CLARITY IBD: Understanding the impact of biologic and immunomodulatory therapy on SARS-CoV-2 Infection and Immunity in Patients with Inflammatory Bowel Disease

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

Datasets: − Demographics

Objective for processing

DARS-NIC-435152-C0H4N-v0: BACKGROUND AND PURPOSE CLARITY IBD www.clarityibd.org (impaCt of bioLogic therApy on saRs-cov-2 Infection and immunity, https://doi.org/10.1186/ISRCTN45176516) is badged as a UK NIHR COVID-19 urgent public health study (1b) (https://www.nihr.ac.uk/covid-studies/). When referencing the evidence submitted, these objectives and processing information refer to Workflow 1 of the study (not Workflow 2). Inflammatory bowel disease (IBD) affects about 1% of the UK population and is usually treated with immunosuppressive drugs. By inhibiting the immune system, these drugs increase the risk of serious infections and prevent vaccines working as effectively as they should. Because COVID-19 has been caused by a new virus, SARS-CoV-2, Royal Devon University Healthcare NHS Foundation Trust (RDUHFT) didn’t know if these drugs increased the risk of infection, life-threatening illness or reduced immunity that usually follows infection or vaccination. As a precaution the UK Government advised patients taking these medicines to follow strict social distancing measures, known as shielding, during lockdown periods. Patients with inflammatory bowel disease (IBD) are usually treated with immunosuppressive drugs. By inhibiting the immune system, these drugs increase the risk CLARITY IBD (www.clarityibd.org) (impaCt of serious infections bioLogic therApy on saRs-cov-2 Infection and prevent vaccines fully working. Because immunity, https://doi.org/10.1186/ISRCTN45176516), led by RDUHFT, is badged as a UK National Institute for Health and Social Care Research (NIHR) COVID-19 is caused by a new virus, SARS-CoV-2, the researchers (Royal Devon and Exeter (RD&E) NHS Foundation Trust) don’t yet know if these drugs increase the risk of infection, life-threatening illness or reduce immunity that usually follows infection or vaccination. As a precaution the UK Government advised patients taking these medicines to follow strict social distancing measures, known as shielding, during lockdown periods. urgent public health study. This study will investigate is investigating the impact of specific drugs and shielding on COVID-19 infection and subsequent [21 words unchanged] as well as millions of other UK patients treated with immunosuppressive drugs. 1. “What are the objectives of processing the data?” It is comprised of three workflows; only two of these require/required NHS England (then NHS Digital) data: a. To conduct research: - Workflow 1 was a non-consented cohort study (11,000 patients) which looked at the seroprevalence of SARS-Cov-2 during the early phase of the pandemic, seroconversion in patients with confirmed infection by nasal/throat swab (both seroprevalence and seroconversion explained in lay person terms below), magnitude of SARS-Cov-2 antibodies and demographic factors associated with COVID-19 diseases in patient with inflammatory bowel disease who were being treated with immunosuppressive medication. This workflow has now been completed and the Demographics data supplied by NHS England (then NHS Digital) destroyed. This workflow is now complete and no NHS England data is held for this purpose but detail on this historical flow is provided for clarity. This workflow enabled RDUHFT to define: “The data is required to support the following research objectives: • seroprevalence (number of persons in a population who test positive for a COVID-19 based on nasal/throat swab polymerase chain reaction, commonly performed to assess for acute infection) of SARS-CoV-2 through the early phase of the pandemic In patients with inflammatory bowel disease, on immunosuppressive medication, RD&E aim to define: • seroconversion (time period during which SARS-CoV-2 antibodies develop and become detectable in the blood) in patients with confirmed infection by nasal/throat swab - seroprevalence (number of persons in a population who test positive for a COVID-19 based on nasal/throat swab polymerase chain reaction, commonly performed to assess for acute infection) of SARS-CoV-2 through the early phase of the pandemic • the magnitude (extent) of SARS-Cov-2 antibodies in patients with confirmed infection - seroconversion (time period during which SARS-CoV-2 antibodies develop and become detectable in the blood) in patients with confirmed infection by nasal/throat swab • demographic factors associated with COVID-19 disease, including gender, age, and deprivation - the magnitude (extent) of SARS-Cov-2 antibodies in patients with confirmed infection - Workflow 2 is 40-week prospective, observational, UK-wide, consented cohort study (approx. 7229 patients) designed to determine whether anti-TNF therapy (drugs that help to stop inflammation such as infliximab and vedolizumab) impacts SARS-CoV2 seroprevalence, the magnitude/durability of serological responses (antibody response) and the proportion of patients who acquire COVID-19 after seroconversion. - Demographic factors associated with COVID-19 disease, including gender, age, and deprivation Researchers at RDUHFT regularly assess (via questionnaire) the clinical status of patients recruited to workflow 2 of the study and performing SARS-CoV-2 antibody (nucleocapsid and spike) testing on submitted samples from patients at pre-defined timepoints. 2. “What is your justification for each individual dataset?” The research project has received ethics approval from the Surrey Borders Research Ethics Committee (20/HRA/3114) and Health Research Authority (IRAS: 283251, Protocol number: 2102102). To achieve these goals outlined in the CLARITY IBD research study, RD&E wish to collect the following data from the Demographics dataset: COHORT - NHS Numbers: For approx. 7,500 patients in whom RD&E have performed SARS-CoV-2 antibody testing on, RD&E require their NHS numbers in order to obtain further information from Public Health England on throat/nasal swab polymerase chain reaction results. RD&E have an agreement in place with Public Health England to supply them with nasal/throat swab polymerase chain reaction COVID-19 testing results. For workflow 1, the data subjects were a non-consented cohort of approx. 11,000 patients across the UK diagnosed with inflammatory bowel disease on immunosuppressive medication. This cohort was selected to provide a robust sample size to investigate variations impact of immunosuppressive therapy on SARS-CoV-2 infection and immunity, in line with RDUHFT’s objectives, and therefore contains a mix of demographics (age, gender, ethnicity) in order to provide a suitably representative sample. Recruitment took place from 09-02-2020 to 30-10-2020. - Post code: For approx. 