Improving outcomeS for Women diagnosed with early breast cancer through adhErence to adjuvant Endocrine Therapy (SWEET)

Newcastle Upon Tyne Hospitals NHS Foundation Trust requires access to NHS England data for the purpose of the following research project: the SWEET research programme (Supporting Women with adhErence to adjuvant Endocrine Therapy (AET) following breast cancer).

This Data Sharing Agreement (DSA) refers only to Phase II (feasibility) of the SWEET study.

The following is a summary of the aims of the research project provided by Newcastle Upon Tyne Hospitals NHS Foundation Trust:

SWEET is a research programme funded by the National Institute for Health and Care Research (NIHR) (£2.7 million grant) focussed on supporting women with oestrogen receptive positive (ER+) breast cancer to adhere to AET. The research programme commenced in May 2020 and is anticipated to run for 80 months in total. The SWEET study has three distinct phases:

(i) development of the support package (intervention – HT&Me);

(ii) feasibility study (the stop-go assessment follows the completion of the feasibility study) and;

(iii) full randomised controlled trial (RCT).

The purpose of the SWEET study is to:

(i) Develop and evaluate an intervention to reduce poor adherence to AET.

(ii) Improve cancer-specific Health-Related Quality of Life (HRQoL).

This rationale for the development and evaluation (adherence measurement) of a theoretically-informed intervention to improve AET adherence arises from the fact that adherence to these treatments are known to not be as recommended. This is despite evidence showing that AET significantly reduces the risk of breast cancer, recurrence, death from breast cancer, and (hence) death from any cause when taken for at least five years. Around 20-40% of women display suboptimal implementation of AET (generally defined in this context as taking <80% of the recommended dose). To date, there are no effective interventions to improve AET adherence; the SWEET project aims to fill this gap in care.

The SWEET intervention targets potentially modifiable factors associated with non-adherence including:

(i) the way in which women judge their personal need to take AET including beliefs, relative to their concerns about taking it (recurrence risk and side effects such as severe hot flushes, joint pain, weight gain, and depression);

(ii) attitudes to taking a long term medication and the desire to move on from a cancer diagnosis;

(iii) motivation and ability to take AET (coping skills, medication management, and forgetfulness); and

(iv) facilitating a good patient-healthcare professional relationship.

The SWEET feasibility study started in October 2022 and is anticipated to run through until April 2024. It has two work streams:

(i) sub-study I which is assessing the feasibility and acceptability of the support package (minimum target n=45 ; recruitment final total n=59) and;

(ii) sub-study II which is assessing the feasibility of obtaining prescription encashment data to measure adherence to AET (minimum target n=45 ; recruitment final total n=56) for women with breast cancer initially prescribed AET by hospital/consultant recommendation. Recruitment of women to sub-study II was completed by the end of August 2023.

Feasibility sub-study II data subjects (minimum target n=45 ; recruitment is finished, total n=56) are women, aged 18+, diagnosed with ER positive invasive stage I-III breast cancer, treated with curative intent and prescribed oral AET (tamoxifen or an aromatase inhibitor) within the previous 9-36 months. These women will have completed surgery and chemotherapy (if applicable). Women on anti-HER2 therapies, or ovarian suppression drugs are also potential data subjects as long as they fulfil all other criteria listed above, as will women who have had neo-adjuvant endocrine therapy and women who have had a previous primary breast cancer (as long as they did not have AET to treat their first cancer). Exclusion criteria for potential data subjects are as follows: male, evidence of metastatic disease (M1 regardless of T and N status), adjuvant CDK4/6 inhibitor (abemaciclib) prescription, cognitive impairment sufficient to preclude participation (judged by the clinical team), unable to read and understand English, previous AET use for another breast cancer and no breast cancer surgery. Data subjects are identified from hospital records (clinician’s files, hospital systems, medical records, hospital pharmacy records) based on a first prescription for oral AET in the relevant time window. A member of hospital staff will review the women’s medical records to assess eligibility.

