TRANSFUSION MEDICINE EPIDEMIOLOGY REVIEW

The University of Edinburgh (UoE) requires access to NHS England data for the purpose of the following project: The Transfusion Medicine Epidemiology Review (TMER).

The following is a summary of the aims of the project provided by the UoE:

The Transfusion Medicine Epidemiology Review (TMER) is a collaborative project between the the National CJD Research & Surveillance Unit (NCJDRSU) which is part of the University of Edinburgh, and the UK Blood Services (UKBS), which incorporates NHS Blood and Transplant (NHSBT), the Welsh Blood Service (WBS), the Scottish National Blood Transfusion Service (SNBTS) and Northern Ireland Blood Transfusion Service (NIBTS). The TMER project was set up in 1997 with the aim of investigating whether CJD/vCJD may be transmitted via the blood supply.

The NCJDRSU will use mortality data provided by NHS England to support its surveillance and research programme by using the data to look at the date and cause(s) of death of recipients of blood from, and donors of blood to, cases of CJD/vCJD as part of the TMER study. This study helped identify, in 2004, the first case of transfusion transmitted infection of vCJD – in a patient who had received blood from a blood donor who had, subsequent to the donation, later gone on to develop vCJD. This finding, along with later reports and publications from the study have informed health guidance and policy decision making in the UK and overseas.

This is a public health surveillance activity, which requires ongoing long-term monitoring to identify instances of transfusion-associated transmission. The individuals to be flagged by NHS England under this project are supplied by NHSBT based on data from the UK national blood services. National mortality data for all four nations (England, Wales, Scotland, Northern Ireland) is required. This Data Sharing Agreement covers data from the English and Welsh cohort only.

For the purposes of public health monitoring and risk assessment, the study team will continue to request this information on a long-term regular basis. This will help identify further instances where transfusion-related transmission of Creutzfeldt Jakob Disease (CJD) and its variant form (vCJD) may occur in a timely manner, thus informing policy makers in the reassessment and quantification of risk. Data is required for the whole of the UK, as this is a UK-wide national project, and no subjects are excluded.

As close to 100% ascertainment of deaths is needed as is possible. The blood services do not routinely collect death information for blood donors or transfusion recipients, the NCJDRSU has no contact with the recipients and donors and there is no alternative source of this information. NCJDRSU therefore cannot reasonably achieve the above other than using the national mortality data under this Data Sharing Agreement.

NCJDRSU research programme includes processing data, such as those used in this study, for reasons of public health including public health monitoring. Unresolved scientific questions relating to the risk of CJD/vCJD transmission in blood and of developing disease, potentially large numbers of sub-clinically infected donors and the absence of a blood test for CJD/vCJD that can be used in routine practice, mean that indirect approaches, such as those detailed in this Data Sharing Agreement are required to better understand the risk of transfusion associated transmission as well as help identify instances where this may have occurred.

The NCJDRSU is a Department of Health and Social Care and Scottish Government Health Department funded programme which has been running since 1990 with a remit to monitor the characteristics of all forms of CJD, to identify trends in incidence rates, to study risk factors for the development of disease and to contribute to improving the quality of care for those with CJD. Integral to CJD surveillance is the referral of suspected cases of CJD to the NCJDRSU, for clinical and pathological examination, epidemiological assessment and diagnosis, according to internationally recognised standard diagnostic criteria.

The following NHS England data will be accessed:

• Civil Registration Mortality

• Demographics

These datasets are necessary to provide timely results, which can be used to inform public health policy nationally and internationally aimed at minimising the risk of further transmission, which has profound implications for mitigating health risk at the individual as well as population level.

Data received from NHS England relates to recipients from, and donors to, cases of CJD/vCJD. The details of whether the individuals flagged have died and their date of death allows NCJDRSU to be consistent with previous analyses and enables more accurate estimates of the period between transfusion/donation and death, and thereby the quantification of risk; the place and cause(s) of death will allow the study team to check whether any of these individuals may have had a diagnosis of CJD/vCJD, which in turn will allow the study team to identify instances where transfusion –related transmission may have occurred. Risk assessments can then be updated and refined.

Previously, the use of this information has helped demonstrate that CJD/vCJD can be transmitted via the blood supply and enabled this to be done in a timely manner. However, for the purposes of public health monitoring and risk assessment, the study team will continue to require this information in the longer term and on a regular basis to help identify further instances where this may occur, thus informing policy makers and enabling the reassessment and quantification of risk.

The level of the data will be identifiable – necessary to flag specific individuals who meet the criteria for inclusion in the review. Information on individual cases of CJD will be held on the NCJDRSU database to be linked with current and archived datasets held by the four national blood services within the UK and UK hospital blood banks. There is no common identifier that can be used to link information across these sources. As well as flagging individuals with NHS England, cross checks are also carried out on the NCJDRSU database to determine whether any of these individuals are recorded as a case of CJD.

The data will be minimised as follows:

• Limited to a study cohort of 674 English based individuals and any additional recipients from and donors to cases of CJD/vCJD identified by the University of Edinburgh.

• Limited to latest available data. The TMER study team have considered the data fields requested and use the minimum level of data required without compromising the accuracy of the project; data requirements are reviewed at renewal of the Data Sharing Agreement and will also be reviewed if project requirements change.

University of Edinburgh is the controller as the organisation responsible for ensuring that the data will only be processed for the purpose described above.

The data will be stored on the AIMES Trustworthy Research Environment (Liverpool) at all times. No data are stored outside the AIMES TRE. Only the University of Edinburgh has access to this data.

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

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

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

Article 9(2)(i) – processing is necessary for reasons of public interest in the area of public health, such as protecting against serious cross-border threats to health or ensuring high standards of quality and safety of health care and of medicinal products or medical devices, on the basis of Union or Member State law which provides for suitable and specific measures to safeguard the rights and freedoms of the data subject, in particular professional secrecy.

This processing is in the public interest because it adheres to the UK Policy Framework for Health and Social Care Research, which protects and promotes the interests of patients, service users and the public, and aims to produce generalisable and publicly available information to inform future decisions over patients’ treatments or care.

The funding is provided by the Department of Health and Social Care. The funding is specifically for the project described. Funding is in place until 31st March 2024. Funding to continue the work described will be sought on an ongoing basis.

With respect to public involvement and engagement and transparency, blood donors are provided with information describing how their information may be used and information about the TMER study specifically is provided by NCJDRSU and NHSBT through their websites and privacy notices, and included in scientific publications.

Prior to donation, when consenting to donate blood, donors are asked to read the donor welcome leaflet which describes how their data can be also used for purposes other than donation, including for research and surveillance activities: “to ensure the safety of all donors and patients and the traceability of donations … for research … this may include linkage of your information to your other NHS records”. The TMER study is just one of many possible projects that donor data may be used for and it is not feasible to provide detailed information for each and all of these. Instead the blood services have taken the approach of alerting donors to possible uses of their data through donor information and privacy notices, providing more project specific information on websites which are reviewed regularly by the respective organisations.

Information about the TMER study is made available on the NHSBT and NCJDRSU websites, and on demand.

NHSBT gives information on a number of national projects of which the TMER project is one. At the top of the NHSBT Donor facing Give Blood page there is a link taking readers to the research and surveillance pages with further information available.

There are also annual reports on the SHOT (Serious Hazards of Transfusion) website which includes transfusion transmission infection (TTI) of which vCJD/prion disease is a category.

Detail about the TMER study, including methods, results and publications are provided in the TMER section of the NCJDRSU website which is updated as new results become available.

The expected outputs of the processing will be:

• Annual report of findings to the Department of Health and Social Care and the Scottish Government Health Department.

• Submissions to peer reviewed journals resulting in research publications, in open-access format where possible.

• Presentations at conferences

• The TMER study team section of the NCJDRSU website

The outputs will not contain NHS England data and will only contain aggregated information with small numbers suppressed as appropriate in line with the relevant disclosure rules for the dataset(s) from which the information was derived. Although the journal choice depends on the focus of the research question, NCJDRSU tries to make all peer-reviewed publications available in open-access.

Blood donors are provided with information describing how their information may be used and information about the TMER study specifically is provided by NCJDRSU and NHSBT through their websites and privacy notices and included in scientific publications.

The outputs will be communicated to relevant recipients through the following dissemination channels:

• Journals

• Posters displayed at conferences pertaining to the subject matter.

• Website of the National CJD Research & Surveillance Unit showing information and results from the project

The timeframe of benefit is continuous and ongoing. To date the project has demonstrated that it is able to identify instances of probable transfusion transmitted infection, and it will remain vigilant to the possibility of further instances into the longer term.

Results from the vCJD arm of the project identified four instances of probable transfusion transmitted infection: in 3 cases of vCJD and a separate pre-clinical infection in a blood recipient. There have been no new cases of transfusion-associated vCJD since 2007. The last diagnosis of a transfusion-associated case was late 2006. The last diagnosis of a vCJD case (which was non transfusion-associated) was 2016.

The identification of vCJD, the positing of a risk of blood-related secondary transmission of vCJD and the later actual identification of such transmission (of infection and disease) indicated that person-to-person spread of vCJD through blood and blood products was a real problem. This information and supporting data informed public health risk assessments and subsequent policy, allowing rational design and implementation of precautions that almost certainly prevented further transmissions and have critically limited the possibility of a self-sustaining blood-related secondary epidemic, including:

Withdrawal and recall of blood and associated products obtained from donors who develop vCJD (1997).

• Importation of plasma for UK plasma fractionation (1998/1999)

• Leucodepletion of all blood components (1998/1999)

• Deferral of blood donors meeting certain criteria

• The promotion of more appropriate blood/blood product use in the NHS.

All of these policies are continually reviewed – informed in part by data being provided by the NCJDRSU through the TMER study.

It is vital to continue studies such as the TMER so that any models can be ‘calibrated’ against actual observations and then risk assumptions potentially reconsidered. Results from all other types of CJD included in the project have not so far shown any evidence of transfusion transmission.

The exact levels of infectivity in blood, the precise distribution of infection in the different blood components, and the details of how these might change over time in a given individual, in humans in either the preclinical or clinical stages of vCJD remain unknown. Assumptions have, however, been made (on the basis of available evidence) and used in risk assessments. It is vital to continue studies such as the TMER so as any models can be ‘calibrated’ against actual observations and then risk assumptions potentially reconsidered.

