RECOVERY - Pneumonia

The Nuffield Department of Population Health (NDPH) at the University of Oxford requires access to NHS England Data for the purpose of the following clinical trial:

RECOVERY Pneumonia

The following is a summary of the aims of the clinical trial:

The RECOVERY trial began in March 2020 and was set-up initially to identify treatments that may be of benefit to participants with COVID-19. This research (which included data linkage from NHS England and other Data Providers) identified 5 treatments that were of benefit to participants (including dexamethasone), 1 that caused harm, and 10 that had no effect). The University of Oxford has a separate Data Sharing Agreement for this work (DARS-NIC-365354).

As of November 2021 (for influenza) and September 2023 (for community acquired pneumonia (CAP)) the RECOVERY trial protocol has been adapted to include participants hospitalised with other types of pneumonia. The first non-COVID-19 participant was randomised on 7th March 2023. This Agreement will not cover the COVID-19 patients recruited in the RECOVERY trial, only non-COVID-19 pneumonia patients recruited.

Eligible patients are randomly allocated between one or more treatment arms, each to be given in addition to the usual standard of care in the participating hospital. The study is adaptive, and treatments are added and removed as results and suitable treatments become available, or as new infectious respiratory threats emerge.

The main trial outcomes are death, discharge, need for ventilation and need for renal replacement therapy. For the main analyses, follow-up will be censored at 28 days after randomisation. Additional information on longer term outcomes are collected through review of medical records or linkage to medical databases where available (such as those managed by NHS England and equivalent local, regional or national organisations).

The following NHS England Data will be accessed:

• Civil Registration Mortality – necessary to identify information about death (which is the primary outcome).

• Demographics – necessary to identify when to censor participants during follow-up. This dataset also contributes to identifying deaths.

• Hospital Episode Statistics

o Admitted Patient Care – necessary to identify trial non-fatal outcomes, including diagnoses (ICD 10 codes), procedures (OPCS4 codes), discharge date and type.

o Critical Care – necessary to identify use of organ support following randomisation, including use of invasive mechanical ventilation (a secondary outcome for this study).

• Emergency Care Data Set (ECDS) – necessary to identify safety outcomes occurring in the study participants after discharge from hospital.

• Medicines dispensed in Primary Care - necessary to assess the effects of the treatments on outcomes after discharge from hospital. For example, effects on the development of long term lung problems, diabetes, liver disease, or on infections. Also used to identify relevant subgroups, and supplement information derived from the HES data regarding prior hospitalisations.

The level of the Data will be:

• Identifiable – necessary for the purpose of data linkage and quality assurance of that linkage. The Data includes a range of detailed information that is necessary for analysis of the safety and effectiveness of the treatment.

The Data will be minimised as follows:

• Limited to a study consented cohort identified by the NDPH, University of Oxford. RECOVERY participants consented to take part in the study, and are identified by their care team after being admitted to hospital. Participants include individuals who have been hospitalised with pneumonia, as diagnosed by a clinician, with one of the following diagnoses:

a) Confirmed SARS-CoV-2 infection (including patients with influenza coinfection)

b) Confirmed influenza A or B infection (including patients with SARS-CoV-2 coinfection)

c) Community-acquired pneumonia with planned antibiotic treatment (excluding patients with suspected or confirmed SARS-CoV-2, influenza, active pulmonary tuberculosis or Pneumocystis jirovecii pneumonia)

No medical history that might, in the opinion of the attending clinician, put the patient at significant risk if he/she were to participate in the trial

Patients who have been previously recruited into RECOVERY are eligible to be recruited again as long as their previous randomisation was >6 months ago. Patients will not be recruited into the same randomised comparison (e.g. sotrovimab vs. usual care) on more than one occasion, regardless of how far apart they occur. The cohort will only include RECOVERY participants who have been flagged as having flu and/or CAP.

• For HES APC and Medicines Dispensed in Primary Care the Data will be limited to records between 2018/19 to Latest Available, with annual updates thereafter until the expiry of this Data Sharing Agreement.

