Real-world effectiveness of the Oxford/AstraZeneca covid-19 vaccine and investigation of the epidemiology of thrombotic thrombocytopenia and other adverse events of interest following COVID-19 vaccination in England - SDE Analysis

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

Objective for processing

***This agreement will cover 2 purposes: The Real-world effectiveness of the Oxford/AstraZeneca covid-19 vaccine and investigation of the epidemiology of thrombotic thrombocytopenia and other adverse events of interest following COVID-19 vaccination in England - SDE Analysis Study covers 3 purposes: PURPOSE 1: *** The objective Data will be processed for processing the requested data is this purpose to support delivery of a real-world effectiveness study for COVID-19 vaccines in [22 words unchanged] one dose of the vaccine, overall and by age group and time period after 1 dose. The secondary objective of the study would be to: a) assess the vaccine effectiveness in people who have received the two doses; the timing after the 1st and 2nd doses, interval between the two doses and comorbidity status b) replicate the above analyses in people receiving the Pfizer-BioNTech as opposed to the Oxford/AstraZeneca vaccine. ***PURPOSE 2: The secondary objective of the study is to: Broadly, the objective for this analysis is to investigate the epidemiology of thrombotic thrombocytopenia syndrome (TTS) and also to investigate the association between risk of TTS following a COVID-19 vaccine. TTS is a new, very rare blood-clotting condition linked to the COVID-19 vaccine (Blood clots are common and not all types of blood clot that occur after vaccination will be linked to the vaccine). It occurs when a person has blood clots (thrombosis) as well as low platelet counts (thrombocytopenia). a) assess the vaccine effectiveness in people who have received the two doses; the timing after the 1st and 2nd doses, interval between the two doses and comorbidity status b) replicate the above analyses in people receiving the Pfizer-BioNTech as opposed to the Oxford/AstraZeneca vaccine. PURPOSE 2: These analyses will include other Medicines and Healthcare products Regulatory Agency (MHRA)-approved COVID-19 vaccines. Broadly, the objective for this analysis is to investigate the epidemiology of thrombotic thrombocytopenia syndrome (TTS) and also to investigate the association between risk of TTS following a COVID-19 vaccine. TTS is a new, very rare blood-clotting condition linked to the COVID-19 vaccine (Blood clots are common and not all types of blood clot that occur after vaccination will be linked to the vaccine). It occurs when a person has blood clots (thrombosis) as well as low platelet counts (thrombocytopenia). [1 paragraph unchanged] 1)Estimate 1) Estimate occurrence of thrombotic thrombocytopenia, thromboembolism, and thrombocytopenia (definitions including sub-setting for specific [6 words unchanged] definitions section), overall and split by age, gender and known risk factors. [4 paragraphs unchanged] 6) Conduct exploratory assessment of case definitions and disease aetiology using artificial intelligence (AI)-based approaches. This will utilise prediction modelling to identify potential risk factors of TTS. **** Access to the data requested in this Agreement will be via the NHS Digital Trusted Research Environment (TRE). No record level data will leave NHS Digital. PURPOSE 3: Existing TRE users will migrate to the Secure Data Environment (SDE). SDE is a data storage and access platform that enables approved users to access de-identified data and analytical tools for approved projects. Users must identify themselves via a multi-factor authentication mechanism and are only able to access the datasets detailed within this Agreement. Users can request that aggregated outputs are exported from the system following approval by trained NHSD staff. The access and use of the system is fully auditable, and all users must comply with the use of the data as specified in this Agreement. 1) To report the vaccine effectiveness of booster doses (3rd dose) of COVID-19 vaccine and investigate their risk of developing thrombotic thrombocytonpenia, thromboembolism and thrombocytopenia within a pre-defined time interval (these analyses may include other MHRA-approved vaccines other than Pfizer-BioNTech and ChAdOx1). The study team's primary age of interest are people 16 years or older who were eligible to receive the vaccine. Age for the purpose of this study is their age on 31st March 2021 - the index data selected in the UK by the Joint Committee for Vaccination and Immunisation (JCVI). However, the study also wish to look at data for all ages reasons for this are detailed below; COMMERCIAL ELEMENT: • Vaccination may occur before an individual’s 16th birthday. Additionally, the study team require baseline data and all the available medial history for vaccines, but also for to examine their comparability among comparison groups. The study team therefore required their lifelong medical data. This may date from before their vaccination date. Evidence demonstrating the effectiveness and safety of the vaccines may increase policymaker, healthcare professionals (HCP) and public confidence in the vaccines which could lead to an increase in use of the AstraZeneca COVID-19 vaccine, however it should be noted that the AstraZeneca COVID-19 vaccine is no longer offered as primary series or booster in UK. The primary benefit of the study to AstraZeneca is to allow AstraZeneca to fulfil their regulatory commitments, and thus maintain their license. • Also, levels of community infection impacts of vaccine effectiveness. The study team need to have some indication of the extent to which vaccines have been exposed to community infection. The studies are not conducted with the intention of generating profit. The primary focus will be on developing a further understanding of the efficacy and safety of the vaccines being administered globally. • Vaccination age has been extended to children and young people aged 12 to 15 years old with comorbidities, or for all children and young adults aged 12 to 17 years old. Childhood vaccination is taking place internationally and is now authorised in Europe and the United States – generally from ages 12 to 17 years old. Results of the studies will aim to improve the confidence of the vaccines and increase uptake of the vaccine. Astra Zeneca UK may benefit from use of the service as it could also be assumed that the processing will result in increased intelligence on the product. NHS organisations may not recognise the potential of the product if it is not being utilised appropriately through use of the service. The patient benefits possible by providing the service to support increased knowledge within the NHS result may result in a companies product being used, therefore this connection could also be assumed as a commercial benefit. • Models of vaccine effectiveness need to include information about household size and population levels of