R7.1 - HDR UK Consented research cohorts - identify susceptibility & resilience factors in cohorts - Data (HES & Mortality on IBD patients)

This Data Sharing Agreement permits the retention of the data provided under previous iterations of this Agreement for an interim period. This is a pragmatic approach to provide an active Agreement whilst enabling The Institute of Cancer Research to complete the necessary actions to enable a subsequent application to extend the Agreement meeting all applicable data sharing standards as published in NHS Digital’s website (see: https://digital.nhs.uk/services/data-access-request-service-dars/dars-guidance).

BioResource is a collaboration between clinicians and researchers based in BioResource centres across the country with thousands of volunteers. Studies investigate the link between genes, the environment and health and disease. Volunteers help to ensure that research can be completed quickly making it possible to identify new treatments. BioResource is a bank of genetic information.

The National Institute for Health and Care Research (NIHR) BioResource Centre has over 150,000 participants, both with and without health conditions, who are willing to be approached to participate in research studies investigating the links between genes, the environment, health and disease.

Volunteers who join the NIHR BioResource Centre donate their DNA via a blood or saliva sample which is used together with other information, such as gender and ethnicity, to match them to specific research studies. Volunteers are free to choose which studies they would like to take part in, allowing the NIHR BioResource Centre to provide researchers with groups of participants, tailor-made to the research study.

The NIHR BioResource is a major project funded by the Department of Health and Social Care through the National Institute for Health Research, funding is routed through the NIHR Cambridge Biomedical Research Centre which is a long-term partnership between the Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge. Cambridge University Hospitals NHS Foundation Trust are the data controller who also processed data for this study.

NIHR BioResource Centre has been recruiting patients with Inflammatory Bowel Disease (IBD) since 2017, under the banner of the NIHR IBD BioResource. It now has over 34,000 participants, recruited from over 100 NHS Trusts in England. A cohort size of 30,802 was submitted for this study. The participants all contributed samples and data to research, and agreed to be re-contacted to take part in further experimental medicine studies. Nine such studies have been approved in the last year, ranging from an observational study of bowel health, to an online survey of childlessness, to clinical trials. Data contributed includes a detailed self-reported Health & Lifestyle Survey, with annual repeats and a clinical report. Samples are being used primarily for genetic analysis and stratification into trials. The NIHR is a Department of Health and Social Care funding stream, and the NIHR BioResource has existed in its current form since 2012. Continued recruitment and analysis is funded until 2022.

NIHR BioResource Centre obtained HES, Civil Registration mortality data and Hospitalisation in England Surveillance System (CHESS) data on these IBD patients for two urgent COVID-19-related research questions and NIHR have confirmed that the proposed linkages support a number of priority questions included on the SAGE report under How do we best understand and protect vulnerable populations?

1. What is the outcome (hospital admission/Intensive Care Unit admission/death) for patients with IBD on immunosuppressant or anti-TNF therapies who test positive for COVID-19? Are their outcomes worse, the same or possibly better than matched people with IBD not on these drugs?

2. What are the risk factors, including genetic risk factors, associated with susceptibility to, and severity of, infection?

Research Question 1

“Could we compare the outcomes data for patients who are receiving / not receiving immunosuppressants and validate whether this population group are more vulnerable?”

This is a challenging objective, as many of the IBD patients were asked to shield themselves, and so most will not have been exposed to COVID-19.

Some were placed in the high risk group (according to the Shielded Patient List, to which IBD clinicians contributed). These are:

~ People on immunosuppression therapies sufficient to significantly increase risk of infection.

Others were thought to be at Moderate Risk:

~ Those [not on the High Risk list and] with a weakened immune system caused by a medical condition

or

~ medications such as steroid tablets or chemotherapy.

This analysis hopes to shed light on whether these were the correct categorisations. This is not of mere academic interest: patients remain uncertain as to whether they should un-shield themselves as lockdown eased, and prescribing could change if the evidence supports it.

Research Question 2

“How can we ensure that we fully understand variations in response to COVID-19 infection at the molecular, environmental, social and economic levels, by effectively coordinating the UK's longitudinal population studies to gain a much richer understanding of disease progression and outcomes? “

The NIHR BioResource Centre is one of the studies included in this brief, and it is contributing to a bigger national effort, to consider risk factors of COVID-19. Broad objectives are:

1) Clarify clinical risk factors associated with COVID-19 status and prognosis in order to inform targeted preventative measures (e.g. prioritisation of vaccinations when available) by linkage of e-health records and COVID 19 status/outcome.

2) Establish molecular factors associated with susceptibility to, and clinical trajectory of, COVID-19.

3) Understand resilience to (and recovery from) severe clinical consequences of SARS-CoV-2 infections.