The feasibility sub-study II wishes to use the Data described in this DSA for the following purpose:

- Assess the timeliness and completeness of AET NHSBSA prescription data.

- Determine if it is possible to compute an objective measure of AET adherence using NHSBSA data.

- Determine whether the NHSBSA data available on other medications prescribed are suitable for use within a health economic assessment.

- Refine the methodology and data processing of NHSBSA data required for the future large-scale RCT (phase III) within the wider SWEET research programme (due to commence January 2024 and looking to assess adherence to AET in a larger group of recruited women).

The data used in this DSA will only be reported in the SWEET feasibility study, though the project’s findings will inform the scope of wider SWEET programme findings.

The following NHS England Data will be accessed:

• Medicines Dispensed in Primary Care NHS Business Services Authority data set – (NHSBSA) – necessary to calculate measures of AET adherence (e.g. medication possession ratio (MPR), proportion of days covered (PDC), continuous measure of medication acquisition (CMA), continuous measure of medication gaps (CMG), continuous single interval measure of medication acquisition (CSA), continuous single interval measure of medication gaps (CSG), or a dichotomous adherent or not measure).

Specific NHSBSA data requested is as follows: AET prescription(s) encashed and any associated medications (e.g. bisphosphonates) including details on: drug name, strength, quantity, dosing instructions, quantity/item count, date of first issues, date of all recurrent issues, date stopped, number and date of drug issues, any record of previously recorded AET (which may suggest that a patient has switched from one therapy to another), and the number of concurrent medications.

The SWEET Sub-study II will use NHSBSA data to determine an indirect, objective measure of medication adherence. Previous research has shown that a combination of indirect (objective) and direct (subjective) measures of adherence provide a more balanced assessment of overall adherence. Therefore, in the planned future Randomised Control Trial (RCT) (SWEET programme phase III), NHSBSA prescription data (if suitable/feasible) will be combined with women’s self-reported adherence (questionnaire self-report) to enhance the reporting of each women’s adherence to AET.

Data will be restricted to cohort participants only (minimum target n=45 ; recruitment finished, total n=56) who have provided consent to obtain this information. Data is only requested for the purposes described above.

Prescribing data is sought for each woman for a period of approximately 9-36 months prior to (according to the Date of First Diagnosis of Breast cancer), and up to, the latest available Data listed within the NHSBSA dataset at the time the extraction is run. This timeframe has been selected to cover the period before and during the women’s recruitment to the feasibility sub-study II as well as allowing for assessment of the delays (“lag”) in the women’s prescription encashment data being available through the NHSBSA dataset for release. The geographical spread of the data requested reflects the area in which the women reside within England, along with their proximity to one of the feasibility sites delivering the SWEET feasibility intervention.

The level of the Data will be:

• Identifiable Record-level – necessary to enable linkage of the NHSBSA data with data collected from the participants in sub-study II at the time of recruitment (i.e. oestrogen receptor status, tumour stage, tumour grade, surgery receipt, chemotherapy receipt, and radiotherapy receipt).

There are no alternative, less intrusive ways to obtain encashment level data on AET prescriptions for the purpose of this study other than through an application to NHS England.

Data is only requested for the small number of women who have consented to be part of the Sub-study and will only be used for the purpose of assessing AET (and associated bisphosphonate) adherence and undertaking a health economic assessment as part of the SWEET programme’s feasibility study (Phase II) only.

Newcastle Upon Tyne Hospitals NHS Foundation Trust 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. The SWEET Sub-study II (feasibility) is in the public interest as it aims to determine an indirect, objective measure of medication adherence which will feed into the overall development of the SWEET study, which aims to improve cancer-specific Health-Related Quality of Life (HRQoL) for those women with breast-cancer.

The funding is provided by the NIHR. The NIHR have no role in this application as either a Controller or Processor, nor will they have access to the NHS England Data as described in this DSA. Funding is in place until January 2027, conditional on the programme passing a “stop-go” assessment at the end of 2023. Representatives of the funder will see aggregated data with small number suppression applied as per the NHSBSA dataset guidance in annual reports to the funder and through the “stop-go” assessment.

