MR1415 - Application for ONS mortality data to be used for flagging and analysis of the RADICALS trial, which is a large phase III randomised controlled trial for people with prostate cancer (ISRCTN 40814031).

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Objective for processing

Prostate cancer is a major health problem world-wide and accounts for nearly one fifth of all newly diagnosed male cancers. In the UK, approximately 50,000 were diagnosed with prostate cancer in 2018, and around 11,900 men died from the disease. [4 paragraphs unchanged] The first consent for the trial was taken in November 2007. A total of 2,863 patients were recruited in England & Wales (cohort size is now 2,699). [1 paragraph unchanged] The Medical Research Council Clinical Trials Unit (MRC CTU) at University College London (UCL) is concerned that sites will not be able to follow patients as intensely as required over the full period of the trial. Flagging data from NHS Digital will allow MRC CTU to ensure that most deaths are captured and included and will also help with cause of death review. MRC CTU is aware that flagging data has been very valuable in previous Randomised Clinical Trials. Furthermore, no man should die from prostate cancer without prior progression so a reported death will allow MRC CTU to check that events are not being missed on the Case Report Forms that clinicians are directly completing for these consenting patients. The participants were diagnosed with non-metastatic adenocarcinoma of the prostate, had undergone radical prostatectomy, had postoperative PSA of 0·2 ng/mL or less, and at least one specified risk factor before entering the trial. MRC CTU will also, for the purposes of survival analysis, be able to assume that patients are alive at a set point in time if not reported dead, thereby increasing reliability of data. Finally, based on previous discussions with ONS statisticians MRC CTU will make assumptions about the survival of patients not reported as dead. The first consent for the trial was taken in November 2007. A total of 2,864 patients were recruited in England & Wales. To take part in RADICALS-RT and RADICALS-HD, participants agreed for us to collect information on their clinical outcomes such as long-term survival and failure-free survival, which can be accessed from routine data sources such as the ONS death registration data and cancer registration. Recruitment ended on 30 December 2016. The Medical Research Council Clinical Trials Unit (MRC CTU) at University College London (UCL) is concerned that some trial sites will find it difficult to maintain full follow-up of patients in the long-term five-years post treatment, especially if patients move location. Flagging data from NHS Digital will allow MRC CTU to ensure that deaths and cancer events are captured, and will also help with the cause of death review. Linked data from NHS Digital will therefore improve the estimates of survival and may also reduce the burden on NHS sites. MRC CTU is aware that flagging data has been very valuable in previous Randomised Clinical Trials. Furthermore, no man should die from prostate cancer without prior progression so a reported death will allow MRC CTU to check that events are not being missed on the Case Report Forms (CRF) that clinicians are directly completing for these consenting patients. MRC CTU will also, for the purposes of survival analysis, be able to assume that patients are alive at a set point in time if not reported dead, thereby increasing reliability of data for this study. Accessing the Demographics data will ensure that men who died outside of England and Wales are also identified, to provide a better estimate of overall survival. Finally, based on previous discussions with ONS statisticians MRC CTU will make assumptions about the survival of patients not reported as dead. For the pre-specified analysis survival time, the MRC CTU uses the date of death to the nearest day (collected on the Death CRF), or time to the day the patient was last known to be alive for individuals who are censored. The aim is to maintain this level of precision in any analyses using information from external sources; using routine data that records time to death or censoring to the nearest day (as opposed to the nearest week or month) enhances the precision with which the MRC CTU will be able to distinguish a difference in survival between two treatment groups. Provided that the statistical models are correct, this enables MRC CTU's estimates of the survival difference for patients allocated to one treatment relative to another to reflect as closely as possible the reality of any survival difference attributable to treatment allocation in the study setting; and to obtain a greater degree of confidence in understanding of the true effect on survival of a new treatment strategy based on the data available to us. This can have important implications for the treatment future patients receive: if the evidence collected is strong enough to conclusively suggest a survival advantage gained from a treatment strategy, it is more likely that this treatment will be made available to those patients. Conversely, if the analysis suggests the treatment strategy is effective but the MRC CTU at UCL are not sufficiently confident in the strength of the evidence to support this, the findings are less likely to translate into a real difference for patients. [1 paragraph unchanged] The General Data Protection Regulation Articles 6 (1) (e) [processing linkage requested is necessary for the performance of a task in the public interest…] and Article 9 (2) (j) [processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes…] are the legal basis for the processing of the requested data. The trial is in the public interest (UK GDPR article 6:1[e]) because it is looking to see whether particular at treatment approaches to improve long-term disease-based outcomes, notably based in the survival or distant spread of prostate cancer. Processing is also necessary for scientific research purposes in accordance with UK GDPR article 9:2[j]. University College London (UCL) is the sole Data Controller. Medical Research Clinical Trials Unit at UCL is the data processor on behalf of UCL. Funding for the RADICALS trial was provided by Cancer Research UK, MRC Clinical Trials Unit, and Canadian Cancer Society. These organisations have no role in the day-to-day running of the trial, or with the handling of data.

