Naevoid melanoma: Comparing prognosis of two subtypes

This agreement relates to a collaborative project with the University of Manchester (Cancer Research UK Manchester Institute) and Royal Surrey County Hospital NHS Foundation Trust which asks for follow-up data for the Naevoid Melanoma Study, a longitudinal observational study that has shown that two different subtypes of naevoid melanomas have distinct clinical, histopathological and immunochemical profiles that may be prognostically significant (Cook et al. 2017). These comprise of papillomatous and maturing naevoid melanomas. Nevoid melanoma is a type of skin cancer. It begins when the melanocytes in the skin grow out of control and form tumours. Melanocytes are the cells responsible for making melanin, the pigment that determines the colour of the skin.

Preliminary clinical follow-up data suggests different outcomes for these two naevoid melanoma.

A cohort of 151 patients that were identified by a Consultant Histopathologist at Royal Surrey County Hospital NHS Foundation Trust as melanomas that have been classified as naevoid melanomas, comprising of two subtypes; papillomatous and maturing, identified retrospectively from the time period 01/04/2004 and 30/06/2017 at Royal Surrey County Hospital NHS Foundation Trust. These 151 patients are the only cohort of patients that will are looking at.

This research is very important and is hoped to directly benefit patients and their families. One of these subtypes of naevoid melanoma requires very minimal follow up whereas the other subtype can require extensive follow up and treatments involved over a patients lifespan. This study will increase the precision of diagnosis and positively influence the different managements of these subtypes of melanoma.

It is in the public interest to obtain the full follow up data of these 151 patients that have been observed, leading to improved understanding of disease and opportunities for improved treatment resulting in lives saved and improved health.

NHS Digital Civil Registration (Deaths) data is required to inform the current status (alive/dead) and dates and causes of death. This data specifically informs the prime question of the study, helping to identify prognostic indicators (within causes of death) and the time from diagnosis until death (all-cause mortality), an important measure of health status and outcome). This data needs to be provided for the specific 151 individuals (by linkage through NHS number with verification by month/year of birth) to allow appropriate data for personal level risk model development and evaluation. As a longitudinal study, it is important to follow as many subjects as possible until death, the plan will be to ask for data on all patients that were diagnosed as naevoid melanoma by a Consultant Pathologist at Royal Surrey County Hospital NHS Foundation Trust between 2004- 2017. Therefore data will only include patients that have been diagnosed at Royal Surrey County Hospital NHS Foundation Trust within this time period. Alternative methods of assessing mortality status (e.g. re-contacting individuals) would be either more intrusive (likely to cause harm/distress), less informative or incomplete.

Patient identifiable information has been collected and used for linkage directly from subjects (NHS Number, Date of Birth, First Name and Surname) and a unique Study ID is added . NHS Digital use these identifiers for linkage to NHS Digital data sets to extract the required data, and then remove the identifiers, leaving only the Study ID and Data returned is subsequently linked only via the unique Study ID.

It is proposed to access Civil Registration (Deaths) data to ascertain who among the naevoid melanoma cohort has died. Since this is a retrospective cohort, consent cannot be gained from these deceased participants, but the same global reasons pertain to them as for those still alive for not obtaining consent as explained above and to the canvassed melanoma patients, CEO of Melanoma UK and CAG. The Melanoma UK charity supports the use of melanoma patient information in this study and believes the use of the data is appropriate for the achievement of the aims of the study.

A proportion of the study patients with naevoid melanoma will have died since diagnosis, either from their melanoma or unrelated causes. Since the death of a patient is not known since diagnosis, this needs to be ascertained through the mortality data.

It is essential that it is ascertained that they have died and their cause of death at the outset for the following reasons:

1) It is hugely labour-saving. Immediately tell which of the study patients has died and their cause of death, saving many months of work in tracing and contacting multiple doctors per patient and seeking responses about vital status and details of death (if applicable).

2) It advances the time of project completion by directly ascertaining one of the main study outcomes: melanoma-specific death in the study cohort.

3) There is no undue extra work requested by project staff and potentially many past doctors about their patients in the study if date of death of those patients is known. This would also eliminate the distress caused to the participants family, if by contacting a study candidate without knowing if they have died

Royal Surrey County Hospital NHS Foundation Trust will be joint Data Controller with the University of Manchester (Cancer Research UK Manchester Institute). Royal Surrey County Hospital NHS Foundation Trust and the University of Manchester (Cancer Research UK Manchester Institute) will also process the data.

