AML16- A programme of development for older patients with acute myeloid leukaemia and high risk myelodysplastc syndrome

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Objective for processing

Treatment choice and outcome substantially decided by age. Cardiff University requires access to NHS England data for the purpose of the following clinical trial: A programme of development for older patients with acute myeloid leukaemia and high risk myelodysplastc syndrome (AML16) Patients <60 years have a significantly improved survival. This trial investigated treatment for acute myeloid leukaemia (AML) and high risk myelodysplastic syndrome (MDS). MDS is called high risk if more than 10% of the patients’ bone marrow is made up of immature cells called blasts. Of patients >60 years treated intensively over the last 15 years there is little evidence of improvements in survival, CR rate not improved beyond 60% and relapse in 85% of patients. The study was split into two parts: Large groups of patients >60 years are not considered fit for intensive treatment - median survival 4 months. 1) Intensive treatment. This part of the study recruited participants between 04/08/2006 and 31/05/2012. The main aim of this part of the trial was to look at a number of different drugs to find out which was best at stopping AML coming back and caused the fewest side effects. Participants had 2 or more of the following drugs: Daunorubicin, Cytarabine, Clofarabine, Etoposide, Gemtuzumab ozogamicin. Median age of disease is 65 years 2) Non-intensive treatment. This part of the study recruited participants between 04/08/2006 and 30/11/2011. The main aim of this part of the trial was to compare different drugs or combinations of drugs with the standard treatment of low dose cytarabine to find out other drugs could improve the length of time people lived (survival). A ’Pick A Winner’ trial design was used to find out early on which drugs had potential to help and which were unlikely to improve survival by looking at whether the drugs could increase the number of people who had no signs of leukaemia left after treatment (going into remission). The trial looked at the following drugs, either on their own or alongside cytarabine: Clofarabine, Gemtuzumab ozogamicin (GO), Tipifarnib (Zarnestra), Arsenic trioxide (Trisenox), Sapacitabin As the general population lives longer, the number of patients in this age group will increase. The trial is complete. Completion has been reported to the regulatory authorities and results were reported in 2011. Medicines and Healthcare products Regulatory Agency (MHRA) guidance stipulates that clinical trials should retain data for at least 15 years after completion of the trial. Cardiff University would like to retain this Data to ensure reconstruction of the trial analysis is possible if required. Urgent need to find new treatments for patients >60 years who are not catered for in most trials. No additional data will be requested from NHS England. This Data Sharing Agreement (DSA) permits processing of the Data for the purpose of secure storage and back up. This DSA does not permit any further processing that involves analysis or linkage other than for the purpose of verifying findings in line with the original objectives of the study by repeating previous analyses described in this DSA. Following publication of the study findings, it is possible that the findings will be questioned or challenged by third parties through direct contact with Cardiff University, contact via the publishing journal or an open letter. In such circumstances, Cardiff University may repeat the previously analyses undertaken to verify that the published results were accurate and may write a response to be issued directly to the challenger or published. Cardiff University may not undertake different analyses to those undertaken during the original analysis. This DSA does not permit any onward sharing of the Data with the exception that the Data may be viewed for the purpose of an audit by a regulator such as the Medicines and Healthcare products Regulatory Agency (MHRA). The MHRA maintains a list of all clinical trials registered with them and reserve the right to audit the trial at any point from when the trial is opened to 5-year post trial closure. A sponsoring organisation and/or the data controller itself may also exercise the right to audit. This DSA permits the necessary processing of the Data for the purposes of permanently destroying, deleting or erasing the Data once it is no longer required for the purpose for which it was collected. Once destroyed/deleted or erased, Cardiff University must confirm destruction to NHS England. If any further data processing is required in addition to the above purposes or if the Data needs to be moved to a different location/organisation Cardiff University must submit an Amendment request to NHS England before Data is accessed. Data from the following NHS England datasets will be retained: - MRIS - Flagging Current Status Report - MRIS - Cause of Death Report - MRIS - Members and Postings Report - MRIS - Cohort Event Notification Report The level of the data being retained will be: > Identifiable - This is necessary because: The MRIS data held under this DSA could not be minimised to exclude identifiable data at the time of dissemination. Historical trial records do not evidence exactly which individual data fields were merged for which participants. Therefore, whilst Cardiff University is confident that there is reliance on only a small proportion of the original data set provided to Cardiff University by NHS England under this Agreement, the exact level of reliance is unclear, and deletion of data that did not contribute to the final dataset is not practical or possible. The data was minimised prior issue as follows: - Limited to data for a study cohort identified by, and provided to NHS England, by Cardiff University ; cohort size 972 participants registered to the AML16 trial : trial ID, NHS number, forename, surname, initials, address, postcode, and date of birth; - Limited to the following participant geographic areas: England and Wales - Limited to data between 2006 and 2017; Cardiff University is the research Sponsor and sole data controller for the data provided by NHS England, 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 provided under this DSA and the 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 GDPR is: Article 9(2)(j) - processing is necessary for archiving purposes in the public interest 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. The funding is provided by Cardiff University. The funding is specifically for the trial described. The funder(s) will have no ability to suppress or otherwise limit the publication of findings. University of Birmingham is a processor acting under the instructions of Cardiff University. University of Birmingham's role was limited to providing clinical trial management of the trial prior to closure of the trial. The trial master file was transferred from Birmingham University to Cardiff University following trial closure. Birmingham University hold the original database for regulatory archiving purposes. Birmingham University is not involved in decisions about the processing of the data. Microsoft Limited (Azure) provides cloud server back up services to Cardiff University and will store copies of electronic data held on Cardiff University Servers, as contracted by Cardiff University. Cardiff University has outsourced long term archiving of the hard copy Trial Master File to DeepStore Limited.

