MR1462 - Data linkage request for the Febuxostat versus Allopurinol Streamlined Trial (FAST).

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

Objective for processing

Gout affects at least 1% of the population in Western countries and is the most common inflammatory joint disease in men older than 40 years of age. The UK prevalence of gout was reported to be 1.4% in 1999. Historically a disease of affluent, middle-aged or older men, gout has now affected more women and a wider range of socioeconomic groups. Gout progresses from episodic flare-ups of acute inflammatory arthritis to a disabling chronic disorder characterised by deforming arthropathy, destructive deposits of crystals (tophi) in bones, joints and other organs, impairment of kidney functions and urolithiasis. University of Dundee requires access to NHS England data for the purpose of the following research project: Cardiovascular disease is frequently observed in patients with elevations in uric acid. While theories as to the specific causal relationship between uric acid and cardiovascular disease/mortality vary, the correlation between the two is widely recognised. Uric acid levels are increasingly believed to be an independent predictor of death in patients at high risk of cardiovascular disease. The FAST (Febuxostat versus Allopurinol Streamlined Trial) study Allopurinol and febuxostat have each shown to be safe and effective drugs for the treatment of gout. However, initial clinical trials of febuxostat suggested that it may be associated with increased cardiovascular risk. Subsequent studies have not supported this risk and a definitive study to confirm or refute this safety concern is still required. The European Union (EU) Risk Management Plan (RMP) for febuxostat (Version 2.0; 19 February 2008) indicates that a post marketing study to evaluate cardiovascular effects of febuxostat is to be conducted as part of the Pharmacovigilance Plan. The FAST (Febuxostat versus Allopurinol Streamlined Trial) study is designed to find out whether febuxostat is safer, less safe or just as safe as allopurinol for long term use in practice. The FAST study will focus on the cardiovascular safety profile of febuxostat versus allopurinol, when taken for an average of 3 years in patients aged 60 years or older with chronic hyperuricaemia, in conditions where urate deposition has already occurred. The following is a summary of the aims of the research project provided by University of Dundee: The secondary study objectives are to evaluate other cardiovascular adverse events for both products. This information will be of great value to everyone who needs to take these drugs on a regular basis. It will allow doctors to make the best choice for people with gout, not just for their joint pain and arthritis but also for any associated medical disorders they may have and for their general health. Gout affects at least 1% of the population in Western countries and is the most common inflammatory joint disease in men older than 40 years of age. The UK prevalence of gout was reported to be 1.4% in 1999. Historically a disease of affluent, middle-aged or older men, gout has now affected more women and a wider range of socioeconomic groups. Gout progresses from episodic flare-ups of acute inflammatory arthritis to a disabling chronic disorder characterised by deforming arthropathy, destructive deposits of crystals (tophi) in bones, joints and other organs, impairment of kidney functions and urolithiasis. Cardiovascular disease is frequently observed in patients with elevations in uric acid. While theories as to the specific causal relationship between uric acid and cardiovascular disease/mortality vary, the correlation between the two is widely recognised. Uric acid levels are increasingly believed to be an independent predictor of death in patients at high risk of cardiovascular disease. The FAST study is an EMA (European Medicines Agency) requested safety study as a result of their risk assessment following the licensing of Febuxostat (Adenuric) in the EU. The study received ethics approval 8th August 2011. To fulfil the pharmacovigilance requirements of the EMA it is essential to ensure that all events that may meet the criteria for reporting as Significant Adverse Events (SAEs) or study endpoints, are captured. Allopurinol and febuxostat have each shown to be safe and effective drugs for the treatment of gout. However, initial clinical trials of febuxostat suggested that it may be associated with increased cardiovascular risk. Subsequent studies have not supported this risk and a definitive study to confirm or refute this safety concern is still required. The European Union (EU) Risk Management Plan (RMP) for febuxostat indicated that a post marketing study to evaluate cardiovascular effects of febuxostat is to be conducted as part of the Pharmacovigilance Plan. Aside from meeting the European Medicines Agency regulatory commitments, establishing that this drug is safe in patients who are at risk of cardiovascular disease is of clear benefit, offering an important alternative for managing this condition in a group of patients who are at risk of gout. Other aspects of drug safety are also assessed in the course of this trial by reporting of Serious Adverse Events through the pharmacovigilance process. The FAST study was designed to find out whether febuxostat is safer, less safe or just as safe as allopurinol for long term use in practice. The FAST study focussed on the cardiovascular safety profile of febuxostat versus allopurinol, when taken for an average of 3 years in patients aged 60 years or older with chronic hyperuricaemia, in conditions where urate deposition had already occurred. Secondary objectives were to evaluate other cardiovascular adverse events. It was anticipated that this information would allow doctors to make the best choice for people with gout, not just for their joint pain and arthritis but also for any associated medical disorders they may have and for their general health. Originally, participants were recruited to the FAST study using informed patient consent. These were individuals aged 60 or over who were taking allopurinol to treat their gout symptoms at the time of consent. Recruitment started in December 2011 and ended in September 2017, approximately 1,500 participants were recruited in England for which this Agreement solely applies. The FAST study was an EMA (European Medicines Agency) requested safety study as a result of their risk assessment following the licensing of Febuxostat (Adenuric) in the EU. To fulfil the pharmacovigilance requirements of the EMA it was essential to ensure that all events that may meet the criteria for reporting as Significant Adverse Events (SAEs) or study endpoints, were captured. Aside from meeting the EMA regulatory commitments, establishing that this drug is safe in patients who are at risk of cardiovascular disease was of clear benefit, offering an important alternative for managing this condition in a group of patients who are at risk of gout. Other aspects of drug safety were also assessed in the course of this trial by reporting of SAEs through the pharmacovigilance process The cohort is already held by NHS Digital and as recruitment has ended, this will not be added to. The estimated ratio of male to female patients is 70% to 30% respectively. Other countries including Scotland and Sweden are involved in the FAST Study but are not included under this Agreement. Patient selection was performed from general practice, hospital or at clinics, or from searches of databases of participants who have previously agreed to take part in future research, such as UK Biobank or SHARE. Patients who met the trial criteria were contacted directly by their physician or the consented database owner by letter or invited to an information meeting where they were informed about the current treatment options for gouty conditions and the rationale for the trial. A patient information leaflet was provided to patients interested in the study and an appointment for a screening visit was scheduled. Patients are randomised to either an optimised dose of allopurinol or febuxostat. Follow-up is scheduled at two monthly intervals by phone, letter or visit to the patient by the study nurses or medical staff. NHS England Data was used to identify potentially unreported SAEs. Received NHS England Data were matched to data already in the study database reported by the participants, study nurses and study doctors. Where NHS England Data identified new SAEs not previously reported to the study team these data were supplemented and validated with information gathered from participants, their GPs, hospitals and or registry offices by the study nurses and doctors. Based on this, the NHS England Data was used to improve the accuracy of data captured. It was verified by other sources, and supplemented with additional information, to create the “analysis dataset” which was a source of outputs for the FAST study. No NHS England Data is held in the "analysis dataset". Outputs made available to the Medicines and Healthcare products Regulatory Agency (MHRA) and Menarini Pharma SAS were based on the "analysis dataset". Principal Investigators (PIs) for the study are employed by regional recruitment centres across the UK. The PIs do not make any decisions regarding the data under this Agreement and will only have access to aggregated outputs (with small numbers suppressed). Each PI will only be given data for participants in their region, and this will NOT contain NHS Digital supplied data but any SAEs generated as a result of the information will be supplied to them. The PIs were not involved in the protocol development as it was approved ahead of their appointment and their responsibilities are set out in formal contracts. The FAST study completed on 31/08/2020. MHRA guidance stipulates that clinical trials should retain data post trial for archiving. The University of Dundee would like to retain this Data to ensure reconstruction of the trial analysis is possible if required. Since February 2018 the study has had full support under section 251 of the NHS Act 2006 from HRA CAG to follow-up the cohort. No additional data will be requested from NHS England. This Data Sharing Agreement (DSA) permits processing of the Data for the purpose of secure storage and back up. The data-sets linked to the participant data are: This DSA does not permit any further processing that involves analysis or linkage other than for the purpose of verifying findings in line with the original objectives of the study by repeating previous analyses described in this DSA. - HES Admitted Patient Care Following publication of the study findings, it is possible that the findings will be questioned or challenged by third parties through direct contact with University of Dundee, contact via the publishing journal or an open letter. In such circumstances, University of Dundee may repeat the previously analyses undertaken to verify that the published results were accurate and may write a response to be issued directly to the challenger or published. University of Dundee may not undertake different analyses to those undertaken during the original analysis. - Flagging Current Status reports This DSA does not permit any onward sharing of the Data with the exception that the Data may be viewed for the purpose of an audit by a regulator such as the Medicines and Healthcare products Regulatory Agency (MHRA). The MHRA maintains a list of all clinical trials registered with them