MR1314 : FRAGMATIC: A randomised phase III clinical trial investigating the effect of FRAGMin® Added to standard Therapy In patients with lung Cancer.

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 Cardiff University 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).

Mortality and NHS Registration (MRIS) data were supplied to Cardiff University for the purpose of a research study called “FRAGMATIC: A randomised phase III clinical trial investigating the effect of FRAGMin® Added to standard Therapy In patients with lung Cancer”, as specified via the eligibility criteria specified in the FRAGMATIC protocol.

The trial assessed the effect of adding dalteparin (FRAGMIN) for 24 weeks to the standard treatment as required for the patients (intervention arm, n=1101) compared to standard treatment alone (control arm, n=1101). The primary outcome measure of the trial was overall survival (OS; defined as time from the randomisation until the date of death). The 1-year OS rate in the control arm was expected to be 25% of the total number of patients within the control group. To detect an advantage of 5% in OS at 1 year (taking the survival rate up to 30%) a total of 2202 patients were randomised from 130 UK hospitals (1101 in each arm - 2110 in England and Wales and the remainder in Scotland and Northern Ireland). Participants were followed up for a minimum of 2 years after the date of randomisation.

The case report form included a form to collect mortality data (date and cause of death) from the recruiting hospital site, but if a participant was lost to follow-up (i.e., no longer seeing their FRAGMATIC hospital doctor), the Wales Cancer Trials Unit (WCTU, now known as the Centre for Trials Research (CTR)) contacted the participant’s GP to obtain information on the participant’s status. If needed, and the participant had given the necessary consent, they were traced via the Medical Research Information Service at NHS Digital (under previous alternations); participants recruited in England or Wales) or national equivalent (participants recruited in Scotland or Northern Ireland). This was to ensure that any participant lost would still contribute to the analysis and was considered the most practical and least intrusive approach. The identifying routine data requested included date and cause of death, patient name, date of birth and NHS number to facilitate linking of traced data to data held in the clinical database. The data was requested at the end of the study following preliminary data cleaning. Routine data requests were minimised to a cohort of consenting participants only. Data was not requested for participants who had withdrawn consent to do so. NHS Digital data was only entered into the clinical trial database if the same data had not already been provided by the relevant participating site or differed to that provided by site. The mortality data provided was used to derive the primary outcome measure (OS) and secondary outcome measures (venous thromboembolism (VTE)-free, metastasis-free survival), and to support identification of toxicities that resulted in mortality. The primary analysis was conducted after 2,013 deaths as the intended number of events of 2,047 deaths was not obtained.

Recruitment to the trial took place over a 4-year period from 31/07/2007, closing 16/12/2011. Patient follow up, data cleaning and trial closure with research ethics were completed in 2014. For clarity, ‘trial closure’ refers to the dates upon which the study was closed with REC and MHRA as per the definition of trial closure under the UK Medicines for Human Use (Clinical Trial) Regulations (MHRA), i.e. when the last patient had completed protocol treatment) ended 08/06/2012. REC (date of last data capture, e.g. including long term follow up via NHS Digital) ended 09/10/2014. The date of final analysis was 20/11/2014 (i.e., date database was closed to edit rights, equivalent to hard lock.) Study data must be retained for a minimum of 15 years from the later of these two closure dates, that is, the REC closure date of 09/10/2014, i.e., until 09/10/2029, for regulatory archiving purposes. NHS Digital current policy means that Agreement extensions for archiving purposes can only be permitted for a maximum of 5 years at a time.

As FRAGMATIC is the largest randomised trial in lung cancer patients that addresses this important clinical uncertainty about how patients should be managed, its results are of great importance to national and international health professionals and researchers. The study data has been published in four publications to date as specified in the "Outputs" section.

Cardiff University has completed all study-specific primary and secondary outcome measure data analysis approved in the original FRAGMATIC study REC approval.

These ancillary studies include processing of the data of the two trial arms which may have different adverse event profiles and outcomes that might translate into different costs, effects and cost-effectiveness. This work will look at trial data collected about on the study case report forms about dalteparin received, other anticancer treatments, management of Severe adverse events (SAE), hospital admission episodes (all patient nights by speciality) and day case visits. It will also analyse data collected via a patient-completed EQ-5D questionnaire which enables scores to be converted into Quality Adjusted Life Years (QALs) to determine the cost per QALY in a Cost Utility Analysis (CUA) framework, and dyspnoea, anxiety and depression via a patient- completed Hospital Anxiety and Depression Scale (HADS) questionnaire. As death is a potential outcome of SAEs and SAEs are being analysed in the context of cost utility, this work might require further processing of mortality data supplied by NHS Digital.

