NHS Digital Data Release Register - reformatted

University Of Southampton

Project 1 — DARS-NIC-148382-7KTF1

Opt outs honoured: Y

Sensitive: Sensitive

When: 2016/12 — 2017/02.

Repeats: Ongoing

Legal basis: Section 251 approval is in place for the flow of identifiable data

Categories: Identifiable

Datasets:

  • MRIS - Scottish NHS / Registration

Objectives:

Our aim is to describe and interpret patterns of mortality and cancer incidence in extended follow-up of historical cohorts of workers exposed to styrene, phenoxy herbicides and formaldehyde. The information obtained will be used to inform regulatory risk assessment and management for the chemicals, both in the UK and internationally. Optimal risk management is important since workers must be adequately protected, but at the same time, unwarranted restrictions on exposure could have adverse impacts on people's quality of life.


Project 2 — DARS-NIC-189166-R0Y9Y

Opt outs honoured: N

Sensitive: Non Sensitive

When: 2016/12 — 2017/02.

Repeats: Ongoing

Legal basis: Informed Patient consent to permit the receipt, processing and release of data by the HSCIC

Categories: Identifiable

Datasets:

  • MRIS - Members and Postings Report

Benefits:

In September 2009, National Institute of Clinical Excellence (NICE) approved the use of cetuximab for patients with k-RAS wild type tumours who have inoperable liver-only metastases. It is a further requirement that a hepatic surgeon reviews the patients’ images and so formally determine inoperability. The NICE decision is appropriate as there is some evidence of cetuximab benefit for this group of patients. The New EPOC trial is studying patients with operable colorectal liver metastases. These patients were specifically excluded from the NICE approval at the time and consequently, funding of cetuximab from Primary Care Trusts was unlikely to be approved. This was because there was no data on the benefit of cetuximab in patients with operable disease and therefore the question being addressed by the New EPOC trial was critically important. The interim result (as determined in Nov 2012) pointed towards a conclusion that was not expected and there have been a number of publications refuting it. Therefore gaining the current patient status data is critical to inform whether cetuximab affects overall survival and not just time to progression. In the UK, Cetuximab is used in the palliative setting which can and does often include liver metastasis. It is currently off NICE for use as downsizing strategy in borderline operable patients but is still used in other countries. Reliable Overall Survival data is crucial to understanding the degree of detriment that occurred. If cetuximab has utility for downsizing but results in earlier progression that does not result in more deaths that is one thing. This is possible if it simply brings forward the point at which progression would have occurred or of progressive disease is still treatable with curative intent The interim result has been widely published and circulated amongst oncologists at both European Society of Medical Oncology (ESMO) and American Society of Clinical Oncology (ASCO) meetings. However until the primary end point has been reached the trial cannot be closed. The Clinical Trials Unit at the University of Southampton believe that they are now at that point. In order to undertake this analysis, the data pertaining to patient survival is key. Therefore the SCTU are requesting the data in order to complete the final analysis and so hope to alter practice in the NHS, and worldwide. Following the independent Data Monitoring and Ethics Committee (DMEC) review in October 2016, the trial will come to a close following receipt and processing of 1 final cause of death report. Upon closure, the Clinical Study Report will therefore be written before within 12 months. Publications will also be generated from this final data. The details of the publication strategy will be further developed following the end of the trial.

Outputs:

Publications will be written following analysis and agreement from DMEC/TMG. The Trial Management Group would be aiming for high impact journals such as the New England Journal of Medicine, The Lancet or similar. Poster presentations would be expected at the American Society of Clinical Oncology (ASCO) meeting in early 2017 and the European equivalent meeting later in the year. The Clinical Study Report will be written within 12 months of the End of Trial. Upload of aggregated dataset with small numbers suppressed to EudraCT would follow the clinical study report publication since, from 21 July 2014, it has become mandatory for sponsors to post summary clinical trial results in the European Clinical trials Database (EudraCT), managed by the European Medicines Agency (EMA). This is mandated under the UK and EU legislation which underpins clinical trial work and as a requirement will become publically available to being greater transparency for the public who are involved in clinical research or who may to be in the future. This date corresponds to the finalisation of the programming of the database as referred to in a European Commission guideline, in application of the current clinical trials Directive 2001/20/EC. For any publications, outputs will contain only aggregate level data with small numbers suppressed in line with Hospital Episode Statistics (HES) Analysis Guide. The following publications or oral presentations have already been delivered: American Society of Clinical Oncology (ASCO) meeting 2013, oral presentation. Conclusions: Although the data are immature, the accumulation of more events is unlikely to change this result. In patients with resectable liver metastases and K-RAS wild type tumours the addition of cetuximab to chemotherapy is not beneficial. http://meetinglibrary.asco.org/content/112298-132 National Cancer Research Institute conference 2013, oral presentation – Conclusion: The addition of cetuximab to chemotherapy in patients with operable or borderline operable CRLM increases the pre-operative response rate in line with prior studies. Despite this the PFS is significantly worse in the cetuximab treated patients. In this setting the presence of KRAS wild-type is insufficient to predict benefit. Further translational work is needed to determine the nature of the interaction leading to this unexpected outcome and also to determine whether there may be circumstances in which cetuximab may be of benefit http://conference.ncri.org.uk/abstracts/2013/abstracts/ClinicalShowcase1.html European Society of Medical Oncology 2013, poster - http://eccamsterdam2013.ecco-org.eu/Scientific-Programme/Abstract-search.aspx# American Society of Clinical Oncology (ASCO) meeting 2014, posters: http://meetinglibrary.asco.org/content/128283-144 - Conclusions: Both the distribution of progressive disease and further treatment are as expected for such a cohort and are evenly balanced between the arms. Despite this there is a trend towards an inferior survival post progression in those receiving cetuximab for whom revisional surgery is not appropriate. http://meetinglibrary.asco.org/content/129363-144 - Conclusions: The addition of cetuximab to chemotherapy and surgery for operable CRLM in KRAS wild-type patients results in an inferior PFS. More stringent selection of an all WT cohort does not significantly alter the detriment observed in the KRAS WT population. http://meetinglibrary.asco.org/content/129221-144 - Conclusions: The trial demonstrated for the first time that miR31-3p expression is predictive of cetuximab effects and replicated association of its expression with PFS in patients receiving cetuximab. Furthermore miR31-3p allowed identification of a subgroup of patients in which cetuximab with chemotherapy had a detrimental effect on PFS. Eventually the correlation of miR31-3p expression in metastases and primary tumors in the control arm, but not in the cetuximab arm, suggests cetuximab has an effect on miR31-3p expression, supporting its involvement in the EGFR pathway. European Society of Medical Oncology 2014, posters: http://annonc.oxfordjournals.org/content/25/suppl_4/iv185.1.full.pdf+html?sid=3f34ecbf-150b-4078-af28-a3232efa426e Conclusions: In this study the addition of cetuximab to chemotherapy and surgery for operable CRLM in KRAS wild-type patients resulted in an inferior PFS. More stringent selection of an all RAS WT cohort did not alter the detriment observed. BRAF mutation is uncommon and likely reflects the selection of a relatively good prognosis cohort. Differences in mutational status between primary and metastasis were infrequent and could reflect either a treatment effect or clonal outgrowth. Initial pyrosequencing failed to detect <1% of mutations subsequently detected and most new mutations were discovered in previously un-interrogated sequences. http://annonc.oxfordjournals.org/content/25/suppl_4/iv185.2.full.pdf+html?sid=967c6813-1c2d-4048-98ba-327cfc53589f Conclusions: The trial demonstrated that miR-31-3p expression is predictive of cetuximab effects. Furthermore, the trial identified a subgroup of patients with high miR-31-3p expression in which cetuximab with chemotherapy had a detrimental effect on PFS. The correlation of miR-31-3p expression in metastases and primary tumors in the chemotherapy arm, but not in the chemotherapy plus cetuximab arm, suggests that cetuximab affects on miR-31-3p expression, supporting its involvement in the EGFR pathway. Lancet oncology 2014, publication - http://www.ncbi.nlm.nih.gov/pubmed/24717919 - Conclusions: Addition of cetuximab to chemotherapy and surgery for operable colorectal liver metastases in KRAS exon 2 wild-type patients results in shorter progression-free survival. Translational investigations to explore the molecular basis for this unexpected interaction are needed but at present the use of cetuximab in this setting cannot be recommended. American Society of Clinical Oncology (ASCO) meeting 2015, poster: http://meetinglibrary.asco.org/content/145968-156 Conclusions: In a trial that showed substantial detriment with EGFR inhibition a subgroup has been identified who derived significant benefit from cetuximab. The loss of correlation between primary tumors and CRLM suggests that cetuximab may modulate miR-31-3p and c-Met expression and that these may be implicated in the mechanism by which earlier progression occurred in these patients.

Processing:

Participating patients consented to the University of Southampton Clinical Trials Unit (SCTU) obtaining ‘information about [their] health status’ from ‘information held by the NHS and maintained by The NHS Information Centre’ (now NHS Digital) ‘and the NHS Central Register’ – then the provider of the Medical Research Information Service (MRIS) and now part of NHS Digital – ‘to enable long-term follow-up’. The identifying details of the study cohort were supplied to NHS Digital (then NHS IC) and the patients’ entries were ‘flagged’ on the MRIS computer system in April 2013. NHS Digital has provided adhoc reports (typically annually) on the patients' health status including details of removals from or re-entries to NHS registration, details of cancer registrations and details of deaths including cause of death details from ONS mortality data. For patients who have died, the date of death and cause of death will be added into the analysis dataset (patient initials, month/year of birth and patient ID are included in the dataset already). The full date of death is needed so the SCTU statistics team can work out time from randomisation to progression/death for all patients for the trial’s final analysis. Any publication would just show this data in aggregated form by arm (as a graph). Month/year of birth or Age at time of adverse event is required by the Medicines and Healthcare products Regulatory Agency to report Serious Adverse Reactions therefore this data is collected for this trial. For any patient for whom there is no known date of death, the statisticians undertaking the analysis will assume that they are still living in data analyses. Data from NHS Digital is password controlled, stored electronically in a controlled area on the file server with restricted access. Data will only be accessed by authorised individuals who are substantively employed by the University of Southampton. Once no longer required. the data will be destroyed in line with the UK legislation for Clinical trials, DPA and the terms of the DSA. In line with EU Clinical trials - Directive 2001/20/EC and UK law, Clinical Trials of Investigational Medicinal Products (CTIMPs) SI 2004:1031, data from clinical trials must be kept for a minimum of 5 years following end of trial notification. Any publications (aiming for high impact journals such as New England Journal of Medicine, The Lancet or similar) will contain anonymised tables derived from the data supplied by NHS Digital. No individual patient will be able to be identified. Outputs will only contain aggregated data with small numbers suppressed in line with the HES Analysis Guide. This aggregated dataset with small numbers supressed will be uploaded to European Clinical Trials Database (EudraCT), in line with EU Clinical Trial Regulations. Again this will not identify any particular patient. Their requirements for Interventional Clinical Trials that ended on or after 21 July 2014 (i.e. the date of finalisation of the programming according to Commission Guideline (2012/C 302/03)) for non-paediatric trials where regulated by Directive 2001/20/EC (this includes this trial) the composition of results includes full data set mandatory and summary attachment(s) optional. (https://eudract.ema.europa.eu/result.html). After the final data has been collected and analysed, the Trial Management Group (TMG) will meet with SCTU to finalise the publication plan.

Objectives:

New EPOC is a prospective randomised open label trial where all patients are given the chemotherapy drugs oxaliplatin or irinotecan with fluorouracil, and then randomised to also have/not have cetuximab - the drug under investigation. These drugs are given pre and post-surgery to patients with resectable colorectal liver metastases requiring chemotherapy. Firstly patients were consented to provide a sample for KRAS gene testing. KRAS genes play an important role in instructing colorectal cancer cells to grow and divide as part of the epidermal growth factor receptor (EGFR) process. If the biomarker test indicates there is a KRAS mutation, drugs that target EGFR (like cetuximab, which is used in this trial) may not benefit the patient. Anyone who has a KRAS mutation is therefore excluded from the trial. Once these results were known, patients were consented to join the trial and then randomly allocated at the start of chemotherapy to receive either: Arm A: Oxaliplatin / irinotecan plus fluorouracil chemotherapy Arm B: Oxaliplatin / irinotecan plus fluorouracil chemotherapy plus cetuximab Patients then received 12 weeks of the randomly allocated chemotherapy, underwent surgery and then received a further 12 weeks of chemotherapy. They are/were then followed up for 5 years at the treating hospital. The trial is looking to see the effect of the drugs on progression free survival, this is the primary endpoint. i.e. whether the introduction of cetuximab makes a difference to the occurrence or rate of the patient’s disease progression. Other endpoints include pre-operative response rate, survival rates, quality of life and cost effectiveness. This trial was funded by Cancer Research UK with the drug under investigation, cetuximab, being supplied for free by Merck, the Pharmaceutical company who manufacture the drug. It is a purely non-commercial trial. Interim results showed that this treatment made patients’ disease progress sooner i.e. the patient’s condition worsened sooner in the cetuximab arm and so further follow up data is required to assess whether this is also true with long term survival data. See publications section for further details – Lancet 2014. The trial is sponsored by the University Hospital Southampton NHS Foundation Trust and is being delivered by the University of Southampton’s Southampton Clinical Trials Unit (SCTU). The trial began recruitment on 15 October 2008 and ceased recruitment and treatment in November 2012. Oncologists at hospitals throughout the UK recruited patients. Patients were informed by letter, approved by REC, that trial recruitment and treatment ceased in November 2012. Data supplied by NHS Digital (formerly known as Health and Social Care Information Centre) has been used for long-term follow up of patients to assess their primary and secondary endpoints. SCTU Statistics Team analyse the data and alongside the chief investigators (a liver surgeon and liver oncologist) write a number of papers which will be published in medical journals. All publications will use any data collected, either directly from the hospital or from NHS Digital, in anonymised form so no patient can be identified. The independent Data Monitoring and Ethics Committee (DMEC) met on the 18th of October 2016 to assess the maturity of the dataset and has recommended that the trial closes and final analysis is completed as soon as possible so the results can be published because there is an urgent need for the clinical community to see these results. However, closure of the trial SCTU felt was dependent upon the acquisition of the most up to date patient flagging data. A final Cause of Death report will still be required shortly thereafter to ensure that details of any participants passing away before this end date are captured.