ProtecT study (Prostate testing for cancer and treatment) ( ODR1617_311 )

The University of Bristol requires access to NHS England data for the purpose of the following research project:

ProtecT study (Prostate testing for cancer and treatment) (ODR1617_311)

The following is a summary of the aims of the research project provided by the University of Bristol:

Men in the intervention group in CAP received an invitation to attend for population-based PSA-testing for prostate cancer and if diagnosed with localised prostate cancer were invited to take part in the ProtecT trial. ProtecT is a pragmatic, cluster Randomised Clinical Trial (RCT) that compares effectiveness of the three treatment modalities (surgery, radiotherapy, active monitoring/surveillance) for patients diagnosed with low- or intermediate-risk clinically localised prostate cancer (PCa).

This trial aims to assess the effectiveness of these treatments in reducing prostate cancer mortality, and its cost-effectiveness (i.e. comparing the health-related costs in the groups in combination with the effectiveness of treatment outcomes, to assist clinicians and policy makers in their decisions about how to achieve the best use of resources).

The University of Bristol has been running this trial since 1999.

GP practices in 8 centres in England and Wales were randomly allocated to either population-based PSA testing, akin to screening (the ProtecT study), or standard (unscreened) practice.

In the intervention (ProtecT) practices, between 1999 and 2009, men aged 50-69 years were invited to undergo PSA testing. The individuals who accepted this invitation were asked to sign a consent form permitting follow-up of their health status. Of the men who took the PSA test, those with PSA levels of 3.0 ng/ml or greater were offered standardised 10-core transrectal ultrasound guided biopsy.

For any individuals registered with intervention practices who did not respond to the invitation for a PSA test, support under section 251 NHS Act 2006 permits access to their data for the purpose of follow-up without informed consent.

Case reviews involve reviewing paper notes and electronic records held by the hospital and not data supplied by NHS England under this Agreement. However, the follow-up data from NHS England is important as it can be the trigger to undertake a case review. These data are also used in the development of ‘proxy’ trial outcome measures. For example, in cases where an individual no longer attends appointments at the hospital trust where they received their initial treatment, and therefore paper and electronic notes held at that hospital are not available, the team will be able to construct indicators of trial outcomes when events within these data suggest that is the case.

This study is linked to existing data sharing agreements, covering a subset of data subjects gave consent and a subset did not, the University of Bristol has two connected Data Sharing Agreements with NHS England relating to this work.

• The Agreement under the reference DARS-NIC-119910-K6W9Q covers the individuals whose data are accessed with informed consent.

• The Agreement under the reference DARS-319171-G7H8K covers the individuals whose data are accessed without consent with support under section 251 NHS Act 2006.

The data generated will provide both clinical and policy relevant data on one of the most controversial issues in health care nationally and internationally: the potential benefits, harms and costs to the UK population of treatments for prostate cancer.

It is unlikely that such a trial would be possible anywhere else in the world because information systems are not as comprehensive across primary and secondary care and across the whole population. The extensive, complete and long-term follow-up of these men is only possible because of the publicly funded national healthcare system the UK NHS and because of NHS England hospital and mortality information systems. These information systems provide comprehensive data on cancer diagnoses, deaths and costs to the NHS enabling very long term and cost-effective follow-up of the outcomes.

The NIHR ProtecT (Prostate testing for cancer and Treatment) trial is the only randomised trial comparing these major treatment modalities for localised prostate cancer. Although some diagnostic and treatments techniques have evolved since ProtecT recruited (1999-2009), no comparable randomised trials exist, and shorter cohort studies of newer techniques have largely replicated ProtecT Patient Reported Outcomes (PROMs). The ProtecT study aims to evaluate whether: 1) High and similar levels of prostate cancer survival between the three groups will persist; 2) The reduction in metastatic disease in the radical treatment groups will translate into a survival advantage for either or both radical options; 3) There will be a difference in effectiveness between the two radical treatment groups.