This study is sponsored by Velindre University NHS Trust. The sponsor is defined by the organisation(s) with legal oversight responsibility for the study. The study is sub-contracted by the Sponsor to conduct some aspects of the study included some data management and data controller activities. FRAGMATIC was developed by the Wales Cancer Trials Unit (WCTU) at Velindre University NHS Trust before the unit moved to Cardiff University in 2008. The FRAGMATIC study came through with support and endorsement from the NIHR Lung Cancer Chemotherapy sub-group and the trial funding application team included representatives of other bodies, e.g., Wales Cancer Trials Network and University of Glamorgan. These organisations are not currently supporting the study. The Cancer Research UK (CRUK) grant was held by WCTU and only funded non-drug resource following standard CRUK practice. WCTU approached Pfizer for an educational grant to run in parallel to CRUK funding to fund the dalteparin (FRAGMIN) drug and its distribution costs for free. Following approval of a previous iteration of this Agreement, the WCTU merged into the Centre for Trials Research (CTR) at Cardiff University. The Centre of Trials Research now manages the study.

Velindre University NHS Trust and Cardiff University are joint data controllers for the FRAGMATIC study with joint responsibility to determine the purposes or means in which the data will be used. Cardiff University will be the sole organisation processing the data.

The Data Controllers do not perceive any moral or ethical issues regarding dissemination of results. The majority of participants will already be deceased due to the advanced cancer at the time of recruitment. It is in the public interest to disseminate study results and a requirement of most funding streams. For example, CRUK funding expects the results to be published on their website for any study funded or endorsed by them. Results have been published in a format that does not allow individual the participants to be identified.

Both joint data controllers for this Agreement - Cardiff University and Velindre University NHS Foundation Trust - rely on Article 6(1)e, ‘processing is necessary for the performance of a task in the public interest or in the exercise of official authority vested in the controller’ and Article 9(2)j, ‘processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes’ of the GDPR for data processing.

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.

The data provided in this agreement for the main study has contributed to five publications to date; one protocol manuscript, three results manuscripts and one conference abstract:

1) FRAGMATIC: A randomised phase III clinical trial investigating the effect of fragmin® added to standard therapy in patients with lung cancer. Griffiths O et al. BMC Cancer 2009, 9:355 doi:10.1186/1471-2407-9-355.

2) Macbeth, F., eta l. (2016) J Clin Oncol. 2016 Feb 10;34(5):488-94. Randomized Phase III Trial of Standard Therapy Plus Low Molecular Weight Heparin in Patients With Lung Cancer: FRAGMATIC Trialdoi: 10.1200/JCO.2015.64.0268. Epub 2015 Dec 23. PMID: 26700124.

3) Macbeth, F. et al. Transl Lung Cancer Res. 2016 Jun;5(3):347-9. Further results of the FRAGMATIC trial of thromboprophylaxis in lung cancer. DOI: 10.21037/TLCR.2016.05.07. pimid: 27413715.

4) Van Es, N. et al. Blood 2017, 130:627. The Khorana Score for the Prediction of Venous Thromboembolism in Patients with Solid Cancer: An Individual Patient Data Meta-Analysis.

5) The results of the study were also presented at the World Lung Conference. J Thoracic Oncology; Vol 8, Suppl 2, S243 (Nov 2013), Fergus Macbeth, Simon Noble, Gareth Griffiths et al ; Preliminary results from the Fragmatic Trial: a randomised phase III clinical trial investigating the effect of Fragmin® added to standard therapy in patients with lung cancer.

A recent health economics secondary outcome measure analysis was conducted by Cardiff University. All associated data analysis related data processing is complete and the aggregated anonymised results are pending publication in 2022. The results of the main study have been published on the CRUK and CTR websites. The CTR Dissemination of Results to Consumers Working Group is currently developing generic processes and guidance to support best practice in dissemination of study results to patients and their carers.

The results of the McMaster study have been published in six publications to-date; one study protocol paper, two results papers documenting primary and secondary outcome analysis, a scoping review and practical guide, and two conference abstracts:

1) https://bmjopen.bmj.com/content/6/4/e010569 (Schünemann, H. et al. BMJ Open 2016;6:e010569. doi:10.1136/BMJOPENM-2015-010569. Use of heparins in patients with cancer: individual participant data meta-analysis of randomised trials study protocol).

