Extended follow-up of the TARGIT A Trial

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Datasets: + Cancer Registration Data; + Civil Registrations of Death; + Hospital Episode Statistics Admitted Patient Care (HES APC); + Hospital Episode Statistics Critical Care (HES Critical Care); + Hospital Episode Statistics Outpatients (HES OP) · − Civil Registrations of Death - Secondary Care Cut

Objective for processing

University College London (UCL) requires access to NHS England data for the purpose of the following research project: Extended follow up of the TARGIT-A randomised trial of targeted intraoperative radiotherapy during lumpectomy for breast cancer. University College London (UCL) are running the study ‘Extended follow up of the TARGIT-A trial’ through the Surgical & Interventional Trials Unit (SITU). The SITU is part of UCL. The SITU specialises in providing infrastructure for running studies and has a history of managing large-scale randomised controlled clinical trials in solid tumours, historically in breast cancer. [1 paragraph unchanged] University College London (UCL) has been awarded a grant from NIHR Health Technology Assessment (HTA) to run the study Extended follow up of the TARGIT-A trial through the Surgical & Interventional Trials Unit (SITU). The SITU is part of UCL. The SITU specialises in providing infrastructure for running studies and has a history of managing large-scale randomised controlled clinical trials in solid tumours, historically in breast cancer. UCL will be the only organisation with access to the record-level data requested from and supplied by NHS Digital. [1 paragraph unchanged] The published results of the TARGIT-A trial show that compared with conventional [20 words unchanged] the same results in terms of breast cancer control (locally and systemically). Interestingly, TARGIT was found to have a significantly lower mortality rate from causes other than breast cancer due to fewer deaths from cardiovascular causes and other cancers. Although the current results are convincing enough for the treatment to be adopted worldwide (over 20,000 women have now had this treatment worldwide), it is essential that all the UK cohort of 608 patients who were randomised into the trial are followed up over a longer period of time and data analysed as per the original TARGIT-A trial protocol. For patients in the UK cohort, their data will come from NHS Digital. The current plan is to analyse as by per-pathology and post-pathology strata as well as subgroup analysis as per hormone receptor status and hormone therapy. Multivariate analysis will also be performed for assessing the predictive value of other tumour and patient factors such as age, tumour size, grade lymph node status, margins, lymphovascular invasion, time since randomisation, etc. The recruitment in the trial was completed in June 2012. The following is a summary of the aims of the research project provided by UCL: This extended follow-up study will enable timely recording of additional local recurrences and deaths. With a higher number of events, it would be possible to perform meaningful subgroup analysis using predictive factors such as hormone receptors (available data suggests that these have a predictive value), tumour grade and lymph node involvement that would allow fine tuning of patient selection criteria. Furthermore the effect on non-breast-cancer and overall mortality will also be ascertained. - To determine if it is feasible to collect follow-up information from a cohort of women enrolled in a randomised trial, instead of the usual method of collecting data from staff in the trial sites. It is expected that the new data (including that from NHS Digital) will significantly influence wider and enthusiastic adoption of this approach that will be greatly welcomed by patients. As a large proportion of such patients are screen-detected, their overtreatment would be avoided by such adoption. - To estimate the completeness and accuracy of the follow-up data by comparing it with the data obtained from NHS England. The following NHS England Data will be accessed: • Hospital Episode Statistics Admitted Patient Care, Critical Care and Outpatients - necessary to enable investigation of the long-term effects of the treatment on the trial patients. • Civil Registration Mortality – necessary to enable efficient long-term follow up. • Cancer Registration - necessary to enable investigation of the long-term effects of the treatment on the trial patients. The level of the Data will be: • Identifiable The Data will be minimised as follows: • Limited to a study cohort identified by University College London (UCL) –382 women aged over 18 years old who were recruited into the TARGIT-A trial from 5 UK-based hospitals (London UCL, London Royal Free, London Whittington, London Guy's and Winchester Royal Hampshire). Recruited between March 2000 - June 2012. • Limited to data between 2017- latest available University College London (UCL) 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. 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)(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. 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 National Institute of Healh Research (NIHR). The funding is specifically for the project described. The funder will have no ability to suppress or otherwise limit the publication of findings. Amazon Web Services (AWS) is a processor acting under the instructions of UCL.. AWS’ role is limited to secure back-up of data stored in UCL’s Data Safe Haven. UCL uses offsite data centre services provided by VIRTUS data centre. VIRTUS does not have access to the data. Data will be accessed by: • An Individual holding an honorary contract under the supervision of a substantive employee of UCL for the purposes described in this DSA only. UCL must maintain records in a single location that cover the following details of this individual under an honorary contract o Their substantive employer; o Their role in respect of the purpose for the processing specified in the DSA; 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. A patient focus group helped refine the purpose of the research, and a lay person (PPI representative) is a member of the oversight Committee (Trial Steering Committee).