The work undertaken by Royal Surrey County Hospital NHS Foundation Trust is funded by Cancer Research UK (CRUK). Their role is to provide funding for the collaborative research between Royal Surrey County Hospital NHS Foundation Trust and CRUK Manchester Institute. They also support and encourage adherence to the highest standards of governance, public dissemination of results and scientific rigour. However, their role does not include a part in the decision making regarding the study methodology, purpose or what data to collect and thus they are not considered a Data Controller.

The data will be minimized by a linkage to identifiers of the 151 patients from Royal Surrey County Hospital NHS Foundation Trust linked to limited fields in the Civil Registration (Deaths) data extract in a single drop of data.

Both the University of Manchester and Royal Surrey County Hospital NHS Foundation Trust rely on the GDPR Article 6(1)(e) for the legal basis for processing data (processing is necessary for the performance of a task in the public interest or in the exercise of official authority vested in the controller). Additionally, as health data is a special category of Personal Data, both Data Controllers rely on 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).

Safeguards are in place that protect the interests of the data subject, these have been judged as proportional to the substantial public interest, including approval by Confidentiality Advisory Board (CAG) under section 251 of the NHS Healthcare Act 2006 (which together with consent also safeguards the common law duty of confidentiality). Safeguards include physical and operational barriers protecting privacy and allowing processing of personal identifying and sensitive data only by staff contractually obliged to fulfil the requirements set out by Royal Surrey County Hospital NHS Foundation Trust Data Protection Policy, compliant with all laws and approvals. There is no alternative way of achieving this purpose of data collection for the study.

Processing activity and storage of personal and sensitive (special category) data is limited according to Royal Surrey County Hospital’s best practice (both in terms of scope and timing), but recognising that longitudinal studies require long-term data linkage and that research studies require anonymised and pseudonymised data to be available for a significant amount of time.

The flow of data into NHS Digital is limited to personal identifying information required for linkage (NHS number) and for verification of that linkage: Unique Study ID, Surname, Forename, Date Of Birth, and NHS Number.

1. Royal Surrey County Hospital NHS Foundation Trust provide a cohort of 151 study participants, to include identifiers: Study ID, NHS Number, Date of Birth, First Name, and Surname via Secure Electronic File Transfer (SEFT) service.

2. NHS Digital applies National Data Opt out, and then extract the Date of Death and Cause of Death fields for 151 participants, remove identifiers, and provide pseudonymised data extract back to Royal Surrey County Hospital NHS Foundation Trust via Secure Electronic File Transfer (SEFT) service.

Royal Surrey County Hospital NHS Foundation Trust have obtained support under section 251 of the NHS Act 2006 from CAG to permit the processing of confidential data without consent.

Data Minimisation

Royal Surrey County Hospital NHS Foundation Trust aim to follow up the outcomes of patients who have been diagnosed with one of two distinct subtypes of naevoid melanoma, in order to assess possible important differences in prognosis between them. This knowledge will help guide treatment of such melanomas in future patients with these subtypes.

For this study Royal Surrey County Hospital NHS Foundation Trust have been granted access to patient identifiable data (patient’s name and hospital number) without patient consent (under section 251), because results of this project will have no bearing on these patients’ treatments or outcomes. In many instances the melanoma was diagnosed long in the past and indeed many of the patients may have already passed away. Hence the need to ascertain who in the naevoid melanoma cohort has died so that Royal Surrey County Hospital NHS Foundation Trust know not to send letters to their doctors asking about their health and if their melanoma is still active (has recurred) (second step for those not known to have died).

In order to obtain the first step of these novel clinical outcome data, exact month and year of death is needed for precise analysis of survival time since age at death is too imprecise (age at death is compatible with a 2-year range of dates of death which would introduce substantial error).

Causes of death are also critical for the study team as the study must be able to distinguish melanoma-related deaths from deaths due to other causes. This will allow the study team to confirm the relative aggressiveness of the two different subtypes of naevoid melanoma: they expect the suspected aggressive naevoid subtype will cause melanoma deaths, the maturing subtype will not.

