Protect-C: Population Based Germline Testing for Early Detection and Prevention of Cancer - Recruitment Agreement

Queen Mary University of London (QMUL) requires access to NHS England data for the purpose of the following study: ‘Population Based Germline Testing for Early Detection and Prevention of Cancer’ (PROTECT-C).

The following is a summary of the aims of PROTECT-C, provided by QMUL:

The overall objective is to evaluate the impact of implementing a population-based genetic testing strategy for high and moderate penetrance cancer susceptibility genes along with common genetic variants for personalised breast cancer (BC) and ovarian cancer (OC) risk in general population women. The study will identify women at moderate/high risk of breast, ovarian, endometrial, and bowel cancer. The study will evaluate impact on health behaviour, psycho-social health, participant experience, satisfaction, screening and prevention uptake, and cost effectiveness.

For the PROTECT-C study to achieve its objectives, 5000 people will need to be recruited.

To recruit this number of individuals, it is expected that 50,000 individuals will need to be invited to the PROTECT-C Study using the NHS DigiTrials Recruitment service. NHS England may identify further eligible individuals to be contacted about the PROTECT-C Study, should the recruitment target not be met with 50,000 invitations.

PROTECT-C is a completely digital study. Potential participants will be directed to the PROTECT-C website to register their interest. They will need to provide a valid email address and will be asked to answer a few questions to confirm that they are able to take part in the study.

The PROTECT-C study team will review the participants registration information, and then then invite eligible participants via email to enrol in the study. At this point, the person will be able to access the PROTECT-C app, which can be downloaded using a smartphone or tablet, or can be accessed on any internet browser using a computer or laptop.

The PROTECT-C app will be available on app stores including Apple and Android systems. A guide on how to download and use the app will be available on the PROTECT-C website and in the email invitation. This app will serve as an information giving decision aid, which can be accessed at the participants convenience.

PROTECT-C is part of a series of recruitment pilots testing new user cases and capabilities for minimal viable product (MVP) NHS DigiTrials recruitment service. As part of the pilot, QMUL will provide suitable feedback regarding response rates to the invitations in order for NHS DigiTrials to undertake suitable analysis of the service.

PROTECT-C is performing a Study Within a Trial (SWAT) to evaluate the uptake of participants to the study, based on the invitation letter received. Whilst this SWAT does not form part of this Data Sharing Agreement, NHS England will be processing data on behalf of QMUL but there will be no release of personal data outside of this DSA.

The following NHS England Data will be accessed:

• Personal Demographics Service – necessary for the purposes of identifying individuals who are eligible to participate in the PROTECT-C Study; and providing key information to the third-party mailing provider who have been contracted to contact potential participants.

The level of the Data will be as follows:

Identifiable – necessary because the third-party mailing provider require enough information to be able to contact potential participants.

Limited to individuals identified by NHS England as meeting the following criteria:

• Reside in England

• Female

• Age 18 years or older

The PROTECT-C study has additional eligibility criteria as detailed on the study protocol. These criteria cannot be identified by NHS England Data available to the Recruitment Service and will be applied by the study team at the time of registration of interest on the PROTECT-C website.

QMUL are 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 Health Regulatory Authority (HRA) Confidentiality Advisory Group (CAG) provided support to temporarily lift the Common Law Duty of Confidentiality under section 251 of the National Health Service Act 2006 and its current Regulations, the Health Service (Control of Patient Information) Regulations 2002, for the purpose of contacting potentially eligible participants.

People who have previously opted out of sharing their health data for planning and research purposes, by submitting a National Data Opt-out, will not be invited to take part in the PROTECT-C study. In addition, a study specific opt-out is available via the NHS England website for members of the public to specifically request not to be contacted for involvement in the PROTECT-C Study.

QMUL will display this information via their trial webpage and the NHS England Recruitment Service will display this information via a dedicated opt-out webpage for the study on its website. The study specific opt-out will be published shortly after this Data Sharing Agreement (DSA) is approved. NHS England will record these requests not to take part and ensure that anyone who has registered for this will be excluded from the cohort selection. As a result, their details will not be on the list passed to the third-party mailing provider (PSL Print Management Ltd and Datagraphic Ltd – see more information below) for invitations to be sent.

PROTECT-C is funded by Yorkshire Cancer Research. Funding is in place until 31/01/2031.

