MR1378 - BEST2 - Evaluation of a Non-Endoscopic Immunocytological Device (Cytosponge™ for Barrett's Esophagus Screening)

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

Objective for processing

[1 paragraph unchanged] The data is required for follow-up of the consented participants of the BEST2 study cohort, using cancer outcome data in order to collect long-term efficacy and safety data. [2 paragraphs unchanged] The data controllership for the project has now changed from QMUL to a joint data controller venture with University of Cambridge and Cambridge University Hospitals NHS Foundation Trust. A Data Destruction certificate has been received and approved by NHS Digital. [5 paragraphs unchanged] From April 2018, there will be no sending of pseudo-anonymised data to Queen [21 words unchanged] secure transfer and deleted at QMUL via approved NHS Digital processes. UoC will become is the sole processor of the data. [1 paragraph unchanged] The data will not be used for any purpose other than to [30 words unchanged] be anonymised (i.e. aggregated data) and not presented at the individual level. Data over the last year has fed into high-level publications (with a further 2 in the review process) in the field including: Gut. 2017 Oct 30. pii: gutjnl-2017-314026. doi: 10.1136/gutjnl-2017-314026. [Epub ahead of print] Methylation panel is a diagnostic biomarker for Barrett's oesophagus in endoscopic biopsies and non-endoscopic cytology specimens. Chettouh H(1), Mowforth O(1), Galeano-Dalmau N(1), Bezawada N(1), Ross-Innes C(1), MacRae S(1), Debiram-Beecham I(1), O'Donovan M(2), Fitzgerald RC(1). A large primary care trial to test whether the Cytosponge™ could be introduced to detect the condition earlier for cancer prevention is now underway in England with 5000 patients recruited to date. Continuing long-term outcome data from the BEST2 cohort is essential to inform the trial (https://www.best3trial.org) and for future directions in the field more generally.

Processing activities

[8 paragraphs unchanged] The data will not be used for any purpose other than to meet objectives as stated in the trial protocol and will not be shared with any third party organisation. Any information which is used for publication in peer reviewed journals will be anonymised (i.e. aggregated data) and not presented at the individual level The BEST2 study trial site and sponsor organisation (UoC) propose to provide the identifiable data to NHS Digital, for all participants that have consented to this, for linkage. NHS Digital will return the linked data set with any patient identifiable information (NHS number, names etc) that UoC previously sent to the HSCIC along with requested data sets. Identifiable data is requested so that UoC can update any new information on the cohort in order to contact participants. UoC will not contact the patients directly but will inform the participants' GP who in turn will discuss with the participant. All data received at the UoC (School of Clinical Medicine) is stored on a secure safe haven network firewalled off from the rest of the network for analysis as well as entered into CRFs (on a participant-level on the trial database). There will be no data linkage undertaken with NHS Digital data provided under this agreement that is not already noted in the agreement. Data will only be accessed and processed by substantive employees of The University of Cambridge and will not be accessed or processed by any other third parties not mentioned in this agreement.