11,000 patients in whom RD&E have performed SARS-CoV-2 antibody testing on, RD&E require their residential post code. This will be to investigate the hypothesis that there are regional differences in COVID-19 infection across the UK, and that COVID-19 infection and severity differs across deprivation area. RDUHFT tested more than 15,000 serum samples from IBD patients for SARS-CoV-2 antibodies. These included i) surplus serum samples from UK therapeutic drug monitoring laboratories retained since 09-02-2020 and ii) serum samples from patients recruited to the UK NIHR IBD Bioresource project. For each sample the supplier of the sample (the therapeutic drug monitoring laboratory or the UK NIHR IBD Bioresource) provided the NHS number, date of birth, sex of the patient, postcode (if available), the date of the serum sample, the drug tested and the name of the referring hospital. The study used the surplus serum samples from UK clinical laboratories saved following therapeutic drug monitoring tests. Additional serum samples were obtained from the UK NIHR IBD Bioresource. Please note that there is no biological reason for results not to be extrapolated to patients who are on anti-TNF medicine for non-IBD indications. It is hoped that results will directly be relevant, therefore, to any patent on anti-TNF/biologic therapy studied, including arthritis and psoriasis (the two most common non-IBD indications). For workflow 2, the data subjects were a consented cohort of approx. 7229 patients who attended one of the inflammatory bowel disease clinics in the participating NHS Trusts during a three-month period in 2020. If a patient displayed an interest in joining the study, participant information sheets and consent forms, both of which have been approved by the Research Ethics Committee, were sent out electronically. For patients who did not have access to electronic devices the information was sent via Royal Mail. Patients may also have been provided with this information at the time of the infusion and were given sufficient time to decide whether they would like to take part and given the opportunity to ask questions. Patients who lacked capacity to consent were not recruited. 3. “Who are the data subjects?” DATA SUMMARY The data subjects are a non-consented cohort of approx. 11,000 patients across the UK diagnosed with inflammatory bowel disease on immunosuppressive medication. This cohort was selected to provide a robust sample size to investigate variations impact of immunosuppressive therapy on SARS-CoV-2 infection and immunity, in line with our objectives, and therefore contains a mix of demographics (age, gender, ethnicity) in order to provide a suitably representative sample. Recruitment took place from 09-02-2020 to 30-10-2020 and is now complete so the cohort size will not increase. To meet the objectives of workflow 1, RDUHFT required the following variables from the Demographics dataset: RD&E will test >15,000 serum samples from IBD patients for SARS-CoV2 antibodies. These include i) surplus serum samples from UK therapeutic drug monitoring laboratories retained since 09-02-2020 and ii) serum samples from patients recruited to the UK NIHR IBD Bioresource project. For each sample the supplier of the sample (the therapeutic drug monitoring laboratory or the UK NIHR IBD Bioresource) will provide the NHS number, date of birth, sex of the patient, postcode (if available), the date of the serum sample, the drug tested and the name of the referring hospital. These data will be provided for a COVID-19 purpose to the Royal Devon and Exeter NHS Foundation Trust. The study will use surplus serum samples from UK clinical laboratories saved following therapeutic drug monitoring tests. Additional serum samples will be obtained from the UK NIHR IBD Bioresource. - NHS number: For approx. 7,500 patients who RDUHFT had performed SARS-CoV-2 antibody testing on, RDUHFT required their NHS numbers to obtain further information from Public Health England (now dissolved) on throat/nasal swab polymerase chain reaction results. RDUHFT had an agreement in place with Public Health England to supply them with nasal/throat swab polymerase chain reaction COVID-19 testing results. 4. “How have you minimised your data request to what is absolutely necessary for your stated objectives?” - Post Code: For approx. 11,000 patients who RDUHFT had performed SARS-CoV-2 antibody testing on, RDUHFT required their residential postcode. This was needed to investigate the hypothesis that there are regional differences in COVID-19 infection across the UK, and that COVID-19 infection and severity differs across deprivation area. “The following data minimisation options have been considered: RD&E are only requesting two variables (NHS number and Post Code)" To meet the objectives of workflow 2, RDUHFT required COVID-19 Vaccination Status data. By obtaining COVID-19 Vaccination Status data (including date, first or second dose, and type received) alongside the already obtained patient identifiers, more detailed analysis can be carried out on SARS-CoV-2 antibody responses. This will provide a clearer picture of the impact of COVID-19 infection and vaccination on patients with inflammatory bowel disease on immunosuppressive therapies. COVID-19 Vaccination Status can only be used for the purposes set out in the Direction (COVID-19 Public Health Directions 2020), currently limited to COVID-19 purposes. 5. “Under what GDPR legal basis will you be processing this data?” LEGAL BASIS – COMMON LAW DUTY OF CONFIDENTIALITY “The Royal Devon and Exeter NHS Foundation Trust relies on GDPR Article 6(1)(e) – “processing is necessary for the performance of a task carried out in the public interest or in the exercise of official authority vested in the controller”. RDUHFT relied on Regulation 3 (1) of the Health Service Control of Patient Information (COPI) Regulations 2002 to temporarily lift the Common Law Duty of Confidentiality in respect of workflow 1. In direct relation to the study objectives, Regulation 3(1) confirms that confidential patient information may be processed for: Justification: The Royal Devon and Exeter NHS Foundation Trust is a NHS hospital, which is considered a public authority under the Data Protection Act 2018. It was legally established under a royal charter which states that one of its functions is to carry out research. This particular research is considered to be in the public interest because of the potential benefits to patient health, including to improve the quality of care for people living with inflammatory bowel disease. The data requested is necessary to this research as the same outputs and benefits could not otherwise be achieved. The Royal Devon and Exeter NHS Foundation Trust relies on GDPR 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 right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject”. Justification: The data requested is necessary in order to meet the research objectives and has been minimised in a way that is proportionate to the intended purpose. RD&E has considered the interests of the data subjects including providing a transparent privacy notice that explains this use of data and the rights of data subjects, and data will be securely handled with role-based access controls to limit usage.” 