2) J Thromb Haemost. 2020;18:1940–1951 Primary results and has been accepted for publication by Lancet Oncology with actual publication pending renewal of this agreement.

3) Lancet Haematol 2020; 7: e746–55. Secondary results, and investigates the prediction of venous thromboembolism, for individual participant data meta-analysis investigating the effects of low-molecular heparin among oncologic patients

4) Ventresca, M. et al. BMC Medical Research Methodology (2020) 20:113. Obtaining and managing data sets for individual participant data meta-analysis: scoping review and practical guide.

5) Abstract, primary results - http://www.bloodjournal.org/content/130/Suppl_1/626

6) Abstract, secondary results - http://www.bloodjournal.org/content/130/Suppl_1/627

Primary results of the McMaster study have also supported the development of various documents comprising the American Society of Haematology (ASH) Clinical Practice Guidelines on Venous Thromboembolism 2018.

The publishing process for all scientific manuscripts described above involved rigorous independent scientific peer review, providing reassurance to the funder, the public and other researchers that the methods and results are of high quality.

The research outputs generated from the Agreement yielded the following benefits:

1) The International Society on Thrombosis and Haemostasis (ISTH) Guidelines now recommend consideration of LMWHs for VTE prophylaxis in ambulant lung cancer patients receiving chemotherapy.

2) Contributed to the American Society of Haematology (ASH) Clinical Practice Guidelines on VTE which recommend the use of thromboprophylaxis with Low Molecular Weight Heparins (LMWHs) in hospitalized patients with cancer.

Note that evidence-based guidelines from ASH and other professional organizations e.g. ISTH provide clinicians with a balanced resource for the use of anticoagulants in the specific management of patients with cancer.

3) A research paper has been published highlighting that the Khorana score was unable to stratify patients with lung cancer based on their VTE risk and that thromboprophylaxis with LMWHs was safe and effective and in patients with a high-risk Khorana score.

4) The limitations inherent in the FRAGMATIC study, i.e. the majority of patients having advanced cancers, led to the development of a new clinical trial; Effect of Low Molecular Weight Heparin: Tinzaparin in Lung Tumours (TILT) which aims to investigate the effects of the LMWH Tinzaparin on overall survival in patients with completely resected stage I, II or IIIA (T3N1) histologically confirmed non-small-cell lung cancer.

5) A research paper has been published exploring the psychological, emotional and cognitive domains of participation in the FRAGMATIC trial. This publication considers the potential harms and benefits of participation in non-placebo trials amongst patients with advanced lung cancer and identifies several implications for future research with and care for patients with advanced cancer.

Note that in addition to the afore-mentioned yielded benefits the publication of lay summaries of the research outputs on publicly accessible websites e.g. CRUK and CTR is critical as Public engagement is a priority for funders of higher education. Funders expect CU to demonstrate the impact of research on the public, how the university is meeting the needs of wider society, and the relevance and responsiveness of their research. Moreover the benefits of such public engagement are particularly recognised for medical and health research were time and again the evidence shows that service user involvement results in outcomes that are more relevant and useful to patients and their families.

Mortality and NHS Registration data were supplied to Cardiff University for the purpose of a research study called “FRAGMATIC: A randomised phase III clinical trial investigating the effect of FRAGMin® Added to standard Therapy In patients with lung Cancer.”

Velindre University NHS Trust and Cardiff University are joint data controllers for the FRAGMATIC study with joint responsibility to determine the purposes or means in which the data will be used. Cardiff University will be the sole organisation processing the data.

The Data Controllers do not perceive any moral or ethical issues regarding dissemination of results. The majority of participants will already be deceased due to the advanced cancer at the time of recruitment. It is in the public interest to disseminate study results and a requirement of most funding streams. For example, CRUK funding expects the results to be published on their website for any study funded or endorsed by them. Results will be published in a format that does not allow individual the participants to be identified.