and reserve the right to audit the trial at any point from when the trial is opened to 5-year post trial closure. A sponsoring organisation and/or the controller itself may also exercise the right to audit. - Cohort Event Notification reports This DSA permits the necessary processing of the Data for the purposes of permanently destroying, deleting or erasing the Data once it is no longer required for the purpose for which it was collected. Once destroyed/deleted or erased, University of Dundee must confirm destruction to NHS England. - Cause of Death reports If any further data processing is required in addition to the above purposes or if the Data needs to be moved to a different location/organisation University of Dundee must submit an Amendment request to NHS England before Data is accessed. Data was provided from 2011 - 2018 as historic data and then bi-annually until 2020. The study requires data covering the period up to the end of January 2020. Data from the following NHS England Data will be retained: Linkage of the cohort data to national data including hospital admissions, deaths and cancer diagnoses is the primary method of identifying Serious Adverse Events (SAEs) and potential cardiovascular endpoints in the FAST study. • Hospital Episode Statistics - Admitted Patient Care The University of Dundee is the sole Data Controller for the purposes of this Agreement. The University of Dundee requests access to national data-sets of hospital admissions, deaths and cancer diagnoses as the primary method of identifying Serious Adverse Events and potential cardiovascular endpoints in the FAST study. Identification of all hospitalisations, deaths and diagnoses of cancer allows assessment of the safety of the study interventions, febuxostat and allopurinol. Record linkage output will only be used to identify Serious Adverse Events and study endpoints. The requested data is the minimum necessary to detect study serious adverse events, potential endpoints and primary and secondary outcomes on consented patients from their date of consent into the FAST study. • Deaths and Case of Death via Flagging Current Status reports, Cohort Event Notification reports and Cause of Death Reports. The study is an academic study grant funded by Menarini Pharma SAS under a full legal agreement between Menarini and the University of Dundee, with the University of Dundee being the study sponsor and Menarini representatives having only observer status on the steering committee. Menarini is the European Licence holder for Adenuric (Febuxostat), although febuxostat is now off patent. Though the study is funded by Menarini Pharma SAS and has been requested by the EMA, the study is academically initiated, run and owned by the University of Dundee. Menarini has no input or involvement in the study design, administration, management, or outputs – the study is primarily approved by and required by the EMA (not Menarini). Only the University of Dundee as sole Data Controller is responsible for making decisions on the data under this Agreement. The level of the Data was identifiable – necessary for the linkage of the Data data collected from other sources, including the participant, their GPs, hospitals and or registry offices. The data under this Agreement is required as an EMA requested safety report and as such will not be used for commercial purposes as this is an academic study involving the University of Dundee (data controller) and the University of Glasgow (data processor) only. The Data was minimised as follows: Record-level data will be received by the Robertson Centre for Biostatistics at the University of Glasgow (the Data Processor). Potential Serious Adverse Events will be identified there, and a pseudonymised report of these containing study numbers will be available to authorised members of MEMO Research at the University of Dundee on a controlled-access server hosted by the University of Glasgow. There is a formal agreement between the two organisations to govern these activities. The University of Glasgow acts on the instruction of the University of Dundee and with no discretion as to how the data is analysed. The University of Glasgow does not form part of the ‘Study Team’ responsible for determining the purposes for or the manner in which the data under this Agreement will be processed. The University of Glasgow is strictly a data processor. The University of Glasgow is not a data controller. • Limited to approximately 1500 participants who consented to take part in the FAST study from December 2011 and September 2017. Participants were aged 60 or over taking allopurinol to treat their gout symptoms at the time of consent. No other universities form part of the ‘Study Team’ responsible for determining the purposes for or the manner in which the data under this Agreement will be processed. No other universities or organisations other than the University of Dundee are data controllers. • Limited to Data from 2011 up to May 2020. HES APC Data were limited to Episode Start Date less than, or equal to, the 31st January 2020 were included. No other universities are involved in the processing of NHS Digital supplied study data in any other way. They act as recruiting centres with their own local PIs, as is standard for the way clinical trials are organised. The chief investigator with overall investigator responsibility is based in the University of Dundee. University of Dundee is the research sponsor and the controller as the organisation responsible for ensuring that the Data will only be processed for the purpose described above. Local clinical teams request further information about potential endpoint events from the healthcare services involved with the episode of care. This additional clinical information (which does not contain data from NHS Digital) is pseudonymised by the study team (i.e. directly identifying details are removed and a study ID is used to distinguish individuals) and submitted to a blinded endpoint committee for adjudication, allowing the robust identification of primary and secondary endpoints. Analysis of this data will determine the output of this study. The lawful basis for processing personal data under the UK GDPR is: The results of the FAST study will be disseminated through peer reviewed journals and scientific meetings. Other collaborating academic institutions will not be given access to record level data but only aggregate data (with small numbers suppressed in line with the HES Analysis Guide) for further analysis. The study has been approved by Research Ethics Committee, the MHRA, The European Medicines Agency and local NHS Research and Development offices. 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 Robertson Centre for Biostatics (part of the University of Glasgow, as Data Processor) will provide: The lawful basis for processing special category data under the UK GDPR is: - Data management (including e-CRF design, database setup and management, data validation) Article 9(2)(j) - processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject. - Statistical analysis and reporting (final report, Independent Data Monitoring Committee reports) This processing is in the public interest because the data was required to allow the FAST study to determine the relative cardiovascular safety of two commonly used gout medications. This study was requested by the EMA and was of public benefit as the information gained was of use in informing safe prescribing. - Data management and statistical support to record linkage The funding was provided by Menarini Pharma SAS for the study described. Menarini Pharma SAS had no input or involvement in the study design, administration or management. Funding to cover this version of the Data Sharing Agreement is provided by the University of Dundee. Menarini have no ability to suppress or otherwise limit the publication of findings. - provision of support for issues relating to data quality and use of endpoint adjudication system University of Glasgow is a processor acting under the instructions of University of Dundee. - project management and quality assurance Iron Mountain provides IT back up services to University of Glasgow and will store back-up tapes as contracted by University of Glasgow. Iron Mountain do not process the data and has no access to the data. - health economic analysis and reporting Data will also be accessed by individuals holding an honorary contract under the supervision of a substantive employee of University of Dundee for the purposes described in this DSA only. University of Dundee must maintain records in a single location that cover the following details of each individual given access under an honorary contract : The University of Glasgow uses a third-party IT provider, Iron Mountain, as a storage location. Iron Mountain does not process the data and has no access to the data. Iron Mountain will only store back-up data on Glasgow's behalf. o Their substantive employer; The University of Dundee has determined that there is unlikely to be any potential harm arising from the dissemination of this data as all data will be sent and stored securely with password access for approved personnel only. o Their role in respect of the purpose for the processing specified in the DSA; Under the General Data Protection Regulation, Article 6 (1) (e) and Article 9 (2) (j) will apply to the processing of the data under this Agreement as the requested data is processed in the public interest. The data is required to allow the FAST study to determine the relative cardiovascular safety of two commonly used gout medications. This study has been requested by the European Medicines Agency and is of public benefit as the information gained will be of use in informing safe prescribing. o The start date and end date of the duration in which the Data will be accessed by the individual under an honorary contract; o The necessity for the Data to be accessed by the person(s) holding an honorary contract, instead of a substantive employee of an organisation named as controller or a processor in this DSA; o Confirmation that an appropriate contract is in place which follows the relevant guidance and is countersigned by the substantive employer of the honorary contract holder FAST had an independent Trial Steering Committee (TSC), an independent study end-point committee and Independent Data Monitoring Committee (IDMC) to oversee the progress and safety of FAST and reported to the trial sponsor. None of these committees had access to the raw study data. The IDMC were provided with unblinded aggregate data reports generated by the study’s independent statistician (based at the Robertson Centre for Biostatistics (processor)) to allow them the review the study for safety. The end-point committee reviewed SAEs that might also be study endpoints and the supporting redacted verification documents. Study funding was provided by Menarini Pharma SAS – the marketing authorisation holder of febuxostat, but the study is academically initiated, run and owned. It is sponsored by the University of Dundee – the sole Data Controller. The study funder had no input or involvement in the study design, administration, management, or outputs. Both study drugs (febuxostat and allopurinol) are now off patent. Menarini Pharma SAS has no ability to suppress any findings that might be considered to be unfavourable to their commercial interests. Febuxostat is now generic and manufactured by multiple companies the study is very unlikely to confer commercial benefit to Menarini Pharma SAS.