As look-back studies of blood transfusion in Creutzfeldt-Jakob disease commonly rely on reported history from surrogate witnesses, data from the TMER project were analysed to determine the accuracy of blood donation history provided by the relatives of cases. The results showed that only a small percentage of cases were found to be registered as donors on UKBS databases when there was no family report of blood donation. In contrast, a history of reported donation was less accurate. As there are potential public health implications of even a small percentage of CJD blood donors not being identified, a revision to the protocol of the CJD arm of the project has recently being made whereby all cases of CJD (definite and probable) will be notified to UKBS regardless of their reported donation history.

The Transfusion Medicine Epidemiology Review (TMER) is a collaborative project between the UK National CJD Research & Surveillance Unit (NCJDRSU), which is part of the University of Edinburgh, and the UK Blood Services (UKBS), which incorporates NHS Blood and Transplant (NHSBT), the Welsh Blood Service (WBS), the Scottish National Blood Transfusion Service (SNBTS) and Northern Ireland Blood Transfusion Service (NIBTS). This agreement covers data from English Hospitals only. The TMER project was set up in 1997 with the aim of investigating whether Creutzfeldt Jakob Disease (CJD) and its variant form (vCJD) may be transmitted via the blood supply.

The NCJDRSU will use mortality data provided by NHS Digital to support its surveillance and research programme, by using the data to look at the date and cause(s) of death of recipients of blood from, and donors of blood to, cases of CJD/vCJD as part of the TMER study. This study helped identify, in 2004, the first case of transfusion transmitted infection of vCJD – in a patient who had received blood from a blood donor who had, subsequent to the donation, later gone on to develop vCJD. This finding, along with later reports and publications from the study have informed health guidance and policy decision making in the UK and overseas.

The data are being processed under Article 6 (1) (e) which is the legal basis used for performing tasks that are carried out in the public interest (a public task), identifying and monitoring of risk factors for the transmission of CJD/vCJD, as a core function of the University of Edinburgh, under the Universities (Scotland) Act 1966. The processing of special category data is justifiable under Article 9(2)(i), as processing is necessary for public health with a basis in law.

NCJDRSU research programme includes processing data, such as those used in this study, for reasons of public health including public health monitoring. Unresolved scientific questions relating to the risk of CJD/vCJD transmission in blood and of developing disease, potentially large numbers of sub-clinically infected donors and the absence of a blood test for CJD/vCJD that can be used in routine practice, mean that indirect approaches, such as those detailed in this application, are required to better understand the risk of transfusion associated transmission as well as help identify instances where this may have occurred.

Data from the NCJDRSU on cases of CJD/vCJD are linked using patient identifiers to data from the national blood services who provide details of recipients / donors to these CJD/vCJD cases. Details of these recipients / donors are then cross checked on the CJD Unit database to determine any cases of CJD/vCJD. The recipients / donors are also sent to NHS Digital for flagging (previously undertaken by HSCIC) for date, place and cause of death. As close to 100% ascertainment of deaths is needed as is possible. The blood services do not routinely collect death information for blood donors or transfusion recipients, the NCJDRSU has no contact with the recipients and donors and there is no alternative source of this information. NCJDRSU therefore cannot reasonably achieve the above other than using the national mortality data, as requested in this application.

Being able to access the date, place and cause of death of recipients from, and donors to, CJD/vCJD cases, using data provided through NHS Digital, provides NCJDRSU with a means of identifying when these individuals died and whether any of these individuals died of CJD/vCJD, thereby helping to quantify risk. The data are required to provide timely results, which can be used to inform public health policy nationally and internationally aimed at minimising the risk of further transmission, which has profound implications for mitigating health risk at the individual as well as population level. This comes under public interest in the area of public health as depicted in Schedule 1 Part 1(3) of the Data Protection Act 2018.

Consent is not feasible, for the following reasons. Data collection is retrospective and does not include contact with patients, or analysis of stored blood samples. The majority of individuals (ie the majority of recipients and a small proportion of the donors) included in this application are deceased by the time of flagging, therefore consent cannot be sought. Contacting the relatives of deceased individuals would cause unnecessary distress and confusion, the same applies to living recipients / donors, particularly as there are no actions or treatment that could be given to these individuals to mitigate the, at present, theoretical risk of transmission of CJD infection. When the project started in 1997 ethical approval was sought and approved but in 2014 was re-categorised as surveillance, not research, and as such not requiring ethical approval. The exception to the above is variant CJD in which a policy decision was made by the Department of Health, following evidence of transfusion transmission of this condition, to inform recipients of labile blood products of the risk of variant CJD. Living recipients of any vCJD-implicated blood transfusion are now deferred from themselves donating blood, which prevents the potential spread of infection and propagation of a transfusion-related vCJD epidemic from sub-clinical carriers of the infectious prion agent. When consenting to give blood, donors agree to the use of their blood / data for purposes other than donation, however consenting all donors specifically for this study would be unfeasible (over a million units of blood are donated each year). Consent cannot be sought prospectively from all those receiving transfusions, either, due to the usual emergency nature of transfusions. The data processing methods have been assessed by CAG and approved.

Data received from NHS Digital relates to recipients from, and donors to, cases of CJD/vCJD. The details of whether the individuals flagged have died and their date of death allows NCJDRSU to be consistent with previous analyses and enables more accurate estimates of the period between transfusion/donation and death, and thereby the quantification of risk; the place and cause(s) of death will allow the study team to check whether any of these individuals may have had a diagnosis of CJD/vCJD, which in turn will allow the study team to identify instances where transfusion –related transmission may have occurred. Risk assessments can then be updated and refined.

Previously, the use of this information has helped demonstrate that CJD/vCJD can be transmitted via the blood supply, and enabled this to be done in a timely manner. However for the purposes of public health monitoring and risk assessment, the study team will continue to request this information in the longer term and on a regular basis to help identify further instances where this may occur, thus enabling and informing policy makers in the reassessment and quantification of risk.

The NCJDRSU is a Department of Health and Scottish Government Health Department funded programme which has been running since 1990 with a remit to monitor the characteristics of all forms of CJD, to identify trends in incidence rates, to study risk factors for the development of disease and to contribute to improving the quality of care for those with CJD. Integral to CJD surveillance is the referral of suspected cases of CJD to the NCJDRSU, for clinical and pathological examination, epidemiological assessment and diagnosis, according to internationally recognised standard diagnostic criteria.

In 1996, NCJDRSU reported a novel form of CJD, now termed ‘variant’ CJD, which was caused by infection with the agent of Bovine spongiform encephalopathy (BSE) in cattle. Following the identification of vCJD, there was concern about the potential for secondary, human to human, spread of vCJD via blood and blood products. Although this had never been identified with other forms of human prion disease in clinical practice (and the NCJDRSU had undertaken research in the past with negative results), vCJD was a novel disease with evidence of unusually significant reticulo-endothelial involvement. The significant uncertainty around this possibility meant uncertainty as to what precautions should be taken with these essential therapeutic items. The TMER study began the following year, also funded by the Department of Health and Scottish Government Health Department, as a collaborative study between the NCJDRSU, part of the University of Edinburgh, and the UK blood services, with the principle aim of investigating whether CJD/vCJD was transmissible via blood transfusion.

Until 2004 in was generally accepted that CJD had not been transmitted by blood transfusion. Preliminary findings from sheep studies indicated that BSE and scrapie (a fatal, degenerative disease affecting the nervous systems of sheep and goats) could be transmitted by blood transfusion and it was vital to find out whether this also applied to human transmissible spongiform encephalopathies (TSEs) and, in particular, vCJD. The UK is the only country where a significant outbreak of vCJD has occurred and was in a unique position to study this question which has important implications for public health.

To date, the TMER study has identified three clinical cases of vCJD who were infected by non‐leucodepleted blood derived from asymptomatic donors who later developed the condition. With the use of mortality data supplied previously, it was possible to identify the first instance of probable transfusion transmitted infection of vCJD in a timely manner.

The exact levels of infectivity in blood, the precise distribution of infection in the different blood components, and the details of how these might change over time in a given individual, in humans in either the preclinical or clinical stages of vCJD remain unknown. Assumptions have, however, been made (on the basis of available evidence) and used in risk assessments.

The nature of the work described in this application is a part of a wider program of research and surveillance undertaken by the NCJDRSU, which involves the long-term monitoring of disease occurrence and investigation of risk. The project is run by the NJDRSU in collaboration with the UK blood services. It requires data on individual CJD cases held on the NCJDRSU core surveillance database to be linked with information held on current and archived databases held by the UK blood services and their associated UK hospital blood banks, in order to identify recipients of blood from, or donors of blood to, CJD/vCJD cases. Results from this project have been used to inform public health policy nationally and internationally aimed at minimising the risk of further transmission. This involves collaboration with bodies such as the UK departments of Health, Public Health England, Health Protection Scotland and various expert panels and committees, including the CJD Incidents Panel (now defunct), the Advisory Committee on Dangerous Pathogens (ACDP) and the independent Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO).

This is a public health surveillance activity, which requires ongoing long-term monitoring to identify instances of transfusion-associated transmission. The individuals to be flagged by NHS Digital under this project are supplied by NHS Blood and Transplant based on data from the UK national blood services. National mortality data for all four nations is required. Previously this was provided to NCJDRSU by HSCIC. Information on date, place and cause(s) of death supplied to NCJDRSU by NHS Digital as a result of the flagging exercise will only be processed by the University of Edinburgh acting through the NCJDRSU. Data is requested on a quarterly basis, to ensure deaths are detected in a timely manner. Processing will always be within the terms of the DSA with NHS Digital.

The data subjects are individuals who have ever either received blood from, or donated blood to, a case or cases of CJD/vCJD.

NCJDRSU research programme includes processing data, such as those used in this study, for reasons of public health including public health monitoring. Unresolved scientific questions relating to the risk of CJD/vCJD transmission in blood and of developing disease, potentially large numbers of sub-clinically infected donors and the absence of a blood test for CJD/vCJD that can be used in routine practice, mean that indirect approaches, such as those detailed in this application, are required to better understand the risk of transfusion associated transmission as well as help identify instances where this may have occurred.

Data relate to recipients from, and donors to, cases of CJD/vCJD. The datasets requested from NHS Digital are the date, place and cause(s) of death of NCJDRSU-flagged individuals (ie. recipients from, or donors to, cases of CJD/vCJD).

Data from the NCJDRSU on cases of CJD/vCJD are linked to data from the national blood services who provide details of recipients / donors to these CJD/vCJD cases. Details of these recipients / donors are then cross checked on the CJD Unit database to determine any cases of CJD/vCJD. The recipients / donors are also sent to NHS Digital for flagging (previously undertaken by HSCIC) for date, place and cause of death.