disease. Larger households have a higher risk of infection and high levels of childhood infection in a locality are associated with a population-wide increased number of cases. The pseudonymised datasets requested in this application for access in the NHS Digital TRE are as follows: > Hospital Episode Statistics (HES) Admitted Patient Care (APC) (2019/20 to latest provisional data) > Hospital Episode Statistics Critical Care (CC) (2019/20 to latest provisional data) > Civil Registration - Deaths (March 2020 to latest available) > ***HES- Civil Registration (Deaths) bridge*** > COVID-19 Second Generation Surveillance System (SGSS) (April 2020 to latest available) > COVID-19 UK Non-hospital Antibody Testing Results (Pillar 3) (September 2020 to latest available) > COVID-19 UK Non-hospital Antigen Testing Results (Pillar 2) (April 2020 to latest available) > COVID-19 Vaccination Status (December 2020 to latest available) > ***COVID-19 Vaccination Adverse Reactions *** > GPES Data for Pandemic Planning and Research (COVID-19) (latest available) > Uncurated Low Latency Hospital Data Set - Admitted Patient Care (2019/20 to latest provisional data) > ***Uncurated Low Latency Hospital Data Set - Outpatients*** The size of the cohort will be every citizen registered with a GP practice in England who have not registered a Type 1 opt-out. These datasets were required to adequately define a cohort of vaccinated and unvaccinated patients and to assess relevant demographic clinical characteristics, exposures and outcomes to robustly match patients and to assess the study outcomes. The cohort has now been defined. Data will be pseudonymised record-level data to allow linkage across datasets and patient-level analysis. Outputs of the study will be aggregated and suppressed according to disclosure rules of each data set. The datasets are also being requested as an extract to flow to University of Oxford under data sharing agreement DARS-NIC-459114-J3C1F to be linked to the data in the University of Oxford trusted research environment to develop analysis code and algorithms for analyses in a smaller cohort to which they will be linked, prior to these analysis code (epidemiological[a] models) and algorithms (ontological[b] algorithms for case identification[c]) being deployed in the national level data. [a] relating to the branch of medicine which deals with the incidence, distribution, and control of diseases. [b] showing the relations between the concepts and categories in a subject area or domain. [c] timely disease notification is an essential first step in initiating infectious disease case management. [1 paragraph unchanged] The University of Oxford are Joint Data Controllers with and AstraZeneca Limited UK Limited (also known as AstraZeneca Global). The Global) are joint data controllers as both organisations are jointly responsible for ensuring that the data will only be processed by University of Oxford and by Momentum Data. University of Oxford have subcontracted a part of for the analysis to Momentum Data who will solely be acting as data processors on the instructions from University of Oxford and AstraZeneca UK Limited. purpose described above. The data will only be processed by University of Oxford & Momentum Data. University of Oxford have subcontracted a part of the analysis to Momentum Data who will solely be acting as data processors on the instructions from University of Oxford and AstraZeneca UK Limited. [1 paragraph unchanged] The lawful basis for processing data under GDPR has been reviewed and been assessed as acceptable. The University of Oxford process data under Article 6(1)(e): "processing is necessary for the performance of a task in the public interest or in the exercise of official authority vested in the controller" as they are a Public Authority. The lawful basis for processing personal data under the UK GDPR is: AstraZeneca UK Limited process data under Article 6(1)(f): “Legitimate interests: the processing is necessary for your legitimate interests or the legitimate interests of a third party, unless there is a good reason to protect the individual’s personal data which overrides those legitimate interests. (This cannot apply if you are a public authority processing data to perform your official tasks.)” For University of Oxford: Additionally, the University of Oxford and AstraZeneca UK Limited process the Special Category Health Data under 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" as the data are required for research purposes in the public interest. 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; COMMERCIAL PURPOSE For AstraZeneca: AstraZeneca is a co-partner with the University of Oxford in the development, manufacture and supply of the Oxford AstraZeneca COVID-19 Vaccine. Article 6(1)(f) - processing is necessary for the purposes of the legitimate interests pursued by the controller or by a third party, except where such interests are overridden by the interests or fundamental rights and freedoms of the data subject which require protection of personal data, in particular where the data subject is a child. AstraZeneca has determined the processing is necessary for its legitimate interests in being able to provide evidence that helps to grow public confidence in vaccine effectiveness which is highly important to minimize vaccine hesitancy and increase uptake of vaccine to help bring an end to the COVID-19 pandemic. The studies are not conducted with the intention of generating profit. The primary focus will be on developing a further understanding of the efficacy and safety of the vaccines being administered globally. Results of the studies will improve the confidence of the vaccines and increase uptake of the vaccine. The lawful basis for processing special category data under the UK GDPR is: For University of Oxford and AstraZeneca: Article 9(2)(j) - processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject. The data are required for research purposes in the public interest - meeting the conditions in the DPA 2018 Schedule 1 Part 1 (4) - which GDPR Recital 52(2) determines is an appropriate derogation from the prohibition on processing special categories of personal data. In accordance with GDPR Article 89(1) processing is subject to appropriate safeguards. These include: i. The data will be pseudonymised prior to access being provided by NHS England to the data recipient, ii. The data recipient’s technical and organisational measures to safeguard the data have been assessed and meet NHS England’s acceptance criteria; iii. The requested data has been assessed as proportionate to the aim pursued; iv. Controls, data retention and processing activities have been assessed to ensure respect to the essence of the right to data protection; v. Measures to protect the rights and freedoms of data subjects have been assessed including transparency (fair processing) publishing subject’s rights to withdraw consent and/or have their data erased or rectified, etc. The funding is provided by AstraZeneca.