Processing activities

The data will be used for the long-term assessment of men in [25 words unchanged] both the protocol and the Statistical Analysis Plan. This data will be joined linked with the data that are requested on the study Case Report Forms [19 words unchanged] rationale for their inclusion will always be included in all presented results. MRC CTU at UCL is not permitted to re-identify individuals under this agreement and will not make any attempts to re-identify individuals. There will not be any access to the data by any third parties. [1 paragraph unchanged] The data will be held on the UCL data Data Safe Haven using UCL approved computers. The Data Safe Haven is UCL's technical solution for transferring and storing research information that is highly confidential. It meets the requirements of NHS Digital DSP Toolkit and ISO 27001 Information Security Standard. Access is controlled by the ‘Information Information Asset Owner’ Owner, and all UCL staff complete training in confidentiality and data protection, which is renewed annually. System access is from UCL approved computers and is secure requiring the [23 words unchanged] with a pin and regularly updated password of specified length and complexity. Therefore, the Medical Research Council Clinical Trials Unit (MRC CTU) is not added as a storage or processing location. The IG Lead for UCL has confirmed no other disaster recovery sites. 1. The trial team will supply a list of cohort identifiers to NHS Digital containing Trial Number, NHS Number, Date of Birth, full names and postcode. The processing activities are as follows: 2. NHS Digital will use the supplied information to extract death information and send back reports using the specified transfer method. The reports will contain the Trial Number, Date of Death if applicable and no other identifiers. 1. The RADICALS trial team will identify the trial participants for linkage to NHS Digital data (those who have consented to linkage), and inform the MRC CTU Head of Data Management Systems (DMS) or delegate (active as the Cohort Contributor). The team will provide Trial Number (study ID) and date of birth to the Head of DMS. 3. Using the secure PID database, the Head of DMS will link these records back to the study-specific trial number and prepare an output file for trial statisticians containing no identifiers other than the full date of death. 2. The Head of DMS has a secure database of patient identifiable data in UCL’s Data Safe Haven, and will extract the relevant data linked to the Trial Number. 4. This output file is placed in a secure directory (UCL Safe Haven) with access limited only to people listed in the Data Sharing Agreement, all of whom are substantive employees of UCL. 3. The Head of DMS supplied a list of cohort identifiers to NHS Digital containing Trial Number (study ID), NHS Number, Date of Birth, full names and postcode. Note that this step has now been completed. 5. Trial statisticians undertake data cleaning/validation activities. 4. NHS Digital used the supplied information to extract death information and send back reports using the specified transfer method. The reports contained the Trial Number, the requested data fields and no other identifiers. 6. The data extract received from NHS Digital then serves three aspects: 5. Using the secure PID database, the Head of DMS will link these records back to the study-specific trial number and prepare an output file for trial statisticians containing no identifiers other than the full date of death. 6. This output file is placed in a secure directory (UCL Safe Haven) with access limited only to people listed in the Data Sharing Agreement, all of whom are substantive employees of UCL. 7. Trial statisticians undertake data cleaning/validation activities. 8. The data extract received from NHS Digital then serves three aspects: [4 paragraphs unchanged] For the purpose of the renewal under the latest iteration of this agreement, the step outlined in point 1 above has been completed as this was a one-off. Going forward, the trial team will not be supplying any more cohort identifiers to be flagged by NHS Digital. The trial team would like to continue to receive the reports from NHS Digital, using the specified transfer method, for those trial participants who have already been flagged. If a trial participant wishes to opt-out the trial team would remove the trial participant from the cohort and no longer collect further information on them.