Using data provided through NHS Digital, provides NCJDRSU with a means of identifying when these individuals died and whether any of these individuals died of CJD/vCJD, thereby helping to quantify risk. The details of whether the individuals flagged have died and their date of death allows NCJDRSU to be consistent with previous analyses and enables more accurate estimates of the period between transfusion/donation and death, and thereby the quantification of risk; knowing the place and cause(s) of death will allow the study team to check medical records to determine whether any of these individuals may have had a diagnosis of CJD/vCJD, which in turn will allow the study team to identify instances where transfusion –related transmission may have occurred.

Confidential patient information is required to flag specific individuals who meet the criteria for inclusion in the review. Information on individual cases of CJD will be held on the NCJDRSU database to be linked with current and archived datasets held by the four national blood services within the UK and UK hospital blood banks. There is no common identifier that can be used to link information across these sources. There have also been discussions previously with CAG as to whether NHSBT could flag recipients and donors rather than passing this information back to NCJDRSU and for NCJDRSU to then receive pseudonymised data from HSCIC (now NHS Digital) for analysis purposes. However, as well as flagging individuals with HSCIC (now NHS Digital), cross checks are also carried out on the NCJDRSU database to determine whether any of these individuals are recorded as a case of CJD and for the purpose of this check NCJDRSU require fully identifiable details.

For the purposes of public health monitoring and risk assessment, the study team will continue to request this information on a long term regular basis. This will help identify further instances where transfusion-related transmission of CJD/vCJD may occur in a timely manner, thus informing policy makers in the reassessment and quantification of risk. Data is required for the whole of the UK, as this is a UK-wide national project and no subjects are excluded. Previously this information was provided to NCJDRSU by HSCIC.

As close to 100% ascertainment of deaths is needed as is possible. The blood services do not routinely collect death information for blood donors or transfusion recipients, the NCJDRSU has no contact with the recipients and donors and there is no alternative source of this information. NCJDRSU therefore cannot reasonably achieve the above other than using the national mortality data, as requested in this application. There are no alternative less obtrusive ways of achieving the purpose.

The TMER study team have considered the data fields requested and use the minimum level of data required without compromising the accuracy of the project; data requirements are reviewed at renewal of DSAs and will also be reviewed if project requirements change. This will be held securely on UoE premises within a DSPT compliant environment according to the terms of the DSA. It will be kept confidential by NCJDRSU, used only for the purposes of the study and will be deleted once it has been processed.

The University of Edinburgh is the data controller and will be the only organisation who will have access to, and process, the data supplied by NHS Digital.

The data will not be used for any external commercial purposes and will not be provided at record level form to any third party. Any data processing will be done under a data sharing agreement and data sharing framework contract between NHS Digital and the University of Edinburgh.

The four national UK blood services in the UK (NHSBT, WBS, SNBTS, NIBTS) do not process NHS Digital data. Their role is to identify recipients of blood from, and donors of blood to, cases of CJD/vCJD and pass this information back to NCJDRSU.

There are no finders/commissioners involved in this project.

This agreement does not support any separate current or planned PhD/postgraduate research study. If the analysis were to contribute to such studies in the future an amendment to this agreement would be submitted to NHS Digital.

Data from this project will be included in:

a. Annual reports to Department of Health and Social Care and Scottish Government Health Department.

b. The TMER section of the NCJDRSU website

c. Submissions to peer reviewed journals resulting in research publications, in open-access format where possible.

d. Presentations at conferences.

The following articles have already been produced using the data from the TMER.

•Llewelyn CA, Hewitt PE, Knight RSG, Amar K, Cousens S, Mackenzie J, Will RG. Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion. Lancet 2004; 363: 417-421.

•Peden AH, Head MW, Ritchie DL, Bell JE, Ironside JW. Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet 2004; 364: 527-529.

•Health Protection Agency. New case of transfusion-associated variant-CJD. CDR Weekly 2006; 16(6).

•Hewitt PE, Llewelyn CA, Mackenzie J, Will RG. Creutzfeldt-Jakob disease and blood transfusion: results of the UK Transfusion Medicine Epidemiology Review study. Vox Sanguinis 2006; 91: 221-230.

•Wroe SJ, Pal S, Siddique D, Hyare H, Macfarlane R, Joiner S, Linehan JM, Brandner S, Wadsworth JD, Hewitt P, Collinge J. Clinical presentation and pre-mortem diagnosis of variant Creutzfeldt-Jakob disease associated with blood transfusion: a case report. Lancet 2006; 368: 2061-2067.

•Health Protection Agency. Fourth case of transfusion-associated variant-CJD infection. Health Protection Report 2007; 1(3).

•Gillies M, Chohan G, Llewelyn CA, Mackenzie J, Ward HJT, Hewitt PE, Will RG. A retrospective case note review of deceased recipients of vCJD-implicated blood transfusions. Vox Sanguinis 2009; 97: 211-218.

•Ward HJT, Mackenzie JM, Llewelyn CA, Knight RSG, Hewitt PE, Connor N, Molesworth A, Will RG. Variant Creutzfeldt-Jakob disease and exposure to fractionated products. Vox Sanguinis 2009; 97: 207-210

•Chohan G,Llewelyn C, Mackenzie J, Cousens S, Kennedy A, Will RG, Hewitt PE. Variant Creutzfeldt-Jakob disease in a transfusion recipient: coincidence or cause? Transfusion 2010; 50: 1003-1006.

•Davidson LRR, Llewelyn CA, Mackenzie JM, Hewitt, PE, Will RG. Variant CJD and blood transfusion: are there additional cases? Vox Sanguinis 2014 DOI: 10.1111/Vox 12161.

•Urwin PJM, Mackenzie JM, Llewelyn CA, Will RG, Hewitt PE. Creutzfeldt-Jakob disease and blood transfusion: updated results of the UK Transfusion Medicine Epidemiology Review Study. Vox Sanguinis 2016; 110: 310-316.

•Mackenzie JM, Turner M, Morris K, Field S, Molesworth AM, Pal S, Will RG, Llewelyn CA, Hewitt PE. Accuracy of a history of blood donation from surrogate witnesses: data from the UK TMER Study. Vox Sanguinis 2018; doi: 10.1111/vox 12661.

All outputs will be aggregated with small numbers suppressed in line with the HES analysis guidance and no personal identifying information will be included in any outputs. Although the journal choice depends on the focus of the research question, NCJDRSU tries to make all peer-reviewed publications available in open-access.

Blood donors are provided with information describing how their information may be used and information about the TMER study specifically is provided by NCJDRSU and NHSBT through their websites and privacy notices, and included in scientific publications.

Donor information:

Prior to donation, when consenting to donate blood, donors are asked to read the donor welcome leaflet which describes how their data can be also used for purposes other than donation, including for research and surveillance activities: “to ensure the safety of all donors and patients and the traceability of donations…for research…this may include linkage of your information to your other NHS records”. The TMER study is just one of many possible projects that donor data may be used for and it is not feasible to provide detailed information for each and all of these. Instead the blood services have taken the approach of alerting donors to possible uses of their data through donor information and privacy notices, providing more project specific information on websites which are reviewed regularly by the respective organisations (information about the TMER study is made available on the NHSBT and NCJDRSU websites), and on demand.

Websites:

NHS Blood & Transplant are co-investigators on this project which gives information on a number of national projects of which the TMER project is one. At the top of the NHSBT Donor facing Give Blood page there is a link taking readers to the research and surveillance pages with further information available.

There are also annual reports on the SHOT (Serious Hazards of Transfusion) website. Chapter 20 relates to transfusion transmission infection (TTI) of which vCJD/prion disease is a category.

Detail about the TMER study, including methods, results and publications are provided in the TMER section of the NCJDRSU website which is updated as new results become available.

In addition, the TMER study management team comprising co-investigators, the study coordinator and supporting staff meet twice a year; all issues in relation to study management, progress and findings are discussed and the meeting is minuted.

A report to the funding body is produced annually. Submissions to peer reviewed journals, conferences and updates to website will occur when new results are available.

Under previous DSAs, previously stated target dates/deliverables have been realised.

This project does not have any associated EU funding.

Results from the vCJD arm of the project identified four instances of probable transfusion transmitted infection: in 3 cases of vCJD and a separate pre-clinical infection in a blood recipient. There have been no new cases of transfusion-associated vCJD since 2007. The last diagnosis of a transfusion-associated case was late 2006. The last diagnosis of a vCJD case (which was non transfusion-associated) was 2016.

The identification of vCJD, the positing of a risk of blood-related secondary transmission of vCJD and the later actual identification of such transmission (of infection and disease) indicated that person-to-person spread of vCJD through blood and blood products was a real problem. This information and supporting data informed public health risk assessments and subsequent policy, allowing rational design and implementation of precautions that almost certainly prevented further transmissions and have critically limited the possibility of a self-sustaining blood-related secondary epidemic, including:

• Withdrawal and recall of blood and associated products obtained from donors who develop vCJD (1997).

• Importation of plasma for UK plasma fractionation (1998/1999)

• Leucodepletion of all blood components (1998/1999)

• Deferral of blood donors meeting certain criteria

• The promotion of more appropriate blood/blood product use in the NHS.

All of these policies are continually reviewed and currently remain in place – informed in part by data being provided by the NCJDRSU through the TMER study.

It is vital to continue studies such as the TMER so that any models can be ‘calibrated’ against actual observations and then risk assumptions potentially reconsidered. Results from all other types of CJD included in the project have not so far shown any evidence of transfusion transmission.

The exact levels of infectivity in blood, the precise distribution of infection in the different blood components, and the details of how these might change over time in a given individual, in humans in either the preclinical or clinical stages of vCJD remain unknown. Assumptions have, however, been made (on the basis of available evidence) and used in risk assessments. It is vital to continue studies such as the TMER so as any models can be ‘calibrated’ against actual observations and then risk assumptions potentially reconsidered.

As look-back studies of blood transfusion in Creutzfeldt-Jakob disease commonly rely on reported history from surrogate witnesses, data from the TMER project were analysed to determine the accuracy of blood donation history provided by the relatives of cases. The results showed that only a small percentage of cases were found to be registered as donors on UKBS databases when there was no family report of blood donation. In contrast, a history of reported donation was less accurate. As there are potential public health implications of even a small percentage of CJD blood donors not being identified, a revision to the protocol of the CJD arm of the project has recently being made whereby all cases of CJD (definite and probable) will be notified to UKBS regardless of their reported donation history.