Processing activities

No record level data will be extracted out of NHS Digital under this Data Sharing Agreement. Only aggregated data with small number suppression applied as per the relevant data set disclosure rules will be extracted out of the TRE under this Data Sharing Agreement (DSA). All processing will be conducted within the NHS Digital Trusted Research Environment (TRE) by University of Oxford and Momentum Data substantive employees who are appropriately qualified and trained in data protection and confidentiality. No identifiable data items will be accessed by either the Data Controller or Data Processor for the purpose of processing these data. No attempt will be made to reidentify individuals. DATA Under this Agreement, substantive employees of the University of Oxford and Momentum Data will use the Trusted Research Environment (TRE) service for England to enable analyses of linked, nationally collated healthcare datasets to enumerate the impact of the COVID-19 vaccination programme on the population of England. Access to the data requested in this Agreement will be via the NHS England's Controlled Environment. No record level data will leave NHS England. The pseudonymised datasets requested in this application for access in NHS England's Controlled Environment are as follows: Individually authorised analysts employed by University of Oxford and Momentum Data will be granted remote secure access to the Trusted Research Environment (TRE) within NHS Digital’s data platform, the Data Processing Service (DPS). · Hospital Episode Statistics Admitted Patient Care (HES APC) Within the TRE, the analysts will be able to access pseudonymised linked data only from the datasets outlined above. No data which directly identify data subjects, such as names, NHS Numbers, etc., will be accessible within the TRE. · Hospital Episode Statistics Critical Care (HES Critical Care) Analysts will be authorised to access only the data they are permitted to see under this Agreement and can utilise a variety of analytical tools available within the TRE platform. · Uncurated Low Latency Hospital Data Sets - Admitted Patient Care Only summary, aggregate results data (data will be aggregated with small numbers suppressed in line with the relevant data set disclosure rules) will be exported from the TRE and this will be subject to review and approval by the NHS Digital team providing the TRE. The objective of this will be to ensure that no output contains information which could be used either on its own or in conjunction with other data to breach an individual's privacy. · Uncurated Low Latency Hospital Data Sets – Outpatient · Civil Registrations of Death · COVID-19 General Practice Extraction Service (GPES) Data for Pandemic Planning and Research (GDPPR) · COVID-19 SGSS First Positives (Second Generation Surveillance System) · COVID-19 UK Non-hospital Antigen Testing Results (Pillar 2) · Covid-19 UK Non-hospital Antibody Testing Results (Pillar 3) · COVID-19 Vaccination Adverse Reactions · COVID-19 Vaccination Status These datasets are required to adequately define a cohort of vaccinated and unvaccinated patients and to assess relevant demographic clinical characteristics, exposures and outcomes to robustly match patients and to assess the study outcomes. Data will be pseudonymised record-level data to allow linkage across datasets and patient-level analysis. Outputs of the study will be aggregated and suppressed according to disclosure rules of each data set. COHORT The study's age interest is those aged 16 years or older who were eligible to receive the vaccine as of 31st March 2021 - the index data selected in the UK by the Joint Committee for Vaccination and Immunisation (JCVI). However, the study also wishes to look at data for all ages reasons for this are detailed below; • Vaccination may occur before an individual’s 16th birthday. Additionally, the study team require baseline data and all the available medical history for vaccines, but also to examine their comparability among comparison groups. The study team therefore required their lifelong medical data. This may be covered by data prior to their vaccination date. • Also, the study seeks to analyse the affects of levels of community infection on vaccine effectiveness. The study team need to have some indication of the extent to which vaccines have been exposed to community infection. • Vaccination age has been extended to children and young people aged 12 to 15 years old with comorbidities, or for all children and young adults aged 12 to 17 years old. Childhood vaccination is taking place internationally and is now authorised in Europe and the United States – generally from ages 12 to 17 years old. • Models of vaccine effectiveness need to include information about household size and population levels of disease. Larger households have a higher risk of infection and high levels of childhood infection in a locality are associated with a population-wide increased number of cases. The size of the cohort will be every citizen registered with a GP practice in