Expected output

This Agreement permits the secure retention of the data only and no other processing. No new outputs will be produced under this Data Sharing Agreement. [1 paragraph unchanged] Data outputs produced will not contain any patient-identifiable data or be shared with any third-party organisation. The only outputs produced will be publications for research purposes using aggregated data with small number suppression in line with the HES Analysis Guide. Data over the last year has fed into high-level publications (with a further 2 in the review process) in the field including: All outputs will contain only data that is aggregated with small numbers suppressed in line with the HES Analysis Guide Gut. 2017 Oct 30. pii: gutjnl-2017-314026. doi: 10.1136/gutjnl-2017-314026. [Epub Information about the study can be found at the study websites: ahead of print] https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/a-study-to-see-how-well-a-new-way-screening-for-barretts-oesophagus-works-best2#undefined Methylation panel is a diagnostic biomarker for Barrett's oesophagus in https://www.mrc-cu.cam.ac.uk/research/rebecca-fitzgerald/clinical-studies/BEST2Folder. endoscopic biopsies and non-endoscopic cytology specimens. The BEST2 dataset was pivotal for informing the direction of the BEST3 trial (a large scale clinical trial with 5000 patients in primary care which assessed whether the Cytosponge™ test could be introduced into GP surgeries for the earlier detection of oesophageal cancer), and the ongoing scientific basis for the test. Chettouh H(1), Mowforth O(1), Galeano-Dalmau N(1), Bezawada N(1), Ross-Innes Previous data from this study have fed into high-level publications. C(1), MacRae S(1), Debiram-Beecham I(1), O'Donovan M(2), Fitzgerald RC(1). Development and validation of a risk prediction model to diagnose Barrett's oesophagus (MARK-BE): a case-control machine learning approach. A large primary care clinical trial to test whether the Cytosponge™ could be introduced to detect the condition earlier for cancer prevention is now underway in England with 5000 patients recruited to date. Continuing long-term outcome data from the BEST2 cohort is essential to inform the trial (https://www.best3trial.org) and for future directions for introducing the Cytosponge™ test to patients in the next 5 years. Rosenfeld A, Graham DG, Jevons S, Ariza J, Hagan D, Wilson A, Lovat SJ; BEST2 study group, Sami SS, Ahmad OF, Novelli M, Rodriguez Justo M, Winstanley A, Heifetz EM, Ben-Zecharia M, Noiman U, Fitzgerald RC, Sasieni P, Lovat LB. Lancet Digit Health. 2020 Jan 1;2(1):E37-E48. doi: 10.1016/S2589-7500(19)30216-X. Epub 2019 Dec 5.PMID: 32133440 Risk Stratification of Barrett’s oesophagus using a non-endoscopic sampling method coupled with a biomarker panel: a cohort study. Ross-Innes CS, Chettouh H, Achilleos A, Galeano-Dalmau N, Debiram-Beecham I, MacRae S, Fessas P, Walker E, Varghese S, Evan T, Lao-Sirieix PS, O'Donovan M, Malhotra S, Novelli M, Disep B, Kaye PV, Lovat LB, Haidry R, Griffin M, Ragunath K, Bhandari P, Haycock A, Morris D, Attwood S, Dhar A, Rees C, Rutter MD, Ostler R, Aigret B, Sasieni PD, Fitzgerald RC; BEST2 study group. Lancet Gastroenterol Hepatol. 