This study is sponsored by Velindre University NHS Trust. The sponsor is defined by the organisation(s) with legal oversight responsibility for the study. The study is sub-contracted by the Sponsor to conduct some aspects of the study included some data management and data controller activities. FRAGMATIC was developed by the Wales Cancer Trials Unit (WCTU) at Velindre University NHS Trust before the unit moved to Cardiff University in 2008. The FRAGMATIC study came through with support and endorsement from the NIHR Lung Cancer Chemotherapy sub-group and the trial funding application team included representatives of other bodies, e.g. Wales Cancer Trials Network and University of Glamorgan. These organisations are not currently supporting the study. Ongoing and future data processing will not involve these bodies and will be conducted at Cardiff University only. The Cancer Research UK (CRUK) grant was held by WCTU and only funded non-drug resource following standard CRUK practice. WCTU approached Pfizer for an educational grant to run in parallel to CRUK funding to fund the dalteparin (FRAGMIN) drug and its’ distribution costs for free. Following approval of a previous iteration of this agreement, the WCTU merged into the Centre for Trials Research (CTR) at Cardiff University. The Centre of Trials Research now manages the study.

The trial assessed the effect of adding dalteparin (FRAGMIN) for 24 weeks to standard treatment (trial arm) compared to standard treatment alone (control arm). The primary outcome measure of the trial was overall survival. The 1 year survival rate in the control arms was expected to be 25%. To detect an advantage of 5% in overall survival at 1 year (to 30%) a total of 2202 patients were randomised (1101 in each arm - 2110 in England and Wales and 87 in Scotland). Participants were followed up for a minimum of 2 years after the date of randomisation.

If a participant was lost to follow-up (i.e. no longer seeing their FRAGMATIC hospital doctor), the WCTU (now known as the CTR) contacted the participant’s GP to obtain information on the participant’s status. If needed and the participant had given the necessary consent, they were traced via the Medical Research Information Service at NHS Digital (under previous alternations). This was to ensure that any participant lost would still contribute to the analysis.

Recruitment to the trial commenced 31/07/2007 and closed 16/12/2011. Patient follow up, data cleaning and trial closure with research ethics were completed in 2014. For clarity, ‘trial closure’ refers the dates upon which the study was closed with REC and MHRA as per the definition of trial closure under the UK Medicines for Human Use (Clinical Trial) Regulations. MHRA (i.e. when the last patient had completed protocol treatment) ended on 08/06/2012. REC (date of last data capture, e.g. including long term follow up via NHS Digital) ended on 09/10/2014. Correspondence with both regulatory bodies usually continues beyond date of closure and notification of date of closure based on the final reporting requirements for each body. The latest report specifies the date of final analysis as 20/11/2014 (i.e. date database was closed to edit rights, equivalent to hard lock.) The study needs to be retained for a minimum of 15 years from the later of two closure dates - 09/10/2029 based on REC closure being the latter.

As FRAGMATIC is the largest randomised trial in lung cancer patients that addresses this important clinical uncertainty about how patients should be managed, its results are of great importance to national and international health professionals and researchers. The study data has been published in four publications to date as specified in the "Outputs" section.

Future data processing objectives of Cardiff University include completion of ongoing health economic analysis and further analysis of the data set to further investigate and publish other secondary outcome measures (e.g. VTE, Khorana score etc.) included in the original REC approval.

These ancillary studies include processing of the data of the two trial arms which may have different adverse event profiles and outcomes that might translate into different costs, effects and cost-effectiveness. This work will look at trial data collected about on the study case report forms about dalteparin received, other anticancer treatments, management of Severe adverse events (SAE), hospital admission episodes (all patient nights by speciality) and day case visits. It will also analyse data collected via a patient-completed EQ-5D questionnaire which enables scores to be converted into Quality Adjusted Life Years (QALs) to determine the cost per QALY in a Cost Utility Analysis (CUA) framework, and dyspnoea, anxiety and depression via a patient- completed Hospital Anxiety and Depression Scale (HADS) questionnaire. As death is a potential outcome of SAEs and SAEs are being analysed in the context of cost utility, this work might require further processing of mortality data supplied by NHS Digital.

The main study research publication has been published: FRAGMATIC: A randomised phase III clinical trial investigating the effect of fragmin® added to standard therapy in patients with lung cancer. Griffiths O et al. BMC Cancer 2009, 9:355 doi:10.1186/1471-2407-9-355.

The results of the main study have been analysed and anonymised results published in three separate publications to date:

1) Main Publication: Macbeth, F., eta l. (2016) J Clin Oncol. 2016 Feb 10;34(5):488-94. Randomized Phase III Trial of Standard Therapy Plus Low Molecular Weight Heparin in Patients With Lung Cancer: FRAGMATIC Trialdoi: 10.1200/JCO.2015.64.0268. Epub 2015 Dec 23. PMID: 26700124.