England who have not registered a Type 1 opt-out. The data will be limited to data between 2019/20 – latest available. NHS England’s Controlled Environment is a data storage and access platform that enables approved users to access de-identified data and analytical tools for approved projects. Users must identify themselves via a multi-factor authentication mechanism and are only able to access the datasets detailed within this agreement. Users can request that aggregated outputs are exported from the system following approval by trained NHSE staff. The access and use of the system is fully auditable, and all users must comply with the use of the data as specified in this agreement. All processing will be conducted within the NHS England's Controlled Environment by University of Oxford's & Momentum Data's substantive employees who are appropriately qualified and trained in data protection and confidentiality. Within NHS England's Controlled Environment, the analysts will be able to access pseudonymised linked data only from the datasets outlined above. No data which directly identify data subjects, such as names, NHS Numbers, etc., will be accessible within NHS England's Controlled Environment. Analysts will be authorised to access only the data they are permitted to see under this Agreement and can utilise a variety of analytical tools available within NHS England's Controlled Environment platform. No attempt will be made to reidentify individuals. Only summary, aggregate results data (data will be aggregated with small numbers suppressed in line with the relevant data set disclosure rules) will be exported from NHS England's Controlled Environment and this will be subject to review and approval by the NHS England team providing NHS England's Controlled Environment. The objective of this will be to ensure that no output contains information which could be used either on its own or in conjunction with other data to breach an individual's privacy. [1 paragraph unchanged] > Provision of data products in the NHS Digital TRE England's Controlled Environment by NHS Digital Staff England staff [4 paragraphs unchanged] LIMITATION OF COVID-19 VACCINE DATA USAGE AstraZeneca has ethical approval to process data on MHRA-approved COVID-19 vaccines, the analyses will be focussed on individuals who have received two specific COVID-19 vaccines i.e AstraZeneca and Pfizer. However, in order to categorise unvaccinated individuals and individuals vaccinated with other vaccine brands such as Moderna, Jansen etc, the analysts will process all COVID-19 vaccines for categorization purposes. AstraZeneca has ethical approval to process data on only two specific COVID-19 vaccines. Therefore, the Data Processors, for this Agreement and until further ethical approval has been granted, should only process and analyse data on the two specific COVID-19 vaccines they have permission to study. University of Oxford and Momentum Data will use the data to enable analyses of linked, nationally collated healthcare datasets to enumerate the impact of the COVID-19 vaccination programme on the population of England. Amazon Web Services is strictly a data processor in the sense that NHS Digital data are hosted and manipulated on their infrastructure. By design, AWS themselves cannot access or read any of the NHS Digital data in the TRE that are hosted on their infrastructure, nor can anyone else who is not specifically granted individual access to NHS Digital data via a Data Sharing Agreement. Therefore, any access to the data held under this Agreement would be considered a breach of the Agreement. This includes granting of access to the database[s] containing the data. Amazon Web Services UK are compliant with standard security frameworks, including ISO 9001, 27001, 27017, 27018; the Cloud Security Alliance certification and UK Cyber Essentials Plus. Amazon Web Services will only be storing NHS Digital data on UK based servers. [1 paragraph unchanged] For GPES Data for Pandemic Planning and Research (COVID-19) - Whilst there [8 words unchanged] public consumption should follow the Government (ONS) Statistical Service disclosure controls. NHS Digital England recommend that users review and follow the disclosure control guidelines as set out within the HES Analysis Guide. Some, but not all requirements are outlined below: [12 paragraphs unchanged] For COVID-19 Second Generation Surveillance System (SGSS), COVID-19 UK Non-hospital Antibody Testing Results (Pillar 3), COVID-19 UK Non-hospital Antigen Testing Results (Pillar 2) and the Vaccination data - As standard, all disseminations for these data set will adhere to the following business rules, as agreed with the IAO, on top of normal exclusion criteria: 1. Always filter the extract to be England only. This should be applied using the subjects home postcode, or country (if derived from subjects home postcode)** postcode). NHS England would action this before data is made available to AZ. Only pseudo data will be accessed by AZ in NHS England's Controlled Environment [10 paragraphs unchanged]