The Transfusion Medicine Epidemiology Review (TMER) is a collaborative project between the UK National CJD Research & Surveillance Unit (NCJDRSU), which is part of the University of Edinburgh, and the UK Blood Services (UKBS), which incorporates NHS Blood and Transplant (NHSBT), the Welsh Blood Service (WBS), the Scottish National Blood Transfusion Service (SNBTS) and Northern Ireland Blood Transfusion Service (NIBTS). This agreement covers data from English Hospitals only. The TMER project was set up in 1997 with the aim of investigating whether Creutzfeldt Jakob Disease (CJD) and its variant form (vCJD) may be transmitted via the blood supply.

The NCJDRSU will use mortality data provided by NHS Digital to support its surveillance and research programme, by using the data to look at the date and cause(s) of death of recipients of blood from, and donors of blood to, cases of CJD/vCJD as part of the TMER study. This study helped identify, in 2004, the first case of transfusion transmitted infection of vCJD – in a patient who had received blood from a blood donor who had, subsequent to the donation, later gone on to develop vCJD. This finding, along with later reports and publications from the study have informed health guidance and policy decision making in the UK and overseas.

The data are being processed under Article 6 (1) (e) which is the legal basis used for performing tasks that are carried out in the public interest (a public task), identifying and monitoring of risk factors for the transmission of CJD/vCJD, as a core function of the University of Edinburgh, under the Universities (Scotland) Act 1966. The processing of special category data is justifiable under Article 9(2)(i), as processing is necessary for public health with a basis in law.

NCJDRSU research programme includes processing data, such as those used in this study, for reasons of public health including public health monitoring. Unresolved scientific questions relating to the risk of CJD/vCJD transmission in blood and of developing disease, potentially large numbers of sub-clinically infected donors and the absence of a blood test for CJD/vCJD that can be used in routine practice, mean that indirect approaches, such as those detailed in this application, are required to better understand the risk of transfusion associated transmission as well as help identify instances where this may have occurred.

Data from the NCJDRSU on cases of CJD/vCJD are linked using patient identifiers to data from the national blood services who provide details of recipients / donors to these CJD/vCJD cases. Details of these recipients / donors are then cross checked on the CJD Unit database to determine any cases of CJD/vCJD. The recipients / donors are also sent to NHS Digital for flagging (previously undertaken by HSCIC) for date, place and cause of death. As close to 100% ascertainment of deaths is needed as is possible. The blood services do not routinely collect death information for blood donors or transfusion recipients, the NCJDRSU has no contact with the recipients and donors and there is no alternative source of this information. NCJDRSU therefore cannot reasonably achieve the above other than using the national mortality data, as requested in this application.

Being able to access the date, place and cause of death of recipients from, and donors to, CJD/vCJD cases, using data provided through NHS Digital, provides NCJDRSU with a means of identifying when these individuals died and whether any of these individuals died of CJD/vCJD, thereby helping to quantify risk. The data are required to provide timely results, which can be used to inform public health policy nationally and internationally aimed at minimising the risk of further transmission, which has profound implications for mitigating health risk at the individual as well as population level. This comes under public interest in the area of public health as depicted in Schedule 1 Part 1(3) of the Data Protection Act 2018.

Consent is not feasible, for the following reasons. Data collection is retrospective and does not include contact with patients, or analysis of stored blood samples. The majority of individuals (ie the majority of recipients and a small proportion of the donors) included in this application are deceased by the time of flagging, therefore consent cannot be sought. Contacting the relatives of deceased individuals would cause unnecessary distress and confusion, the same applies to living recipients / donors, particularly as there are no actions or treatment that could be given to these individuals to mitigate the, at present, theoretical risk of transmission of CJD infection. When the project started in 1997 ethical approval was sought and approved but in 2014 was re-categorised as surveillance, not research, and as such not requiring ethical approval. The exception to the above is variant CJD in which a policy decision was made by the Department of Health, following evidence of transfusion transmission of this condition, to inform recipients of labile blood products of the risk of variant CJD. Living recipients of any vCJD-implicated blood transfusion are now deferred from themselves donating blood, which prevents the potential spread of infection and propagation of a transfusion-related vCJD epidemic from sub-clinical carriers of the infectious prion agent. When consenting to give blood, donors agree to the use of their blood / data for purposes other than donation, however consenting all donors specifically for this study would be unfeasible (over a million units of blood are donated each year). Consent cannot be sought prospectively from all those receiving transfusions, either, due to the usual emergency nature of transfusions. The data processing methods have been assessed by CAG and approved.

Data received from NHS Digital relates to recipients from, and donors to, cases of CJD/vCJD. The details of whether the individuals flagged have died and their date of death allows NCJDRSU to be consistent with previous analyses and enables more accurate estimates of the period between transfusion/donation and death, and thereby the quantification of risk; the place and cause(s) of death will allow the study team to check whether any of these individuals may have had a diagnosis of CJD/vCJD, which in turn will allow the study team to identify instances where transfusion –related transmission may have occurred. Risk assessments can then be updated and refined.

Previously, the use of this information has helped demonstrate that CJD/vCJD can be transmitted via the blood supply, and enabled this to be done in a timely manner. However for the purposes of public health monitoring and risk assessment, the study team will continue to request this information in the longer term and on a regular basis to help identify further instances where this may occur, thus enabling and informing policy makers in the reassessment and quantification of risk.

The NCJDRSU is a Department of Health and Scottish Government Health Department funded programme which has been running since 1990 with a remit to monitor the characteristics of all forms of CJD, to identify trends in incidence rates, to study risk factors for the development of disease and to contribute to improving the quality of care for those with CJD. Integral to CJD surveillance is the referral of suspected cases of CJD to the NCJDRSU, for clinical and pathological examination, epidemiological assessment and diagnosis, according to internationally recognised standard diagnostic criteria.

In 1996, NCJDRSU reported a novel form of CJD, now termed ‘variant’ CJD, which was caused by infection with the agent of Bovine spongiform encephalopathy (BSE) in cattle. Following the identification of vCJD, there was concern about the potential for secondary, human to human, spread of vCJD via blood and blood products. Although this had never been identified with other forms of human prion disease in clinical practice (and the NCJDRSU had undertaken research in the past with negative results), vCJD was a novel disease with evidence of unusually significant reticulo-endothelial involvement. The significant uncertainty around this possibility meant uncertainty as to what precautions should be taken with these essential therapeutic items. The TMER study began the following year, also funded by the Department of Health and Scottish Government Health Department, as a collaborative study between the NCJDRSU, part of the University of Edinburgh, and the UK blood services, with the principle aim of investigating whether CJD/vCJD was transmissible via blood transfusion.

Until 2004 in was generally accepted that CJD had not been transmitted by blood transfusion. Preliminary findings from sheep studies indicated that BSE and scrapie (a fatal, degenerative disease affecting the nervous systems of sheep and goats) could be transmitted by blood transfusion and it was vital to find out whether this also applied to human transmissible spongiform encephalopathies (TSEs) and, in particular, vCJD. The UK is the only country where a significant outbreak of vCJD has occurred and was in a unique position to study this question which has important implications for public health.

To date, the TMER study has identified three clinical cases of vCJD who were infected by non‐leucodepleted blood derived from asymptomatic donors who later developed the condition. With the use of mortality data supplied previously, it was possible to identify the first instance of probable transfusion transmitted infection of vCJD in a timely manner.

The exact levels of infectivity in blood, the precise distribution of infection in the different blood components, and the details of how these might change over time in a given individual, in humans in either the preclinical or clinical stages of vCJD remain unknown. Assumptions have, however, been made (on the basis of available evidence) and used in risk assessments.

The nature of the work described in this application is a part of a wider program of research and surveillance undertaken by the NCJDRSU, which involves the long-term monitoring of disease occurrence and investigation of risk. The project is run by the NJDRSU in collaboration with the UK blood services. It requires data on individual CJD cases held on the NCJDRSU core surveillance database to be linked with information held on current and archived databases held by the UK blood services and their associated UK hospital blood banks, in order to identify recipients of blood from, or donors of blood to, CJD/vCJD cases. Results from this project have been used to inform public health policy nationally and internationally aimed at minimising the risk of further transmission. This involves collaboration with bodies such as the UK departments of Health, Public Health England, Health Protection Scotland and various expert panels and committees, including the CJD Incidents Panel (now defunct), the Advisory Committee on Dangerous Pathogens (ACDP) and the independent Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO).

This is a public health surveillance activity, which requires ongoing long-term monitoring to identify instances of transfusion-associated transmission. The individuals to be flagged by NHS Digital under this project are supplied by NHS Blood and Transplant based on data from the UK national blood services. National mortality data for all four nations is required. Previously this was provided to NCJDRSU by HSCIC. Information on date, place and cause(s) of death supplied to NCJDRSU by NHS Digital as a result of the flagging exercise will only be processed by the University of Edinburgh acting through the NCJDRSU. Data is requested on a quarterly basis, to ensure deaths are detected in a timely manner. Processing will always be within the terms of the DSA with NHS Digital.

The data subjects are individuals who have ever either received blood from, or donated blood to, a case or cases of CJD/vCJD.

NCJDRSU research programme includes processing data, such as those used in this study, for reasons of public health including public health monitoring. Unresolved scientific questions relating to the risk of CJD/vCJD transmission in blood and of developing disease, potentially large numbers of sub-clinically infected donors and the absence of a blood test for CJD/vCJD that can be used in routine practice, mean that indirect approaches, such as those detailed in this application, are required to better understand the risk of transfusion associated transmission as well as help identify instances where this may have occurred.

Data relate to recipients from, and donors to, cases of CJD/vCJD. The datasets requested from NHS Digital are the date, place and cause(s) of death of NCJDRSU-flagged individuals (ie. recipients from, or donors to, cases of CJD/vCJD).

Data from the NCJDRSU on cases of CJD/vCJD are linked to data from the national blood services who provide details of recipients / donors to these CJD/vCJD cases. Details of these recipients / donors are then cross checked on the CJD Unit database to determine any cases of CJD/vCJD. The recipients / donors are also sent to NHS Digital for flagging (previously undertaken by HSCIC) for date, place and cause of death.

Using data provided through NHS Digital, provides NCJDRSU with a means of identifying when these individuals died and whether any of these individuals died of CJD/vCJD, thereby helping to quantify risk. The details of whether the individuals flagged have died and their date of death allows NCJDRSU to be consistent with previous analyses and enables more accurate estimates of the period between transfusion/donation and death, and thereby the quantification of risk; knowing the place and cause(s) of death will allow the study team to check medical records to determine whether any of these individuals may have had a diagnosis of CJD/vCJD, which in turn will allow the study team to identify instances where transfusion –related transmission may have occurred.