Processing activities

The University of Glasgow have provided identifying fields to NHS Digital to facilitate linkage to participants medical records. All of these fields were sourced from data collected from consented patients in the FAST trial. In addition to the identifying fields listed below, date of consent was provided to NHS Digital to act as a cut-off date for outputs: No Data will flow to NHS England for the purposes of this Data Sharing Agreement (DSA). - NHS Number University of Glasgow holds the relevant records from Hospital Episode Statistics - Admitted Patient Care, Deaths and Case of Death via Flagging Current Status reports, Cohort Event Notification reports and Cause of Death Reports. The Data will contain directly identifying details (specifically NHS Number, Name, Date of Birth, Postcode, Gender and a unique person ID) for the cohort to be linked with NHS England data. - Member Number (patient study identifier) No additional data will be disseminated by NHS England for the purposes of this DSA. This DSA permits processing of the Data for the purpose of secure storage and back up. - Surname This DSA does not permit any further processing that involves analysis or linkage other than for the purpose of verifying findings in line with the original objectives of the study by repeating previous analyses described in this DSA. - Forename This DSA does not permit any onward sharing of the Data with the exception that the Data may be viewed for the purpose of an audit by a regulator such as the Medicines and Healthcare products Regulatory Agency (MHRA). - Date Of Birth The Data will be stored on servers at University of Glasgow and on back-up tapes at Iron Mountain. - Gender The Data will be accessed onsite at the premises of University of Glasgow. The Data will be accessed by authorised personnel via remote access. - Postcode The Controller(s) must confirm and provide evidence upon audit by NHS England that access via any remote device complies with the data security obligations within this DSA and the Data Sharing Framework Contract. NHS Digital already hold the identifying details for the cohort and, as recruitment has ended, no further identifying data will be sent to NHS Digital. NHS Digital identify participants using the details provided by the University of Glasgow. These details are linked to the following data-sets: For remote access: - Hospital Episode Statistics Admitted Patient Care - Remote access will only be from secure locations situated within the territory of use (as further restricted elsewhere within the DSA if so done) stated within this DSA; - Civil Registration Mortality - Access controls granting users the minimum level of access required are in place; - Cancer Registrations - Remote access is only via secure connections (e.g., VPNs or secure protocols) to protect data; - Personal Demographics Service - Multifactor authentication (MFA) is required for remote access; NHS Digital provide linked extracts from these datasets to the University of Glasgow for each participant. When data is returned to the University of Glasgow, only the study patient identifier are returned along with the medical data and no other identifiers. - Device security, including up-to-date software and operating systems, antivirus software, and enabled firewalls are utilised for the remote access; Historic HES data from 2011 is disseminated plus bi-annual, future data. The MRIS data requested is latest available plus future, bi-annual data. Data requested includes hospital admissions, deaths and cancer diagnoses as the primary method of identifying Serious Adverse Events and potential cardiovascular endpoints in the FAST study. - All remote access is undertaken within the scope of the organisation’s DSPT (or other security arrangements as per this DSA) and complies with the organisation’s remote access policy. Data returned to Robertson Centre for Biostatistics are loaded directly to a restricted-access database. Summary tables are populated from any files received using a sub-set of the fields included in the file layouts – these fields are selected specifically to allow the date, place, admission type and coded events to be presentable for review. ICD10 decoding is carried out on the Robertson Centre for Biostatistics summary tables. Existing FAST SAEs are linked in to the datasets for the purposes of report generation i.e. to allow the new events to be seen in the context of events already reported in the system. Adjudication reports are created from the Robertson Centre for Biostatistics summary tables and these are made available to MEMO staff at University of Dundee on a password controlled Remote Desktop environment for review and mark-up to determine any new potential SAEs. MEMO staff cannot download or remove any data from this remote environment. After review has been completed, output from the adjudication reports is used to generate new SAEs in the FAST eCRF database using the information summarised in the RCB tables. Only items flagged for SAE creation will be added at this stage. Other items will be flagged as reviewed and not reported. The above applies in addition to any condition set out elsewhere within the DSA (e.g. who may carry out processing, and for what purpose). In the FAST trial it is critical that data can be traced through to the original patient records for safety event reporting and to tie in with events already reported through eCRF system. Staff with access to the study patient identifiers will be able to trace data back to the source patients on the eCRF system. Remote processing will be from secure locations within the UK. The Data will not leave the UK at any time. The primary outcome and its individual components (cardiovascular death, non-fatal stroke and hospitalisation for non-fatal myocardial infarction/biomarker positive ACS) will be analysed including the randomised treatment group and strata (previous cardiovascular events) as co-variates. Statistical significance for treatment effects will have 95% confidence intervals applied for the estimated hazard ratio comparing febuxostat to allopurinol. The data may not be transferred to any other location and may only be accessed by substantive employees of University of Glasgow for the purposes described above. The primary analysis will be a non-inferiority analysis of the primary outcome based on the per-protocol (on randomised therapy) population. A supporting non-inferiority analysis will then be performed on the intention-to-treat (ITT) population. If non-inferiority is demonstrated, a superiority analysis will be carried out based on the ITT population. This DSA is required for the following reasons: A prospective sensitivity analysis will also be carried out for both primary and secondary outcomes by censoring participant follow-up at 90 days beyond per-protocol period to ascertain if withdrawal is a presage of disease. The possibility of differential drop out in the per-protocol analysis will be adjusted for by in a further analysis adjusting for age, sex, cholesterol levels, systolic blood pressure, smoking status and past medical history of diabetes, hypertension and cardiovascular disease. (1) The raw datasets (and any associated datasets and syntax files) may need to be accessed for the purpose of audit; NHS Digital data will not be shared outside of the University of Glasgow and the University of Dundee. An audit may be required during the period of this DSA. This would involve a systematic and independent review of trial-related activities and documents, to determine whether data were recorded, analysed and accurately reported. Without all the raw datasets this cannot be done. Any data derived from NHS Digital data which is shared outside of the University of Glasgow and the University of Dundee will contain only data that is aggregated (with small numbers suppressed) in line with the HES Analysis Guide. This applies to: (2) Further analysis is expected on these datasets in future; i. Summary reports of serious adverse events and suspected unexpected serious adverse reaction reports which are made to the Medicines and Healthcare products Regulatory Agency (MHRA) in line with clinical trials requirements; Any further analysis will only take place following an amendment to this Agreement that would allow further processing of the Data. ii. Any publications arising from the FAST trial that have made use of NHS Digital data . (3) Clinical trial data needs to be retained and accessible for 15 years after trial completion this requirement would be subject to further data extension requests – no Data will be retained without a DSA being in place. There are contractual obligations to provide data listings to the study funders as part of their legally required safety reporting which are derived from NHS Digital data (as is standard for clinical study reports in order to adequately report on pharmacovigiliance within the trial and in accordance with the approved protocol). This is a requirement of the EMA in order to benefit patient safety in the future. The listings are anonymised to the Funder and EMA as individuals are identified by study number and the recipients have no access to the study database. All personnel accessing the Data have been appropriately trained in data protection and confidentiality. At the end of the study (after database lock) the study PIs will be sent a copy of the study data for participants from their region which will include SAE reports derived from the information received (but extensively supplemented by data obtained directly from clinical records with patient consent) – not NHS Digital data. Summary reports of serious adverse events and suspected unexpected serious adverse reaction reports are made to the Medicines and Healthcare products Regulatory Agency (MHRA) in line with clinical trials requirements. No NHS Digital data is shared with the EMA, funders, the PIs or with the MHRA. All organisations party to this Agreement must comply with the Data Sharing Framework Contract requirements, including those regarding the use (and purposes of that use) by “Personnel” (as defined within the Data Sharing Framework Contract i.e.: employees, agents and contractors of the Data Recipient who may have access to that data).