The Newcastle University is a processor acting under the instructions of Newcastle-upon-Tyne NHS Hospitals NHS Foundation Trust.

A number of organisations will be involved in recruitment of women to the SWEET programme at feasibility study recruitment sites. These sites, in additional to Newcastle-upon-Tyne NHS Hospitals NHS Foundation Trust, are as follows:

- Oxford University Hospitals NHS Foundation Trust, Oxford.

- Imperial College Hospital Trust, London.

- Great Western Hospital NHS Foundation Trust, Swindon.

- Queen Elizabeth Hospital, Gateshead.

These clinical sites will have no access to the record-level NHS England Data as described in this DSA.

A range of other academic, NHS, and third sector organisations are partners in the SWEET programme and provide input in various ways (e.g. provision of clinical expertise, leading on intervention development, patient and public involvement (PPI) input); in addition, individuals from several other similar organisations provide an independent oversight role on behalf of the funder (i.e. Independent Steering Committee (PSC)). None of these organisations will have access to the NHS England Data as described in this DSA.. Once data has been processed, aggregated data with small number suppression applied as per the NHSBSA dataset guidance in the form of findings will be shared with other co-applicants, research staff, and PSC members at these partner organisations.

The SWEET study has engaged patient representatives who have been actively involved from the start, consulting widely with members of local support groups, their own social networks, colleagues on the then National Cancer Research Institute (NCRI) Consumer Forum and through Independent Cancer Patient Voices and have actively fed views back into the development process. The SWEET Study established a Patient Advisory Group (PAG) which includes a diverse group of 13 women with a range of experiences of AET, and who have been closely involved in co-designing the intervention web-app and in developing the scripts for the initial and follow-up consultations. They have also reviewed the patient-facing documents for the feasibility study and provided input to the choice of questionnaires for assessing outcomes and mediators. For the later stages of the programme PAG members who wish to be involved in analysis of study data will be given relevant training by team members. The PAG will also provide a patient perspective on the write-up of papers, will help produce lay summaries, and with presenting the study findings results at conferences, support groups and charity group open days.

The SWEET study also established a wider PPI group called a Community of Interest (CoI). The CoI includes 28 women with breast cancer who have been prescribed AET. The CoI is consulted, mainly by email, on an ad hoc basis, as and when needed.

Beyond PPI, the SWEET study has also engaged extensively with a wide range of stakeholders. In developing the programme, they sought advice from consultants in breast cancer, breast cancer nursing groups (e.g. Pan London Breast Care Nurses) and the third sector (Breast Cancer Now, Macmillan Cancer Support). The programme has the support of the NCRI Breast and Psychosocial and Survivorship Groups and Breast Symptoms Working Group. The SWEET study also works closely with Breast Cancer Now, who are partners in the programme.

These stakeholders will have no access to the record-level NHS England Data as described in this DSA.

Newcastle-upon-Tyne Hospitals NHS Foundation Trust will securely transfer data to NHS England. The data will consist of identifying details (specifically NHS Number and Date of Birth for the cohort to be linked with NHS England Data). The Date of First Diagnosis of Breast Cancer and a unique study ID will also be provided by Newcastle-upon-Tyne Hospitals NHS Foundation Trust.

NHS England will provide the relevant records from the NHSBSA dataset to Newcastle University. The Data will contain no direct identifying data items but will contain the provided unique study ID which can be used to link the Data with other record level data already held by the study team.

Newcastle University will seek to examine the completeness of data, assess the suitability for computing different measures of adherence (e.g. MPR, PDC, CMA, CMG, CSA, CSG) and undertake a health economic evaluation. The deidentified dataset will be housed on a secure University network accessible only to named employees working for the Data Processor. The data will be worked on and saved to this secure drive. Policies and procedures are in place at Newcastle University which will be followed in the unlikely event that there is an accidental loss, destruction, or damage to the data during storage. There is no linkage in this application of data to a matched publicly available dataset.