6. “How are you addressing the common law duty of confidentiality?” The Royal Devon and Exeter NHS Foundation Trust relies on Regulation 3 (4) of the Health Service Control of Patient Information (COPI) Regulations 2002 to temporarily lift the Common Law Duty of Confidentiality. Patient consent for SARS-CoV-2 antibody testing was not sought and no prospective study visits are required. Justification: "The COPI notice can be relied upon for the processing of confidential patient information for the purposes set out in Reg 3(1) of COPI in order to support the COVID-19 response. In direct relation to the study objectives, Regulation 3(1) confirms that confidential patient information may be processed for: [3 paragraphs unchanged] o • the delivery, efficacy and safety of immunisation programmes The CLARITY study looks at the risk of infection of COVID-19 amongst patients with inflammatory bowel disease treated [15 words unchanged] have an impact and inform COVID-19 vaccine immunisation strategy/prioritisation for these patients. Where processing takes place under Reg3(1) COPI, the COPI notice states that confidential patient information must be processed solely for a COVID-19 purpose. In terms of Reg (3) - the processing of confidential patient information for the purposes specified in paragraph (1) may be undertaken by — RDUHFT, in relation to workflow 2, also sought the informed consent of participants. Regulation 3 (1) of the Health Service COPI Regulations 2002 was relied on in previous Agreements, and now consent is relied on to address the common law duty of confidentiality. (a)the Public Health Laboratory Service [Public Health England will use the NHS numbers and post codes of patients to link to COVID-19 nasal/throat swab polymerase chain reaction results]; DATA CONTROLLERSHIP (b)persons employed or engaged for the purposes of the health service [the processor of the data, is employed by the Royal Devon and Exeter Hospital, will use the data for Public Health England data linkage only]. RDUHFT is the sole data controller that also processes the NHS England data disseminated. Imperial College London is a data processor acting under the instruction of the controller to conduct the T-cell experiments relating to vaccine response. The research project has received approval from the Surrey Borders Research Ethics Committee (20/HRA/3114) and Health Research Authority (IRAS: 283251, Protocol number: 2102102). Hull University and Hull University Hospital have provided financial assistance for the project but have had no input as to the purposes or means of the processing of NHS England data and do not access or process the NHS England data disseminated. The funders have no impact on the design or any inputs on the outputs of the study. They will have no access to any NHS Digital data. AMENDMENT REQUEST DARS-NIC-435152-C0H4N-v1: In addition to the cohort linkage for the previous workflow, stated above, the researcher would like access to the COVID-19 Vaccination Status dataset. The vaccination data, including date, first or second dose, and type received; is being requested for approx. 7,229 patients who are part of the CLARITY-IBD, prospective, multicenter (pan-UK) study. This is a new cohort of patients. The researchers are regularly assessing (via questionnaire) these patients’ clinical status and performing SARS-CoV-2 antibody (nucleocapsid and spike) testing on submitted samples from these patients at pre-defined timepoints. By obtaining COVID-19 vaccination data with the already obtained patient identifiers, more detailed analysis can be carried out on SARS-CoV-2 antibody (nucleocapsid and spike) responses. This will provide a clearer picture of impact of COVID-19 infection and vaccination on patients with inflammatory bowel disease on immunosuppressive therapies. The patient data is flowing to NHS Digital under the COPI notice. CLARITY IBD is an investigator-led, UK National Institute for Health Research COVID-19 urgent public health study. [1 paragraph unchanged] The study sponsor is the Royal Devon and Exeter NHS Foundation Trust. RDUHFT. The study is funded by the Royal Devon and Exeter NHS Foundation Trust, RDUHFT, Hull University Teaching Hospital NHS Trust and by unrestricted educational grants from: [1 paragraph unchanged] By using these assays, and publishing methodology as to how they are [82 words unchanged] product, and potentially, increased use of them, which may be a commercial benefit benefit. [4 paragraphs unchanged] All four drug companies companies, who have funded the study study, are aware of each other’s funding/contribution to the study. None of the [13 words unchanged] collection or analysis, writing or presentation of the findings of the research, or decision to submit for publication, nor suppress any of the findings of the research. [1 paragraph unchanged] It There is possible, a potential commercial benefit where there is equipoise in terms of treatment impact on COVID-19 infection and vaccination, vaccination and results of this study may influence choice of treatment by the treating physician only, not the drug manufacturer, so any commercial or non-commercial impact for any of the funders is unlikely in this regard. physician. [1 paragraph unchanged] None of the funding bodies have had, or will have, any role in study design, data collection or analysis, writing or presentation of the findings of the research, or decision to submit for publication, nor suppress any of the findings of the research. LEGAL BASIS FOR PROCESSING Involvement of other organisations RDUHFT have a legal basis for processing personal data and special categories of personal data under the following provisions of the General Data Protection Regulation (GDPR): Hull University and Hull University Hospital have provided financial assistance for the project, but have had no input as to how the data should be acquired or processed. They do not determine the purpose or means of the project. They will have no access to NHS Digital data. - 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”. One of the co-chief investigators of the study is at Imperial College London. This investigators team are conducting the T-cell experiments relating to vaccine response. They are completing this under instruction of RD&E and are therefore not a data controller but however, have been listed as a data processor. - 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 right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject”. The RDUHFT is an NHS hospital, which is considered a public authority under the Data Protection Act 2018. It was legally established under a Royal Charter which states that one of its functions is to carry out research. This particular research is considered to be in the public interest because of the potential benefits to patient health, including to improve the quality of care for people living with inflammatory bowel disease. [2 paragraphs unchanged] An electronic survey was conducted to gauge the opinion of patients with [57 words unchanged] patients. All but one patient expressed either equal or strong preference for computer-based forms including 82% of patients expressing a strong preference. Every patient surveyed wanted to be informed of the test result despite the fact the researchers don’t know if a positive test means an individual is immune from further infection. computer-based forms including 82% of patients expressing a strong preference. Every patient surveyed wanted to be informed of the test result despite the fact the researchers don’t know if a positive test means an individual is immune from further infection. [2 paragraphs unchanged]