Expected output

Results will be reported in a peer-reviewed journal and at major scientific and clinical meetings. The research team believe that the results of this study would be of interest to a high impact factor journal such as the Lancet or New England Journal of Medicine. The journal publication will be open-access to allow maximum access to the results. The research team will organise press releases to coincide with the publication to promote knowledge mobilisation of the study results. The timescale for this is expected to be summer 2020. The expected outputs of the processing will be to create an analysis dataset for the following purposes: The data under this Agreement will add information to the study report submitted to the EMA at the end of the study. The EMA will get access to the full study data (aggregated, with small numbers suppressed). The results will be scrutinised by the EMA and the research team will respond to questions from them as far as is possible. The results will also be made publicly available on the University of Dundee website and all investigators will be encouraged to make them available within their regions. Target date summer 2020. • Submissions to peer reviewed journals, including the Lancet and New England Journal of Medicines. The results will be reported as aggregate data with small numbers suppressed in publications and presentations. Other obligations under clinical trials stipulate requirements to report pharmacovigilance to MHRA and EMA. This may include reporting events in single patients (anonymised), however all participants gave written consent to take part in the study and this is a general requirement for clinical trials in the UK/Europe. • Presentations at major cardiovascular and rheumatology scientific and clinical meetings. The results will be ‘owned’ by the University of Dundee. The funding pharmaceutical company (Menarini) shall have a Royalty Free licence to the study results and aggregated report. • Reports to the GP practices and lay summaries for patients. Results will be sent to participating GP practices and made available to all participants in the study. The study results will provide un-confounded evidence to assist with the process of the regulation of medicines in Europe and elsewhere. • Reports to the European Medicines Agency (EMA), MHRA, and Menarini Pharma SAS The research team will present the findings at major cardiovascular and rheumatology scientific and clinical meetings. Target date summer 2020. The analysis dataset does not include NHS England Data. No outputs will not contain NHS England Data and will only contain aggregated information with small numbers suppressed as appropriate in line with the relevant disclosure rules for the dataset(s) from which the information was derived. The research team will also send copies of the results to guideline groups such as NICE (National Institute for Health and Care Excellence) and SIGN (Scottish Intercollegiate Guidelines Network) and ask that they are considered and incorporated appropriately into revisions of guidelines. Target date Autumn 2020. The outputs will be communicated to relevant recipients through the following dissemination channels: The research team will produce a non-technical summary of the results which the research team will send to patients who participated in the trial, patient groups and gout charities and the research team will work to generate media coverage of the study results and communicate these to the wider public. Target date 2020. High impact journals. All outputs will only contain results in highly aggregated format and as statistical summaries and measures of association. Small numbers will be suppressed in line with the HES Analysis Guide. Record level information will not be released to any third party. The study team will also send copies of the results to guideline groups such as NICE (National Institute for Health and Care Excellence) and SIGN (Scottish Intercollegiate Guidelines Network) and ask that they are considered and incorporated appropriately into revisions of guidelines. The study team have already produced a non-technical summary of the results which the research team sent to patients who participated in the trial, patient groups and gout charities and the research team will work to generate media coverage of the study results and communicate these to the wider public. The study closed in 31/08/2020 and was reported in The Lancet and results disseminated to the investigators. Under this version of the DSA the analysis dataset will continue to be analysed and results of these additional analyses will be published in peer reviewed journals and presented at scientific meetings.