The Data received under this Data Sharing Agreement and identifiable patient data received at the time of consent to sub-study II from clinical sites will be stored separately. The pseudonymised dataset will be processed in used in such a way to allow the study to address its key aims.

Pulsant is where the Newcastle University servers are co-located. This means that the University rents secure rack space at this location where the University hosts its servers. Pulsant only provides a secure managed location and does not have access to any hardware. Pulsant will have no access to the NHS England Data as described in this DSA.

Data processing will only be carried out by employees and agents of Newcastle University. These individuals will have been appropriately trained in data protection and confidentiality which will be reviewed on an annual basis. Annual General Data Protection Regulation (GDPR) training will be required for all employees using NHS England Data.

Access to NHS England record-level Data by authorised personnel will be either on-site at Newcastle University or via remote access. For remote access, the study team will comply with the following terms:

• 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;

• Access controls granting users the minimum level of access required are in place;

• Remote access is only via secure connections (e.g., VPNs or secure protocols) to protect data;

• Multifactor authentication (MFA) is required for remote access;

• Device security, including up-to-date software and operating systems, antivirus software, and enabled firewalls are utilised for the remote access;

• 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.

The above applies in addition to any condition set out elsewhere within the DSA.

The Data will not leave England at any time.

The Controller 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.

There will be no student access to the data. Data from NHS England will not be used for any purpose other than that stated in this application.

Linked data will only remain available for 5 years following any publication after which retention will be reviewed. )

The SWEET study aims to produce a number of outputs as a result of data processing which hopes to target a wide audience (researchers, scientists, innovative technology-focused organisations, research participant audiences, patient groups, general population, and commissioners). Dissemination outputs will consider a number of mediums (journal publications, conference presentations, a website, public events, scientific writing, webinars, and newsletters).

In the first instance, a report from the findings of the SWEET feasibility study will be produced for submission to the NIHR. There will also be continuous reporting to the funder of further SWEET study findings throughout the short, medium, and long term of the programme.

Study outputs will be limited to aggregate data with small number data suppression as per the NHS BSA dataset suppression guidance.

Outputs will also take on the form of peer reviewed publications – most likely research in specialty journals in breast cancer survivorship (e.g. Journal of Cancer Survivorship, Supportive Care in Cancer) and psycho-oncology/behavioural science (e.g. Psycho-Oncology, Implementation Science, Patient Education and Counselling). Publication of the feasibility’s study’s findings in peer-reviewed scientific and clinical journals is anticipated as a medium-term goal of the SWEET programme (up to 2 year timescale).

Feasibility study publications will build on the number of abstracts already published from the early phases of the wider SWEET project work. There are currently two SWEET publication: (i) a paper exploring the theoretical-based, modifiable influences on non-adherence in breast cancer ; and (ii) a paper describing the HT&Me intervention development from an earlier phase of the SWEET programme. In addition to this, a systematic review of previous reviews of determinants of adherence and a further SWEET research programme protocol paper are both currently under review. These short-term outputs are anticipated soon (2023/24).

To assist with dissemination to the wider clinical team, patient groups, and commissioners the programme aims to utilise social media, lay communications, and briefings (paper, digital, and events). To reach patient and general populations, regular updates will be posted on the SWEET project website to assist with dissemination. Such postings are envisioned to include key project messages crafted with the assistance of the PPI panel. For the feasibility study, in the short term, the research team will report to the participants and the wider clinical team on the feasibility of obtaining prescription encashment data and using this information to generate a measure of adherence as well as the potential to scale up such data processing for the future SWEET RCT to follow. There are also plans to pursue a dissemination event for breast cancer survivors and healthcare professionals should there be sufficient interest in doing so. This event may also include a livestream to other locations (e.g. collaborating centres). Also, if of use to interested groups, parts of this livestream may also be recorded and posted on the SWEET website. Such an event is currently anticipated to fall towards the end of the research programme (January 2027).