• For HES CC and ECDS the Data will be limited to records between 2022/23 to Latest Available, with annual updates thereafter until the expiry of this Data Sharing Agreement.

The University of Oxford is the controller as the organisation responsible for ensuring that the Data will only be processed for the purpose described above.

The lawful basis for processing personal data under the UK GDPR is:

Article 6(1)(e) - processing is necessary for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller.

The lawful basis for processing special category data under the UK GDPR is:

Article 9(2)(j) - processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject.

The funding is provided by Flu Lab, a philanthropic organisation that funds research into influenza and related diseases. The funding is specifically for the trial described. Funding is in place until 30th June 2026.

The funder will have no ability to suppress or otherwise limit the publication of findings. Nor will they have access to any data, including NHS England data.

The interim trial results are monitored by an independent Data Monitoring Committee (DMC), in accordance with the DMC charter (available from https://www.recoverytrial.net/uk/for-site-staff/site-set-up-1/data-monitoring-committee-correspondence). The DMC assess unblinded data on the efficacy and safety of the study treatments, and whether the randomised comparisons in the study have provided evidence that is strong enough to affect national and global treatment strategies. In such a circumstance, the DMC will inform the Trial Steering Committee who will make the results available to the public and amend the trial arms accordingly.

To be able to evaluate the safety and efficacy of the study treatments the Data Monitoring Committee need to have complete, up-to-date information on the major outcomes in the trial on which to base their decisions. If they find compelling evidence of efficacy or identify safety concerns then that arm may be stopped and – if effective – added to standard care across the NHS.

The RECOVERY Trial Steering Committee has an advisory and oversight capacity for making major organisational and policy decisions and providing scientific advice. It includes 19 members from a range of academic institutions and with a range of clinical and statistical expertise. Its purpose is to determine the strategy of the trial and oversee its delivery.

While the study is in progress, access to results of study outcomes by treatment allocation will not be available to members of the Trial Steering Committee (unless the DMC advises otherwise).

Data will be accessed only by individuals who are substantive employees of the University of Oxford.

Neither the sponsor nor the trial investigators have a financial interest in the treatments being tested. However, RECOVERY may collaborate with treatment manufacturers if this aligns with the trial aims, as was done successfully to make effective treatments available for patients with COVID-19. At present one influenza treatment being tested in RECOVERY (baloxavir marboxil) is being donated by Roche. Commercial collaboration has so far consisted only of manufacturer donations of the treatments being tested.

The onward sharing of data with manufacturers may be used to develop those treatments. Though there are clear benefits to patients in the use of these treatments within the trial, it is recognised that they are also being developed as commercial products. Thus, results of this study may contribute towards commercial work that results in tangible or intangible benefit to commercial companies.

RECOVERY has utilised Public and Patient Involvement and Engagement throughout the trial, initially using the Nuffield Department of Public Health public advisory panel and subsequently established a ‘bespoke’ public advisory group comprised of patient volunteers who had been participants in RECOVERY. The PPIE panels have been engaged on numerous aspects of the trial including the design and content of patient information sheets, consent forms and newsletters; a proposed adaptation of the RECOVERY platform to trial treatment for flu/pneumonia and public facing outputs from the trial.

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

NHS England will provide the relevant records from the HES, ECDS, deaths, demographics and NHSBSA datasets to the University of Oxford. The Data will contain directly identifying data items including NHS Number and Date of Birth which are required to verify the cohort linkage and to link the Data at record level with data already held by the recipient.

The Data will be stored on servers at the Nuffield Department of Population Health, University of Oxford.

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

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

For remote access:

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

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

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

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

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

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

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

Remote processing will be from secure locations within England/Wales. The data will not leave England/Wales at any time.

Access to the Data is restricted to individuals within the Nuffield Department of Population Health of the University of Oxford who have roles in the trial that require them to access the Data. All such individuals are substantive employees of the University of Oxford.