Processing activities

DARS-NIC-435152-C0H4N-v0: This Agreement covered/covers two separate data flows: 1. “Is there any data flowing to NHS Digital?” 1) Demographics data: The Royal Devon and Exeter NHS Foundation Trust will transfer to NHS Digital the patient identifiers for approximately 11,000 patients. The identifiers included will be name, date of birth, gender, and NHS number (where applicable) paired with a unique identifier to support pseudonymisation. The data is identifiable and is not available in the public domain. i) The RDUHFT supplied NHS England with patient identifiers (name, date of birth, gender and NHS number (where available) plus unique study ID) for approximately 11,000 patients via Secure Electronic File Transfer (SEFT). The patient identifiers will be provided to NHS Digital so that this can be linked to the requested datasets (Demographics data with two identifiable fields - NHS number and/or Post Code). NHS Digital will use the patient identifiers via the Patient Demographic Service for the 11,000 identified patients provide back NHS numbers and/or Post Code only for those patients, thus minimising the total amount of data requested. ii) NHS England linked the patient identifiers to Demographics data and supplied participants’ NHS number and/or Post Code to RD&E. By obtaining NHS numbers and Post Codes with the already obtained patient identifiers, more detailed analysis can be carried out on SARS-CoV-2 nasal/throat swab polymerase chain results. This will provide a clearer picture of impact of COVID-19 on patients with inflammatory bowel disease on immunosuppressive therapies.” iii) RDUHFT supplied NHS number and/or Post Code to Public Health England in order to obtain SARS-CoV-2 nasal and throat swab polymerase chain reaction results, which is not public available at record-level, for each patient. The data Public Health England supplied to RD&E was record-level, identifiable data. 2. “What steps will specific data go through, how will it be processed and accessed and what is being done with it at each stage? iv) RDUHFT pseudonymised the data provided by Public Health England and securely destroyed all identifying data. “1. NHS Digital will send the NHS number and/or Post Code to the Royal Devon and Exeter NHS Foundation Trust. Participants’ NHS number and/or Post Code were required to supplement the already obtained patient identifiers and allow for a more detailed analysis to be carried out on the SARS-CoV-2 nasal/throat swab polymerase chain results provided by Public Health England. This provided a clearer picture of the impact of COVID-19 on patients with inflammatory bowel disease on immunosuppressive therapies. 2. The Royal Devon and Exeter NHS Foundation Trust will provide that NHS number and/or Post Code to Public Health England in order to obtain SARS-CoV-2 nasal and throat swab polymerase chain reaction results for each patient. The data was pseudonymised as soon as possible (i.e. after receipt but before analysis) so that only the minimum necessary data for this purpose were processed. 3. Public Health England will then supply this information to the Royal Devon and Exeter NHS Foundation Trust. As workflow 1, for which the Demographics data was required, has now been completed RDUHFT have destroyed the data and supplied NHS England with a data destruction certificate evidencing this. 4. The Royal Devon and Exeter NHS Foundation Trust will pseudonymise this data, and securely destroy the identifiable data. 2) COVID-19 vaccination status data: 5. The Royal Devon and Exeter NHS Foundation Trust will carry out statistical analysis to support the objectives of the CLARITY IBD study on the pseudonymised data set only. The RDUHFT will transfer data to NHS England. The data will consist of identifying details (specifically name, date of birth, gender, and NHS number plus unique study ID) for the cohort to be linked with NHS England data. 6. The Royal Devon and Exeter NHS Foundation Trust will analyse the full pseudonymised dataset as part of the CLARITY IBD objectives. NHS England will provide the relevant records from the COVID-19 vaccination status to RDUHFT. The data will contain no direct identifying data items but will contain a unique study ID which can be linked to the data with other record level data already held by the recipient. Both organisations require identifiable data in order to gather patient-level clinical data in the first instance. However, data will be pseudonymised in order to carry out statistical analysis. Although identifiable data will be received and shared, this is necessary to link clinical datasets. COVID-19 Vaccination status data received from NHS England will be compared with the information self-reported by participants (date of vaccination, and name of vaccine received). In the event of a discrepancy, the data received by NHS England will be used in the analysis. The Royal Devon and Exeter NHS Foundation Trust have a role in all objectives, and the data will be pseudonymised as soon as possible (ie - after receipt, but before analysis) so that only the minimum necessary data for this purpose is processed. Staff within The Royal Devon and Exeter NHS Foundation have specific expertise relating to care of patients with inflammatory bowel disease on immunosuppressive therapy that will form an important part of this analysis and support the overall objectives.” The identifiable data will be stored in a separate database to the linked dataset used for analysis. All analyses will use the pseudonymised dataset. There will be no requirement and no attempt to re-identify the individuals when using the pseudonymised dataset. Data will be accessed onsite and via remote access. Remote access is via devices that are maintained by RDUHFT or Imperial College London and complies with the respective organisational policy relevant to remote access. 3. “Are there any organisations involved in the project other than the controller(s), processor(s) or funder(s) mentioned elsewhere in the application? Data will remain on encrypted servers at all times and no data will be held locally on remote devices. Data will only be accessed by authorised personnel who are substantive employees of RDUHFT or Imperial College London, for the purposes described above. All personnel accessing the data have been appropriately trained in data protection and confidentiality. “There are no additional organisations involved in this use of data other than the organisations already mentioned elsewhere in this agreement.” Data access, including remote access, is within England / Wales. 4. “Will you be linking to any other datasets?” “1. NHS Digital to Public Health England linkage: a. The dataset to be linked is the SARS-CoV-2 nasal/throat swab polymerase chain reaction, which is under the data controllership of Public Health England. This data is record level and identifiable. b. The dataset is not publicly available at record level, although aggregate summaries are published. c. Linkage to this dataset will provide a clearer view of the impact of immunosuppressive therapies in patients with inflammatory bowel disease on SARS-CoV-2 infection and immunity. As a result, results from this study may impact future care of patients on immunosuppressive therapy. The Public Health England dataset contains polymerase chain reaction COVID-19 results that are not available in the Personal Demographics Service. d. The linkage will be on a basis using NHS number and/or Post Code. This is the only way to link the datasets. e. Patients have not given their explicit consent for their data to be linked; the common law duty of confidentiality does apply, but is temporarily lifted under Regulation 3 (4) of the Health Service Control of Patient Information (COPI) Regulations 2002. f. Data must be processed in a clear identifiably form in order to support linkage, but identifiers will be removed once linkage is completed. The linked data will then be pseudonymised when analysing the data. This will be done at the point of receipt to The Royal Devon and Exeter NHS Foundation Trust.” 5. “Will you be attempting to re-identify individuals?” “The Royal Devon and Exeter NHS Foundation Trust has no requirement nor will attempt to re-identify the supplied data.” 6. “Will anyone who is not an employee of a named data controller or processor access the data?”” “Data will only be accessed and processed by substantive employees of the data controller and its processors and will not be accessed or processed by any other third parties not mentioned in this agreement. Third party organisations would have to make a formal NHS digital data access request in order to obtain the data-set.” AMENDMENT REQUEST DARS-NIC-435152-C0H4N-v1: In addition to the cohort linkage for the previous workflow stated above, details for the amendment to the processing activities are given below: The Royal Devon and Exeter NHS Foundation Trust will transfer to NHS Digital the patient identifiers for approximately 7,229 patients. The identifiers included will be name, date of birth, gender, and NHS number paired with a unique identifier to support pseudonymisation. The data is identifiable and is not available in the public domain. The patient identifiers will be provided to NHS Digital so that this can be linked to the COVID-19 vaccination data. NHS Digital will use the patient identifiers to filter COVID-19 vaccination data for the identified patients since the start of the COVID-19 vaccination programme and provide back only the data for the patients requested, thus minimising the total amount of data requested. 1. NHS Digital will send the linked pseudonymised COVID-19 vaccination data to the Royal Devon and Exeter NHS Foundation Trust. 2. Only the Royal Devon and Exeter NHS Foundation Trust will act as a data controller. One of the co-chief investigators of the study is at Imperial College London. They are completing this under instruction of RD&E and are therefore not a data controller but however, have been listed as a data processor. 3. The Royal Devon and Exeter NHS Foundation Trust will have access to pseudonymised record-level data. The Royal Devon and Exeter NHS Foundation Trust will carry out statistical analysis to support the objectives of the CLARITY IBD study on the pseudonymised data set only. The process for keeping the identifiable data and pseudonymised datasets separate at Royal Devon & Exeter NHS Foundation Trust is as follows: • There is only one person who will be accessing the identifiable data within the Royal Devon & Exeter NHS Foundation Trust, and no other study team personnel will be able to access the identifiable data. Each study participant has been given a study ID, and first and last name, along with other identifying demographic features and these are only available to that one person All other study personnel only access study participant's files by study ID. • Study personnel will have access to the pseudonymised data from NHS Digital. • The identifiable data and the pseudonymised data from NHS Digital will be stored on a NHS-encrypted server but separately and only accessed by the named person.