Expected output

[1 paragraph unchanged] There is a plan to report early results from RADICALS-RT during 2019, using an outcome measure that includes deaths from prostate cancer. This will be timed to coincide with two similar studies in other countries, the results of which will be combined in a meta-analysis providing the most definitive answer to date of when radiotherapy should be given to non-metastatic prostate cancer patients. In RADICALS-RT the rate at which distant metastases events have occurred has increased in the last year, and the main results from this comparison are now expected by the end of 2021. Results from RADICALS-HD are not expected until approximately 2024. Deaths reported by ONS alone will not be included in any analyses. Early results from RADICALS-RT were reported during 2019, using an outcome measure that includes deaths from prostate cancer. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31553-1/fulltext. Peer reviewed publications and high impact medical journals - either cancer-specific journal (like Journal of Clinical Oncology or Lancet Oncology) or a general medical journal (like Lancet, The Journal of the American Medical Association, The New England Journal of Medicine) will be approached. MRC CTU will look to general journals first but will review the results and whether they might or might not appeal to a general audience. This was timed to coincide with two similar studies in other countries, the results of which were combined in a meta-analysis providing the most definitive answer to date of when radiotherapy should be given to non-metastatic prostate cancer patients. MRC CTU will communicate the RADICALS results using at least: In 2019, we applied for, and were awarded, a costed amendment based on the following rationale: In 2017, the ICECaP surrogacy work (Xi, 2017, J Clin Oncol) demonstrated that where there is a substantial effect size on a survival-based outcome measure for localised prostate cancer, a metastasis-based outcome measure is a good surrogate. Their recommendation is that trials in localised prostate cancer should now use a metastasis-based outcome measure, rather than DSS or overall survival. ICECaP’s recommendations are directly applicable to RADICALS and the Trial Management Group therefore amended the RADICALS-HD protocol accordingly. Based on this, the primary outcome measure was changed to metastasis-free survival (MFS) with the aim of presenting mature primary outcome measure results from RADICALS RT and both comparisons in RADICALS-HD by Q3-2022. Deaths reported by ONS alone will not be included in any analyses. The future results will be submitted to a widely read peer reviewed medical journal. The first results for RADICAL RT were previously published in the L:ancet. MRC CTU will also communicate the RADICALS results using at least: [1 paragraph unchanged] • Publication in high-impact peer-reviewed journals [3 paragraphs unchanged] To communicate results of the 2019 Lancet Paper to participants, a participant summary was written and disseminated via each site to their RADICALS participants. [2 paragraphs unchanged]

Expected measurable benefits

It is expected that results of analyses will be more accurate because of improved recording of deaths occurring in patients in England and Wales, and also improved by attributing cause of death more accurately. [6 paragraphs unchanged]

Benefits reported

Comparison of Mortality data with deaths of patients reported by study sites has shown that in most cases the study sites have reported deaths in a timely and accurate manner. The researchers have been liaising with sites to identify 17 deaths which had been registered but not previously reported by the site. The linkage to NHSD data has enabled improvements to RADICALS data quality in three ways: In addition, there have been 7 cases in which discrepancies in cause of death have been identified and corrected through liaison with staff at sites, in each case so far these have been patients who died outside hospital and hospital staff had been uncertain about cause of death. The reassurance of well-reported data coming from study sites has helped the trial management group in planning the future of the trial. 1. Some patient deaths were identified that had not been known about or reported by trial sites. 2. Cause of death could be verified enabling accurate identification of deaths due to prostate cancer. 3. In patients who died from prostate cancer, earlier disease progression should have been reported, this was queried if not and some unreported disease events were identified as a result. With ONS data we have therefore improved our estimation of disease progression, prostate cancer mortality, and overall mortality. We obtained data from trial sites on 33 deaths which we had not been aware of, and which were identified with ONS data. This further emphasises the importance of using the datasets to support long-term follow-up of participants. The RADICALS Trial has already led to improvements in standard care for prostate cancer and MRC CTU at UCL has already reported practice-changing results: - RADICALS-RT found that having radiotherapy soon after surgery did not make a substantial difference to the time people had a PSA rise or needed further hormone therapy. - The study also found that giving radiotherapy to all men soon after surgery slightly increased the chances of experiencing side effects on the bladder and bowel, but only in a small minority of men. These results from RADICALS-RT have been widely accepted as practice defining and mean that many men with non-metastatic intermediate risk prostate cancer will be spared radiotherapy that is of no benefit, and is potentially harmful.

Text removed is struck through; text added is underlined. Unchanged paragraphs are summarised rather than repeated.

Datasets: + Cancer Registration Data; + Civil Registrations of Death; + Demographics

Unchanged: Objective for processing, Processing activities, Expected output, Expected measurable benefits, Benefits reported.