bed-day exceeds £1800 and delivery of critical care to patients with ALI accounts for a significant proportion of ICU capacity. Based on available data, in the UK and Ireland it is estimated that up to 45,000 cases of ALI occur, with an estimated 13,000-22,000 deaths per year in patients with ALI. Only 54% of survivors are able to return to work 12 months after hospital discharge. The high incidence, mortality, long-term consequences and high economic costs mean that ALI is an extremely important problem. Benefits from this study’s processes aimed to identify viable solutions for addressing these problems. These outputs will generate new information to inform patient care and generate new research hypotheses to be tested to improve patient care. The benefits can be measured by the data generating future clinical trials, which inform patient care including informing in the guidelines for the care of patients with ARDS. This will be captured in Researchfish (a platform used to track research and evidence impact - https://researchfish.com/). The main expected benefit of the study was to show if simvastatin is effective in improving clinical outcomes in patients with ARDS. If this was not proven, there was still expected to be a benefit to publishing the results of the study, in that it should prevent similar research being carried out unnecessarily.

Benefits reported

While mortality was collected at certain points in the study, the use of NHS Digital England data allowed more complete data to be gathered at the follow up stage than would have been available from other sources. The results of the trial showed that simvastatin is not effective in [58 words unchanged] condition in which a statin is normally indicated (e.g. coronary heart disease). This study has informed guidance in the Scandinavian clinical practice guideline on fluid and drug therapy in adults with ARDS, which recommended that statins are not used in the treatment of ARDS. [1] Furthermore, this work has been included in two systematic reviews of randomised clinical trials in critically ill patients with severe sepsis, which concluded that statin therapy should not be recommended in the management of ARDS or severe sepsis in critically ill patients.[2],[3]. 1. Claesson J, Freundlich M, Gunnarsson I, Laake JH, Møller MH, Vandvik PO, et al. Scandinavian clinical practice guideline on fluid and drug therapy in adults with acute respiratory distress syndrome. Acta Anaesthesiol Scand 2016;60:697–709. https://doi.org/10.1111/aas.12713 The wider research community have access to the results of this study and should therefore be aware that simvastatin is not effective in improving clinical outcomes in patients with ARDS. This is expected to ensure that no undue risk and burden is put upon additional patients through a similar study to get the same results. 2. Thomas G, Hraiech S, Loundou A, Truwit J, Kruger P, Mcauley DF, et al. Statin therapy in critically-ill patients with severe sepsis: a review and meta-analysis of randomized clinical trials. Minerva Anestesiol 2015;81:921–30. 3. Nagendran M, McAuley DF, Kruger P, Papazian L, Truwit J, Thompson BT, et al. Statin therapy for acute respiratory distress syndrome: an individual patient data meta-analysis of randomised clinical trials. Intensive Care Med 2017;43:663–71. https://doi.org/10.1007/s00134-016-4649-0