Expected output

[1 paragraph unchanged] - Summary baseline characteristics of population (demographics, comorbidities, other relevant treatments) - Vaccination information (Vaccine received, dose number, when received) - COVID-19 outcomes (hospitalisation, critical care, mortality associated with COVID-19 infection) - All cause outcomes (hospitalisation, critical care, mortality for any reason) Small numbers will be supressed suppressed as required following standard statistical disclosure control methods. There has been a significant delay in initially receiving access to the data. The first read out of the vaccine effectiveness studies using data [5 words unchanged] as of 13th October 2022. A manuscript is in preparation for publication. Currently, Follow-up work is being done was then conducted on the national population using the same statistical scripts within NHS England's Controlled Environment. All the NHS Digital TRE. analyses related to vaccine effectiveness (Purpose 1) have been completed. The aim is methodology and study design were presented as a poster at a conference in the summer of 2022. The results have been submitted to complete the final analysis MHRA and European Medicines Agency (EMA) regulatory authorities. These regulatory authorities will require further clarification on the results, therefore processing will persist for Purpose 1 for this reason. Manuscripts are currently being written for the vaccine effectiveness studies by December 2022. The focus will then be on the analysis for the TTS studies and aim to complete them by June 2023. different stages of Purpose 1 analysis. Analyses for Purpose 2 and 3 are due to be completed at the end of 2023. The study team are planning to disseminate findings immediately after conducting the analysis, Therefore, the analysis target date will be dependent on the date data will be supplied by NHS Digital. expecting a further clarification period for results of this analyses. The medical writers are currently writing the manuscript for the vaccine effectiveness studies and the aim is to submit this to an international journal by the end of November 2022. The methodology and study design were presented as a poster at a conference in the summer of 2022. [1 paragraph unchanged]

Expected measurable benefits

The vaccine has been proven to be effective in trials thus far, [40 words unchanged] government roll-out strategy is critical to gaining control of the COVID-19 pandemic. The following expected benefits relate to the outcomes of each of the purposes described within this data sharing agreement which aim to ultimately address the effectiveness and risks associated with the vaccines. ****Additionally, Additionally, a rare syndrome of thrombosis (TTS) associated with low platelets has been [55 words unchanged] thrombotic thrombocytopenia or its relationship with prior COVID-19 infection or COVID-19 vaccination. This study will explore if there is a causal association of the syndrome with COVID-19 vaccination. The results will have an impact on policies related vaccination.**** to vaccination. The anticipated benefit expected from processing the data ***for both purposes ***is is to demonstrate the effectiveness of the COVID-19 vaccines and the UK vaccine [5 words unchanged] in England. Understanding of this effectiveness is expected to benefit citizens, healthcare professionals (HCPs), professionals, government and policy makers, vaccine manufacturers and researchers. AstraZeneca and University of [77 words unchanged] vaccine roll-out plan with regards to staggered age groups and vulnerable groups. In just over Over the course of 12 months, Oxford-AstraZeneca have developed a vaccine that is highly effective against [54 words unchanged] medicines is paramount both during clinical development and once approved for use. [2 paragraphs unchanged] The benefits Oxford-AstraZeneca hope will be identified for the various stakeholders are [51 words unchanged] position to be able to generate this evidence on a national level. This is on top of the health and emotional benefits to citizens gained through avoidance of severe COVID disease. This is on top of the health and emotional benefits to citizens gained through avoidance of severe COVID disease.

Benefits reported

Initial outputs have been about the vaccine effectiveness of the 2 vaccines. Additionally, the University of Oxford have been able to show the vaccine effectiveness in the older age group (> 65years). To date, the University of Oxford have been able to show the vaccine effectiveness in the older age group (> 65years). These results will hopefully inform policy change in future vaccination strategies. However, the University of Oxford are still awaiting analyses to be completed to be able to get the complete benefit of carrying out this study. The data processors have had only partial data from NHS England to date which is not yet enough to provide any conclusive analysis for the study. Therefore, no Yielded Benefits have yet been attained. AstraZeneca has completed the analyses to investigate vaccine effectiveness within ORCHID and the results are currently being written up as a manuscript. These analyses have been focussed on the vaccine effectiveness in older age groups i.e. over 65’s and immunocompromised individuals. Analysis of the study to investigate vaccine effectiveness in the entire national population have begun. As of May 2023, analysis related to Purpose 1 has been completed, however outputs from this analysis are currently being assessed by regulatory authorities. Any benefits expected from this analysis will be realised once these outcomes have been clarified by regulatory authorities and published. Analysis performed within Purposes' 2 & 3 are yet to be finalised before outputs from these areas are produced for the purpose of the benefits outlined above. These results will hopefully inform policy change in future vaccination strategies. However, the University of Oxford are still awaiting analyses to be completed to be able to get the complete benefit of carrying out this study. The data processors have had only partial data from NHS Digital to date which is not yet enough to provide any conclusive analysis for the study. Therefore, no Yielded Benefits have yet been attained. .