Expected output

DARS-NIC-435152-C0H4N-v0: Outputs from the CLARITY IBD study: Findings will be written up and submitted to a peer-reviewed scientific journal - Gut, the highest ranking gastroenterology journal in the world (hopefully within one month from date of receipt of data to inform both clinical care and public health policy nationally and internationally.). 1. Lin S et al – ‘Antibody decay, T cell immunity and breakthrough infections following two SARS-CoV-2 vaccine doses in inflammatory bowel disease patients treated with infliximab and vedolizumab’ Nature Communications (March 2022) - https://pubmed.ncbi.nlm.nih.gov/35296643/. Findings will be presented by the study team at national and international conferences including the British Society of Gastroenterology annual meeting and the European Crohn’s and Colitis meeting. The study team will prepare a lay summary of the study findings for dissemination to the members of the national patient group, Crohn’s and Colitis UK. 2. Chanchlani N et al – ‘Adalimumab and infliximab impair SARS-CoV-2 antibody responses: results from a therapeutic drug monitoring study in 11422 biologic-treated patients’ Journal of Crohn’s and Colitis (September 2021) - https://academic.oup.com/ecco-jcc/article/16/3/389/6362487. There is also a study management group that meets weekly, whom interim and final results are distributed through. Over 20 consultants across the UK working in district general and tertiary centres working with both children and adults, are members of this group. In this paper, RDUHFT found that rates of PCR-confirmed SARS-CoV-2 infection were similar across treatment groups. Seroprevalence rates (number of persons in a population who test positive for a COVID-19 based on nasal/throat swab polymerase chain reaction, commonly performed to assess for acute infection) were lower in infliximab- and adalimumab- than vedolizumab-treated (immunosuppressive therapies) patients, and the magnitude of SARS-CoV-2 reactivity was similar in infliximab- vs adalimumab treated patients, but higher in vedolizumab-treated patients. This has led RDUHFT to conclude that adalimumab-treated patients, like infliximab-treated patients, have similar serological responses to COVID-19 infection, and likely, COVID-19 vaccination. To the best of RDUHFT's knowledge this is one of the only well-powered studies to look at the outcomes of adalimumab-treated patients to COVID-19 infection. RD&E have also produced a patient facing video for the study that has been shared through social media, Crohn’s and Colitis UK charity, and senior figureheads (both clinical and non-clinical) who are ‘IBD champions’. 3. Chee D et al – ‘Patient-led Remote IntraCapillary pharmacoKinetic Sampling (fingerPRICKS) for therapeutic drug monitoring in patients with inflammatory bowel disease’ Journal of Crohn’s and Colitis (July 2021) - https://academic.oup.com/ecco-jcc/article-abstract/16/2/190/6325142?redirectedFrom=PDF. AMENDMENT REQUEST 4. Kennedy NA et al – ‘Infliximab is associated with attenuated immunogenicity to BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines in patients with IBD’ Gut (April 2021) - https://pubmed.ncbi.nlm.nih.gov/33903149/. DARS-NIC-435152-C0H4N-v1: 5. Kennedy NA et al – ‘Anti-SARS-CoV-2 antibody responses are attenuated in patients with IBD treated with infliximab’ Gut (May 2021) - https://gut.bmj.com/content/70/5/865. Researchers will continue to publish results from the vaccination data in high impact journals which will inform the scientific and vaccine community, as well as inform public health strategies for vaccinating people with IBD. Researchers aim to work to a similar timescale for this proposed project. Further outputs from the CLARITY IBD study: 1. Lin S*, Kennedy NA*, Saifuddin A*, Sandoval DM*, Reynolds CJ, Seoane RC, Kottoor SH, Pieper FP, Lin KM, Butler DK, Chanchlani N, Nice R, Chee D, Bewshea C, Janjua M, McDonald TJ, Sebastian S, Alexander JL, Constable L, Lee JC, Murray CD, Hart AL, Irving PM, Jones GR, Kok KB, Lamb CA, Lees CW, Altmann DM, Boyton RJ*, Goodhand JR*, Powell N*, Ahmad T*; CLARITY IBD study. Antibody decay, T cell immunity and breakthrough infections following two SARS-CoV-2 vaccine doses in inflammatory bowel disease patients treated with infliximab and vedolizumab. Nature Communications. 2022 Mar 16;13(1):1379. 2. Chanchlani N*, Lin S*, Chee D, Hamilton B, Nice R, Zehra A, Bewshea C, Cipriano B, Derikx LAAP, Dunlop A, Greathead L, Griffiths RL, Ibraheim H, Kelleher P, Kok KB, Lees CW, MacDonald J, Sebastian S, Smith PJ, McDonald TJ, Irving PM, Powell N, Kennedy NA, Goodhand JR, Ahmad T. Adalimumab and infliximab impair SARS-CoV-2 antibody responses: results from a therapeutic drug monitoring study in 11422 biologic-treated patients. J Crohns Colitis. 2021 Sep 2:jjab153. doi: 10.1093/ecco-jcc/jjab153. 3. Chee D*, Nice R*, Hamilton B, Jones E, Hawkins S, Redstone C, Cairnes V, Pohl K, Chanchlani N, Lin S, Kennedy NA, Ahmad T, Goodhand JR*, McDonald TJ*. Patient-led Remote IntraCapillary pharmacoKinetic Sampling (fingerPRICKS) for therapeutic drug monitoring in patients with inflammatory bowel disease. J Crohns Colitis. 2021 Jul 21:jjab128. 4. Kennedy NA*, Lin S*, Goodhand JR*, Chanchlani N, Hamilton B, Bewshea C, Nice R, Chee D, Cummings JF, Fraser A, Irving PM, Kamperidis N, Kok KB, Lamb CA, Macdonald J, Mehta S, Pollok RC, Raine T, Smith PJ, Verma AM, Jochum S, McDonald TJ, Sebastian S, Lees CW, Powell N*, Ahmad T*. Contributors to the CLARITY IBD study. Infliximab is associated with attenuated immunogenicity to BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines in patients with IBD. Gut. 2021 Apr 26:gutjnl-2021-324789. 5. Kennedy NA*, Goodhand JR*, Bewshea C, Nice R, Chee D, Lin S, Chanchlani N, Butterworth J, Cooney R, Croft NM, Hart AL, Irving PM, Kok KB, Lamb CA, Limdi JK, Macdonald J, McGovern DP, Mehta SJ, Murray CD, Patel KV, Pollok RC, Raine T, Russell RK, Selinger CP, Smith PJ, Bowden J, McDonald TJ, Lees CW, Sebastian S, Powell N*, Ahmad T*; Contributors to the CLARITY IBD study. Anti-SARS-CoV-2 antibody responses are attenuated in patients with IBD treated with infliximab. Gut. 2021 May;70(5):865-875. [4 paragraphs unchanged] Multiple newsletters for patients have been distributed throughout the study period. Four newsletters Newsletters have been sent to all participants of the CLARITY IBD study (>7000 [28 words unchanged] study has an active twitter account (https://twitter.com/clarityibd) with almost 1000 followers where RD&E RDUHFT communicate up-to-date patient related information. [1 paragraph unchanged] Findings will be presented by the study team at national and international conferences including the British Society of Gastroenterology annual meeting and the European Crohn’s and Colitis meeting. The study team will prepare a lay summary of the study findings for dissemination to the members of the national patient group, Crohn’s and Colitis UK. There is also a study management group that meets weekly with whom interim and final results are distributed through. Over 20 consultants across the UK working in district general and tertiary centres working with both children and adults are members of this group. Researchers will continue to publish results from the vaccination data in high impact journals which will inform the scientific and vaccine community, as well as inform public health strategies for vaccinating people with IBD. Researchers aim to work to a similar timescale for this proposed project.

Expected measurable benefits

DARS-NIC-435152-C0H4N-v0: This study addresses clinically relevant priority research questions relating to SARS-CoV-2 in a specific patient group. Obtaining estimates of the proportion of those patients already exposed to COVID-19 helps inform knowledge and future planning in this research field. A greater understanding of the impact of immunosuppressive drugs on SARS-CoV-2 acquisition, illness and immunity is needed to help define at risk patient groups and to determine the impact of preventative social distancing strategies. This study addresses clinically relevant priority research questions relating to SARS-CoV-2 in a specific patient group. Obtaining estimates of the proportion of those patients already exposed to COVID-19 helps inform our knowledge and future planning. A greater understanding of the impact of immunosuppressive on SARS-CoV-2 acquisition, illness and immunity is needed to help define at risk patient groups and to determine the impact of preventative social distancing strategies. The data from this study may inform: 1. Alternative prescribing behaviour of immunosuppressive medication during the COVID pandemic if specific immunosuppressive therapies are associated with greater risks of severe COVID disease. 2. Alternative vaccination strategies if immunosuppressive drugs are associated immunosuppressive medication. AMENDMENT REQUEST DARS-NIC-435152-C0H4N-v1: [2 paragraphs unchanged] 2. Alternative vaccination strategies (ie - (i.e. booster doses, high dose vaccinations, alternative vaccination timing) if immunosuppressive drugs are associated immunosuppressive medication. None of the funding bodies have had, or will have, any role in study design, data collection or analysis, writing or presentation of the findings of the research, or decision to submit for publication, nor suppress any of the findings of the research.