The Study Team will not provide or otherwise make available the NHS England registry data to any third party or allow use of it or them by or on behalf of any third party, in whole or in part, whether by way of sale, resale, loan, transfer, hire or any other form of exploitation except and exclusively in the following circumstances:

1. In circumstances when an inspector from a regulatory agency may see an individual record with a medical event or death recorded, which may have been supplied by NHS England.

2. When the trial is required to provide de-identified data to regulatory agencies as part of the annual regulatory reporting procedures. These reports contain counts of serious adverse events including hospitalisations and deaths among the trial participants. Small numbers cannot be suppressed in these regulatory reports.

3. Where data is onwardly shared with manufacturers and regulators worldwide. In this case the level of data is manipulated to the extent that when they are received by these parties the data is rendered anonymised in context.

The following information describes the processes that will be used to onwardly share data (ADaM and SDTM) with manufacturers and regulators:

The University of Oxford has designed two types of data outputs which the RECOVERY Pneumonia trial needs to onwardly share:

• Analysis Data Model (ADaM) output

• Study Data Tabulation Model (SDTM) output

These trial analysis datasets, are developed using data provided by NHS England under this DSA along with data from other sources, and are subject to a range of processing in line with standards published by the Clinical Data Interchange Standards Consortium (or CDISC).

The ADaM and SDTM outputs for the RECOVERY trial have undergone technical assessment and IG assessment by NHS England and NHS England has determined that, subject to being shared under strict conditions (specified below), the datasets are sufficiently low risk and can be onward shared by the University of Oxford with the manufacturer or regulator where necessary.

SDTM output:

Based on a desk review, responses to specific questions from the University of Oxford and a general self-certification from the University of Oxford, NHS England has concluded that none of the fields examined in the SDTM output can be used on their own or with other information in the onwardly transferred file or in the public domain to fully reconstitute fields in the data provided to the University of Oxford. A highly motivated and technically literate intruder could attempt to do this for a subset of the information in a specific field but this would not be the information in the field in its entirety and accuracy in doing this could not be proven or guaranteed.

ADaM output:

Based on a desk review and further information from the RECOVERY team at the University of Oxford in response to specific questions, NHS England has concluded that none of the fields examined in the ADaM output can be used on their own or with other information in the onwardly transferred file or in the public domain to fully reconstitute fields in the data provided to the University of Oxford under this Agreement.

Based on the above assessments, the SDTM and ADaM datasets can be onwardly shared under the following conditions:

1. The dataset may be shared with the manufacturer of the treatment(s) evaluated in the RECOVERY trial for the purpose of the manufacturer using the data in ongoing research in the development programme for the treatment (for example, evaluating additional beneficial or harmful effects of the treatment or evaluating the effects of the treatment in particular patient populations). Any such uses will comply with the following controls.

2. The dataset may be shared by either the University of Oxford or the manufacturer with a competent authority (regulator) in circumstances where the RECOVERY trial has a legal obligation to disclose data with the regulator to allow trial results to be evaluated to demonstrate the safety and effectiveness of the treatment(s) tested. Regulators include the Medicines & Healthcare products Regulatory Agency (MHRA) in the UK, the Food and Drug Administration (FDA) in the United States, and any competent authority in the European Medicines Agency (EMA).

3. The dataset shared must conform to the SDTM and ADaM outputs agreed with NHS England and may not contain additional variables.

4. The dataset must not be shared alongside any source data provided under this Agreement.

5. The dataset may only be shared under the conditions that the recipient(s):

i. must not combine it with other datasets which could potentially increase the risk of reidentification for individuals in the dataset;

ii. must not attempt to re-identify individuals in the dataset;

iii. must not onwardly share the dataset other than permitted sharing between the manufacturer and the regulatory authority as required;

iv. must not use the dataset for any purpose other than those defined above, and

v. must not publish the data sourced under this Agreement.

6. University of Oxford has contractual controls in place with manufacturers, which will prevent re-identification of trial participants and limit the purposes for use of the data.

The datasets to be onwardly shared contain no dates nor the order of randomisation.