The NHS Digital pseudonymised data extracts are downloaded directly from the secure electronic file transfer (SEFT) system to an encrypted drive on a dedicated Royal Surrey County Hospital NHS Foundation Trust NHS N3 server computer. This computer is only accessible to a limited number of qualified staff and is password protected within a managed environment.

Data supplied by NHS Digital is processed for inclusion into the naevoid melanoma database. The data is linked at patient level with data in the naevoid melanoma database using the subject specific unique Study ID only. When the data is received from NHS Digital, the date of death and cause of death of these patients will be obtained. This will then be correlated with their subtype of naevoid melanoma to determine whether this outcome data is prognostically significant.

Royal Surrey County Hospital NHS Foundation Trust will then send the pseudonymised record-level data on to the University of Manchester (Cancer Research UK Manchester Institute) via secure encrypted NHS Mail as per the NHS Digital Secure Email specifications. The pseudonymised data extracts are downloaded directly to the Data Safe Haven (DSH) environment at the University of Manchester and further processing is conducted only on this server.

The University of Manchester’s Data Safe Haven (DSH) environment provides a walled garden security model via virtual desktop infrastructure and virtual applications. The DSH has been purpose built for the secure management and processing of personal, special category and confidential information.

Access to DSH is protected by strict project level access controls and multi-factor authentication.

The principle of least privilege is applied to all projects hosted within the DSH environment. Only the PI and Study IG Lead can move data in or out of the environment and the PI also has to approve researcher access to data within the project.

Role based access control is managed on a per project basis via Active Directory groups. A Standard Operating Procedure (SOP) is in place to govern data transfers by the PI and Study IG Lead: UM/17/SOP/NHSIGTK004 The Data Safe Haven. All other authorised project team members can only process the data within the secure DSH environment. File transfers, copy/paste and print functionality has been disabled within the DSH.

Statistical data analysis will be carried out via University of Manchester owned remote device connected to the Data Safe Haven either directly in person or remotely, using an appropriate statistical package. To remotely access the devices requires a secure 2-factor authenticator (VPN) and users are then able to securely access the secure server on the University’s IT framework. All data analysis will be conducted within the confines of the University’s secure server, and will not be downloaded to remote devices for storage or processing.

There will be no attempt to re-identify individuals nor any linkage to other data sets not already described in this agreement.

The ultimate flow of data is into publications made publicly available for the benefit of the wider research community. Special care is taken to ensure confidentiality is maintained and re-identification is not possible. All outputs will be aggregated with small number suppressed as per the HES analysis guide.

After processing is complete, the pseudonymised data on the Royal Surrey and Data Safe Haven at the University of Manchester will be destroyed and one copy of the data stored for archiving purposes on a secure data network at the CRUK Manchester Institute Molecular Oncology for a period of 12 months before being destroyed. This network is only accessible to authorised University of Manchester study staff and is password protected. Data will be located in folders that have secure access permissions for named study staff only.

All hardware is in secure environments: servers within the Institute and computers within research buildings with swipe-access control. Procedural control ensures that computers are never left accessible. All data is stored on servers (rather than individual computers/held on the M drive) and is backed-up routinely with the same level of protection (i.e. the encrypted server has an encrypted back-up).

The DSH infrastructure is hosted and processed within an ISO27001 certified Equinix data centre located geographically separate from the University of Manchester (UoM) campus. All server, storage and network infrastructure used by UoM within the data centre is owned by the University of Manchester, and operated and maintained by University of Manchester IT staff and is securely caged off from other Equinix customer’s equipment. The University of Manchester lease physically secure hosting space from Equinix. Therefore, any access to the data held under this agreement by Equinix would be considered a breach of the agreement. This includes granting of access to the database[s] containing the data.

Additionally, encrypted data back-ups are hosted and securely stored in a Digital Reality data centre located geographically separate from the University of Manchester (UoM) campus. All server, storage and network infrastructure used by UoM within the data centre is owned by the University of Manchester, and operated and maintained by University of Manchester IT staff and is securely caged off from other Digital Reality customer’s equipment. The University of Manchester lease physically secure hosting space from Digital Reality. Therefore, any access to the data held under this agreement by Equinix would be considered a breach of the agreement. This includes granting of access to the database[s] containing the data.