Expected measurable benefits

The outcome of the FAST study will provide provided much needed clarity on the relative cardiovascular safety of febuxostat and allopurinol. This information will be of benefit to benefited doctors, patients and regulatory authorities and will guide the provided choice of the most appropriate treatment for patients suffering from gout, the most common inflammatory arthritis. gout. Patients with gout often have reduced quality of life due to symptoms [31 words unchanged] condition and thus the impact of the results of the FAST study will be great as it will give provided further evidence on the relative cardiovascular safety of febuxostat and allopurinol, an issue that is currently under much debate. allopurinol. [1 paragraph unchanged] This research will ensure ensured that the regulatory authorities have more information on the relative cardiovascular safety [13 words unchanged] prescribing can be made. Presentation to the research and health service audience will ensure ensures that results can be implemented in local practice if required. Production of a final study report for the EMA will fulfil fulfilled their requirement for a post-licensing safety study of febuxostat to clarify the cardiovascular safety of the drug. This data dissemination will allow allowed the timely completion of an EMA mandated post-licensing safety evaluation. This dissemination will ensure ensured that the results reach reached the relevant health professionals in a timely fashion, that they will feed [46 words unchanged] ensure that the findings are widely known by healthcare professionals and patients. [2 paragraphs unchanged] Results of the FAST study are expected to be available in summer 2020. Given the extent of the study and the volume of data collected, a lot of analysis is ongoing which the research team anticipate will also provide benefits to both prescribers of gout medication and those suffering from gout. The study team have already produced a non-technical summary of the results which the research team sent to patients who participated in the trial, patient groups and gout charities and the research team have worked and will work to generate media coverage of the study results and communicate these to the wider public.

Benefits reported

The previous data received from NHS Digital England has been processed to identify 50 new potential study endpoints and 700 new SAEs within the study. The study closed on 31st August 2020 and main results of FAST were published in the Lancet in November 2020 (https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(20)32234-0.pdf) at the same time as it was presented at the Congress of the American College of Rheumatologists. The final report has been submitted to the EMA by the MPA - Menarini. The research team anticipate the findings will feed into the safety advice for febuxostat. The FAST study has provided important new information about the long-term cardiovascular safety of febuxostat and allopurinol in patients with gout. Patient outcomes were key endpoints in the FAST study and data shared by NHS England allowed these outcome (eg myocardial infarction, stroke, cardiovascular death) to be detected reliably in the study population. A summary of the FAST results suitable for lay people was posted on the MEMO Research website. As a result of the FAST study, it is likely that prescribing guidance regarding febuxostat will be reviewed by agencies such as the European Medicines Agency (EMA), US Food and Drug Administration (FDA) and Medicine and Healthcare products Regulatory Agency (MHRA). Following review of the FAST study results, it is possible that febuxostat could be made more widely available to patients with a history of cardiovascular disease than is currently the case. This could have major impact for patients with gout worldwide as febuxostat may be easier to use and better tolerated in some patients with gout. It provides a choice to patients and prescribers, particularly for patients who have side effects from taking allopurinol (the main alternative).

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Objective for processing

[15 paragraphs unchanged] Data is was provided from 2011 - 2018 as historic data and then bi-annually until 2020. The study requires data covering the Agreement period up to the end date. of January 2020. [19 paragraphs unchanged]

Unchanged: Processing activities, Expected output, Expected measurable benefits, Benefits reported.