The following NHS England Data is being accessed:

· NDRS-Linked Hospital Episode Statistics Outpatients (OP) and Admitted Patient Care (APC)

. NDRS Systemic Anti-Cancer Therapy Dataset (SACT)

. NDRS National Radiotherapy Dataset (RTDS)

. Diagnostic Imaging Data Set (DID)

. NDRS Cancer Registrations

The level of the Data will be

- Identifiable: Necessary because without identifiable data the trained researchers would be unable to extract information from the medical records to compose the detailed case vignettes which are then used to validate the cause of death.

The Data will be minimised as follows:

· Limited to a study cohort identified by the University of Bristol, consisting of men aged 50 to 69 who were invited for a PSA test and were diagnosed with prostate cancer between 1999 and 2009. These individuals were recruited under informed patient consent.

The University of Bristol is 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.

Public interest is defined here as: provide an evidence base for public policy decision-making; provide an evidence base for decisions which are likely to significantly benefit the UK economy, society or quality of life of people in the UK; and to replicate, validate or challenge existing research. Results from follow-up will directly inform UK policy on prostate cancer treatment and have a wide influence internationally.

University of Bristol has previously shared identifying details with Public Health England (agreement now transferred to NHS England) (including Name, NHS Number, Date of Birth, and a unique person ID) for the cohort to be linked. No data will flow to NHS England for the purposes of this Data Sharing Agreement.

NHS England will not provide any additional data under this Data Sharing Agreement.

Data will continue to be held under this Data Sharing Agreement, previously supplied by PHE – including Cancer Registry data, linked HES admitted patient and outpatient, DIDs, RTDS, and SACT. The Data:

· contains directly identifying data items including: Names, NHS Number and Date of Birth which are required to extract information from the medical records to compose the detailed case vignettes which are then used to validate the cause of death.

The data will be held within a secure research environment at University of Bristol.

The data will be stored on servers at University of Bristol.

The University of Bristol uses offsite back-up services provided by Virtus and AQL.

The Data will be accessed onsite at the premises of University of Bristol.

The Data will not leave England/Wales at any time.

Access is restricted to employees or agents of the University of Bristol who have authorisation from the Principal Investigator.

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

The Data are held within the Microsoft Hyper-V eVM. These data can be linked at person record level with data collected within the study by clinical research staff and self-reported data from participants, these additional data would be imported into this file space.

The patient identifying details are stored in a separate database to the linked dataset used for analysis. All analyses will use the pseudonymised dataset, and there will be no requirement and no attempt to reidentify individuals when using the pseudonymised dataset.

Researchers will use these data to support the ProtecT randomsied trial of treatment for prostate cancer. Triggering targeted note review (for example in instances of metastases) and developing proxy trial outcome measures for analysis.

In this new, median 20-year analyses of the ProtecT trial, the team intend to produce the following outputs:

• Peer-reviewed academic journal publications. The team will submit the main oncological findings to the New England Journal of Medicine in 2027 (as with the previous follow-ups - https://doi.org/10.1056/NEJMoa1606220, https://doi.org/10.1056/NEJMoa2214122 ), or another high impact general journal. The team plan additional papers considering the trade-offs for patients between the median 20-year clinical outcomes and previous analyses of patient-reported outcomes of treatment side-effects, and comparisons between findings from routine NHS data and medical note reviews.

• Conference presentations. The team anticipate strong interest in the findings from the urological and oncological communities and so will plan to present the main findings at a major scientific meeting (such as EAU - European Association of Urology; AUA – American Urological Association) at the same time as journal paper publication (as in 2022).

• Guidelines. The team will submit the findings to guideline bodies, and, as with previous analyses, expect incorporation of the findings in prostate cancer treatment guidelines in the UK (NICE), Europe (EAU and national committees), and US (American Urological Association).

• UK National Screening Committee (NSC). The team will alert this committee to the findings of the analysis, as previously, before publication, so that they can be ready for results that may affect their recommendations.

• Social media posts, study website, blogs, web-based and hard copy magazine interviews short video clips, articles with charities such as Cancer Research UK which has publicfacing section on ProtecT study results, and links with patient-support groups such as Active Surveillance Patients International (ASPI) (which gave ProtecT a special award for services to AS in 2024).