Confidential patient information is required to flag specific individuals who meet the criteria for inclusion in the review. Information on individual cases of CJD will be held on the NCJDRSU database to be linked with current and archived datasets held by the four national blood services within the UK and UK hospital blood banks. There is no common identifier that can be used to link information across these sources. There have also been discussions previously with CAG as to whether NHSBT could flag recipients and donors rather than passing this information back to NCJDRSU and for NCJDRSU to then receive pseudonymised data from HSCIC (now NHS Digital) for analysis purposes. However, as well as flagging individuals with HSCIC (now NHS Digital), cross checks are also carried out on the NCJDRSU database to determine whether any of these individuals are recorded as a case of CJD and for the purpose of this check NCJDRSU require fully identifiable details.

For the purposes of public health monitoring and risk assessment, the study team will continue to request this information on a long term regular basis. This will help identify further instances where transfusion-related transmission of CJD/vCJD may occur in a timely manner, thus informing policy makers in the reassessment and quantification of risk. Data is required for the whole of the UK, as this is a UK-wide national project and no subjects are excluded. Previously this information was provided to NCJDRSU by HSCIC.

As close to 100% ascertainment of deaths is needed as is possible. The blood services do not routinely collect death information for blood donors or transfusion recipients, the NCJDRSU has no contact with the recipients and donors and there is no alternative source of this information. NCJDRSU therefore cannot reasonably achieve the above other than using the national mortality data, as requested in this application. There are no alternative less obtrusive ways of achieving the purpose.

The TMER study team have considered the data fields requested and use the minimum level of data required without compromising the accuracy of the project; data requirements are reviewed at renewal of DSAs and will also be reviewed if project requirements change. This will be held securely on UoE premises within a DSPT compliant environment according to the terms of the DSA. It will be kept confidential by NCJDRSU, used only for the purposes of the study and will be deleted once it has been processed.

The University of Edinburgh is the data controller and will be the only organisation who will have access to, and process, the data supplied by NHS Digital.

The data will not be used for any external commercial purposes and will not be provided at record level form to any third party. Any data processing will be done under a data sharing agreement and data sharing framework contract between NHS Digital and the University of Edinburgh.

The four national UK blood services in the UK (NHSBT, WBS, SNBTS, NIBTS) do not process NHS Digital data. Their role is to identify recipients of blood from, and donors of blood to, cases of CJD/vCJD and pass this information back to NCJDRSU.

There are no finders/commissioners involved in this project.

This agreement does not support any separate current or planned PhD/postgraduate research study. If the analysis were to contribute to such studies in the future an amendment to this agreement would be submitted to NHS Digital.

5c. Specific Outputs Expected, Including Target Date:

Data from this project will be included in:

a. Annual reports to Department of Health and Social Care and Scottish Government Health Department.

b. The TMER section of the NCJDRSU website

c. Submissions to peer reviewed journals resulting in research publications, in open-access format where possible.

d. Presentations at conferences.

The following articles have already been produced using the data from the TMER.

•Llewelyn CA, Hewitt PE, Knight RSG, Amar K, Cousens S, Mackenzie J, Will RG. Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion. Lancet 2004; 363: 417-421.

•Peden AH, Head MW, Ritchie DL, Bell JE, Ironside JW. Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet 2004; 364: 527-529.

•Health Protection Agency. New case of transfusion-associated variant-CJD. CDR Weekly 2006; 16(6).

•Hewitt PE, Llewelyn CA, Mackenzie J, Will RG. Creutzfeldt-Jakob disease and blood transfusion: results of the UK Transfusion Medicine Epidemiology Review study. Vox Sanguinis 2006; 91: 221-230.

•Wroe SJ, Pal S, Siddique D, Hyare H, Macfarlane R, Joiner S, Linehan JM, Brandner S, Wadsworth JD, Hewitt P, Collinge J. Clinical presentation and pre-mortem diagnosis of variant Creutzfeldt-Jakob disease associated with blood transfusion: a case report. Lancet 2006; 368: 2061-2067.

•Health Protection Agency. Fourth case of transfusion-associated variant-CJD infection. Health Protection Report 2007; 1(3).

•Gillies M, Chohan G, Llewelyn CA, Mackenzie J, Ward HJT, Hewitt PE, Will RG. A retrospective case note review of deceased recipients of vCJD-implicated blood transfusions. Vox Sanguinis 2009; 97: 211-218.

•Ward HJT, Mackenzie JM, Llewelyn CA, Knight RSG, Hewitt PE, Connor N, Molesworth A, Will RG. Variant Creutzfeldt-Jakob disease and exposure to fractionated products. Vox Sanguinis 2009; 97: 207-210

•Chohan G,Llewelyn C, Mackenzie J, Cousens S, Kennedy A, Will RG, Hewitt PE. Variant Creutzfeldt-Jakob disease in a transfusion recipient: coincidence or cause? Transfusion 2010; 50: 1003-1006.

•Davidson LRR, Llewelyn CA, Mackenzie JM, Hewitt, PE, Will RG. Variant CJD and blood transfusion: are there additional cases? Vox Sanguinis 2014 DOI: 10.1111/Vox 12161.

•Urwin PJM, Mackenzie JM, Llewelyn CA, Will RG, Hewitt PE. Creutzfeldt-Jakob disease and blood transfusion: updated results of the UK Transfusion Medicine Epidemiology Review Study. Vox Sanguinis 2016; 110: 310-316.

•Mackenzie JM, Turner M, Morris K, Field S, Molesworth AM, Pal S, Will RG, Llewelyn CA, Hewitt PE. Accuracy of a history of blood donation from surrogate witnesses: data from the UK TMER Study. Vox Sanguinis 2018; doi: 10.1111/vox 12661.

All outputs will be aggregated with small numbers suppressed in line with the HES analysis guidance and no personal identifying information will be included in any outputs. Although the journal choice depends on the focus of the research question, NCJDRSU tries to make all peer-reviewed publications available in open-access.

Blood donors are provided with information describing how their information may be used and information about the TMER study specifically is provided by NCJDRSU and NHSBT through their websites and privacy notices, and included in scientific publications.

Donor information

Prior to donation, when consenting to donate blood, donors are asked to read the donor welcome leaflet which describes how their data can be also used for purposes other than donation, including for research and surveillance activities: “to ensure the safety of all donors and patients and the traceability of donations…for research…this may include linkage of your information to your other NHS records”. The TMER study is just one of many possible projects that donor data may be used for and it is not feasible to provide detailed information for each and all of these. Instead the blood services have taken the approach of alerting donors to possible uses of their data through donor information and privacy notices, providing more project specific information on websites which are reviewed regularly by the respective organisations (information about the TMER study is made available on the NHSBT and NCJDRSU websites), and on demand.

Websites

NHS Blood & Transplant are co-investigators on this project which gives information on a number of national projects of which the TMER project is one. At the top of the NHSBT Donor facing Give Blood page there is a link taking readers to the research and surveillance pages with further information available.

There are also annual reports on the SHOT (Serious Hazards of Transfusion) website. Chapter 20 relates to transfusion transmission infection (TTI) of which vCJD/prion disease is a category.

Detail about the TMER study, including methods, results and publications are provided in the TMER section of the NCJDRSU website which is updated as new results become available.

In addition, the TMER study management team comprising co-investigators, the study coordinator and supporting staff meet twice a year; all issues in relation to study management, progress and findings are discussed and the meeting is minuted.

A report to the funding body is produced annually. Submissions to peer reviewed journals, conferences and updates to website will occur when new results are available.

Under previous DSAs, previously stated target dates/deliverables have been realised.

This agreement does not have any associated EU funding.

Results from the vCJD arm of the project identified four instances of probable transfusion transmitted infection: in 3 cases of vCJD and a separate pre-clinical infection in a blood recipient. There have been no new cases of transfusion-associated vCJD since 2007. The last diagnosis of a transfusion-associated case was late 2006. The last diagnosis of a vCJD case (which was non transfusion-associated) was 2016.

The identification of vCJD, the positing of a risk of blood-related secondary transmission of vCJD and the later actual identification of such transmission (of infection and disease) indicated that person-to-person spread of vCJD through blood and blood products was a real problem. This information and supporting data informed public health risk assessments and subsequent policy, allowing rational design and implementation of precautions that almost certainly prevented further transmissions and have critically limited the possibility of a self-sustaining blood-related secondary epidemic, including:

• Withdrawal and recall of blood and associated products obtained from donors who develop vCJD (1997).

• Importation of plasma for UK plasma fractionation (1998/1999)

• Leucodepletion of all blood components (1998/1999)

• Deferral of blood donors meeting certain criteria

• The promotion of more appropriate blood/blood product use in the NHS.

All of these policies are continually reviewed and currently remain in place – informed in part by data being provided by the NCJDRSU through the TMER study.

It is vital to continue studies such as the TMER so that any models can be ‘calibrated’ against actual observations and then risk assumptions potentially reconsidered. Results from all other types of CJD included in the project have not so far shown any evidence of transfusion transmission.

The exact levels of infectivity in blood, the precise distribution of infection in the different blood components, and the details of how these might change over time in a given individual, in humans in either the preclinical or clinical stages of vCJD remain unknown. Assumptions have, however, been made (on the basis of available evidence) and used in risk assessments. It is vital to continue studies such as the TMER so as any models can be ‘calibrated’ against actual observations and then risk assumptions potentially reconsidered.

As look-back studies of blood transfusion in Creutzfeldt-Jakob disease commonly rely on reported history from surrogate witnesses, data from the TMER project were analysed to determine the accuracy of blood donation history provided by the relatives of cases. The results showed that only a small percentage of cases were found to be registered as donors on UKBS databases when there was no family report of blood donation. In contrast, a history of reported donation was less accurate. As there are potential public health implications of even a small percentage of CJD blood donors not being identified, a revision to the protocol of the CJD arm of the project has recently being made whereby all cases of CJD (definite and probable) will be notified to UKBS regardless of their reported donation history.

The Transfusion Medicine Epidemiology Review (TMER) is a collaborative project between the UK National CJD Research & Surveillance Unit (NCJDRSU), which is part of the University of Edinburgh, and the UK Blood Services (UKBS), which incorporates NHS Blood and Transplant (NHSBT), the Welsh Blood Service (WBS), the Scottish National Blood Transfusion Service (SNBTS) and Northern Ireland Blood Transfusion Service (NIBTS). This agreement covers data from English Hospitals only. The TMER project was set up in 1997 with the aim of investigating whether Creutzfeldt Jakob Disease (CJD) and its variant form (vCJD) may be transmitted via the blood supply.