Benefits reported

In reference to this application’s stated ‘objectives for processing’: In patients with inflammatory bowel disease, on immunosuppressive medication, RD&E defined in workflow 1 of CLARITY IBD: In patients with inflammatory bowel disease, on immunosuppressive medication, RD&E defined in workflow 1 of CLARITY IBD, which has subsequently been published (citation above): [4 paragraphs unchanged] Data supplied as part of the original and amendment applications contributed to the publication of the following manuscript: The use of data produced from the CLARITY IBD including outputs produced using data from NHS Digital have led to recommendations related to the COVID-19 vaccination schedule which seeks to get the best immune response possible to improve protection against COVID-19 infection and / or severe disease resulting from COVID-19 infection and so reduce mortality and morbidity in IBD patients treated with immuno-suppressive medication. 1. Chanchlani N*, Lin S*, Chee D, Hamilton B, Nice R, Zehra A, Bewshea C, Cipriano B, Derikx LAAP, Dunlop A, Greathead L, Griffiths RL, Ibraheim H, Kelleher P, Kok KB, Lees CW, MacDonald J, Sebastian S, Smith PJ, McDonald TJ, Irving PM, Powell N, Kennedy NA, Goodhand JR, Ahmad T. Adalimumab and infliximab impair SARS-CoV-2 antibody responses: results from a therapeutic drug monitoring study in 11422 biologic-treated patients. J Crohns Colitis. 2021 Sep 2:jjab153. doi: 10.1093/ecco-jcc/jjab153. In this paper, RD&E found that rates of PCR-confirmed SARS-CoV-2 infection were similar across treatment groups. Seroprevalence rates (number of persons in a population who test positive for a COVID-19 based on nasal/throat swab polymerase chain reaction, commonly performed to assess for acute infection) were lower in infliximab- and adalimumab- than vedolizumab-treated (immunosuppressive therapies) patients, and the magnitude of SARS-CoV-2 reactivity was similar in infliximab- vs adalimumab treated patients, but higher in vedolizumab-treated patients. This has led RD&E to conclude that adalimumab-treated patients, like infliximab-treated patients, have similar serological responses to COVID-19 infection, and likely, COVID-19 vaccination. To the best of RD&E's knowledge this is one of the only well-powered studies to look at the outcomes of adalimumab-treated patients to COVID-19 infection. The use of data produced from this substudy, as well as the wider CLARITY-IBD study, including outputs produced using data from NHS Digital have led to recommendations related to the COVID-19 vaccination schedule which seeks to get the best immune response possible to improve protection against COVID-19 infection and / or severe disease resulting from COVID-19 infection and so reduce mortality and morbidity in IBD patients treated with immuno-suppressive medication. [4 paragraphs unchanged]

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

Processing activities

[34 paragraphs unchanged] 2. Only the Royal Devon and Exeter NHS Foundation Trust will act as a data processor or controller. One of the co-chief investigators of the study is at Imperial College London. They are completing this under instruction of RD&E and are therefore not a data controller but however, have been listed as a data processor. [5 paragraphs unchanged]

Expected output

[8 paragraphs unchanged] Further outputs from the CLARITY IBD study: 1. Lin S*, Kennedy NA*, Saifuddin A*, Sandoval DM*, Reynolds CJ, Seoane RC, Kottoor SH, Pieper FP, Lin KM, Butler DK, Chanchlani N, Nice R, Chee D, Bewshea C, Janjua M, McDonald TJ, Sebastian S, Alexander JL, Constable L, Lee JC, Murray CD, Hart AL, Irving PM, Jones GR, Kok KB, Lamb CA, Lees CW, Altmann DM, Boyton RJ*, Goodhand JR*, Powell N*, Ahmad T*; CLARITY IBD study. Antibody decay, T cell immunity and breakthrough infections following two SARS-CoV-2 vaccine doses in inflammatory bowel disease patients treated with infliximab and vedolizumab. Nature Communications. 2022 Mar 16;13(1):1379. 2. Chanchlani N*, Lin S*, Chee D, Hamilton B, Nice R, Zehra A, Bewshea C, Cipriano B, Derikx LAAP, Dunlop A, Greathead L, Griffiths RL, Ibraheim H, Kelleher P, Kok KB, Lees CW, MacDonald J, Sebastian S, Smith PJ, McDonald TJ, Irving PM, Powell N, Kennedy NA, Goodhand JR, Ahmad T. Adalimumab and infliximab impair SARS-CoV-2 antibody responses: results from a therapeutic drug monitoring study in 11422 biologic-treated patients. J Crohns Colitis. 2021 Sep 2:jjab153. doi: 10.1093/ecco-jcc/jjab153. 3. Chee D*, Nice R*, Hamilton B, Jones E, Hawkins S, Redstone C, Cairnes V, Pohl K, Chanchlani N, Lin S, Kennedy NA, Ahmad T, Goodhand JR*, McDonald TJ*. Patient-led Remote IntraCapillary pharmacoKinetic Sampling (fingerPRICKS) for therapeutic drug monitoring in patients with inflammatory bowel disease. J Crohns Colitis. 2021 Jul 21:jjab128. 4. Kennedy NA*, Lin S*, Goodhand JR*, Chanchlani N, Hamilton B, Bewshea C, Nice R, Chee D, Cummings JF, Fraser A, Irving PM, Kamperidis N, Kok KB, Lamb CA, Macdonald J, Mehta S, Pollok RC, Raine T, Smith PJ, Verma AM, Jochum S, McDonald TJ, Sebastian S, Lees CW, Powell N*, Ahmad T*. Contributors to the CLARITY IBD study. Infliximab is associated with attenuated immunogenicity to BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines in patients with IBD. Gut. 2021 Apr 26:gutjnl-2021-324789. 5. Kennedy NA*, Goodhand JR*, Bewshea C, Nice R, Chee D, Lin S, Chanchlani N, Butterworth J, Cooney R, Croft NM, Hart AL, Irving PM, Kok KB, Lamb CA, Limdi JK, Macdonald J, McGovern DP, Mehta SJ, Murray CD, Patel KV, Pollok RC, Raine T, Russell RK, Selinger CP, Smith PJ, Bowden J, McDonald TJ, Lees CW, Sebastian S, Powell N*, Ahmad T*; Contributors to the CLARITY IBD study. Anti-SARS-CoV-2 antibody responses are attenuated in patients with IBD treated with infliximab. Gut. 2021 May;70(5):865-875. Patient engagement videos: Feb 2021 - https://www.youtube.com/watch?v=GZNFNAicRV4 Feb 2022 - https://www.youtube.com/watch?v=R67WUchmazA&t=8s Charity endorsement: https://www.crohnsandcolitis.org.uk/support/coronavirus/research-into-the-coronavirus-and-crohns-and-colitis/clarity Multiple newsletters for patients have been distributed throughout the study period. Four newsletters have been sent to all participants of the CLARITY IBD study (>7000 individuals) via email as well as all principal investigators, research nurses, and healthcare staff involved in the study (>120 UK hospitals). They can be found here: https://www.clarityibd.org/news. The study has an active twitter account (https://twitter.com/clarityibd) with almost 1000 followers where RD&E communicate up-to-date patient related information. Awarded best investigator-initiated study at European Crohn's Colitis Annual Conference in 2021.