To maximise the value of this research, the NIHR BioResource Centre needed timely information about study participants͛' health status, both prior to diagnosis with COVID-19 and, as the outbreak progresses, during and after treatment.

When the researcher looks at immediate patient impact, the main consideration is: what can we change?

Clinicians could change the message to patients re shielding, if their drug categorisations were incorrect.

Prescribing habits could change if e.g. immunosuppressants are actually a benefit in reducing the severity of COVID-19 in those affected.

Wider public health questions include:

~ could some of the medications in wide-spread use amongst seriously ill IBD patients be re-purposed to fight the more severe symptoms of COVID-19? Or should some be abandoned (across a wider patient group) for the duration of this pandemic?

Additional risk factors for catching, being tested for, and severity of outcome of COVID-19 were being considered as part of a wider consortium of cohorts. The cohorts provided information on e.g. genetics and self-reported lifestyle, while NHS Digital data linked to the IBD cohort provided the medical history and outcomes for this cohort. Communication of risk factors will become urgent, if any of them are both novel and modifiable. However, the main aim was longer term, as complications post-infection already look severe in some, which may have a genetic basis. If so, genetic testing may provide the basis for shielding in future waves or access to specific treatments.

The Shielded Patient List (SPL) was not part of this data request but data will enable research into the factors used to create the SPL.

The legal basis for processing personal data for this purpose falls under Article 6(1)(e) of the General Data Protection Regulations (GDPR), i.e. “a task carried out in the public interest”. It also falls under Article 9(2)(j), “processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes”. The processing of data for this study is a task of public interest as it will facilitate urgent COVID-19-related analyses to inform patient care and public health.

Cambridge University Hospitals NHS Foundation Trust are the data controller who also process data. The University of Cambridge own the IT network upon which the NIHR BioResource recruitment team use, they have no access to the NHS Digital data. The recruitment team also uses the offices at this location (although not to access record level data). The University of Cambridge are not data controllers or data processors of the NHS Digital data.

AIMES Management Services are a data processor. Identifiable data was transferred securely over the NHS network to the NIHR BioResource Centre tenancy at AIMES Management Services Ltd, a secure data centre in Liverpool. Therefore, AIMES is listed as a Data Processor. Their staff supplied the infrastructure, and technical expertise to provide the required level of security.

Under this Agreement, the data may be securely stored but not otherwise processed. No new data will be provided by NHS Digital under this Agreement.

The NIHR BioResource previously requested:

~ Hospital Episode Statistics

~ Civil Registration Mortality data

~ Hospitalisation in England Surveillance System (CHESS) data

NIHR BioResource flowed the following cohort identifiers to NHS Digital:

~ Name

~ address

~ NHS Number

~ Date of birth

~ Participant identifier

NHS Digital flowed back the NHS Digital data with a study ID and no identifying data, this data was linked to the IBD data via the study ID.

The NIHR BioResource is not currently recruiting new patients – almost all non-COVID-19 research is paused –so this list was sent from the NIHR BioResource to NHS Digital just once. The cohort submitted for use in this application were all recruited under versions 4 and 5 of the consent form (25,066 under Version 4 and 5,736 under Version 5) and versions 5 and 6 of the patient information sheet.

The NHS Digital data was linked back to the IBD data already held – genetics, lifestyle, clinical reports at record level by a study ID.

• HES data was requested from 2017. The earlier data years will tell analysts about the severity of a patient’s disease, and recent data about in- and out- patient activity, and whether the patient has COVID-19 or not

• Civil Registration Mortality data was sought, to see if any of the participants had COVID-19 on a death certificate – around 0.5% have died since recruitment

• COVID-19 Hospitalisation in England Surveillance System (CHESS) was requested to provide detail on patients submitted to intensive care and provide treatment and outcome data for those patients with a confirmed COVID-19 diagnosis.

HES data and CHESS data was requested quarterly, Civil Registration death data was requested monthly.

Data was transferred securely over the NHS network to the NIHR BioResource tenancy at AIMES Management Services Ltd, a secure data centre in Liverpool. Therefore, AIMES is listed as a Data Processor. AIMES supplied the infrastructure, and technical expertise to provide the required (very high) level of security.

At AIMES, data was linked by NIHR BioResource staff to personal data already held by a study ID and transferred securely to a Trustworthy Research Environment (TRE), also hosted by AIMES.

For this analysis, data was record level, reversibly pseudonymised (means participants are identified by a code, and that some people (those that recruited them at clinic, staff in the NIHR BioResource recruitment team) know how to turn that code back into a real person):

1. The analytic group is largely clinicians, for whom some of the participants are also their patients. The analysis was intended to realise immediate clinical benefit, and so obfuscating the relationship between research subject and real person by rendering the data irreversibly de-identified, is unhelpful.