Any outputs from these data will not contain NHS England Data and will only contain aggregated information with small numbers suppressed as appropriate in line with the relevant disclosure rules for the dataset(s) from which the information was derived.

The findings will be published in scientific journals and included in guidelines to ensure the NHS can plan and deliver optimal care for patients with prostate cancer. Findings will be posted through websites, blogs, social media, and support groups. Our PPI group will develop further dissemination plans to ensure patients will be able consider the trade-offs between short- and long-term risks and benefits over 20 years.

These data being retained will support research being undertaken, triggering targeted note review and development of proxy measures for publication and dissemination in 2027.

The overarching research question is to determine the comparative effectiveness of the three treatment modalities (surgery, radiotherapy, active monitoring/surveillance) for patients diagnosed with low- or intermediate-risk clinically localised prostate cancer (PCa). These findings are expected to contribute to evidence-based decision making for clinicians and patients and inform best practice.

The team will submit the findings to guideline bodies, and, as with previous analyses, expect incorporation of the findings in prostate cancer treatment guidelines in the UK (NICE), Europe (EAU and national committees), and US (American Urological Association). The dissemination of these results will benefit patients by providing patients and clinicians with evidence to inform treatment decision making and clinical best practice.

The publication and presentation of the findings will add to the body of evidence considered by bodies, organisations (including NICE) and individual care practitioners charged with making policy decisions for or within the NHS or treatment decisions in relation to specific patients.

The team will discuss outputs and the interpretation and presentation of findings for patients and the public in detail with our PPI representatives and the two groups of public contributors convened during the research. Initial discussions with PPI representatives considered our previous dissemination through journals, guidelines, scientific conferences, study website (with links to charities), social media, web-based and hard copy magazine interviews, blogs, participant newsletters, plain English summaries, short video clips, and contacts with charities and patient support groups. PPI representatives have suggested the team should continue with most of these methods of dissemination, plus some additional engagement with newly diagnosed patients and members of the public about nuanced details about PCa more generally, including its risk levels, types of treatment, and screening issues. They feel this is needed because of the nature of current publicity, primarily originating from celebrities, calling for screening without setting this in the context of the risk-profile of PCa and potential benefits and harms.

The main outcomes of the trial are the comparative effectiveness of the three treatment modalities (surgery, radiotherapy, active monitoring/surveillance) for patients diagnosed with low- or intermediate-risk clinically localised prostate cancer (PCa).

To date ProtecT results have been published in the New England Journal of Medicine for 10 and 15 year results - https://doi.org/10.1056/NEJMoa1606220, https://doi.org/10.1056/NEJMoa2214122

These results have impacted treatment guidelines for clinical practice.

In this new, median 20-year analyses of the ProtecT trial, the team intend to produce the following outputs:

• Peer-reviewed academic journal publications. The team will submit the main oncological findings to the New England Journal of Medicine in 2027 (as with the previous follow-ups - https://doi.org/10.1056/NEJMoa1606220, https://doi.org/10.1056/NEJMoa2214122 ), or another high impact general journal. The team plan additional papers considering the trade-offs for patients between the median 20-year clinical outcomes and previous analyses of patient-reported outcomes of treatment side-effects, and comparisons between findings from routine NHS data and medical note reviews.

• Conference presentations. The team anticipate strong interest in the findings from the urological and oncological communities and so will plan to present the main findings at a major scientific meeting (such as EAU - European Association of Urology; AUA – American Urological Association) at the same time as journal paper publication (as in 2022).

• Guidelines. The team will submit the findings to guideline bodies, and, as with previous analyses, expect incorporation of the findings in prostate cancer treatment guidelines in the UK (NICE), Europe (EAU and national committees), and US (American Urological Association).

• UK National Screening Committee (NSC). The team will alert this committee to the findings of the analysis, as previously, before publication, so that they can be ready for results that may affect their recommendations.

• Social media posts, study website, blogs, web-based and hard copy magazine interviews short video clips, articles with charities such as Cancer Research UK which has publicfacing section on ProtecT study results, and links with patient-support groups such as Active Surveillance Patients International (ASPI) (which gave ProtecT a special award for services to AS in 2024).