Benefits reported

The use of this data has led to changes in vaccination schedules to get the best immune response possible to improve protection against COVID-19 infection and / or severe disease resulting from COVID-19 infection and so reduce mortality and morbidity in IBD patients treated with immuno-suppressives. In reference to this application’s stated ‘objectives for processing’: In patients with inflammatory bowel disease, on immunosuppressive medication, RD&E defined in workflow 1 of CLARITY IBD, which has subsequently been published (citation above): - seroprevalence (number of persons in a population who test positive for a COVID-19 based on nasal/throat swab polymerase chain reaction, commonly performed to assess for acute infection) of SARS-CoV-2 through the early phase of the pandemic. - seroconversion (time period during which SARS-CoV-2 antibodies develop and become detectable in the blood) in patients with confirmed infection by nasal/throat swab. - the magnitude (extent) of SARS-Cov-2 antibodies in patients with confirmed infection. - demographic factors associated with COVID-19 disease, including gender, age, and deprivation. Data supplied as part of the original and amendment applications contributed to the publication of the following manuscript: 1. Chanchlani N*, Lin S*, Chee D, Hamilton B, Nice R, Zehra A, Bewshea C, Cipriano B, Derikx LAAP, Dunlop A, Greathead L, Griffiths RL, Ibraheim H, Kelleher P, Kok KB, Lees CW, MacDonald J, Sebastian S, Smith PJ, McDonald TJ, Irving PM, Powell N, Kennedy NA, Goodhand JR, Ahmad T. Adalimumab and infliximab impair SARS-CoV-2 antibody responses: results from a therapeutic drug monitoring study in 11422 biologic-treated patients. J Crohns Colitis. 2021 Sep 2:jjab153. doi: 10.1093/ecco-jcc/jjab153. In this paper, RD&E found that rates of PCR-confirmed SARS-CoV-2 infection were similar across treatment groups. Seroprevalence rates (number of persons in a population who test positive for a COVID-19 based on nasal/throat swab polymerase chain reaction, commonly performed to assess for acute infection) were lower in infliximab- and adalimumab- than vedolizumab-treated (immunosuppressive therapies) patients, and the magnitude of SARS-CoV-2 reactivity was similar in infliximab- vs adalimumab treated patients, but higher in vedolizumab-treated patients. This has led RD&E to conclude that adalimumab-treated patients, like infliximab-treated patients, have similar serological responses to COVID-19 infection, and likely, COVID-19 vaccination. To the best of RD&E's knowledge this is one of the only well-powered studies to look at the outcomes of adalimumab-treated patients to COVID-19 infection. The use of data produced from this substudy, as well as the wider CLARITY-IBD study, including outputs produced using data from NHS Digital have led to recommendations related to the COVID-19 vaccination schedule which seeks to get the best immune response possible to improve protection against COVID-19 infection and / or severe disease resulting from COVID-19 infection and so reduce mortality and morbidity in IBD patients treated with immuno-suppressive medication. CLARITY IBD is referenced by current UK national and Canadian Task Forces who make recommendations related to COVID-19 vaccination schedules for patients on immunosuppressive therapies, including the biological agents infliximab, adalimumab, and vedolizumab (the primary treatments that this study is assessing): British Society of Gastroenterology Inflammatory Bowel Disease section and IBD Clinical Research Group position statement on SARS-CoV2 Vaccination (https://www.bsg.org.uk/wp-content/uploads/2021/01/BSG-IBD-Vaccine-Position-Statement-Updated-14th-September-2021.pdf). See in particular FAQ4 for reference to the Clarity study. Crohn’s and Colitis Canada (COVID-19 and IBD: vaccines: https://crohnsandcolitis.ca/About-Crohn-s-Colitis/COVID-19-and-IBD/Vaccines#Recommendations): “On August 24, 2021, the Crohn's and Colitis Canada COVID-19 and IBD Task Force convened to discuss the issue of booster vaccines in people with inflammatory bowel disease (IBD). The Task Force members reviewed the latest pre-print manuscript (not yet peer-reviewed) from the CLARITY-IBD study, and research in people without IBD who have compromised immune systems. The CLARITY-IBD study demonstrated that people with IBD who are using anti-TNF biologic therapies generally responded well to two doses of either an mRNA vaccine (BNT162b2, produced by Pfizer/BioNTech) or adenovirus-vector vaccine (ChAdOx1 nCOV-19, produced by Oxford/AstraZeneca), although not as well as people using vedolizumab to treat their IBD (a biologic that does not systemically suppress the immune system). In addition, the concentration of anti-COVID antibodies in people using infliximab dropped below the level thought necessary to provide immunity approximately 14–18 weeks after the second dose, which was not seen in those on vedolizumab or in healthy controls. The authors concluded that people with IBD receiving systemic immune-suppressing therapy should carefully follow public health guidelines on masking and physical distancing and should be considered for booster doses to improve immunity.” Crohn’s and Colitis UK, the national charity for IBD continue to regularly support and endorse the CLARITY IBD study to its patients: Coronavirus vaccine for people with Crohn’s or Colitis: https://www.crohnsandcolitis.org.uk/support/coronavirus/research-into-the-coronavirus-and-crohns-and-colitis/clarity, https://www.crohnsandcolitis.org.uk/news/latest-coronavirus-vaccine-for-people-with-crohns-or-colitis. These webpages outline, in detail, the utility of the results from the CLARITY IBD study, including how RD&E’s understanding of immunosuppressive medications used in the treatment of IBD impact COVID-19 infection and vaccination has improved. Data is referenced and cited directly from the CLARITY IBD output, including data from workflow 1 that has informed the charity’s recommendation, and clearly communicate the findings from the study.

Changed only in punctuation, spacing or capitalisation: Expected measurable benefits, Objective for processing.