2. Analysis took place in a TRE, which is accessed via two-factor authentication, and which passed all data and software tools through a digital airlock, such that uploads and downloads were only permitted if vetted by NIHR BioResource staff

3. The analysts are in a contractual relationship with the Data Controller, through the NHS Research Passport scheme. This, of course, includes a duty of confidentiality

4. The analysts are in a contractual relationship with the NIHR BioResource to limit the purpose of their analysis through each signing a local Data Access Agreement.

Genetic or biochemical results obtained from samples taken for research will not be routinely communicated to participants and only if participants have indicated on their consent form that they wish to be informed in the rare event of being found to be at increased risk of a genetic disease. This information might be relevant to a participant's future health for example if an increased risk of a condition is identified and this condition might be prevented or treated early by the NHS. If the genetic analysis indicated that a participant might be at increased risk of such conditions, and the participant has chosen to be informed about any such risk, the provisional result of the research analysis will be handed back by the IBD team to the participant's consultant or GP for discussion with the participant. A further sample would have been taken for analysis within an accredited NHS diagnostics laboratory to confirm any “incidental finding” A health professional or genetic counsellor would feed back to the participant on the final results.

All researchers accessing the NHS Digital data had an honorary contract as part of the NHS Research Passport scheme with Cambridge University Hospitals NHS Foundation Trust.

The University of Cambridge own the IT network upon which the NIHR BioResource recruitment team work. This team also uses the offices at this location (although not to access record level data).

This Agreement permits the secure retention of the data only and no other processing.

No new outputs will be produced under this Data Sharing Agreement.

Previous Expected Outputs were:

If a workable model of the interaction of medication (and/or other modifiable risk factors) and COVID-19 disease severity or complications was developed, the order of output expected was:

• Report

• Presentations

• Submission to peer reviewed journal

• Modification of risk stratification tool for shielding

All these outputs will be aggregated with small numbers suppressed in line with the HES analysis guide.

However, as clinicians were leading the analysis, and they will communicate as professional members with others in the British Society of Gastroenterology, it is possible (indeed, to be wished for) that some patients may get a message as part of their usual direct care interactions as a result of learning from the analysis.

In terms of dissemination of results, the primary purpose is to try to change policy for patient benefit.

Beyond that:

1. That this analysis is taking place will appear, with a short plain language summary and list of personnel involved, on the NIHR BioResource website

2. Articles arising from NIHR work must be Open Access, and will also be listed on the website

3. The NIHR BioResource is a key contributor to a Health Data Research UK “Hub”, called “Gut Reaction”, which is specifically focused on IBD. The Hub has a Patient and Public Engagement group which is led by staff and volunteers at the charity Crohn’s & Colitis UK; and a communications team. Between them, they will ensure that an academic text is both acceptable to the public, and accompanied by a readable press release and social media exposure

4. “Gut Reaction” has an active commercial arm, that will seek to reach industry with any outputs

5. The clinicians involved (and indeed, other study and charity workers and members) speak regularly at public meetings, where this topic is likely to raise much interest.

The target date was the Autumn of 2020 - this has now been extended. The same clinicians are pursuing many other avenues to expedite this work, including, but not limited to: creating apps to allow patients to self-report outcomes; trying to influence analytic priorities in proprietary GP database systems; collaborating across disease groups to build patient numbers; and reaching out internationally.

Results will be fed through the Department of Health and Social Care, which funds the NIHR BioResource, and through clinical networks such as the British Society of Gastroenterology. The clinical networks' meetings have been cancelled during the pandemic, but the researchers hope to present at the first in-person meeting in 2022.

This Agreement permits the secure retention of the data only and no other processing.

Previous anticipated benefits were:

A risk stratification tool was used to place some IBD patients on the Shielded Patient List in early 2020. With the UK opening up in early 2022, the impact of continued shielding is being measured through lives risked or severely constrained. If there is another COVID-19 surge, there should be further evidence that the algorithm used was appropriate – one of the analytic team wrote the risk stratification tool.

This study has wider implications that just the IBD patients and will impact other categories of patient on immunosuppressant or anti-TNF therapies.

What is the magnitude of the impact? IBD affects 0.5-1.0% of the population – so ~600,000 people nationwide – and costs the UK tax payer > £2 billion p.a. . Even a small change in treatment choices could make a substantial difference

Any rapid change in treatment recommendation will go through NICE, and be monitored for efficacy thereafter

NICE were publishing new guidance around COVID-19 weekly. Research on complications following infection, however, will likely take years.

There have been hints that a particular drug regime was mildly protective - although this is confounded by the fact that the patient-group knew they were at severe risk, and therefore shielded especially thoroughly: NIHR BioResource Centre hear of people still shielding beyond the Government's "freedom day".

Although more data may reveal more, this is now being written up in terms of a vulnerable patient cohort's journey through the pandemic.