The NCJDRSU will use mortality data provided by NHS Digital to support its surveillance and research programme, by using the data to look at the date and cause(s) of death of recipients of blood from, and donors of blood to, cases of CJD/vCJD as part of the TMER study. This study helped identify, in 2004, the first case of transfusion transmitted infection of vCJD – in a patient who had received blood from a blood donor who had, subsequent to the donation, later gone on to develop vCJD. This finding, along with later reports and publications from the study have informed health guidance and policy decision making in the UK and overseas.

The data are being processed under Article 6 (1) (e) which is the legal basis used for performing tasks that are carried out in the public interest (a public task), identifying and monitoring of risk factors for the transmission of CJD/vCJD, as a core function of the University of Edinburgh, under the Universities (Scotland) Act 1966.

NCJDRSU research programme includes processing data, such as those used in this study, for reasons of public health including public health monitoring. Unresolved scientific questions relating to the risk of CJD/vCJD transmission in blood and of developing disease, potentially large numbers of sub-clinically infected donors and the absence of a blood test for CJD/vCJD that can be used in routine practice, mean that indirect approaches, such as those detailed in this application, are required to better understand the risk of transfusion associated transmission as well as help identify instances where this may have occurred.

Data from the NCJDRSU on cases of CJD/vCJD are linked using patient identifiers to data from the national blood services who provide details of recipients / donors to these CJD/vCJD cases. Details of these recipients / donors are then cross checked on the CJD Unit database to determine any cases of CJD/vCJD. The recipients / donors are also sent to NHS Digital for flagging (previously undertaken by HSCIC) for date, place and cause of death. As close to 100% ascertainment of deaths is needed as is possible. The blood services do not routinely collect death information for blood donors or transfusion recipients, the NCJDRSU has no contact with the recipients and donors and there is no alternative source of this information. NCJDRSU therefore cannot reasonably achieve the above other than using the national mortality data, as requested in this application.

Being able to access the date, place and cause of death of recipients from, and donors to, CJD/vCJD cases, using data provided through NHS Digital, provides NCJDRSU with a means of identifying when these individuals died and whether any of these individuals died of CJD/vCJD, thereby helping to quantify risk. The data are required to provide timely results, which can be used to inform public health policy nationally and internationally aimed at minimising the risk of further transmission, which has profound implications for mitigating health risk at the individual as well as population level. This comes under public interest in the area of public health as depicted in Schedule 1 Part 1(3) of the Data Protection Act 2018.

Consent is not feasible, for the following reasons. Data collection is retrospective and does not include contact with patients, or analysis of stored blood samples. The majority of individuals (ie the majority of recipients and a small proportion of the donors) included in this application are deceased by the time of flagging, therefore consent cannot be sought. Contacting the relatives of deceased individuals would cause unnecessary distress and confusion, the same applies to living recipients / donors, particularly as there are no actions or treatment that could be given to these individuals to mitigate the, at present, theoretical risk of transmission of CJD infection. When the project started in 1997 ethical approval was sought and approved but in 2014 was re-categorised as surveillance, not research, and as such not requiring ethical approval. The exception to the above is variant CJD in which a policy decision was made by the Department of Health, following evidence of transfusion transmission of this condition, to inform recipients of labile blood products of the risk of variant CJD. Living recipients of any vCJD-implicated blood transfusion are now deferred from themselves donating blood, which prevents the potential spread of infection and propagation of a transfusion-related vCJD epidemic from sub-clinical carriers of the infectious prion agent. When consenting to give blood, donors agree to the use of their blood / data for purposes other than donation, however consenting all donors specifically for this study would be unfeasible (over a million units of blood are donated each year). Consent cannot be sought prospectively from all those receiving transfusions, either, due to the usual emergency nature of transfusions. The data processing methods have been assessed by CAG and approved.

Data received from NHS Digital relates to recipients from, and donors to, cases of CJD/vCJD. The details of whether the individuals flagged have died and their date of death allows NCJDRSU to be consistent with previous analyses and enables more accurate estimates of the period between transfusion/donation and death, and thereby the quantification of risk; the place and cause(s) of death will allow the study team to check whether any of these individuals may have had a diagnosis of CJD/vCJD, which in turn will allow the study team to identify instances where transfusion –related transmission may have occurred. Risk assessments can then be updated and refined.

Previously, the use of this information has helped demonstrate that CJD/vCJD can be transmitted via the blood supply, and enabled this to be done in a timely manner. However for the purposes of public health monitoring and risk assessment, the study team will continue to request this information in the longer term and on a regular basis to help identify further instances where this may occur, thus enabling and informing policy makers in the reassessment and quantification of risk.

The NCJDRSU is a Department of Health and Scottish Government Health Department funded programme which has been running since 1990 with a remit to monitor the characteristics of all forms of CJD, to identify trends in incidence rates, to study risk factors for the development of disease and to contribute to improving the quality of care for those with CJD. Integral to CJD surveillance is the referral of suspected cases of CJD to the NCJDRSU, for clinical and pathological examination, epidemiological assessment and diagnosis, according to internationally recognised standard diagnostic criteria.

In 1996, NCJDRSU reported a novel form of CJD, now termed ‘variant’ CJD, which was caused by infection with the agent of BSE in cattle. Following the identification of vCJD, there was concern about the potential for secondary, human to human, spread of vCJD via blood and blood products. Although this had never been identified with other forms of human prion disease in clinical practice (and the NCJDRSU had undertaken research in the past with negative results), vCJD was a novel disease with evidence of unusually significant reticulo-endothelial involvement. The significant uncertainty around this possibility meant uncertainty as to what precautions should be taken with these essential therapeutic items. The TMER study began the following year, also funded by the Department of Health and Scottish Government Health Department, as a collaborative study between the NCJDRSU, part of the University of Edinburgh, and the UK blood services, with the principle aim of investigating whether CJD/vCJD was transmissible via blood transfusion.

Until 2004 in was generally accepted that CJD had not been transmitted by blood transfusion. Preliminary findings from sheep studies indicated that BSE and scrapie (a fatal, degenerative disease affecting the nervous systems of sheep and goats) could be transmitted by blood transfusion and it was vital to find out whether this also applied to human transmissible spongiform encephalopathies (TSEs) and, in particular, vCJD. The UK is the only country where a significant outbreak of vCJD has occurred and was in a unique position to study this question which has important implications for public health.

To date, the TMER study has identified three clinical cases of vCJD who were infected by non‐leucodepleted blood derived from asymptomatic donors who later developed the condition. With the use of mortality data supplied previously, it was possible to identify the first instance of probable transfusion transmitted infection of vCJD in a timely manner.

The exact levels of infectivity in blood, the precise distribution of infection in the different blood components, and the details of how these might change over time in a given individual, in humans in either the preclinical or clinical stages of vCJD remain unknown. Assumptions have, however, been made (on the basis of available evidence) and used in risk assessments.

The nature of the work described in this application is a part of a wider program of research and surveillance undertaken by the NCJDRSU, which involves the long-term monitoring of disease occurrence and investigation of risk. The project is run by the NJDRSU in collaboration with the UK blood services. It requires data on individual CJD cases held on the NCJDRSU core surveillance database to be linked with information held on current and archived databases held by the UK blood services and their associated UK hospital blood banks, in order to identify recipients of blood from, or donors of blood to, CJD/vCJD cases. Results from this project have been used to inform public health policy nationally and internationally aimed at minimising the risk of further transmission. This involves collaboration with bodies such as the UK departments of Health, Public Health England, Health Protection Scotland and various expert panels and committees, including the CJD Incidents Panel (now defunct), the Advisory Committee on Dangerous Pathogens (ACDP) and the independent Advisory Committee for the Safety of Blood, Tissues and Organs (SaBTO).

This is a public health surveillance activity, which requires ongoing long-term monitoring to identify instances of transfusion-associated transmission. The individuals to be flagged by NHS Digital under this project are supplied by NHS Blood and Transplant based on data from the UK national blood services. National mortality data for all four nations is required. Previously this was provided to NCJDRSU by HSCIC. Information on date, place and cause(s) of death supplied to NCJDRSU by NHS Digital as a result of the flagging exercise will only be processed by the University of Edinburgh acting through the NCJDRSU. Data is requested on a quarterly basis, to ensure deaths are detected in a timely manner. Processing will always be within the terms of the DSA with NHS Digital.

The data subjects are individuals who have ever either received blood from, or donated blood to, a case or cases of CJD/vCJD.

NCJDRSU research programme includes processing data, such as those used in this study, for reasons of public health including public health monitoring. Unresolved scientific questions relating to the risk of CJD/vCJD transmission in blood and of developing disease, potentially large numbers of sub-clinically infected donors and the absence of a blood test for CJD/vCJD that can be used in routine practice, mean that indirect approaches, such as those detailed in this application, are required to better understand the risk of transfusion associated transmission as well as help identify instances where this may have occurred.

Data relate to recipients from, and donors to, cases of CJD/vCJD. The datasets requested from NHS Digital are the date, place and cause(s) of death of NCJDRSU-flagged individuals (ie. recipients from, or donors to, cases of CJD/vCJD).

Data from the NCJDRSU on cases of CJD/vCJD are linked to data from the national blood services who provide details of recipients / donors to these CJD/vCJD cases. Details of these recipients / donors are then cross checked on the CJD Unit database to determine any cases of CJD/vCJD. The recipients / donors are also sent to NHS Digital for flagging (previously undertaken by HSCIC) for date, place and cause of death.

Using data provided through NHS Digital, provides NCJDRSU with a means of identifying when these individuals died and whether any of these individuals died of CJD/vCJD, thereby helping to quantify risk. The details of whether the individuals flagged have died and their date of death allows NCJDRSU to be consistent with previous analyses and enables more accurate estimates of the period between transfusion/donation and death, and thereby the quantification of risk; knowing the place and cause(s) of death will allow the study team to check medical records to determine whether any of these individuals may have had a diagnosis of CJD/vCJD, which in turn will allow the study team to identify instances where transfusion –related transmission may have occurred. The data are required to provide timely results, which can be used to inform public health policy nationally and internationally aimed at minimising the risk of further transmission, which has profound implications for mitigating health risk at the individual as well as population level.

Confidential patient information is required to flag specific individuals who meet the criteria for inclusion in the review. Information on individual cases of CJD will be held on the NCJDRSU database to be linked with current and archived datasets held by the four national blood services within the UK and UK hospital blood banks. There is no common identifier that can be used to link information across these sources. There have also been discussions previously with CAG as to whether NHSBT could flag recipients and donors rather than passing this information back to NCJDRSU and for NCJDRSU to then receive pseudonymised data from HSCIC (now NHS Digital) for analysis purposes. However, as well as flagging individuals with HSCIC (now NHS Digital), cross checks are also carried out on the NCJDRSU database to determine whether any of these individuals are recorded as a case of CJD and for the purpose of this check NCJDRSU require fully identifiable details.