NHS England are acting as a Processor on behalf of QMUL and are responsible for:

1. Applying the inclusion and exclusion criteria from the invitation request to the datasets to generate a list of invitees

2. Feeding back to QMUL the number of invitees actually fulfilled out of the total target population

3. Removing objections or opt outs (where a national Data opt-out or a study-specific right to object has been registered, as well as special categories of people for whom the data should not be disseminated. The purpose of the restriction is to ensure that patient information that might imply a location is protected.)

4. Sending the list of invitees on to the third-party provider (Datagraphic Ltd) for generating the invitation letters.

5. Agreeing with QMUL key processing timelines

6. Overseeing performance of Datagraphic Ltd and alerting performance issues to QMUL

7. Feeding back to QMUL performance in relation to Key Performance Indicators (KPIs) of Datagraphic Ltd and NHS England

8. Where the number of potential invitees is less than the population available, invoking a system to choose invitees at random

9. Maintaining a record of people invited and ensuring they are excluded from second rounds of invitations, as may be applicable.

PSL Print Management Ltd are acting as a processor on behalf of NHS England and are responsible for maintaining a service contract with NHS England and managing the mailout performed by Datagraphic Ltd. PSL Print Management Ltd will not receive, store or have access to NHS England record level Data under this DSA. *

Datagraphic Ltd are acting as a processor on behalf of NHS England and PSL Print Management Ltd and are responsible for receiving the list of updated cohort participants from NHS England and mailing out to them accordingly.*

* PSL Print Management Ltd and Datagraphic Ltd work in partnership to provide robust, secure and time critical communication solutions. PSL Print Management Ltd provide project management, training and implementation skill and knowledge. Datagraphic Ltd develop, maintain and host the systems that enable secure and resilient communication to occur. Datagraphic Ltd also provide secure data processing, document composition, sortation, mail item production, enclosing, despatch and inbound mail services from their UK Midlands based development and production hub. NHS England maintains a service contract with PSL Print Management Ltd, and Datagraphic Ltd, in turn, are contracted to PSL, therefore both organisations are considered Processors in this DSA.

QMUL lead on all study activity and are supported by the following oversight committees:

1) Trial Management Group (TMG) consisting of trial investigators, selected lead researchers and key research staff to review progress on a regular basis.

2) The independent Trial Steering Committee (TSC) to monitor and supervise progress of the trial, adherence to protocol, and wellbeing of participants and ensure that the trial is conducted to a high standard in line with Guidelines for Good Clinical Practice. The TSC will report to the funder and sponsor on progress of the PROTECT-C Study.

The TMG can make comments, requests, and recommendations to the TSC. In turn, the TSC provides assurances and advice to the funder and to the sponsor. The decision making lies with QMUL.

Access to identifiable data is restricted to substantive employees of NHS England and Datagraphic Ltd only. QMUL will only see identifiable participant data once a person signs up to the PROTECT-C study.

QMUL have engaged extensively with members of the public, patients, and cancer charities in the development of the PROTECT-C Study.

QMUL have also worked closely with charities and support groups - Ovacome, Ovarian cancer Action, Eve Appeal, Target Ovarian Cancer, Breast Cancer Now, BRCA umbrella, BRCA Chat, GO Girls, LSUK, patient group from Yorkshire Cancer Research and EMRI (Ethnic Minority Research Inclusion).

The Wolfson Institute of Population Health at QMUL has a dedicated PPI group who has also supported this research.

Patients/Public representatives and stakeholders have contributed to co-development of the PROTECT-C app design and content including conceptualising and prototype development of the web app. QMUL have undertaken 6 meetings/workshops with groups of representatives for this. The design of the decision aid app will involve approval from a multidisciplinary working group incorporating patients and public group representatives. This will be an iterative process of public testing and incorporation of public and clinician feedback. Additionally, the representatives have inputted into development of all participant facing materials, including the PIS, invitation letter, patient communication and result letters, app videos, and protocol.

They will also be involved in information dissemination, increasing study awareness, membership of oversight committees and dissemination of study findings. There is lay/public representation on the trial management and steering committees.

QMUL are also working with charity support groups (like BRCA Umbrella, BRCA Chat, Breast Cancer Now) who will provide support to individuals found to have genetic faults or mutations in the study, through their established peer support activities and programmes. Individuals found to have genetic faults or mutations will be signposted to these sources of support.