In the longer term, the programme intends to have an impact on clinical policy, specifically through the integration of the SWEET intervention into clinical guidelines so that all women prescribed AET can benefit from the information provided by the HT&Me app. This will ensure that the project’s findings can reach all clinical and geographic communities – not just those with an interest in research driven clinical practice. Commercialisation of the HT&Me app has been explored so far for the initial work on this project but there are plans to expand on such discussion for roll out of the intervention across the whole National Health Service (NHS). Additionally, the RCT aims to consider recurrence risk in women over a longer time frame than that reported in the literature, as well as noting the findings of the intervention on recurrence over a longer time frame. Timescales for such longer-term outputs are 5 years plus.

Dissemination plans align with those for the intended research undertaken. Stakeholders in the project are currently updated quarterly with progress with the SWEET project. These meetings fluctuate between virtual and face to face communication to facilitate access to updates on the study’s progress. Following completion of the feasibility study and the later RCT, stakeholders will receive a report of the outcomes from the programme. There will be continuous reporting of findings throughout the short, medium, and long term of the programme to stakeholders.

Study outputs will be limited to aggregate data with small number data suppression as per the NHS BSA dataset suppression guidance.

Dissemination of the findings of the SWEET study hopes to benefit the provision of health care for women diagnosed with breast cancer and prescribed AET. This is because the study’s intervention fills a gap in the current provision of care, by providing support for women to self-manage their AET thereby promoting adherence. If the findings from the current feasibility phase suggest that the intervention is feasible to deliver and acceptable to women, dissemination of these results and progression to a larger scale RCT, which offers opportunity for wider application of this longer-term care model to support more women living with and beyond hormone receptor positive breast cancer, hopes to result.

Dissemination also supports the promotion of health. The SWEET intervention aims to encourage self-management of breast cancer and associated AET long term use through equipping women with the skills and confidence to manage their condition and treatment. Such skills are especially important in a post COVID-19 NHS which remains both overwhelmed and understaffed. Breast cancer care is becoming increasing personalised, with more nurse, as opposed to consultant led treatment provision. Hence, upskilling patients in self-management is beneficial and may help manage behaviours which may otherwise result in poor adherence (e.g. bothersome side effects which patients may otherwise not feel the need to approach their consultant about). Finally, dissemination may bring benefits to the NHS and wider society. If the intervention is effective in improving adherence, it may reduce rates of breast cancer recurrence saving the NHS money. In the same way, by reducing recurrence and breast cancer mortality, it yields benefits at a societal level.

Dissemination of the study’s findings is in the public’s interest. Breast cancer is the most common cancer in women; it is estimated that there are more than 600,000 women living following a diagnosis of breast cancer in the UK. The overwhelming majority of these women (~80%) will have oestrogen-receptor positive disease and have been prescribed hormone therapy. For women with a hormone receptor positive breast cancer diagnosis prescribed AET, the findings raise awareness of the importance of AET adherence, and the intervention provides opportunities for patients recruited to benefit from prevention of treatment non-adherence. If successful, the outcomes of such an intervention may be beneficial to women beyond those recruited to this study. Additionally, as AET adherence significantly reduces the risk of cancer recurrence, death from breast cancer and hence death from any cause when taken for 5 years, adherence is anticipated to yield the potential associated benefits of increased survival, reduced mortality, and improved quality of life. Such additional benefits will be of interest to many members of the public living with and beyond a breast cancer diagnosis. For example, the findings of the study will raise awareness of the importance of adherence to anti-cancer treatments, which are increasing required to be taken/received long-term. It also raises awareness among the population that it is possible to survive cancer and that actions an individual may take themselves influences prospects of recurrence and survival.

Outputs hope to achieve the stated purposes by raising awareness of current issues with poor AET adherence as the SWEET intervention addresses this problem. Processing prescription data under this DSA hopes to benefit both the SWEET feasibility sub-study II (documenting the ease and suitability of this dataset to measure AET adherence in recruited women) whilst also assisting the onward RCT (scale up of data prescription data access) to a wider group of women.