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

Datasets: − HES:Civil Registration (Deaths) bridge

Objective for processing

[2 paragraphs unchanged] The objective for processing the requested data is to support delivery of a real-world effectiveness study for COVID-19 vaccines in England. The primary objective of this study is the to assess the real world real-world effectiveness of the Oxford/AstraZeneca COVID-19 vaccine among people who receive one dose [31 words unchanged] have received the two doses; the timing after the 1st and 2nd dose , doses, interval between the two doses and comorbidity status b) replicate the above analyses in people receiving the Pfizer-BioNTech as opposed to the Oxford/AstraZeneca vaccine. [1 paragraph unchanged] Broadly, the objective for this analysis is to investigate the epidemiology of [56 words unchanged] person has blood clots (thrombosis) as well as low platelet counts (thrombocytopenia). Purpose 2 aims to: Purpose 2 aims to: [7 paragraphs unchanged] The study team's primary age of interest are people 16 years or older who are currently scheduled to receive the vaccine. Age for the purpose of this study is their age on 31st March 2021 - the index data selected in the UK by the Joint Committee for Vaccination and Immunisation (JCVI). However the study also wish to look at data for all ages reasons for this are detailed below; Existing TRE users will migrate to the Secure Data Environment (SDE). SDE is a data storage and access platform that enables approved users to access de-identified data and analytical tools for approved projects. Users must identify themselves via a multi-factor authentication mechanism and are only able to access the datasets detailed within this Agreement. Users can request that aggregated outputs are exported from the system following approval by trained NHSD staff. The access and use of the system is fully auditable, and all users must comply with the use of the data as specified in this Agreement. The study team's primary age of interest are people 16 years or older who were eligible to receive the vaccine. Age for the purpose of this study is their age on 31st March 2021 - the index data selected in the UK by the Joint Committee for Vaccination and Immunisation (JCVI). However, the study also wish to look at data for all ages reasons for this are detailed below; [2 paragraphs unchanged] • Vaccination age has been extended to children and young people age aged 12 to 15 years old with comorbidities, or for all children and young adults age aged 12 to 17 years old. Childhood vaccination is taking place internationally and [6 words unchanged] the United States – generally from ages 12 to 17 years old. [1 paragraph unchanged] In addition to the above processing activities, the NHS Digital Data Production team have been asked to develop and apply a household key to enable the analysts to establish potential household transmission. For this purpose each individual's address will be used to link individuals to a household. A new work request will be initiated to define and scope the development required to deliver this key if and when approved this will be delivered into the NHS Digital TRE environment. An amendment to this agreement would be required to ensure that the appropriate approvals have been sought for this and that the field is then added to the agreement. [1 paragraph unchanged] > Hospital Episode Statistics (HES) Admitted Patient Care (APC) (2019/20 to latest provisional data) > Hospital Episode Statistics Critical Care (CC) (2019/20 to latest provisional data) > Civil Registration - Deaths (March 2020 to latest available) > ***HES- Civil Registration (Deaths) bridge*** > COVID-19 Second Generation Surveillance System (SGSS) (April 2020 to latest available) > COVID-19 UK Non-hospital Antibody Testing Results (Pillar 3) (September 2020 to latest available) > COVID-19 UK Non-hospital Antigen Testing Results (Pillar 2) (April 2020 to latest available) > COVID-19 Vaccination Status (December 2020 to latest available) > ***COVID-19 Vaccination Adverse Reactions *** > GPES Data for Pandemic Planning and Research (COVID-19) (latest available) > Uncurated Low Latency Hospital Data Set - Admitted Patient Care (2019/20 to latest provisional data) > ***Uncurated Low Latency Hospital Data Set - Outpatients*** [1 paragraph unchanged] These datasets are were required to adequately define a cohort of vaccinated and unvaccinated patients and [7 words unchanged] and outcomes to robustly match patients and to assess the study outcomes. The cohort has now been defined. [14 paragraphs unchanged]