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

Objective for processing

Belfast Health and Social Care Trust (BHSCT) requires access to NHS Digital data for the purpose of the following clinical trial: Hydroxymethylglutaryl-CoA reductase inhibition with simvastatin in Acute lung injury to Reduce Pulmonary dysfunction (HARP2). [4 paragraphs unchanged] The HARP2 study was a clinical trial which ran from 06/12/2010 to 20/06/2016. The Chief Investigator (CI) for the HARP2 study is an employee of [22 words unchanged] project and involved in supporting the CI through the grant application stage. [1 paragraph unchanged] The HARP2 study was a clinical trial which ran from 06/12/2010 to 20/06/2016. The aim of the HARP2 study was to test the hypothesis that [16 words unchanged] therapeutic value in patients with ALI. The study had two distinct objectives: [4 paragraphs unchanged] The trial is now complete. BHSCT originally needed to retain NHS Digital data as part of the Medicines for Human Use (Clinical Trials) legislation which mandates retention of study data for 5 years after the HARP2 study has ended for inspection purposes. BHSCT now wish to retain the data beyond the 5 year minimum requirement under the UK Data Protection Act 2018 - to archive data in the public interest; and because patients consented to their data being retained for 15 years and shared for future research. No additional data will be requested from NHS Digital. This Agreement permits processing of the data for the purpose of secure storage and back up. This Agreement does not permit any onward sharing of the data with the exception that the data may be viewed for the purpose of an audit by a regulator. A sponsoring organisation and/or the data controller itself may also exercise the right to audit. This Agreement permits the necessary processing of the data for the purposes of permanently destroying, deleting or erasing the data once it is no longer required for the purpose for which it was collected. Once destroyed/deleted or erased, BHSCT must confirm destruction to NHS Digital. If any further data processing is required in addition to the above purposes or if the data needs to be moved to a different location/organisation, BHSCT must submit an amendment request to NHS Digital before data is accessed. [8 paragraphs unchanged] • Patient must have ALI• Age over 16 years ALI • Age over 16 years [27 paragraphs unchanged] The data was disseminated under a previous agreement DARS-NIC-155413 (MR1294) and is currently being held, but not processed. The data previously disseminated included sensitive, patient identifiable data. The previous agreement covered the time period of 05/02/2013 to 04/02/2018. This agreement is to cover the retention of this data and no new data will be released under this agreement. The NICTU need to keep access to the data with the possibility of new processing. There was a legal requirement to retain the data for archiving and possible inspection by the Medicines and Healthcare products Regulatory Agency (MHRA) until 5 years after the trial end date (19/06/2021). The study protocol which participants consented to stated that the trial data would be kept for the regulatory required time (in this case 5 years after the end of the trial) and up to 15 years after the end of the trial in total (this would be 19/06/2031). In addition, the patient information sheet provided with the consent form clearly stated that the trial data would be kept for 15 years after the end of the trial and could be used in other research. The original application approved by NHS Digital stated that the data would be kept for 15 years after the end of the trial and used in other research. The sponsor (BHSCT) wants to retain the data for this 15 year period and to use it for future data sharing to further research. Any future sharing would be in the form of fully anonymised data with small number suppression applied unless otherwise agreed with NHS Digital in advance. [7 paragraphs unchanged]

Processing activities

An approved data sharing agreement (DARS-NIC-155413 / MR1294) was created between the Northern Ireland Clinical Trials Unit (NICTU - part of the Belfast Health and Social Care Trust) and NHS Digital. Under this data sharing agreement, data was uploaded to NHS Digital for each patient as below: This study is now completed and closed. This Agreement permits processing only for the purposes given in 'Objectives for Processing'. If any further data processing is required, BHSCT must submit an amendment request to NHS Digital before data is accessed. Data archiving is necessary for the following reasons; (1) The raw datasets (and any associated datasets and syntax files) may need to be accessed for the purpose of audit of trial-related activities and documents. (2) Further analysis is expected on this data in future. (3) Clinical trial data needs to be retained and accessible for 15 years after trial completion this requirement would be subject to further data extension requests – no data will be retained without an Agreement being in place. An approved Data Sharing Agreement (DARS-NIC-155413-MSPHM / MR1294) was created between the Northern Ireland Clinical Trials Unit (NICTU - part of the Belfast Health and Social Care Trust) and NHS Digital. Under this Data Sharing Agreement, data was uploaded to NHS Digital for each patient as below: [12 paragraphs unchanged] The data processing was carried out in accordance with the aims of [28 words unchanged] the Data Protection Act and introduction of the General Data Protection Regulations. A new data sharing agreement is required to enable retention of the data released under NHS Digital’s historic data sharing framework as DARS-NIC-155413 / MR1294. [7 paragraphs unchanged]

Expected output

Data was released to BHSCT under Data Sharing Agreement DARS-NIC-155413 / MR1294. All anticipated data processing was carried out and outputs were produced as below. [3 paragraphs unchanged] The success of the trial depended on the collaboration of doctors, nurses and researchers from across the study sites. Therefore, the results of the trial werereported were reported first to trial collaborators. The trial was reported in accordance with the Consolidated Standards of Reporting Trials (CONSORT) guidelines (www.consort-statement.org). [3 paragraphs unchanged]

Expected measurable benefits

[1 paragraph unchanged] These outputs will generate new information to inform patient care and generate [31 words unchanged] for the care of patients with ARDS. This will be captured in Researchfish. Researchfish (a platform used to track research and evidence impact - https://researchfish.com/).

Unchanged: Benefits reported.