Processing activities

Not stated in the previous version; added here.

No data will flow to NHS England for the purposes of this Data Sharing Agreement (DSA).

Cardiff University holds the relevant records from the MRIS datasets. The Data will

- contain directly identifying data items including Names, NHS Number, Date of Birth, Postcode and Gender which are required to meet Cardiff University's clinical trial regulatory requirements. Exposing the Data in order to remove these fields exposes the data to more risk than restricting access.

No additional data will be disseminated by NHS England for the purposes of this DSA.

This DSA permits processing of the Data for the purpose of secure storage and back up.

This DSA does not permit any further processing that involves analysis or linkage other than for the purpose of verifying findings in line with the original objectives of the study by repeating previous analyses described in this DSA.

This DSA does not permit any onward sharing of the Data with the exception that the Data may be viewed for the purpose of an audit by a regulator such as the Medicines and Healthcare products Regulatory Agency (MHRA).

The Data will be stored on servers at Cardiff University.

Cardiff University uses offsite back-up services provided by Deepstore Ltd.

Cardiff University stores Data on the Cloud provided by Microsoft Azure.

In the event that the data needed to be accessed for the purposes of audit or to enable verification of previous findings, the dataset would be transferred back to the CU servers with authorisation from the Principal Investigator where it can be accessed by the study statistician only for the purposes of verifying results of previous analyses by rerunning analyses that were previously undertaken. Data would be accessible only for as long as is required to enable verification of the analyses and to write a response as appropriate. Responses will adhere to the rules for small number suppression in the HES Analysis Guide.

The data may not be transferred to any other location and may only be accessed by substantive employees of Cardiff University or University of Birmingham for the purposes described above.

If any further data processing is required in addition to the above purposes or if the data needs to be moved to a different location/organisation the applicant must submit an amendment request to NHS England before data is accessed.

This DSA is required for the following reasons;

(1) The raw datasets (and any associated datasets and syntax files) may need to be accessed for the purpose of audit;

An audit may be required during the period of this agreement. This would involve a systematic and independent review of trial-related activities and documents, to determine whether data were recorded, analysed and accurately reported. Without all the raw datasets this cannot be done.

(2) Further analysis is expected on these datasets in future;

Any further analysis will only take place following an amendment to this Agreement that would allow further processing of the data.

(3) Clinical trial data needs to be retained and accessible for 15 years after trial completion this requirement would be subject to further data extension requests – no data will be retained without an Agreement being in place.

Expected output

Not stated in the previous version; added here.

The AML16 trial was supported by the NIHR Cancer Clinical Research Network and is registered on the NIHR CRN study portfolio, EudracT and ISRCTN clinical trial registries.

Results from the AML16 trial were used alongside the results of the AML15 trial to further refine treatments and new trial designs in this patient population. The design of the subsequent AML17 and AML19 trials, in the same population of patients (i.e. patients within the same age range and with the same condition to AML15 but different patients), has been based on emerging results from the AML15 trial. AML17 is closed to recruitment with the results published and intervention monitoring ongoing. The AML19 trial remains active with results publication planned 2024 onwards.

The benefits of individual researchers within the immediate AML study team and wider UK-wide and international AML research communities are multiple scientific and lay results publications. Benefits also include multiple international conference abstract and oral presentations.

The outputs do not contain NHS England Data and 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.

No new outputs are expected to be produced using the data under this Agreement.

Expected measurable benefits

Not stated in the previous version; added here.