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Objective for processing

Initial phase III clinical trials of febuxostat suggested that it may be associated with increased cardiovascular risk. Subsequent studies have not supported this risk and a definitive study to confirm or refute this safety concern is still required. The European Union (EU) Risk Management Plan (RMP) for febuxostat (Version 2.0; 19 February 2008) indicates that a post marketing study to evaluate cardiovascular effects of febuxostat is to be conducted as part of the Pharmacovigilance Plan. An outline synopsis of this study was presented as Annex 5 of the RMP. Gout affects at least 1% of the population in Western countries and is the most common inflammatory joint disease in men older than 40 years of age. The UK prevalence of gout was reported to be 1.4% in 1999. Historically a disease of affluent, middle-aged or older men, gout has now affected more women and a wider range of socioeconomic groups. Gout progresses from episodic flare-ups of acute inflammatory arthritis to a disabling chronic disorder characterised by deforming arthropathy, destructive deposits of crystals (tophi) in bones, joints and other organs, impairment of kidney functions and urolithiasis. The FAST study is intended to fulfil this objective. It is a large safety study of febuxostat versus standard urate lowering therapy with allopurinol for chronic symptomatic hyperuricaemia. This study compares the relative cardiovascular safety of the two treatment strategies, and recruitment began in December 2011. Febuxostat is an effective treatment for gout. Aside from meeting the European Medicines Agency regulatory commitments, establishing that this drug is safe in patients who are at risk of cardiovascular disease is of clear benefit, offering an important alternative for managing this condition in a group of patients who are at risk of gout. Other aspects of drug safety are also assessed in the course of this trial by reporting of Serious Adverse Events through the pharmacovigilance process. Cardiovascular disease is frequently observed in patients with elevations in uric acid. While theories as to the specific causal relationship between uric acid and cardiovascular disease/mortality vary, the correlation between the two is widely recognised. Uric acid levels are increasingly believed to be an independent predictor of death in patients at high risk of cardiovascular disease. University of Dundee requires access to this data for the purpose of a task in the public interest. Allopurinol and febuxostat have each shown to be safe and effective drugs for the treatment of gout. However, initial clinical trials of febuxostat suggested that it may be associated with increased cardiovascular risk. Subsequent studies have not supported this risk and a definitive study to confirm or refute this safety concern is still required. The European Union (EU) Risk Management Plan (RMP) for febuxostat (Version 2.0; 19 February 2008) indicates that a post marketing study to evaluate cardiovascular effects of febuxostat is to be conducted as part of the Pharmacovigilance Plan. The FAST (Febuxostat versus Allopurinol Streamlined Trial) study is designed to find out whether febuxostat is safer, less safe or just as safe as allopurinol for long term use in practice. The FAST study will focus on the cardiovascular safety profile of febuxostat versus allopurinol, when taken for an average of 3 years in patients aged 60 years or older with chronic hyperuricaemia, in conditions where urate deposition has already occurred. Record linkage to national datasets of hospital admissions, deaths and cancer diagnoses is the primary method of identifying Serious Adverse Events and potential cardiovascular endpoints in the FAST study. Identification of all hospitalisations, deaths and diagnoses of cancer allows assessment of the safety of the study interventions, febuxostat and allopurinol. Record linkage output will only be used to identify Serious Adverse Events and study endpoints. The secondary study objectives are to evaluate other cardiovascular adverse events for both products. This information will be of great value to everyone who needs to take these drugs on a regular basis. It will allow doctors to make the best choice for people with gout, not just for their joint pain and arthritis but also for any associated medical disorders they may have and for their general health. The data will not be used for commercial purposes as this is an academic study involving university research groups. Study funding is provided by Menarini Pharma SAS, but the study is academically initiated, run and owned and the study funder has no input or involvement in the study design, administration, management, or outputs. Record level data will only be received by the Robertson Centre for Biostatistics, University of Glasgow. Potential Serious Adverse Events will be identified there, and an anonymised report of these will be sent to the Medicines Monitoring Unit, University of Dundee, where they will be clinically reviewed by medical staff to identify potential endpoints and confirm Serious Adverse Events. This report will not include patient identifiable information, with participants only identified by study number. The FAST study is an EMA (European Medicines Agency) requested safety study as a result of their risk assessment following the licensing of Febuxostat (Adenuric) in the EU. The study received ethics approval 8th August 2011. To fulfil the pharmacovigilance requirements of the EMA it is essential to ensure that all events that may meet the criteria for reporting as Significant Adverse Events (SAEs) or study endpoints, are captured. The study team at the University of Glasgow request further information about potential endpoint events from the healthcare services involved with the episode of care. This additional clinical information (which does not contain data from NHS Digital) is anonymised by the study team and submitted to a blinded endpoint committee for adjudication, allowing the robust identification of primary and secondary endpoints. Analysis of this data will determine the output of this study. Aside from meeting the European Medicines Agency regulatory commitments, establishing that this drug is safe in patients who are at risk of cardiovascular disease is of clear benefit, offering an important alternative for managing this condition in a group of patients who are at risk of gout. Other aspects of drug safety are also assessed in the course of this trial by reporting of Serious Adverse Events through the pharmacovigilance process. The results of the FAST study will be disseminated through peer reviewed journals and scientific meetings. Other collaborating academic institutions will not be given access to record level data but may be given aggregate data (with small numbers suppressed in line with the HES Analysis Guide) for further analysis. All study participants have given written informed consent for the study sponsor to access their electronic or other medical records. The study has been approved by Research Ethics Committee, the MHRA, The European Medicines Agency and local NHS R+D offices. Originally, participants were recruited to the FAST study using informed patient consent. These were individuals aged 60 or over who were taking allopurinol to treat their gout symptoms at the time of consent. Recruitment started in December 2011 and ended in September 2017, approximately 1,500 participants were recruited in England for which this Agreement solely applies. University of Glasgow use a third-party IT provider, Iron Mountain, as a storage location. Iron Mountain do not process the data and have no access to the data, they will only store back-up data on Glasgow's behalf. The cohort is already held by NHS Digital and as recruitment has ended, this will not be added to. The estimated ratio of male to female patients is 70% to 30% respectively. Other countries including Scotland and Sweden are involved in the FAST Study but are not included under this Agreement. Patient selection was performed from general practice, hospital or at clinics, or from searches of databases of participants who have previously agreed to take part in future research, such as UK Biobank or SHARE. Patients who met the trial criteria were contacted directly by their physician or the consented database owner by letter or invited to an information meeting where they were informed about the current treatment options for gouty conditions and the rationale for the trial. A patient information leaflet was provided to patients interested in the study and an appointment for a screening visit was scheduled. Patients are randomised to either an optimised dose of allopurinol or febuxostat. Follow-up is scheduled at two monthly intervals by phone, letter or visit to the patient by the study nurses or medical staff. Principal Investigators (PIs) for the study are employed by regional recruitment centres across the UK. The PIs do not make any decisions regarding the data under this Agreement and will only have access to aggregated outputs (with small numbers suppressed). Each PI will only be given data for participants in their region, and this will NOT contain NHS Digital supplied data but any SAEs generated as a result of the information will be supplied to them. The PIs were not involved in the protocol development as it was approved ahead of their appointment and their responsibilities are set out in formal contracts. Since February 2018 the study has had full support under section 251 of the NHS Act 2006 from HRA CAG to follow-up the cohort. The data-sets linked to the participant data are: - HES Admitted Patient Care - Flagging Current Status reports - Cohort Event Notification reports - Cause of Death reports Data is provided from 2011 - 2018 as historic data and then bi-annually until the Agreement end date. Linkage of the cohort data to national data including hospital admissions, deaths and cancer diagnoses is the primary method of identifying Serious Adverse Events (SAEs) and potential cardiovascular endpoints in the FAST study. The University of Dundee is the sole Data Controller for the purposes of this Agreement. The University of Dundee requests access to national data-sets of hospital admissions, deaths and cancer diagnoses as the primary method of identifying Serious Adverse Events and potential cardiovascular endpoints in the FAST study. Identification of all hospitalisations, deaths and diagnoses of cancer allows assessment of the safety of the study interventions, febuxostat and allopurinol. Record linkage output will only be used to identify Serious Adverse Events and study endpoints. The requested data is the minimum necessary to detect study serious adverse events, potential endpoints and primary and secondary outcomes on consented patients from their date of consent into the FAST study. The study is an academic study grant funded by Menarini Pharma SAS under a full legal agreement between Menarini and the University of Dundee, with the University of Dundee being the study sponsor and Menarini representatives having only observer status on the steering committee. Menarini is the European Licence holder for Adenuric (Febuxostat), although febuxostat is now off patent. Though the study is funded by Menarini Pharma SAS and has been requested by the EMA, the study is academically initiated, run and owned by the University of Dundee. Menarini has no input or involvement in the study design, administration, management, or outputs – the study is primarily approved by and required by the EMA (not Menarini). Only the University of Dundee as sole Data Controller is responsible for making decisions on the data under this Agreement. The data under this Agreement is required as an EMA requested safety report and as such will not be used for commercial purposes as this is an academic study involving the University of Dundee (data controller) and the University of Glasgow (data processor) only. Record-level data will be received by the Robertson Centre for Biostatistics at the University of Glasgow (the Data Processor). Potential Serious Adverse Events will be identified there, and a pseudonymised report of these containing study numbers will be available to authorised members of MEMO Research at the University of Dundee on a controlled-access server hosted by the University of Glasgow. There is a formal agreement between the two organisations to govern these activities. The University of Glasgow acts on the instruction of the University of Dundee and with no discretion as to how the data is analysed. The University of Glasgow does not form part of the ‘Study Team’ responsible for determining the purposes for or the manner in which the data under this Agreement will be processed. The University of Glasgow is strictly a data processor. The University of Glasgow is not a data controller. No other universities form part of the ‘Study Team’ responsible for determining the purposes for or the manner in which the data under this Agreement will be processed. No other universities or organisations other than the University of Dundee are data controllers. No other universities are involved in the processing of NHS Digital supplied study data in any other way. They act as recruiting centres with their own local PIs, as is standard for the way clinical trials are organised. The chief investigator with overall investigator responsibility is based in the University of Dundee. Local clinical teams request further information about potential endpoint events from the healthcare services involved with the episode of care. This additional clinical information (which does not contain data from NHS Digital) is pseudonymised by the study team (i.e. directly identifying details are removed and a study ID is used to distinguish individuals) and submitted to a blinded endpoint committee for adjudication, allowing the robust identification of primary and secondary endpoints. Analysis of this data will determine the output of this study. The results of the FAST study will be disseminated through peer reviewed journals and scientific meetings. Other collaborating academic institutions will not be given access to record level data but only aggregate data (with small numbers suppressed in line with the HES Analysis Guide) for further analysis. The study has been approved by Research Ethics Committee, the MHRA, The European Medicines Agency and local NHS Research and Development offices. The Robertson Centre for Biostatics (part of the University of Glasgow, as Data Processor) will provide: - Data management (including e-CRF design, database setup and management, data validation) - Statistical analysis and reporting (final report, Independent Data Monitoring Committee reports) - Data management and statistical support to record linkage - provision of support for issues relating to data quality and use of endpoint adjudication system - project management and quality assurance - health economic analysis and reporting The University of Glasgow uses a third-party IT provider, Iron Mountain, as a storage location. Iron Mountain does not process the data and has no access to the data. Iron Mountain will only store back-up data on Glasgow's behalf. The University of Dundee has determined that there is unlikely to be any potential harm arising from the dissemination of this data as all data will be sent and stored securely with password access for approved personnel only. Under the General Data Protection Regulation, Article 6 (1) (e) and Article 9 (2) (j) will apply to the processing of the data under this Agreement as the requested data is processed in the public interest. The data is required to allow the FAST study to determine the relative cardiovascular safety of two commonly used gout medications. This study has been requested by the European Medicines Agency and is of public benefit as the information gained will be of use in informing safe prescribing.