Processing activities

The study has been divided into two Work Packages. UCL will transfer data to NHS England. The data will consist of identifying details (specifically Study ID, NHS Number, Date of Birth, and Postcode) for the cohort to be linked with NHS England data. NHS England will provide the relevant records from the HES, Civil Registration Mortality, and Cancer Registration datasets to UCL. Work Package 1: For patients in the UK cohort (England only), continue to gather efficacy, safety and follow-up data to year 10 by contacting patients directly and asking them to consent to have their information collected through Work Package 2 (below), and complete an annual questionnaire. The Data shared with UCL will Work Package 2: Collect death data for UK patients through NHS Digital. • Contain no direct identifying data items but will contain a unique person ID which can be used to link the Data with other record level data already held by the recipient. Collection of death data from UK patients through NHS Digital will help improve the completeness of the data, and will support WP1. The Data will not be transferred to any other location. Identifiers for the cohort who have consented to be in the study will be sent to NHS Digital. Identifiers include: The Data will be stored in the UCL DSH. ~ NHS Number UCL stores Data on the Cloud provided by UCL Data Safe Haven. ~ Date of birth The Data will be accessed by authorised personnel via remote access. ~ Postcode UCL 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. ~ Unique Study ID For remote access: In addition, as part of Work Package 1, the patient will be contacted annually directly by SITU and asked to complete a follow-up (questionnaire) form, and return by post in the pre-paid envelope provided. Patients will be followed up until death or withdrawal of consent. Patients can refuse consent at any time by contacting either SITU or the PI, in which case no further contact will be made. - 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; NHS Digital will then return linked Civil Registration data (death data linked to the study identifier) to the SITU unit at UCL. - Access controls granting users the minimum level of access required are in place; This data file will then be linked to the existing TARGIT A Trial database (using the Unique Study ID). UCL will extract a subset of the data containing no direct patient identifiers and periodically send this to the Trial Statistician for analysis via a secure encrypted electronic process carried out at UCL. Each patient will only be identified by a unique subject number (e.g. TT 018 001 X). - Remote access is only via secure connections (e.g., VPNs or secure protocols) to protect data; SITU do not require direct patient identifiers from NHS Digital. SITU already hold identifiable data on current TARGIT A Trial patients. Identifiable data already held is only accessed by authorised individuals within UCL, all of whom are substantive employees. - Multifactor authentication (MFA) is required for remote access; No attempts will be made to re-identify individuals from the data and the identifiable data will not be made available to any third parties. - Device security, including up-to-date software and operating systems, antivirus software, and enabled firewalls are utilised for the remote access; In order to comply with the requirements of the grant, the patients will be followed up for 5 years in the first instance, as most patients already have 5 years of follow-up and data needs to be collected until they have been in the study for 10 years. NHS Digital civil registration data is only required from patients who were recruited into the TARGIT A trial from 6 UK based hospitals (London UCL, London Royal Free, London Whittington, London Guy's and Winchester Royal Hampshire. - 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. All data obtained will be held securely in UCL. Patient identifiers (such as name, address, etc.) will be held on a separate Data Safe Haven which is a service that provides a technical solution for storing, handling and analysing identifiable data provided within UCL. 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). 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). Remote processing will be from secure locations within England and Wales. The data will not leave England and Wales at any time. Data will only be requested from NHS Digital where patients have provided a complete and valid signed consent form. For avoidance of doubt, the death data will only be requested and will only flow after the consent has taken place. Data will be accessed by an individual with an honorary contract with UCL. The individual will act as an agent of UCL at all times under supervision from employees of UCL. Aside from this individual, access is restricted to employees or agents of UCL who have authorisation from the Principal Investigator. This application relates solely to the follow-up phase of the study. All personnel accessing the Data have been appropriately trained in data protection and confidentiality. The Data will be linked at person record level with the existing TARGIT-A Trial database. The identifying details will be stored in a separate database to the linked dataset used for analysis. All analyses will use the pseudonymised dataset. There will be no requirement and no attempt to reidentify individuals when using the pseudonymised dataset.

Expected output

TARGIT-A data has been published several times at different junctures through the trial follow up. This request to obtain Civil Registration, Cancer Registration and HES data from NHS Digital, England will enable SITU to incorporate death data in order to update the dataset used in this publication. SITU will also aim to publish the results in high impact international journals, such as The Lancet. Patient-level data from NHS Digital Englandl will not be published. [1 paragraph unchanged] The final report of results is anticipated to be submitted to the funder in 2023. 2024. This publication is expected to be open access in a peer reviewed journal such as The Lancet, British Medical Journal, etc. This report will include NHS England data based on groups of subjects and will be restricted to aggregate data with small numbers suppressed in line with the HES Analysis Guide. [5 paragraphs unchanged] By collecting HES data UCL SITU will compare patient reported health outcomes with the information obtain from NHS England, and determine if direct patient contact is an effective way of obtaining outcome data from patients participating in a randomised clinical trial.

Expected measurable benefits

[2 paragraphs unchanged] It is anticipated that the results from this study will add to [83 words unchanged] discharged from hospital clinical care after three years. However, in the trial we UCL SITU want to obtain follow-up data for at least ten years, so obtaining [24 words unchanged] straightforward manner, and “fills the gap” between hospital follow-up and ONS data. [1 paragraph unchanged] The specific benefits from the use of the data will be to generate further high quality research evidence about the use of direct patient contact, to obtain reliable outcomes data of individuals participating in randomised clinical trials. Linking the existing TARGIT databases to NHS England data will permit the study to look at a wide range of public health relevant topics. The potential benefits for the prevention of overall mortality and death due specifically to breast cancer are substantial. Target dates will run from the time of acquiring the data with plans to publish when the study finishes in 2024. As a result of the outputs it is likely that a decision can be made regarding the effectiveness of gathering information on outcome data directly from patients participating in a randomised clinical trial, instead of asking clinical staff to provide this data. This method of collecting data could have a huge economic benefit on the long term data collection in randomised clinical trial where the benefits and risks beyond 10 years are important and would otherwise be difficult to acquire. Benefits will be to academic clinical trials units and funders of health research. These benefits could be achieved soon after publication in 2024.

Benefits reported

Stated in the previous version and removed here.

Yielded Benefits is not a requirement for new applications.