Processing activities

[7 paragraphs unchanged] > Provision of data products in the NHS Digital TRE Environment by NHS Digital Staff > Linkage of data products at a patient record level > Creation of analytical dataset and study variables > Statistical analysis and modelling > Creation of final outputs and results tables. tables [1 paragraph unchanged] AstraZeneca has ethical approval to process data on only two specific COVID-19 vaccines. Therefore Therefore, the Data Processors, for this agreement (v2) Agreement and until further ethical approval has been granted, should only process and analyse data on the two specific COVID-19 vaccines they have permission to study. Amazon Web Services is, strictly, is strictly a data processor in the sense that NHS Digital data are hosted [33 words unchanged] is not specifically granted individual access to NHS Digital data via a data sharing agreement. Data Sharing Agreement. Therefore, any access to the data held under this agreement Agreement would be considered a breach of the agreement. Agreement. This includes granting of access to the database[s] containing the data. [27 paragraphs unchanged]

Expected output

[6 paragraphs unchanged] 1st Interim analysis (after 1st dose) - Target date: July 2021* There has been a significant delay in receiving data. The first read out of the vaccine effectiveness studies using data extract into ORCHID was completed as of 13th October 2022. A manuscript is in preparation for publication. Currently, work is being done on the national population using the same statistical scripts within the NHS Digital TRE. The aim is to complete the final analysis for the vaccine effectiveness studies by December 2022. The focus will then be on the analysis for the TTS studies and aim to complete them by June 2023. 2nd interim analysis - Target date: September 2021 Final analysis (including patients receiving 2nd dose) – November 2021 [1 paragraph unchanged] Publication of results is expected in conference presentations and peer-reviewed journals. Results will be communicated transparently and to relevant audiences (researchers, clinicians, policy makers, general public) at interim and final analyses to ensure knowledge developed by the research can benefit the health system and the general public. The medical writers are currently writing the manuscript for the vaccine effectiveness studies and the aim is to submit this to an international journal by the end of November 2022. The methodology and study design were presented as a poster at a conference in the summer of 2022. [1 paragraph unchanged]

Benefits reported

At the time of this amendment (v2) the data processors have had only partial data from NHS Digital which is not yet enough to provide any conclusive analysis for the study and therefore no Yielded Benefits have yet been attained. Initial outputs have been about the vaccine effectiveness of the 2 vaccines. Additionally, the University of Oxford have been able to show the vaccine effectiveness in the older age group (> 65years). AstraZeneca has completed the analyses to investigate vaccine effectiveness within ORCHID and the results are currently being written up as a manuscript. These analyses have been focussed on the vaccine effectiveness in older age groups i.e. over 65’s and immunocompromised individuals. Analysis of the study to investigate vaccine effectiveness in the entire national population have begun. These results will hopefully inform policy change in future vaccination strategies. However, the University of Oxford are still awaiting analyses to be completed to be able to get the complete benefit of carrying out this study. The data processors have had only partial data from NHS Digital to date which is not yet enough to provide any conclusive analysis for the study. Therefore, no Yielded Benefits have yet been attained. .

Unchanged: Expected measurable benefits.

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

Datasets: + COVID-19 Vaccination Adverse Reactions; + HES:Civil Registration (Deaths) bridge; + Uncurated Low Latency Hospital Data Sets - Outpatient

Objective for processing

The objective for processing the requested data is to support delivery of a real-world effectiveness study for COVID-19 vaccines in England. The primary objective of this study is the assess the real world effectiveness of the Oxford/AstraZeneca COVID-19 vaccine among people who receive one dose of the vaccine, overall and by age group and time period after 1 dose. The secondary objective of the study would be to: a) assess the vaccine effectiveness in people who have received the two doses; the timing after the 1st and 2nd dose , interval between the two doses and comorbidity status b) replicate the above analyses in people receiving the Pfizer COVID-19 vaccine as opposed to the Oxford/AstraZeneca vaccine. ***This agreement will cover 2 purposes: PURPOSE 1: *** The objective for processing the requested data is to support delivery of a real-world effectiveness study for COVID-19 vaccines in England. The primary objective of this study is the assess the real world effectiveness of the Oxford/AstraZeneca COVID-19 vaccine among people who receive one dose of the vaccine, overall and by age group and time period after 1 dose. The secondary objective of the study would be to: a) assess the vaccine effectiveness in people who have received the two doses; the timing after the 1st and 2nd dose , interval between the two doses and comorbidity status b) replicate the above analyses in people receiving the Pfizer-BioNTech as opposed to the Oxford/AstraZeneca vaccine. ***PURPOSE 2: Broadly, the objective for this analysis is to investigate the epidemiology of thrombotic thrombocytopenia syndrome (TTS) and also to investigate the association between risk of TTS following a COVID-19 vaccine. TTS is a new, very rare blood-clotting condition linked to the COVID-19 vaccine (Blood clots are common and not all types of blood clot that occur after vaccination will be linked to the vaccine). It occurs when a person has blood clots (thrombosis) as well as low platelet counts (thrombocytopenia). Purpose 2 aims to: 1)Estimate occurrence of thrombotic thrombocytopenia, thromboembolism, and thrombocytopenia (definitions including sub-setting for specific diagnostic units described in the Case definitions section), overall and split by age, gender and known risk factors. 2) Estimate occurrence of thrombotic thrombocytopenia, thromboembolism, and thrombocytopenia within a pre-defined time interval of receiving ChAdOx1 COVID 19 vaccination overall and split by age, gender and known risk factors. 3) Estimate occurrence of thrombotic thrombocytopenia, thromboembolism, and thrombocytopenia within a pre-defined time interval of receiving Pfizer-BioNTech COVID 19 vaccination overall and split by age, gender and known risk factors. 4) Describe demographic characteristics and medical history of patients with thrombotic thrombocytopenia, thromboembolism, and thrombocytopenia. 5) Evaluate associations of thrombotic thrombocytopenia and pre-defined risk factors. 6) Conduct exploratory assessment of case definitions and disease aetiology using artificial intelligence (AI)-based approaches. This will utilise prediction modelling to identify potential risk factors of TTS. **** [11 paragraphs unchanged] ***HES- Civil Registration (Deaths) bridge*** [4 paragraphs unchanged] ***COVID-19 Vaccination Adverse Reactions *** [2 paragraphs unchanged] ***Uncurated Low Latency Hospital Data Set - Outpatients*** [16 paragraphs unchanged]