For the purposes of public health monitoring and risk assessment, the study team will continue to request this information on a long term regular basis. This will help identify further instances where transfusion-related transmission of CJD/vCJD may occur in a timely manner, thus informing policy makers in the reassessment and quantification of risk. Data is required for the whole of the UK, as this is a UK-wide national project and no subjects are excluded. Previously this information was provided to NCJDRSU by HSCIC.

As close to 100% ascertainment of deaths is needed as is possible. The blood services do not routinely collect death information for blood donors or transfusion recipients, the NCJDRSU has no contact with the recipients and donors and there is no alternative source of this information. NCJDRSU therefore cannot reasonably achieve the above other than using the national mortality data, as requested in this application. There are no alternative less obtrusive ways of achieving the purpose.

The TMER study team have considered the data fields requested and use the minimum level of data required without compromising the accuracy of the project; data requirements are reviewed at renewal of DSAs and will also be reviewed if project requirements change. This will be held securely on UoE premises within a DSPT compliant environment according to the terms of the DSA. It will be kept confidential by NCJDRSU, used only for the purposes of the study and will be deleted once it has been processed.

The University of Edinburgh is the data controller and will be the only organisation who will have access to, and process, the data supplied by NHS Digital.

The data will not be used for any external commercial purposes and will not be provided at record level form to any third party. Any data processing will be done under a data sharing agreement and data sharing framework contract between NHS Digital and the University of Edinburgh.

The four national UK blood services in the UK (NHSBT, WBS, SNBTS, NIBTS) do not process NHS Digital data. Their role is to identify recipients of blood from, and donors of blood to, cases of CJD/vCJD and pass this information back to NCJDRSU.

There are no funders/commissioners involved in this project.

This agreement does not support any separate current or planned PhD/postgraduate research study. If the analysis were to contribute to such studies in the future an amendment to this agreement would be submitted to NHS Digital.

Data from this project will be included in:

a. Annual reports to Department of Health and Social Care and Scottish Government Health Department.

b. The TMER section of the NCJDRSU website

c. Submissions to peer reviewed journals resulting in research publications, in open-access format where possible.

d. Presentations at conferences.

The following articles have already been produced using the data from the TMER.

•Llewelyn CA, Hewitt PE, Knight RSG, Amar K, Cousens S, Mackenzie J, Will RG. Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion. Lancet 2004; 363: 417-421.

•Peden AH, Head MW, Ritchie DL, Bell JE, Ironside JW. Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet 2004; 364: 527-529.

•Health Protection Agency. New case of transfusion-associated variant-CJD. CDR Weekly 2006; 16(6).

•Hewitt PE, Llewelyn CA, Mackenzie J, Will RG. Creutzfeldt-Jakob disease and blood transfusion: results of the UK Transfusion Medicine Epidemiology Review study. Vox Sanguinis 2006; 91: 221-230.

•Wroe SJ, Pal S, Siddique D, Hyare H, Macfarlane R, Joiner S, Linehan JM, Brandner S, Wadsworth JD, Hewitt P, Collinge J. Clinical presentation and pre-mortem diagnosis of variant Creutzfeldt-Jakob disease associated with blood transfusion: a case report. Lancet 2006; 368: 2061-2067.

•Health Protection Agency. Fourth case of transfusion-associated variant-CJD infection. Health Protection Report 2007; 1(3).

•Gillies M, Chohan G, Llewelyn CA, Mackenzie J, Ward HJT, Hewitt PE, Will RG. A retrospective case note review of deceased recipients of vCJD-implicated blood transfusions. Vox Sanguinis 2009; 97: 211-218.

•Ward HJT, Mackenzie JM, Llewelyn CA, Knight RSG, Hewitt PE, Connor N, Molesworth A, Will RG. Variant Creutzfeldt-Jakob disease and exposure to fractionated products. Vox Sanguinis 2009; 97: 207-210

•Chohan G,Llewelyn C, Mackenzie J, Cousens S, Kennedy A, Will RG, Hewitt PE. Variant Creutzfeldt-Jakob disease in a transfusion recipient: coincidence or cause? Transfusion 2010; 50: 1003-1006.

•Davidson LRR, Llewelyn CA, Mackenzie JM, Hewitt, PE, Will RG. Variant CJD and blood transfusion: are there additional cases? Vox Sanguinis 2014 DOI: 10.1111/Vox 12161.

•Urwin PJM, Mackenzie JM, Llewelyn CA, Will RG, Hewitt PE. Creutzfeldt-Jakob disease and blood transfusion: updated results of the UK Transfusion Medicine Epidemiology Review Study. Vox Sanguinis 2016; 110: 310-316.

•Mackenzie JM, Turner M, Morris K, Field S, Molesworth AM, Pal S, Will RG, Llewelyn CA, Hewitt PE. Accuracy of a history of blood donation from surrogate witnesses: data from the UK TMER Study. Vox Sanguinis 2018; doi: 10.1111/vox 12661.

All outputs will be aggregated with small numbers suppressed in line with the HES analysis guidance and no personal identifying information will be included in any outputs. Although the journal choice depends on the focus of the research question, NCJDRSU tries to make all peer-reviewed publications available in open-access.

Blood donors are provided with information describing how their information may be used and information about the TMER study specifically is provided by NCJDRSU and NHSBT through their websites and privacy notices, and included in scientific publications.

Donor information

Prior to donation, when consenting to donate blood, donors are asked to read the donor welcome leaflet which describes how their data can be also used for purposes other than donation, including for research and surveillance activities: “to ensure the safety of all donors and patients and the traceability of donations…for research…this may include linkage of your information to your other NHS records”. The TMER study is just one of many possible projects that donor data may be used for and it is not feasible to provide detailed information for each and all of these. Instead the blood services have taken the approach of alerting donors to possible uses of their data through donor information and privacy notices, providing more project specific information on websites which are reviewed regularly by the respective organisations (information about the TMER study is made available on the NHSBT and NCJDRSU websites), and on demand.

Websites

NHS Blood & Transplant are co-investigators on this project which gives information on a number of national projects of which the TMER project is one. At the top of the NHSBT Donor facing Give Blood page there is a link taking readers to the research and surveillance pages with further information available.

There are also annual reports on the SHOT (Serious Hazards of Transfusion) website. Chapter 20 relates to transfusion transmission infection (TTI) of which vCJD/prion disease is a category.

Detail about the TMER study, including methods, results and publications are provided in the TMER section of the NCJDRSU website which is updated as new results become available.

In addition, the TMER study management team comprising co-investigators, the study coordinator and supporting staff meet twice a year; all issues in relation to study management, progress and findings are discussed and the meeting is minuted.

A report to the funding body is produced annually. Submissions to peer reviewed journals, conferences and updates to website will occur when new results are available.

Under previous DSAs, previously stated target dates/deliverables have been realised.

This agreement does not have any associated EU funding.

Results from the vCJD arm of the project identified four instances of probable transfusion transmitted infection: in 3 cases of vCJD and a separate pre-clinical infection in a blood recipient. There have been no new cases of transfusion-associated vCJD since 2007. The last diagnosis of a transfusion-associated case was late 2006. The last diagnosis of a vCJD case (which was non transfusion-associated) was 2016.

The identification of vCJD, the positing of a risk of blood-related secondary transmission of vCJD and the later actual identification of such transmission (of infection and disease) indicated that person-to-person spread of vCJD through blood and blood products was a real problem. This information and supporting data informed public health risk assessments and subsequent policy, allowing rational design and implementation of precautions that almost certainly prevented further transmissions and have critically limited the possibility of a self-sustaining blood-related secondary epidemic, including:

• Withdrawal and recall of blood and associated products obtained from donors who develop vCJD (1997).

• Importation of plasma for UK plasma fractionation (1998/1999)

• Leucodepletion of all blood components (1998/1999)

• Deferral of blood donors meeting certain criteria

• The promotion of more appropriate blood/blood product use in the NHS.

All of these policies are continually reviewed and currently remain in place – informed in part by data being provided by the NCJDRSU through the TMER study.

Outputs achieved their stated purposes (and thus the benefits of processing). Examples of peer-reviewed publications resulting from the TMER study (available in the public domain) are as follows:

1. Llewelyn CA, Hewitt PE, Knight RSG, Amar K, Cousens S, Mackenzie J, Will RG. Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion. Lancet 2004; 363: 417-421. (This was the first recorded vCJD case who developed vCJD as a result of transfusion transmitted infection).

2. Peden AH, Head MW, Ritchie DL, Bell JE, Ironside JW. Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet 2004; 364: 527-529

3. Health Protection Agency. New case of transfusion-associated variant-CJD. CDR Weekly 2006; 16(6).

4. Hewitt PE, Llewelyn CA, Mackenzie J, Will RG. Creutzfeldt-Jakob disease and blood transfusion: results of the UK Transfusion Medicine Epidemiology Review study. Vox Sanguinis 2006; 91: 221-230.

5. Wroe SJ, Pal S, Siddique D, Hyare H, Macfarlane R, Joiner S, Linehan JM, Brandner S, Wadsworth JD, Hewitt P, Collinge J. Clinical presentation and pre-mortem diagnosis of variant Creutzfeldt-Jakob disease associated with blood transfusion: a case report. Lancet 2006; 368: 2061-2067.

6. Health Protection Agency. Fourth case of transfusion-associated variant-CJD infection. Health Protection Report 2007; 1(3).

7. Gillies M, Chohan G, Llewelyn CA, Mackenzie J, Ward HJT, Hewitt PE, Will RG. A retrospective case note review of deceased recipients of vCJD-implicated blood transfusions. Vox Sanguinis 2009; 97: 211-218.

8. Ward HJT, Mackenzie JM, Llewelyn CA, Knight RSG, Hewitt PE, Connor N, Molesworth A, Will RG. Variant Creutzfeldt-Jakob disease and exposure to fractionated products. Vox Sanguinis 2009; 97: 207-210.

9. Chohan G,Llewelyn C, Mackenzie J, Cousens S, Kennedy A, Will RG, Hewitt PE. Variant Creutzfeldt-Jakob disease in a transfusion recipient: coincidence or cause? Transfusion 2010; 50: 1003-1006.

10. Davidson LRR, Llewelyn CA, Mackenzie JM, Hewitt, PE, Will RG. Variant CJD and blood transfusion: are there additional cases? Vox Sanguinis 2014; 107(3): 220-225.

11. Urwin PJM, Mackenzie JM, Llewelyn CA, Will RG, Hewitt PE. Creutzfeldt-Jakob disease and blood transfusion: updated results of the UK Transfusion Medicine Epidemiology Review Study. Vox Sanguinis 2016; 110: 310-316.