2017 Jan;2(1):23-31. doi: 10.1016/S2468-1253(16)30118-2. Epub 2016 Nov 11. A non-endoscopic device to sample the oesophageal microbiota: a case-control study. Elliott DRF, Walker AW, O'Donovan M, Parkhill J, Fitzgerald RC. Lancet Gastroenterol Hepatol. 2017 Jan;2(1):32-42. doi: 10.1016/S2468-1253(16)30086-3. Epub 2016 Nov 12. Methylation panel is a diagnostic biomarker for Barrett's oesophagus in endoscopic biopsies and non-endoscopic cytology specimens. Chettouh H, Mowforth O, Galeano-Dalmau N, Bezawada N, Ross-Innes C, MacRae S, Debiram-Beecham I, O'Donovan M, Fitzgerald RC. Gut. 2018 Nov;67(11):1942-1949. doi: 10.1136/gutjnl-2017-314026. Epub 2017 Oct 30. Range of pathologies diagnosed using a minimally invasive capsule sponge to evaluate patients with reflux symptoms. Paterson AL, Lao-Sirieix P, O'Donovan M, Debiram-Beecham I, di Pietro M, Miremadi A, Attwood SE, Walter FM, Sasieni PD, Fitzgerald RC; BEST and BEST2 study groups. Histopathology. 2017 Jan;70(2):203-210. doi: 10.1111/his.13039. Epub 2016 Oct 12. Safety and Acceptability of Esophageal Cytosponge Cell Collection Device in a Pooled Analysis of Data From Individual Patients. Januszewicz W, Tan WK, Lehovsky K, Debiram-Beecham I, Nuckcheddy T, Moist S, Kadri S, di Pietro M, Boussioutas A, Shaheen NJ, Katzka DA, Dellon ES, Fitzgerald RC; BEST1 and BEST2 study investigators. Clin Gastroenterol Hepatol. 2019 Mar;17(4):647-656.e1. doi: 10.1016/j.cgh.2018.07.043. Epub 2018 Aug 9. Evaluation of a minimally invasive cell sampling device coupled with assessment of trefoil factor 3 expression for diagnosing Barrett's esophagus: a multi-center case-control study. Ross-Innes CS, Debiram-Beecham I, O'Donovan M, Walker E, Varghese S, Lao-Sirieix P, Lovat L, Griffin M, Ragunath K, Haidry R, Sami SS, Kaye P, Novelli M, Disep B, Ostler R, Aigret B, North BV, Bhandari P, Haycock A, Morris D, Attwood S, Dhar A, Rees C, Rutter MD, Sasieni PD, Fitzgerald RC; BEST2 Study Group. PLoS Med. 2015 Jan 29;12(1):e1001780. doi: 10.1371/journal.pmed.1001780. eCollection 2015 Jan. Data from this study have fed into high-level publicatications, including Gut. 2017 Oct 30. pii: gutjnl-2017-314026. doi: 10.1136/gutjnl-2017-314026. [Epub ahead of print] Methylation panel is a diagnostic biomarker for Barrett's oesophagus in endoscopic biopsies and non-endoscopic cytology specimens. Chettouh H(1), Mowforth O(1), Galeano-Dalmau N(1), Bezawada N(1), Ross-Innes C(1), MacRae S(1), Debiram-Beecham I(1), O'Donovan M(2), Fitzgerald RC(1). Fitzgerald RC, di Pietro M, O'Donovan M, et al. Cytosponge-trefoil factor 3 versus usual care to identify Barrett's oesophagus in a primary care setting: a multicentre, pragmatic, randomised controlled trial. Lancet 2020;396:333–344. Yusuf, A., Fitzgerald, R.C. Screening for Barrett’s Oesophagus: Are We Ready for it?. Curr Treat Options Gastro 19, 321–336 (2021). https://doi.org/10.1007/s11938-021-00342-1 Continuing long-term outcome data from the BEST2 cohort is essential to inform future directions for introducing the Cytosponge™ test to patients. This study has had ethical approval extended till 2024.