Dissemination of the feasibility study’s findings forms the short-term benefits of the SWEET programme and will likely be achieved by April 2024. Data dissemination from the feasibility sub-study II has no direct benefit to the women taking part; however, participants will know that they are doing something that will help with the wider SWEET programme, which will then enable other women in the future to benefit from improved adherence. Primarily, the feasibility study’s findings actions and benefits will include:

(i) an assessment of the feasibility of accessing NHSBSA prescription encashment data;

(ii) determining the utility of NHSBSA data to calculate a measure of adherence for women in this trial (e.g. MPR, PDC, CMA, CMG, CSA, CSG);

(iii) the feasibility of undertaking a health economic evaluation using this data;

(iv) informing phase III of the SWEET study – the RCT – specifically, how medication adherence will be calculated and scaled up in a larger cohort of women and;

(v) provide information to the wider research community on using NHSBSA data for answering research questions.

Benefits will be measured in the first instance using a measure of adherence - an indirect, objective measurement of prescriptions encashed by the women to generate an adherence measurement e.g. MPR, PDC, CMA, CMG, CSA, CSG.

There are also longer term and wider benefits to this SWEET programme. There include:

(i) improved adherence to AET;

(ii) provision of an intervention to support AET adherence long term in women diagnosed with a hormone positive breast cancer and prescribed AET;

(iii) reduced breast cancer recurrence;

(iv) reduced breast cancer mortality; and

(v) improved quality of life.

Ultimately, if successful, the outputs of the wider SWEET study have the potential to result in change to the way that breast cancer patients prescribed AET are managed. Primarily, this pertains to roll out of the SWEET intervention across the NHS so that all women prescribed AET can receive the same support with treatment optimisation for 5 years and beyond. Finally, as poor adherence is not restricted to AET, the principles deployed in the SWEET intervention may be transferable to other novel, oral antineoplastic drugs or treatments for chronic conditions where treatment adherence may be poor. Longer-term project benefits such as recurrence and mortality reduction will be calculated from data on the recruited women at 10-15 years post the RCT commencement. Timescales for reaching such longer-term benefits are anticipated to be realised and evaluated much later in the SWEET programme timetable (some will be realised from January 2025 and for a further 5 years and beyond following RCT commencement).

The mechanisms through which dissemination will be achieved are specified earlier in this DSA; in brief, this will include conference presentations, journal publications, reports for funder, summaries on the project website, and stakeholder events.

The magnitude of the SWEET programme outputs could be substantial. This is because there is evidence that increasing the effectiveness of medication adherence interventions may have a far greater impact on the health of populations than any improvement in specific medical treatments.

There is a significant group of women who potentially can benefit from improved adherence to their AET if the SWEET intervention is shown to be successful. This is because more than 55,000 women are diagnosed with an invasive breast cancer annually and of these women, around 80% will be prescribed AET. Furthermore, if longer term outputs of improvement in recurrence rates and reduced mortality can also be realised, this will likely have organisation benefits as fewer patients will require treatment for recurrence and/or end of life care and this would ease pressures on the healthcare system. For example, in 2009 the estimated cost to manage recurrence was £31,403 and in 2010, costs were £94 million to provide end of life care in the 12 months prior to death in England. Health economic models also suggest that supporting AET adherence could reduce breast cancer recurrence by 9% and deaths by 8.7%. Any interventions are likely to be cost effective, assuming a willingness to pay a threshold of £25,000 per QALY, the expected value of changing a women from non-adherent to adherent with AET has been estimated to be £33,897. Finally, if survival can be improved, fewer deaths may occur (for example, despite breast cancer survival generally being considered high, 11,600 women still died in 2016). Hence, tackling adherence issues may well have a large financial and health incentives.

Primarily, the SWEET study Central Research Team and study sponsor (Newcastle upon Tyne NHS Foundation Trust) will be responsible for achieving these initial benefits.

Yielded Benefits is not a requirement for new applications.