2) Follow up publication: Macbeth, F. et al. Transl Lung Cancer Res. 2016 Jun;5(3):347-9. Further results of the FRAGMATIC trial of thromboprophylaxis in lung cancer. DOI: 10.21037/TLCR.2016.05.07. pimid: 27413715.

3) Van Es, N. et al. Blood 2017, 130:627. The Khorana Score for the Prediction of Venous Thromboembolism in Patients with Solid Cancer: An Individual Patient Data Meta-Analysis.

The results of the study were presented at the World Lung Conference. J Thoracic Oncology; Vol 8, Suppl 2, S243 (Nov 2013), Fergus Macbeth, Simon Noble, Gareth Griffiths et al ; Preliminary results from the Fragmatic Trial: a randomised phase III clinical trial investigating the effect of Fragmin® added to standard therapy in patients with lung cancer.

The results of the main study have been published on the CRUK and CTR websites. The CTR Dissemination of Results to Consumers Working Group is currently developing generic processes and guidance to support best practice in dissemination of study results to patients and their carers.

The results of the McMaster study have been published in a study protocol paper: https://bmjopen.bmj.com/content/6/4/e010569 (Schünemann, H. et al. BMJ Open 2016;6:e010569. doi:10.1136/BMJOPENM-2015-010569. Use of heparins in patients with cancer: individual participant data meta-analysis of randomised trials study protocol).

The results of the McMaster study have been published in two abstracts to date:

1) Abstract, primary results - http://www.bloodjournal.org/content/130/Suppl_1/626

2) Abstract, secondary results - http://www.bloodjournal.org/content/130/Suppl_1/627

McMaster have drafted two journal manuscripts to date. The first includes primary results and has been accepted for publication by Lancet Oncology with actual publication pending renewal of this agreement. The second includes secondary results, and investigates the prediction of venous thromboembolism, for individual participant data meta-analysis investigating the effects of low-molecular heparin among oncologic patients, and is ready for submission to Lancet Oncology pending full authorisation of a separate framework DSA and study-specific DSA between NHS Digital and McMaster.

Primary results of the McMaster study have been used in ASH Clinical Practice Guidelines on Venous Thromboembolism. McMaster intends to publish primary and secondary results at the American Society of Hematology conference in December 2018 following acceptance of two abstracts.

The publishing process for all scientific manuscripts described above involved rigorous independent scientific peer review, providing reassurance to the funder, the public and other researchers that the methods and results are of high quality.

The ongoing processing will result in the publication of results from health economics data analyses in scientific manuscript format in a suitable journal, as well as presentations of data in poster/oral presentation format.

The main publication concluded that there was no evidence of a difference in overall or metastasis-free survival between the two arms. There was a reduction in the risk of VTE in the LMWH arm and no difference in major bleeding events but evidence of an increase in the composite of major and clinically relevant non-major bleeding in the LMWH arm. LMWH did not improve overall survival in the patients with lung cancer in this trial. A significant reduction in VTE is associated with an increase in clinically relevant non-major bleeding. Strategies to target those at greatest risk of VTE are warranted. These results were of great importance to health professionals and researchers not only in the UK but around the world as heparin clearly does not give a clinically significant benefit to newly diagnosed lung cancer patients. The publication has been received 44 citations prior to 24/04/2018.

The two follow up publications concluded that although no survival difference was seen from the addition of dalteparin, there was a significant reduction in the incidence of radiologically confirmed venous thromboembolism (VTE) in both tumour types for those patients randomised to dalteparin. However, this was at the expense of an increase in clinically relevant non-major haemorrhage, thereby making routine thromboprophylaxis difficult to justify. Interestingly, of 910 lung cancer patients receiving chemotherapy and no dalteparin, 108 (11.9%) developed VTE, although the Khorana score had a limited utility in identifying those at greatest risk.

Actual yielded benefits include:

1) Based on the results of the FRAGMATIC study the revised International Society on Thrombosis and Haemostasis (ISTH) Guidelines now recommend consideration of LMWH for VTE prophylaxis in ambulant lung cancer patients receiving chemotherapy.

2) Data has been published highlighting the poor utility of the Korhana score in lung cancer, based on FRAGMATIC data.

3) The limitation of the FRAGMATIC study, i.e the majority of patients being advanced cancers, led to the implementation of other research (TI|LT study) which has recently been reported.