Processing activities

[11 paragraphs unchanged] Creation of final outputs and results tables tables. LIMITATION OF COVID-19 VACCINE DATA USAGE AstraZeneca has ethical approval to process data on only two specific COVID-19 vaccines. Therefore the Data Processors, for this agreement (v2) and until further ethical approval has been granted, should only process and analyse data on the two specific COVID-19 vaccines they have permission to study. [27 paragraphs unchanged] All efforts will be made to ensure no individual (including an individual healthcare professional) can be identified (i.e. any published/shared results are statistically non-disclosive).

Expected measurable benefits

[1 paragraph unchanged] The anticipated benefit expected from processing the data is to demonstrate the effectiveness of the COVID-19 vaccines and the UK vaccine roll-out in the adult population in England. Understanding of this effectiveness is expected to benefit citizens, healthcare professionals (HCPs), government and policy makers, vaccine manufacturers and researchers. AstraZeneca and University of Oxford specifically would get confirmation of the effectiveness of the Oxford-AstraZeneca vaccine which will grow confidence in the product and support strategic decision-making in the future. Citizens and HCPs are hoped to benefit from evidence that will grow confidence in the vaccines, supporting vaccine uptake, and identifying sub groups of patients in whom the vaccines show greatest effect. Government and Policy makers are hoped to gain benefit from the evidence which will demonstrate the effectiveness of the vaccine roll-out plan with regards to staggered age groups and vulnerable groups. ****Additionally, a rare syndrome of thrombosis (TTS) associated with low platelets has been reported in a few cases of recent exposure to COVID-19 vaccine. No causal association with COVID-19 vaccination has yet been established. This syndrome seems to be affecting patients of all ages and both genders; at present there is no clear signal of risk factors. However, there is little data regarding occurrence and risk factors of thrombotic thrombocytopenia or its relationship with prior COVID-19 infection or COVID-19 vaccination. This study will explore if there is a causal association of the syndrome with COVID-19 vaccination. The results will have an impact policies related vaccination.**** The anticipated benefit expected from processing the data ***for both purposes ***is to demonstrate the effectiveness of the COVID-19 vaccines and the UK vaccine roll-out in the adult population in England. Understanding of this effectiveness is expected to benefit citizens, healthcare professionals (HCPs), government and policy makers, vaccine manufacturers and researchers. AstraZeneca and University of Oxford specifically would get confirmation of the effectiveness of the Oxford-AstraZeneca vaccine which will grow confidence in the product and support strategic decision-making in the future. Citizens and HCPs are hoped to benefit from evidence that will grow confidence in the vaccines, supporting vaccine uptake, and identifying sub groups of patients in whom the vaccines show greatest effect. Government and Policy makers are hoped to gain benefit from the evidence which will demonstrate the effectiveness of the vaccine roll-out plan with regards to staggered age groups and vulnerable groups. [5 paragraphs unchanged]

Benefits reported

Not stated in the previous version; added here.

At the time of this amendment (v2) the data processors have had only partial data from NHS Digital which is not yet enough to provide any conclusive analysis for the study and therefore no Yielded Benefits have yet been attained.

Unchanged: Expected output.

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

Benefits reported

Stated in the previous version and removed here.

Yielded Benefits is not a requirement for new applications.

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