Processing activities

All organisations party to this agreement must comply with the Data Sharing Framework Contract requirements, including those regarding the use (and purposes of that use) by “Personnel” (as defined within the Data Sharing Framework Contract ie: employees, agents and contractors of the Data Recipient who may have access to that data). The University of Glasgow have provided identifying fields to NHS Digital to facilitate linkage to participants medical records. All of these fields were sourced from data collected from consented patients in the FAST trial. In addition to the identifying fields listed below, date of consent was provided to NHS Digital to act as a cut-off date for outputs: There will be no linkage of data provided by NHS Digital to any data, other than as described in this document. - NHS Number Any data shared outside of the University of Glasgow will contain only data that is aggregated (with small numbers suppressed in line with the HES Analysis Guide). Summary reports of serious adverse events and suspected unexpected serious adverse reaction reports are made to the Medicines and Healthcare products Regulatory Agency (MHRA) in line with clinical trials requirements. - Member Number (patient study identifier) The Robertson Centre for Biostatics (part of the University of Glasgow, acting as Data Processor) will provide: - Surname - Data management (including e-CRF design, database setup and management, data validation) - Forename - Statistical analysis and reporting (final report, Independent Data Monitoring Committee reports) - Date Of Birth - Data management and statistical support to record linkage - Gender - provision of support for issues relating to data quality and use of endpoint adjudication system - Postcode - project management and quality assurance NHS Digital already hold the identifying details for the cohort and, as recruitment has ended, no further identifying data will be sent to NHS Digital. NHS Digital identify participants using the details provided by the University of Glasgow. These details are linked to the following data-sets: - health economic analysis and reporting - Hospital Episode Statistics Admitted Patient Care Sample size - Civil Registration Mortality 456 positively adjudicated events will be required to show non-inferiority between the two study treatment arms with 80% statistical power, an upper limit of non-inferiority hazard ratio of 1.3 and a one-sided alpha of 0.025. - Cancer Registrations It is estimated that 6142 randomised participants, followed up for an average of 3 years will be sufficient to accrue the required 456 positively adjudicated events, allowing for a 20% drop out from the per protocol population. - Personal Demographics Service Data will be received from NHS Digital and linked to trial data, and potential endpoints will be investigated further by obtaining information from medical records. Endpoint packages will be adjudicated by an endpoint committee blinded to treatment allocation. NHS Digital provide linked extracts from these datasets to the University of Glasgow for each participant. When data is returned to the University of Glasgow, only the study patient identifier are returned along with the medical data and no other identifiers. Data analysis will be carried out according to a pre-determined data analysis plan. Historic HES data from 2011 is disseminated plus bi-annual, future data. The MRIS data requested is latest available plus future, bi-annual data. Data requested includes hospital admissions, deaths and cancer diagnoses as the primary method of identifying Serious Adverse Events and potential cardiovascular endpoints in the FAST study. The primary outcome and its individual components (CV death, non-fatal stroke and hospitalisation for non-fatal myocardial infarction/biomarker positive ACS) will be analysed using Cox proportional hazards models including the randomised treatment group and strata (previous cardiovascular events) as covariates. Statistical significance for treatment effects will be based on the Wald statistic and 95% confidence intervals of for the estimated hazard ratio comparing febuxostat to allopurinol. Data returned to Robertson Centre for Biostatistics are loaded directly to a restricted-access database. Summary tables are populated from any files received using a sub-set of the fields included in the file layouts – these fields are selected specifically to allow the date, place, admission type and coded events to be presentable for review. ICD10 decoding is carried out on the Robertson Centre for Biostatistics summary tables. Existing FAST SAEs are linked in to the datasets for the purposes of report generation i.e. to allow the new events to be seen in the context of events already reported in the system. Adjudication reports are created from the Robertson Centre for Biostatistics summary tables and these are made available to MEMO staff at University of Dundee on a password controlled Remote Desktop environment for review and mark-up to determine any new potential SAEs. MEMO staff cannot download or remove any data from this remote environment. After review has been completed, output from the adjudication reports is used to generate new SAEs in the FAST eCRF database using the information summarised in the RCB tables. Only items flagged for SAE creation will be added at this stage. Other items will be flagged as reviewed and not reported. In the FAST trial it is critical that data can be traced through to the original patient records for safety event reporting and to tie in with events already reported through eCRF system. Staff with access to the study patient identifiers will be able to trace data back to the source patients on the eCRF system. The primary outcome and its individual components (cardiovascular death, non-fatal stroke and hospitalisation for non-fatal myocardial infarction/biomarker positive ACS) will be analysed including the randomised treatment group and strata (previous cardiovascular events) as co-variates. Statistical significance for treatment effects will have 95% confidence intervals applied for the estimated hazard ratio comparing febuxostat to allopurinol. [2 paragraphs unchanged] NHS Digital data will not be shared outside of the University of Glasgow and the University of Dundee. Any data derived from NHS Digital data which is shared outside of the University of Glasgow and the University of Dundee will contain only data that is aggregated (with small numbers suppressed) in line with the HES Analysis Guide. This applies to: i. Summary reports of serious adverse events and suspected unexpected serious adverse reaction reports which are made to the Medicines and Healthcare products Regulatory Agency (MHRA) in line with clinical trials requirements; ii. Any publications arising from the FAST trial that have made use of NHS Digital data . There are contractual obligations to provide data listings to the study funders as part of their legally required safety reporting which are derived from NHS Digital data (as is standard for clinical study reports in order to adequately report on pharmacovigiliance within the trial and in accordance with the approved protocol). This is a requirement of the EMA in order to benefit patient safety in the future. The listings are anonymised to the Funder and EMA as individuals are identified by study number and the recipients have no access to the study database. At the end of the study (after database lock) the study PIs will be sent a copy of the study data for participants from their region which will include SAE reports derived from the information received (but extensively supplemented by data obtained directly from clinical records with patient consent) – not NHS Digital data. Summary reports of serious adverse events and suspected unexpected serious adverse reaction reports are made to the Medicines and Healthcare products Regulatory Agency (MHRA) in line with clinical trials requirements. No NHS Digital data is shared with the EMA, funders, the PIs or with the MHRA. All organisations party to this Agreement must comply with the Data Sharing Framework Contract requirements, including those regarding the use (and purposes of that use) by “Personnel” (as defined within the Data Sharing Framework Contract i.e.: employees, agents and contractors of the Data Recipient who may have access to that data).