Expected measurable benefits

This Agreement permits the secure retention of the data only and no other processing. Continuing long-term outcome data from the BEST2 cohort is essential to inform future directions for introducing the Cytosponge test to patients. The BEST2 study recruited 1550 men and women within the UK with either known Barrett's oesophagus (cases) or individuals with reflux or indigestion symptoms referred for endoscopy (controls). All participants were screened with the Cytosponge™ device to test its potential in determining the risk of cancer progression (in conjunction with biomarkers of risk). The results were then compared to routine endoscopy findings. The study objectives are as follows: Analysis of NHS records will help measure long term effectiveness of the Cytosponge biomarkers to risk stratify patients. In addition to identifying its efficacy in an NHS setting as an alternative to endoscopies. The potential benefits of this research include reducing the use of invasive procedures for patients and by providing evidence for policy decision makers for the use of a safe, minimally invasive, cheaper, and easily administered method to diagnose and screen for this condition. Primary objectives: The Cytosponge test showed a specificity of 92% and a sensitivity of around 80% which increases with segment length and is not compromised in the presence of dysplasia. The Cytosponge TFF3 test could be used to diagnose patients who would otherwise be referred to endoscopy to rule out BE and therefore be a more systematic screening test for use in primary care. UoC are interested in obtaining the data from these patients to link the biomarker work performed on the samples collected and the risk of progression to cancer. Follow-up of all participants is needed to continue monitoring the presence of dysplasia and any risks of cancer progression. Currently guidelines recommend endoscopic screening for BE in individuals with multiple risk factors. However, the cost advantages associated with the Cytosponge TFF3 test means screenings could be offered to a larger number, thereby improving the potential to correctly identify a greater number of newly-diagnosed BE cases. Performance and safety characteristics of the Cytosponge™ test The BEST2 study would like to continue follow-up of these consented participants using cancer outcome data in order to collect long-term efficacy and safety data. The data will not be used for any purpose other than to meet objectives as stated in the trial protocol and will not be shared with any third party organisation. Any information which is used for publication in peer reviewed journals will be anonymised (i.e. aggregated data) and not presented at the individual level. Effectiveness of the Cytosponge™ for diagnosing BE compared with endoscopy, including specificity (from controls) and sensitivity (from cases) For patients with BE, the ability of Cytosponge™ biomarkers to risk stratify patients, according to their future cancer risk in comparison with the dysplasia grade obtained from endoscopic biopsies. Secondary objectives: Differential sensitivity of screening BE with dysplasia (low and high grade) compared to non-dysplastic BE. Determine the reproducibility of the Cytosponge™ result by repeated testing in a subset of individuals Logistics of high-throughput sample processing and automated analysis of Cytosponge™ specimens for use in routine NHS or other health care settings. Surplus material will be used for testing emerging biomarkers. Analysis of NHS records will help measure long term effectiveness of the Cytosponge biomarkers to risk stratify patients. In addition to identifying its efficacy in an NHS setting as an alternative to endoscopies. The potential benefits of this research include reducing the use of invasive procedures for patients and by providing evidence for policy decision makers for the use of a safe, minimally invasive, cheaper, and easily administered method to diagnose and screen for this condition. This step is in the final phase via the BEST3 Trial.

Benefits reported

[1 paragraph unchanged] This Data Sharing Agreement permits the retention of the data for an interim period but no other processing of the data is permitted. The BEST2 dataset was pivotal for informing the direction of the BEST3 trial (a large scale clinical trial with 5000 patients in primary care which assessed whether the Cytosponge test could be introduced into GP surgeries for the earlier detection of oesophageal cancer), and the ongoing scientific basis for the test. Permission to retain the data for the interim period is a practical step to enable the study to comply with the necessary legal and ethical requirements. If, for any reason, it is not possible for the study to meet the necessary requirements, this Agreement will be terminated, and destruction of the data will be required. The current laboratory assay involves a pathological slide based test, however we continue to refine this assay to make it easier to scale. A key scientific paper detailing an alternative method was published based on re-use of BEST2 samples: Methylation panel is a diagnostic biomarker for Barrett's oesophagus in endoscopic biopsies and non-endoscopic cytology specimens. The following information provides background information on the benefits of the original dissemination. No new data will be released under v4 of the agreement, this agreement allows the applicant to hold and not otherwise process any further data that has already been disseminated. The design of BEST2 involved cases and controls – wherein the cases are patients with known Barrett’s. This enabled us to use the cases for testing additional biomarkers indicative of risk for progression for cancer. For this it is essential to have follow-up data on the cancer conversion rate for controls (without Barrett’s) and patients diagnosed with Barrett’s who did or didn’t have dysplasia. BEST2 study do not have the follow-up data since 2016 and a future data request would enable a further 5 years of follow-up which would be helpful to facilitate these risk stratification biomarker studies. This would be especially timely as BEST2 are now in the set-up stages of the BEST4 randomised controlled trial which will be powered to determine whether an offer of Cytosponge reduces the mortality rates from oesophageal cancer. The data from BEST2 will therefore inform the sample size required. A key scientific paper on the risk stratification of patients at risk of BE and oesophageal cancer was published using data received: Methylation panel is a diagnostic biomarker for Barrett's oesophagus in endoscopic biopsies and non-endoscopic cytology specimens. Chettouh H, Mowforth O, Galeano-Dalmau N, Bezawada N, Ross-Innes C(1), MacRae S, Debiram-Beecham I, O'Donovan M, Fitzgerald RC. A large scale clinical trial in primary care is underway in England with 5000 patients enrolled in primary care (BEST3) to assess whether the Cytosponge™ test could be introduced into GP surgeries for the earlier detection of oesophageal cancer. The BEST2 dataset is pivotal for informing the direction of the pragmatic trial and the ongoing scientific basis for the test.