No patients will be contacted and consented about the study as this would cause more harm and distress to patients. Therefore again no patients or relatives will be contacted that have deceased for the same reasons. The Confidential Advisory Group have been approached with this application and has have been given favourable approval to complete this study without approaching patients for their consent.

HES DISCLOSURE CONTROL / SMALL NUMBER SUPPRESSION

In order to protect patient confidentiality, when presenting results calculated from HES record level data, outputs will contain only aggregate level data with small numbers suppressed in line with HES Analysis Guide. When publishing HES data, you must make sure that:

• cell values from 1 to 7 are suppressed at a local level to prevent possible identification of individuals from small counts within the table.

• Zeros (0) do not need to be suppressed.

• All other counts will be rounded to the nearest 5.

Data will not be made available to any third parties other than those specified except in the form of aggregated outputs with small numbers suppressed in line with the HES Analysis Guide.

It is intended to report and disseminate the results of this study through submission to peer reviewed high impact factor dermatological and histological journals (Cancer, Histopathology, Journal of Dermatology etc) and presentations at health-related conferences. The study hopes to present its findings at conferences attended by the Senior Research Scientists and the Project Officer.

When publishing results, only aggregate patient data with small number suppression as per the HES analysis guidance will be presented. No patient identifiable data will be published or presented.

Patient and Public Involvement (PPI)

The study team - during the study - aim to inform patients and the public of this research through the Royal Surrey Research and Development website and the CRUK Manchester Institute website and associated other media platforms. It will be made clear on the study website that any registered objections will be upheld.

The results will also be made available in the relevant GP surgeries and hospital. Patient Information sheets on the study will also be displayed in Royal Surrey Couty Hospital and GP surgeries.

Outputs aim to include;

1. Reports and Publications - It is anticipated that the analysis from this study will be included in internationally renowned oncology, epidemiology and public health journals. A publication will be prepared for late 2021 and will be available on the study website and PubMed. PubMed is a free resource supporting the search and retrieval of free full-text archive of biomedical and life sciences journal literature and is used for literature reviews related to research. The PubMed database contains more than 32 million citations and abstracts of biomedical literature. The PubMed database can be found here: https://pubmed.ncbi.nlm.nih.gov/.

Journals for consideration include:

Cancer

Histopathology

Journal of Dermatology

Scientific Reports

Oncology Letters

More information on past publications can be found on the study website: https://www.cruk.manchester.ac.uk

2. Presentations - The study team aim to give presentations at major cancer conferences for this study. Conferences are expected to include:

American Association for Cancer Research Annual Meeting

National Cancer Research Institute Annual Meeting

European Society of Medical Oncology

European Organisation for Research and Treatment

Scientists, health professionals, policy makers, e.g: NICE, Royal College of Physicians, British Association of Dermatologists are hoped to attend the presentations and read the study papers which will promote the study findings.

The primary aim of this study is to investigate whether there is a difference between two subtypes (papillomatous and maturing) of naevoid melanoma. If it is found that there is a prognostic difference between these 2 subtypes then treatment management plans and pathways can be reviewed that - it is hoped - will benefit the patient and healthcare system.

Looking at the differences between the prognosis of these subtypes aims to allow clinicians to better treat and manage these patients clinically.

Obtaining the outcome data of 151 patients with known naevoid subtypes hopes to better inform future treatment and knowledge of these lesions in relation to patient care.

This study has the potential to change the way patients with these two subtypes of naevoid melanoma are managed in the patient care pathway. The study hopes to benefits patients and also minimise costings to the NHS through better management of patients associated with their prognostic indicators of their melanoma. One of these subtypes of naevoid melanoma requires very minimal follow up whereas the other subtype can require extensive follow up and treatments involved over a patients lifespan. This study hopes to increase the precision of diagnosis and positively influence the different managements of these subtypes of melanoma.

This outcome data aims to support the main data collection, which has already been collected. The aim is for the data to be analysed and disseminated by the end of 2021.

The impact of the results of this study is envisaged to be measured retrospectively by reviewing naevoid melanoma cases to see if treatments relate back to the outcomes for patients for the two different subtypes.

Depending on the findings of this study, this can be translated into the clinical setting with the aim to make changes to patient management corresponding to their subtype. This would be actioned within a suitable timeframe when the minimum 2 year follow up is achieved.

Yielded Benefits is not a requirement for new applications.