Expected output

Results will be reported in a peer-reviewed journal and at major scientific and clinical meetings. The research team believe that the results of this study would be of interest to a high impact factor journal such as the Lancet or New England Journal of Medicine. The journal publication will be open-access to allow maximum access to the results. The research team will organise press releases to coincide with the publication to promote knowledge mobilisation of the study results. The timescale for this is expected to be around summer 2020. The research team believe that the results of this study would be of interest to a high impact factor journal such as the Lancet or New England Journal of Medicine. The research team will organise press releases to coincide with the publication to promote knowledge mobilisation of the study results. The data under this Agreement will add information to the study report submitted to the EMA at the end of the study. The EMA will get access to the full study data (aggregated, with small numbers suppressed). The results will be scrutinised by the EMA and the research team will respond to questions from them as far as is possible. The results will also be made publicly available on the University of Dundee website and all investigators will be encouraged to make them available within their regions. Target date summer 2020. The research team will also present the findings at major cardiovascular and rheumatology scientific and clinical meetings. Target date around 2020 as above. The results will be reported as aggregate data with small numbers suppressed in publications and presentations. Other obligations under clinical trials stipulate requirements to report pharmacovigilance to MHRA and EMA. This may include reporting events in single patients (anonymised), however all participants gave written consent to take part in the study and this is a general requirement for clinical trials in the UK/Europe. The research team will also send copies of the results to guideline groups such as NICE (National Institute for Health and Care Excellence) and SIGN (Scottish Intercollegiate Guidelines Network) and ask that they are considered and incorporated appropriately into revisions of guidelines. Target date 2020 as above. The results will be ‘owned’ by the University of Dundee. The funding pharmaceutical company (Menarini) shall have a Royalty Free licence to the study results and aggregated report. The research team will produce a non-technical summary of the results which the research team will send to patients who participated in the trial, patient groups and gout charities and the research team will work to generate media coverage of the study results and communicate these to the wider public. Target date 2020 as above. Results will be sent to participating GP practices and made available to all participants in the study. The study results will provide un-confounded evidence to assist with the process of the regulation of medicines in Europe and elsewhere. In this case, an additional output will be the determination of adjudicated endpoints/adverse events, which will mean the study can report to the EMA. The research team will present the findings at major cardiovascular and rheumatology scientific and clinical meetings. Target date summer 2020. Outputs will also be shared with funders, but ownership and control of the outputs rests with the University of Dundee. The research team will also send copies of the results to guideline groups such as NICE (National Institute for Health and Care Excellence) and SIGN (Scottish Intercollegiate Guidelines Network) and ask that they are considered and incorporated appropriately into revisions of guidelines. Target date Autumn 2020. The research team will produce a non-technical summary of the results which the research team will send to patients who participated in the trial, patient groups and gout charities and the research team will work to generate media coverage of the study results and communicate these to the wider public. Target date 2020. All outputs will only contain results in highly aggregated format and as statistical summaries and measures of association. Small numbers will be suppressed in line with the HES Analysis Guide. Record level information will not be released to any third party.

Expected measurable benefits

This research will establish whether febuxostat is as safe as allopurinol with respect to cardiovascular outcomes (stroke, myocardial infarction and cardiovascular death). The outcome of the FAST study will provide much needed clarity on the relative cardiovascular safety of febuxostat and allopurinol. This information will be of benefit to doctors, patients and regulatory authorities and will guide the choice of the most appropriate treatment for patients suffering from gout, the most common inflammatory arthritis. Patients with gout often have reduced quality of life due to symptoms including pain and limitation of activities. Gout is the most common inflammatory arthritis and is a painful condition with much morbidity. 1 in 40 people in the UK suffer from the condition and thus the impact of the results of the FAST study will be great as it will give further evidence on the relative cardiovascular safety of febuxostat and allopurinol, an issue that is currently under much debate. Patients will achieve the benefit by receiving the most appropriate therapy for their gout in future. Prescribers will also have better safety information to allow them to make an informed decision for their patients. Gout is a long-term condition and it is important to know which medications are safest for prevention of acute attacks of gout in patients. This research will establish whether febuxostat is as safe as allopurinol with respect to cardiovascular outcomes (stroke, myocardial infarction and cardiovascular death). This research will ensure that the regulatory authorities have more information on the relative cardiovascular safety of allopurinol and febuxostat to ensure that any changes required to advice on prescribing can be made. Presentation to the research and health service audience will ensure that results can be implemented in local practice if required. Production of a final study report for the EMA will fulfil their requirement for a post-licensing safety study of febuxostat to clarify the cardiovascular safety of the drug. This data dissemination will allow the timely completion of an EMA mandated post-licensing safety evaluation. This dissemination will ensure that the results reach the relevant health professionals in a timely fashion, that they will feed into the advice given from the EMA on gout medication, and provide the study participants with the feedback on the outcome of the study which they have been giving up time to take part in. In addition, publication of the findings in high impact journals should ensure that the findings are widely known by healthcare professionals and patients. Gout causes a significant cost burden on the NHS and costs are likely to increase further as the population ages. The results of the FAST study are likely to influence regulatory advice on the prescribing of febuxostat and allopurinol both nationally and internationally. Recent safety advice has been issued since the results of the CARES trial (Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout) were published and the evidence from the FAST trial is eagerly awaited by regulatory authorities. [1 paragraph unchanged] Gout is the most common inflammatory arthritis, affecting around 2.5% of UK patients. It causes significant morbidity and impaired quality of life in patients. Results of the FAST study are expected to be available in summer 2020. Benefits to patients Patients with gout often have reduced quality of life due to symptoms including pain and limitation of activities. Gout is a longterm condition and it is important to know which medications are safest for prevention of acute attacks of gout in patients. Benefits to the NHS Gout causes a significant cost burden on the NHS and costs are likely to increase further as the population ages. Results of the FAST study are expected to be available in 2020.

Benefits reported

Not stated in the previous version; added here.

The previous data received from NHS Digital has been processed to identify 50 new potential study endpoints and 700 new SAEs within the study.

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Objective for processing

[2 paragraphs unchanged] University of Dundee requires access to this data for the purpose of a task in the public interest. [1 paragraph unchanged] The data will not be used for commercial purposes as this is an academic study involving university research groups. Study funding is provided by Menarini Pharma SAS, but the study is academically initiated, run and owned and the study funder has no input or involvement in the study design, administration, management, or outputs. Record level data will only be received by the Robertson Centre for [50 words unchanged] not include patient identifiable information, with participants only identified by study number. [1 paragraph unchanged] The results of the FAST study will be disseminated through peer reviewed journals and scientific meetings. Other collaborating academic institutions will not be given access to record level data, data but may be given aggregate data (with small numbers suppressed in line [36 words unchanged] Committee, the MHRA, The European Medicines Agency and local NHS R+D offices. University of Glasgow use a third-party IT provider, Iron Mountain, as a storage location. Iron Mountain do not process the data and have no access to the data, they will only store back-up data on Glasgow's behalf.

Unchanged: Processing activities, Expected output, Expected measurable benefits.

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

Benefits reported

Stated in the previous version and removed here.

Yielded Benefits is not a requirement for new applications.

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