The SDTM and ADaM datasets has its own set of unique identifiers. It is reversible in the event of a query from a regulatory authority but only by the team in Oxford.

NHS England source data files are not disclosed.

NHS England require the right to be informed of data shared for the above purpose.

NHS England waive the right to audit the regulator or manufacturer of treatment(s) evaluated in the RECOVERY trial.

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

The Study Team need to link to all study participants at person record level with other Electronic Health Registries (which may include):

• NHS Central Register (NHSCR) - Scotland

• Public Health Scotland (PHS) - Scotland

• Secure Anonymised Information Linkage (SAIL) – Wales

• UK Health Security Agency

• UK Obstetric Surveillance System (UKOSS)

All analyses will use a pseudonymised dataset.

Researchers from the NDPH at the University of Oxford will analyse the data for the purposes described above.

The expected outputs of the processing will be:

• Results communicated directly to trial participants by mail and e-mail.

• Results shared with the public via the trial website. (https://www.recoverytrial.net/).

• Submissions to peer reviewed journals such as the New England Journal of Medicine and the Lancet.

• Presentations at appropriate conferences such as the Congress of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and the International Clinical Trials Methodology (ICTMC).

• Posters displayed at departmental, national and international conferences (as above)

• Summaries of key findings will be placed on the study website and disseminated through Oxford University Communications channels.

• Press/media engagement and other public promotion of the research (e.g. via the Nuffield Department of Population Health website (https://www.ndph.ox.ac.uk/), or social media.

• Open lectures and talks

• Advice to government (including NHS England).

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

The first publication for RECOVERY Pneumonia is expected in 2027.

The findings of this clinical trial are expected to contribute to evidence-based decision-making for policy-makers, local decision-makers such as doctors, and patients to inform best practice to improve the care, treatment and experience of patients hospitalised with pneumonia, which is a very common condition and is associated with poor outcomes including death.

The use of the Data could:

• lead to the identification or improvement of treatments to improve health outcomes.

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

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

Specific benefits of RECOVERY Pneumonia will include:

• Providing reliable information on potential treatments for patients hospitalised with pneumonia and potentially changing the standard of care that the NHS offers which could improve outcomes for many thousands of patients in the UK and around the world.

• Improving the health and wellbeing of the whole population by avoiding deaths from pneumonia with benefits both to the individuals suffering from this illness who survive, but also to their family members and wider community.

• Sharing information and expertise to help identify and prepare for future public health challenges.

• Generating important methodological insights, tools and resources to benefit future research especially using NHS England data linkage.

• Allow assessment of the effects of the treatment in people with

(i) certain prior medical conditions, and

(ii) receiving particular medications prior to enrolment

• Allow assessment of the effects of the treatments on long-term outcomes in order to

(i) assess any benefits of the treatment, and

(ii) any potential harms of the treatment after leaving hospital

IMPACTS

• Impact on patients and healthcare providers in the UK and Worldwide

- The treatment of hospitalised patients with pneumonia caused by influenza or bacterial infection has progressed little in the last 20 years and there is substantial uncertainty and disagreement about optimal treatment of these patients. Pneumonia has major effects on the health of those hospitalised and incurs major costs to the NHS and health care providers worldwide. Being able to treat patients more successfully and reduce the risk of death from this disease would result in improved health for patients and significant savings for health care providers.

- RECOVERY Pneumonia will provide important new information, that will inform patients, clinicians and guideline groups globally. It could also provide evidence to submit to regulators to support new and existing licensing and subsequently provide access to better drugs for patients.

• Impact on trial design and cost

- Other clinical trials run by NDPH (including RECOVERY COVID-19) have found that in the UK, routine electronic health data such as that from NHS England, provides a cost-effective method of assessing the impact of treatment on disease (in conjunction with data collected from participants while in hospital).

It is hoped that through publication of findings in appropriate media, the findings of this research will add to the body of evidence that is considered by the bodies, organisations and individual care practitioners charged with making policy decisions for or within the NHS or treatment decisions in relation to specific patients.

Yielded Benefits is not a requirement for new applications.