The Data will be retained:

> to comply with guidance and policy on good clinical practice and regulations.

The NCRI AML trials sought to improve treatments for patients with acute myeloid leukaemia for over 20 years, supported by the UK NCRI AML Working Group. The measure of benefits is reliant on survival status being followed up for all patients, usually well past the end date of the clinical trial itself. It is important to identify any patients or sub-populations that have benefited from trial treatment and any late effects of the treatment given. The tracking of some patients via NHS England allowed the trial data to include patients that may have been lost to follow up at participating trial

centres.

Benefits reported

Yielded Benefits is not a requirement for new applications. The data provided under this Agreement allowed the inclusion of participants lost to follow up at participating trial centres in the final study analysis. The main finding of the study was the identification of sub-populations of patients that might in future benefit from the some of the new treatment drugs and regimes under investigation in the AML16 trial. The AML16 study collected blood samples. Laboratory analyses of these samples, in combination with AML16 clinical data, have supported the development of novel prognostic approaches to improve AML and MDS diagnosis and treatment. The study results have contributed to and impacted on evidence-based health care recommendation, guidance and policy document updates for the treatment of AML and MDS in the UK (e.g. NICE guidelines) and worldwide. Together, the AML15 and AML16 trials demonstrated that a single dose of GO could improve survival by up to 5% in patients who did not have poor risk disease as measured by cytogenetics. These two trials make up about 2/3 of the total randomised data for this drug, and have made GO standard of care in the UK. The trials process is a continuous one in AML – the results of AML15 and AML16 have informed the designs of the successor trials, AML17, AML18, AML19 and AML LI-1. Measurable benefits of the AML16 trial include include: 1) Intensive treatment group. The trial team concluded that people who had GO with chemotherapy had a lower risk of leukaemia or MDS coming back and lived longer than people who had chemotherapy alone. They also found that there was no significant benefit to people having a 3rd cycle of chemotherapy overall, but further work is needed to find out if some subgroups of patients might benefit. AML16 for the first time demonstrated the value of measuring response using sophisticated laboratory techniques to identify patients who, although they might be in remission, will relapse early and are therefore candidates for novel treatments or intensification. 2) Non-intensive treatment group. In 2006 and 2007, the trial recruited 65 people who were randomised to have either low dose cytarabine and tipifarnib or low dose cytarabine alone. Their average age was 74 and most had acute myeloid leukaemia.The leukaemia or MDS completely disappeared in 5 out of 33 people in the cytarabine and tipifarnib group 5 out of 32 people in the cytarabine alone group. But the trial team found that there were slightly more people alive after 12 months in the group who had cytarabine alone than in the group who had both drugs. This meant that tipifarnib was not considered promising and this comparison was stopped under the rules of the ’Pick A Winner’ study design. Between 2007 and 2009, the trial looked at arsenic trioxide (ATO). Researchers compared a combination of low dose cytarabine and ATO to low dose cytarabine alone. A total of 166 patients were randomised between the 2 treatments. As with tipifarnib, results showed that adding ATO did not improve the number of patients going into remission and this comparison was stopped. Between 2006 and 2010, the trial looked at gemtuzumab ozogamicin (GO). Researchers had already started looking at GO in another trial called AML 14 and they have analysed results from both trials together. A total of 495 patients were randomised to have either cytarabine alone or cytarabine and GO. Having GO with cytarabine increased the number of people whose leukaemia responded to treatment from 17% to 30%. But it did not increase the length of time people lived. About 25% of people who had cytarabine alone were alive at 12 months, compared to 27% in the GO group. Between August 2006 and April 2011, 406 patients in this trial were randomised to have either low dose cytarabine or clofarabine. Their average age was 74. The trial team found that the percentage of people whose leukaemia responded to treatment was 19% in the group who had cytarabine 38% in the group who had clofarabine. But the number of people still alive 2 years later was the same in both groups. From these results, the trial team concluded that neither gemtuzumab ozogamicin (GO) nor clofarabine improves survival in this group of patients. The trial embraced the fact that not all older patients are suitable for intensive chemotherapy, and developed a new design, called Pick-A-Winner, to allow rapid identification of potentially beneficial treatments in this group. AML16 unfortunately failed to identify any treatments which improved survival, even though some improved the number of patients entering remission. However, 902 patients were recruited, and 5 novel options investigated – a traditional design would have only allowed two treatments to be evaluated. The researchers will continue to look at sapacitabine in another trial called AML LI-1 and when they analyse the results, they will include results from the people taking part in this trial.

Data controllers: renamed from Cardiff University School of Medicine to Cardiff University. The same organisation under a new name, so not counted as a change.