There will be public representation on the study management and oversight teams. Participant groups and charities will also be involved in increasing awareness, and dissemination of research and research findings.

QMUL have worked with the behavioural scientist team at NHS England to test the invitation letter. Five letters containing a ‘nudge’ and a low-cognitive load version of the letter have been drafted. Nudges are an additional sentences intended to appeal in different ways. QMUL and NHSE have tested nudges with members of the lay public to help finalise an optimum invitation letter.

QMUL and NHSE have also included a low-cognitive load or easy read version of the letter for testing. The invitation letters were distributed to lay people through a survey company, where they each saw only one copy of the letter. They were asked questions which decided which ‘nudge’ was received the best. The findings have been considered in the final invitation letters. By having a combination of both PPI workshops/feedback and testing it ensures participant facing documentation has undergone a quantitative and qualitative PPI review which helps ensure the documentation is more easily understandable and useful for the public.

No data will flow to NHS England for the purposes of this Data Sharing Agreement (DSA). QMUL will provide to NHS England the core eligibility criteria for those potential participants who will receive invitations. The core eligibility criteria will include the minimum and maximum age, sex, postcode sector, and quantity of individuals within those parameters.

NHS England will use the criteria provided by QMUL to identify potential participants who meet the criteria. NHS England will remove any records where a National Data Opt-Out or study-specific opt-out has been registered, as well as special categories of people for whom the data should not be disseminated such as those on a witness protection programme.

NHS England will provide the relevant records of the identified potential participants from the Personal Demographics Service dataset to Datagraphic Ltd via Secure Electronic File Transfer (SEFT). The Data will contain directly identifying data items including Title, First Name, Surname, Address and Postcode, which are required for the purposes of contacting potential participants. Datagraphic Ltd will also receive additional fields which will enable them to ensure that the correct invitation format and template are used for each round of invitations. Datagraphic Ltd will use Research Ethics Committee-approved template invitation letters.

NHS England will also provide an aggregate data quality report with small numbers unsuppressed containing information about gender, age and geographic demographics of the mailing to QMUL for the purposes of confirming that inclusion and exclusion criteria have been met for each mailing. This report will also contain the total number of people who received the letter from Datagraphic Ltd, and the number of people removed from the cohort prior to mailing based on trial-specific opt out, national data opt out, and special categories of people for whom the data should not be disseminated.

The Data will not be transferred to any other location. Datagraphic Ltd will contact individuals as specified by QMUL. All potential participants will receive a letter containing their Forename, Surname, address, postcode and an invitation QR code.

Datagraphic Ltd will send out invitations in approximately 6 batches of letters up to approximately 50,000 total mailouts, using an automated system.

The Data will be stored on servers at Datagraphic Ltd.

Processing will be from secure locations within England. The Data will not leave England at any time.

Access is restricted to substantive employees of NHS England and Datagraphic Ltd only.

QMUL will not have access to NHS England Data as described in this DSA. QMUL will not have access to individual’s data unless they are contacted directly by said individual following the mailout.

All personnel accessing the Data have been appropriately trained in data protection and confidentiality.

The identifiable Data sent to Datagraphic will not be linked with any other data.

Datagraphic Ltd will destroy all data files received from NHS England 2 weeks post mail-out, as instructed by NHS England.

Each time NHS England create and disseminate an extract, the records will be added to a mailing list cohort dataset. Should a fresh extract be produced, it will be checked to ensure that any records appearing in this mailing list dataset are removed in order to prevent potential participants receiving multiple invitations. This mailing list dataset will be maintained for six months after the invitation process is complete in case this is required for analysis purposes by QMUL, however it is anticipated that the data quality report will meet the trial's needs for monitoring how many individuals from different demographics were contacted in each 'mailing'. Only aggregated data would be used for such analysis.

The expected outputs of this recruitment Agreement will be QMUL reaching their recruitment target for the PROTECT-C study, having sent adequate numbers of invitations to potentially eligible participants.

Progress against recruitment targets will inform:

• Reporting to Yorkshire Cancer Research, PROTECT-C study sponsor, oversight committees, and other study partners, and stakeholders through milestone updates

• Lay friendly updates to the PROTECT-C study participants via the study website and newsletter

• Presentations

• Publications

Any 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 from which the information was derived. Identifiable data requested from NHS England will only be used to identify and invite potential participants.