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

Objective for processing

This Data Sharing Agreement permits the retention of the data provided under previous iterations of this Agreement for an interim period. This is a pragmatic approach to provide an active Agreement whilst enabling University of Cambridge to complete the necessary actions to enable a subsequent application to extend the Agreement meeting all applicable data sharing standards as published in NHS Digital’s website (see: https://digital.nhs.uk/services/data-access-request-service-dars/dars-guidance). The following provides background information on the purpose of the original study: [2 paragraphs unchanged] This Data Sharing Agreement permits the retention of the data for an interim period but no other processing of the data is permitted. Permission to retain the data for the interim period is a practical step to enable the study to comply with the necessary legal and ethical requirements. If, for any reason, it is not possible for the study to meet the necessary requirements, this Agreement will be terminated, and destruction of the data will be required. The following information provides background information on the purpose of the original study. No new data will be released under this version of the agreement, and this agreement allows the applicant to hold and not otherwise process any further data that has already been disseminated. The following information provides background on the aim and purpose of the original study. No new data will be disseminated under v4 of this agreement. [15 paragraphs unchanged]

Processing activities

[1 paragraph unchanged] Under this Agreement, the data may be securely stored but not otherwise processed. No new data will be provided by NHS Digital under this Agreement. The study data, including data provided by NHS Digital under previous agreements, are currently held by University of Cambridge. The following provides background on the processing activities undertaken prior to this Agreement: [1 paragraph unchanged] This Data Sharing Agreement permits the retention of the data for an interim period but no other processing of the data is permitted. Permission to retain the data for the interim period is a practical step to enable the study to comply with the necessary legal and ethical requirements. If, for any reason, it is not possible for the study to meet the necessary requirements, this Agreement will be terminated, and destruction of the data will be required. No new or further data will be provided under v4 of the agreement. A short-term extension is in place as a pragmatic approach to enable legal retention of already disseminated data. This agreement allows retention of data, but not permission to otherwise process it. Below is information provided by UoC on background to the study for details of previous disseminations, and also an insight into what is anticipated will happen once access to new data flows and permission to process data is granted in the future. As stated above - this version of the agreement permits retention of data only - permission is not granted to otherwise process the data at this stage until relevant documentation can be provided. [3 paragraphs unchanged]

Expected output

This Agreement permits the secure retention of the data only and no other processing. No new outputs will be produced under this Data Sharing Agreement. [1 paragraph unchanged] This Data Sharing Agreement permits the retention of the data for an interim period but no other processing of the data is permitted. Permission to retain the data for the interim period is a practical step to enable the study to comply with the necessary legal and ethical requirements. If, for any reason, it is not possible for the study to meet the necessary requirements, this Agreement will be terminated, and destruction of the data will be required. No further outputs of the data are permitted to be created under this version of the agreement. The below provides background on to what has already been produced, and what will be produced once data flow and permission to process resumes. [9 paragraphs unchanged]

Expected measurable benefits

This Data Sharing Agreement permits the secure retention of the data for an interim period but only and no other processing of the data is permitted. processing. Permission to retain the data for the interim period is a practical step to enable the study to comply with the necessary legal and ethical requirements. If, for any reason, it is not possible for the study to meet the necessary requirements, this Agreement will be terminated, and destruction of the data will be required. The following information provides background information on the benefits of the original dissemination. No new data will be released under v4 of the agreement, and this agreement allows the applicant to hold and not otherwise process any further data that has already been disseminated. [12 paragraphs unchanged]

Unchanged: Benefits reported.