12. Mackenzie JM, Turner M, Morris K, Field S, Molesworth AM, Pal S, Will RG, Llewelyn CA, Hewitt PE. Accuracy of a history of blood donation from surrogate witnesses: data from the UK TMER study. Vox Sanguinis 2018; 113(5): 489-491. (This paper resulted in a proposal to change the study protocol to check all cases of CJD (as was already the case with vCJD) with the UK blood services, regardless of a reported history of blood donation. Previously only cases who had been reported by the relatives to have been blood donors were sent for checking).

It is vital to continue studies such as the TMER so that any models can be ‘calibrated’ against actual observations and then risk assumptions potentially reconsidered. Results from all other types of CJD included in the project have not so far shown any evidence of transfusion transmission.

The exact levels of infectivity in blood, the precise distribution of infection in the different blood components, and the details of how these might change over time in a given individual, in humans in either the preclinical or clinical stages of vCJD remain unknown. Assumptions have, however, been made (on the basis of available evidence) and used in risk assessments. It is vital to continue studies such as the TMER so as any models can be ‘calibrated’ against actual observations and then risk assumptions potentially reconsidered.

As look-back studies of blood transfusion in Creutzfeldt-Jakob disease commonly rely on reported history from surrogate witnesses, data from the TMER project were analysed to determine the accuracy of blood donation history provided by the relatives of cases. The results showed that only a small percentage of cases were found to be registered as donors on UKBS databases when there was no family report of blood donation. In contrast, a history of reported donation was less accurate. As there are potential public health implications of even a small percentage of CJD blood donors not being identified, a revision to the protocol of the CJD arm of the project has recently being made whereby all cases of CJD (definite and probable) will be notified to UKBS regardless of their reported donation history.

Mortality data was supplied to University of Edinburgh by the Health and Social Care Information Centre (which has since become NHS Digital) for the purpose of a research study referred to as Transfusion Medicine Epidemiology Review.

This Data Sharing Agreement permits the retention of the data for an interim period but no other processing of the data is permitted.

Only storage and retention of the data is permitted under this data sharing agreement. No other processing of the data is permitted to take place.

Permission to retain the data for the interim period is a practical step to enable the study to comply with the necessary legal and ethical requirements. If, for any reason, it is not possible for the study to meet the necessary requirements, this Agreement will be terminated, and destruction of the data will be required.

The following information provides background information on the purpose of the original study.

The purpose of the Transfusion Medicine Epidemiology Review (TMER) is to investigate whether there is any evidence that CJD or vCJD may have been transmitted via the blood supply. The National CJD Research and Surveillance Unit (NCJDRSU) at the University of Edinburgh requires mortality data for use in this project.

Any potential links between CJD cases that are associated with transfusion associated transmission can be identified using and this information can then be used to inform public health policy nationally and internationally aimed at minimising the risk of further transmission. The absence of a blood test for CJD that can be used in routine practice, and unresolved questions relating to the risk of CJD transmission in blood, the risk of developing disease and potentially large numbers of sub-clinically infected donors, means that this study has profound implications for mitigating risk and would fall under Article 9 (2) (i) of the GDPR which states that processing is necessary for reasons of public interest.

Relevant background

The TMER has been running since 1997 and with the use of mortality data supplied previously, it was possible to identify the first instance of probable transfusion transmitted infection of vCJD in a timely manner.

Work being undertaken

The identity of individuals who have been identified by NCJDRSU with a classification of definite or probable CJD are passed to NHS Blood and Transplant (NHSBT) for onward checking with other national blood services as necessary, in order to identify recipients of blood from, and donors to, the CJD cases, and so the blood services can take appropriate public health action with regard to the future handling of any associated stored products. ‘Control’ cases are also included in the dataset sent to NHSBT for the purposes of ‘blinding’. The identities of cases of definite or probable vCJD aged 17 and over are sent to all national blood services directly for checking.

Recipient and donor details from the above are passed to NCJDRSU for NCJDRSU to check against their own records to identify whether they are already known to NCJDRSU. Recipient and donor details are also sent by NCJDRSU to NHS Digital, who in turn will send to NHSCR for donors/recipients residing in Scotland, for flagging of date and cause of death, and thereby whether any have developed or died from CJD. NCJDRSU will be the only organisation who will have access to the record level data supplied by NHS Digital.

Why data is required from NHS Digital

The data on date and cause of death which is requested from NHS Digital is a very important step in NCJDRSU being able to make such connections as described above.

Organisations involved and funding body

The TMER is a public health surveillance activity undertaken by NCJDRSU (sole data controller) in collaboration with the UK national blood services [UKBS] (data processors) to identify transmission of CJD through blood transfusion in order that appropriate actions can be taken where necessary to protect public health. It is funded by Department of Health Policy Research Programme, Grant Number PR-ST-0614-00008.

This Data Sharing Agreement permits the retention of the data for an interim period but no other processing of the data is permitted. Only storage and retention of the data is permitted under this data sharing agreement. No other processing of the data is permitted to take place.

The following articles have already been produced using the data from the TMER.

•Llewelyn CA, Hewitt PE, Knight RSG, Amar K, Cousens S, Mackenzie J, Will RG. Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion. Lancet 2004; 363: 417-421.

•Peden AH, Head MW, Ritchie DL, Bell JE, Ironside JW. Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet 2004; 364: 527-529.

•Health Protection Agency. New case of transfusion-associated variant-CJD. CDR Weekly 2006; 16(6).

•Hewitt PE, Llewelyn CA, Mackenzie J, Will RG. Creutzfeldt-Jakob disease and blood transfusion: results of the UK Transfusion Medicine Epidemiology Review study. Vox Sanguinis 2006; 91: 221-230.

•Wroe SJ, Pal S, Siddique D, Hyare H, Macfarlane R, Joiner S, Linehan JM, Brandner S, Wadsworth JD, Hewitt P, Collinge J. Clinical presentation and pre-mortem diagnosis of variant Creutzfeldt-Jakob disease associated with blood transfusion: a case report. Lancet 2006; 368: 2061-2067.

•Health Protection Agency. Fourth case of transfusion-associated variant-CJD infection. Health Protection Report 2007; 1(3).

•Gillies M, Chohan G, Llewelyn CA, Mackenzie J, Ward HJT, Hewitt PE, Will RG. A retrospective case note review of deceased recipients of vCJD-implicated blood transfusions. Vox Sanguinis 2009; 97: 211-218.

•Ward HJT, Mackenzie JM, Llewelyn CA, Knight RSG, Hewitt PE, Connor N, Molesworth A, Will RG. Variant Creutzfeldt-Jakob disease and exposure to fractionated products. Vox Sanguinis 2009; 97: 207-210

•Chohan G,Llewelyn C, Mackenzie J, Cousens S, Kennedy A, Will RG, Hewitt PE. Variant Creutzfeldt-Jakob disease in a transfusion recipient: coincidence or cause? Transfusion 2010; 50: 1003-1006.

•Davidson LRR, Llewelyn CA, Mackenzie JM, Hewitt, PE, Will RG. Variant CJD and blood transfusion: are there additional cases? Vox Sanguinis 2014 DOI: 10.1111/Vox 12161.

•Urwin PJM, Mackenzie JM, Llewelyn CA, Will RG, Hewitt PE. Creutzfeldt-Jakob disease and blood transfusion: updated results of the UK Transfusion Medicine Epidemiology Review Study. Vox Sanguinis 2016; 110: 310-316.

•Mackenzie JM, Turner M, Morris K, Field S, Molesworth AM, Pal S, Will RG, Llewelyn CA, Hewitt PE. Accuracy of a history of blood donation from surrogate witnesses: data from the UK TMER Study. Vox Sanguinis 2018; doi: 10.1111/vox 12661.

2. Planned outputs

- Data from the TMER are included in annual reports to Department of Health. These are published late summer/early autumn each year.).

- Results from the study also appear on the NCJDRSU website: (http://www.cjd.ed.ac.uk/projects/all-projects/transfusion-medicine-epidemiology-review-tmer).

- Potential future publications

All outputs are aggregated with small number suppression in line with the HES Analysis Guide.

Mortality data was supplied to University of Edinburgh by the Health and Social Care Information Centre (which has since become NHS Digital) for the purpose of a research study referred to as Transfusion Medicine Epidemiology Review.

This Data Sharing Agreement permits the retention of the data for an interim period but no other processing of the data is permitted.

Permission to retain the data for the interim period is a practical step to enable the study to comply with the necessary legal and ethical requirements. If, for any reason, it is not possible for the study to meet the necessary requirements, this Agreement will be terminated, and destruction of the data will be required.

The following information provides background information on the benefits acheived from the original study.

Results from the vCJD arm of the project identified four instances of probable transfusion transmitted infection in 3 cases of vCJD and pre-clinical infection in a recipient with post-mortem confirmation of abnormal prion protein deposition in the spleen. There have been no new cases of transfusion-associated vCJD since 2007.

The identification of vCJD, the positing of a risk of blood-related secondary transmission of vCJD and the later actual identification of such transmission (of infection and disease) have led directly to a number of public health policy changes including:

• Withdrawal and recall of blood and associated products obtained from donors who develop vCJD (1997).

• Importation of plasma for UK plasma fractionation (1998/1999)

• Leucodepletion of all blood components (1998/1999)

• Deferral of blood donors meeting certain criteria

• The promotion of more appropriate blood/blood product use in the NHS

All of these policies are continually reviewed and currently remain in place – dependent on the data being provided by the TMER study.

The exact levels of infectivity in blood, the precise distribution of infection in the different blood components, and the details of how these might change over time in a given individual, in humans in either the preclinical or clinical stages of vCJD remain unknown. Assumptions have, however, been made (on the basis of available evidence) and used in risk assessments. It is vital to continue studies such as the TMER so as any models can be ‘calibrated’ against actual observations and then risk assumptions potentially reconsidered.

Results from all other types of CJD included in the project have not so far shown any evidence of transfusion transmission.

As look-back studies of blood transfusion in Creutzfeldt-Jakob disease commonly rely on reported history from surrogate witnesses, data from the TMER project were analysed to determine the accuracy of blood donation history provided by the relatives of cases. The results showed that only a small percentage of cases were found to be registered as donors on UKBS databases when there was no family report of blood donation. In contrast, a history of reported donation was less accurate. As there are potential public health implications of even a small percentage of CJD blood donors not being identified, a revision to the protocol of the CJD arm of the project has recently being made whereby all cases of CJD (definite and probable) will be notified to UKBS regardless of their reported donation history.