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

• Social Media

• Press / Media engagement

• Academic peer reviewed journals

• Webinars and presentations (academic or stakeholder organisations and lay public)

• Newsletters from subscribers through the PROTECT-C website

QMUL hope to reach their recruitment target for the PROTECT-C study by 31/03/2028

The ability to utilise large letter quantities will help to optimise recruitment, in order to deliver the PROTECT-C study in a timely, effective and resource efficient manner. Using NHS England’s NHS DigiTrials Recruitment Service to generate mailing lists, in order to send invitations to members of the public about joining the PROTECT-C study is expected to significantly increase the recruitment reach of the study. This study will have a paradigm changing impact on applicability of genomics to healthcare in the future, thus benefiting thousands more people and preventing thousands more cancers.

Participants will be able to find out if they carry an inheritable mutation and/or if they are at an increased risk of cancer for which they can take active steps of screening and prevention which will become available to them as a result of the study, thus leading to lives saved. Additionally, family members can undergo testing to detect if they carry the inheritable mutation and take steps to prevent themselves from getting cancer.

This approach at a population level would not be available through the NHS. Hence, this is an added benefit of the study. There is no monetary incentive being provided to participants.

Recruiting individuals into the PROTECT-C study, using the NHS DigiTrials recruitment service, is ultimately expected to provide benefits to health and social care by preventing thousands more cancers.

Outputs from the PROTECT-C study will provide the evidence base to address knowledge gaps and enable decision making on the implementation of population-based testing for cancer susceptibility genes and PRS-based personalised breast cancer and ovarian cancer risk prediction in unselected general population women. Programme impact and outputs will:

• Provide empirical prospective estimates of the detection rates of pathogenic variants (mutations) in the general population and the incremental detection provided by population testing over application of current testing policy.

• Provide prospective data on population stratification using personalised breast cancer and ovarian cancer risk estimates and identification of women at increased risk over and above monogenic cancer susceptibility gene testing. This will enable estimation of the magnitude of its benefit in addition to monogenic cancer susceptibility gene testing.

• Provide data on acceptability, satisfaction, uptake of screening and prevention strategies, impact on quality of life/psychological well-being, VUS monitoring, and cost-effectiveness of panel testing for cancer susceptibility genes along-with personalised breast cancer and ovarian cancer risk prediction in unselected women.

• Provide clinical and cost-effectiveness data of a direct to participant application for decision making for genetic testing.

• Establish a body of empirical ethics and qualitative research to inform the evolution of participant centred guidelines/policy related to population genetic testing.

• Provide new insights and evidence based ethically grounded recommendations for population testing.

• Provide a scalable digitised model for implementing a new paradigm of population pre-test education/counselling and genetic testing.

• Establish the best strategy for variants of uncertain significance management in a panel population testing context.

• Contribute to scientific publications in peer reviewed journals and presentations at conferences/meetings.

• Inform national/international guidelines on population-based genetic testing for cancer screening and prevention.

• Provide evidence needed to facilitate decision regarding implementation of a national population testing programme for cancer susceptibility genes and personalised breast cancer and ovarian cancer risk prediction. Such a programme can prevent thousands more breast cancers, ovarian cancers, womb cancers and bowel cancers than current clinical strategies.

• Identify additional study participants with cancer susceptibility genes, enabling them to access screening programmes and preventive interventions.

• Establish of a bioresource for future research.

Future implementation could prevent thousands more cancers and save thousands more lives. This will serve as an exemplar for implementing population genetic testing and risk stratification for other diseases/other cancers.

The trial team have engaged with various stakeholders, key decision makers, influencers, charities, funders, clinicians, researchers, and the lay public. All these stakeholders will help increase awareness and dissemination of the study to members of the public who are eligible to join the PROTECT-C Study. This will include their own communication channels which will increase familiarity and trust to the letter invite. The PROTECT-C study will also engage with media (news and social media) channels and use digital means to increase study awareness. Extensive PPI work has also been undertaken which will support increasing awareness.

Examples of communication channels include

• PROTECT-C website

• GP practices

• Hospitals

• Integrated Care Boards

• Cancer Alliances

• Research Delivery Networks

• Charities

• Councils

• Healthwatch

• Community Organisations and groups

• RCGP

• NIHR

• UK CGG

• Clinical Research Networks

Yielded Benefits is not a requirement for new applications.