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

Datasets: + COVID-19 Vaccination Status

Objective for processing

DARS-NIC-435152-C0H4N-v0: [22 paragraphs unchanged] Justification: The Royal Devon and Exeter NHS Foundation Trust is a NHS [52 words unchanged] including to improve the quality of care for people living with inflammatory arthritis. bowel disease. The data requested is necessary to this research as the same outputs and benefits could not otherwise be achieved. [15 paragraphs unchanged] AMENDMENT REQUEST DARS-NIC-435152-C0H4N-v1: In addition to the cohort linkage for the previous workflow, stated above, the researcher would like access to the COVID-19 Vaccination Status dataset. The vaccination data, including date, first or second dose, and type received; is being requested for approx. 7,229 patients who are part of the CLARITY-IBD, prospective, multicenter (pan-UK) study. This is a new cohort of patients. The researchers are regularly assessing (via questionnaire) these patients’ clinical status and performing SARS-CoV-2 antibody (nucleocapsid and spike) testing on submitted samples from these patients at pre-defined timepoints. By obtaining COVID-19 vaccination data with the already obtained patient identifiers, more detailed analysis can be carried out on SARS-CoV-2 antibody (nucleocapsid and spike) responses. This will provide a clearer picture of impact of COVID-19 infection and vaccination on patients with inflammatory bowel disease on immunosuppressive therapies. The patient data is flowing to NHS Digital under the COPI notice. CLARITY IBD is an investigator-led, UK National Institute for Health Research COVID-19 urgent public health study. Funding The study sponsor is the Royal Devon and Exeter NHS Foundation Trust. The study is funded by the Royal Devon and Exeter NHS Foundation Trust, Hull University Teaching Hospital NHS Trust and by unrestricted educational grants from: 1. F. Hoffmann-La Roche AG (Switzerland) - manufacture assays to detect anti-SARS-CoV-2 nucleocapsid and spike antibodies. These assays are used in the conduct of this study. By using these assays, and publishing methodology as to how they are used and how they validated the assays, it is possible that other research groups might start to use these assays for COVID-19 related research questions, leading to increased use of the product. Furthermore, it is possible that results will garner interest from the mainstream and scientific media, particularly if the findings change onward practice, such as vaccination schedules. Press releases and media coverage may mention the fact that the assays used are from this commercial provider, leading to increased awareness of the product, and potentially, increased use of them, which may be a commercial benefit 2. Biogen GmbH (Switzerland) – manufacture biosimilar infliximab and adalimumab, which are used to treat inflammatory bowel disease. The study includes participants treated with infliximab 3. Celltrion Healthcare (South Korea) - also manufacture biosimilar infliximab 4. Galapagos NV (Belgium) – currently conducting clinical trials of therapies that may be used in the future treatment of inflammatory bowel disease 5. Takeda UK – manufacture vedolizumab which is used to treat inflammatory bowel disease. The study includes participants treated with vedolizumab All four drug companies who have funded the study are aware of each other’s funding/contribution to the study. None of the funding bodies have had, or will have, any role in study design, data collection or analysis, writing or presentation of the findings of the research, or decision to submit for publication, nor suppress any of the findings of the research. The aim of the study is to increase the understanding of immunosuppressive therapies, infliximab and vedolizumab, on COVID-19 infection and vaccination, through a multi-centre observational study. Manufacturers of both study drugs have contributed funds to the study. Findings are unlikely to have any impact on drug manufacturing or commercialisation of therapies for inflammatory bowel disease in any way. It is possible, where there is equipoise in terms of treatment impact on COVID-19 infection and vaccination, results may influence choice of treatment by the treating physician only, not the drug manufacturer, so any commercial or non-commercial impact for any of the funders is unlikely in this regard. The results of the study will be helpful for drug manufacturers as they will aid theirs, as well as the public’s and healthcare professional’s understanding, on how treatments impact COVID-19 infection and vaccination, but researchers cannot identify any onward benefit apart from increased understanding and education on the topic for the commercial funders. None of the funding bodies have had, or will have, any role in study design, data collection or analysis, writing or presentation of the findings of the research, or decision to submit for publication, nor suppress any of the findings of the research. Involvement of other organisations Hull University and Hull University Hospital have provided financial assistance for the project, but have had no input as to how the data should be acquired or processed. They do not determine the purpose or means of the project. They will have no access to NHS Digital data. One of the co-chief investigators of the study is at Imperial College London. This investigators team are conducting the T-cell experiments relating to vaccine response. They are completing this under instruction of RD&E and are therefore not a data controller but however, have been listed as a data processor. PATIENT & PUBLIC INVOLVEMENT Patient Survey An electronic survey was conducted to gauge the opinion of patients with IBD on the planned research. 250 patients completed the questionnaire from 74 hospitals including 71 patients who regularly attend a biologic infusion unit. All of the proposed research questions were rated as important or very important by at least 83% of participants and 3 of the questions were rated as important or very important by 90% of patients. All but one patient expressed either equal or strong preference for computer-based forms including 82% of patients expressing a strong preference. Every patient surveyed wanted to be informed of the test result despite the fact the researchers don’t know if a positive test means an individual is immune from further infection. Exeter IBD Patient Panel The Exeter IBD Patient panel helped refine the study questions. The group have reviewed the study protocol and supported the writing of the patient information sheet and the practicalities and testing of electronic consent and patient questionnaire. A member of the Exeter IBD patient’s panel sits on the Study management committee ensuring patient involvement in all aspects of study delivery, data analysis and dissemination of findings.

Processing activities

DARS-NIC-435152-C0H4N-v0: [20 paragraphs unchanged] d. The linkage will be on a deterministic basis using NHS number and/or Post Code. This is the only way to link the datasets. [6 paragraphs unchanged] AMENDMENT REQUEST DARS-NIC-435152-C0H4N-v1: In addition to the cohort linkage for the previous workflow stated above, details for the amendment to the processing activities are given below: The Royal Devon and Exeter NHS Foundation Trust will transfer to NHS Digital the patient identifiers for approximately 7,229 patients. The identifiers included will be name, date of birth, gender, and NHS number paired with a unique identifier to support pseudonymisation. The data is identifiable and is not available in the public domain. The patient identifiers will be provided to NHS Digital so that this can be linked to the COVID-19 vaccination data. NHS Digital will use the patient identifiers to filter COVID-19 vaccination data for the identified patients since the start of the COVID-19 vaccination programme and provide back only the data for the patients requested, thus minimising the total amount of data requested. 1. NHS Digital will send the linked pseudonymised COVID-19 vaccination data to the Royal Devon and Exeter NHS Foundation Trust. 2. Only the Royal Devon and Exeter NHS Foundation Trust will act as a data processor or controller. 3. The Royal Devon and Exeter NHS Foundation Trust will have access to pseudonymised record-level data. The Royal Devon and Exeter NHS Foundation Trust will carry out statistical analysis to support the objectives of the CLARITY IBD study on the pseudonymised data set only. The process for keeping the identifiable data and pseudonymised datasets separate at Royal Devon & Exeter NHS Foundation Trust is as follows: • There is only one person who will be accessing the identifiable data within the Royal Devon & Exeter NHS Foundation Trust, and no other study team personnel will be able to access the identifiable data. Each study participant has been given a study ID, and first and last name, along with other identifying demographic features and these are only available to that one person All other study personnel only access study participant's files by study ID. • Study personnel will have access to the pseudonymised data from NHS Digital. • The identifiable data and the pseudonymised data from NHS Digital will be stored on a NHS-encrypted server but separately and only accessed by the named person.

Expected output

DARS-NIC-435152-C0H4N-v0: [4 paragraphs unchanged] AMENDMENT REQUEST DARS-NIC-435152-C0H4N-v1: Researchers will continue to publish results from the vaccination data in high impact journals which will inform the scientific and vaccine community, as well as inform public health strategies for vaccinating people with IBD. Researchers aim to work to a similar timescale for this proposed project.

Expected measurable benefits

DARS-NIC-435152-C0H4N-v0: [4 paragraphs unchanged] AMENDMENT REQUEST DARS-NIC-435152-C0H4N-v1: The data from this study may inform: 1. Alternative prescribing behaviour of immunosuppressive medication during the COVID pandemic if specific immunosuppressive therapies are associated with greater risks of severe COVID disease or failure to mount antibody responses post COVID-19 vaccination. 2. Alternative vaccination strategies (ie - booster doses, high dose vaccinations, alternative vaccination timing) if immunosuppressive drugs are associated immunosuppressive medication. None of the funding bodies have had, or will have, any role in study design, data collection or analysis, writing or presentation of the findings of the research, or decision to submit for publication, nor suppress any of the findings of the research.

Benefits reported

Yielded Benefits is not a requirement for new applications. The use of this data has led to changes in vaccination schedules to get the best immune response possible to improve protection against COVID-19 infection and / or severe disease resulting from COVID-19 infection and so reduce mortality and morbidity in IBD patients treated with immuno-suppressives.