Comparison of Real-World Evidence with Trial data for chemotherapies which have exited the Cancer Drug Fund

The Newcastle Upon Tyne Hospital NHS Foundation Trust (NuTH) requires access to NHS England data for the purpose of the following research programme: “Comparison of Real-World Evidence with Trial data for chemotherapies which have exited the Cancer Drug Fund”

NuTH is one of the country's top performing trusts in terms of the number of research studies it has supported, with 501 studies delivered by the trust in 2018/2019. Northern Medical Physics and Clinical Engineering (NMPCE) is a Clinical Directorate within NuTH, with research interests and a track record going back 40 years in the development and evaluation of health technology interventions including medical devices, diagnostics, and interventional procedures. Since 2011, NuTH has hosted one of the National Institute for Health and Care Excellence (NICE)’s External Assessment Groups (EAGs, formerly described as External Assessment Centres or EACs). The Newcastle EAG is based in the NMPCE Directorate at the Freeman Hospital in Newcastle (staff are substantially employed by NuTH), and has a subcontract in place with Newcastle University for the provision of literature searching, statistical and health economic expertise. The EAG is commissioned by NICE to evaluate healthcare technologies and interventional procedures and answer specific research questions raised by the NICE Medical Technologies Advisory Committee (MTAC), Diagnostics Advisory Committee (DAC), Interventional Procedures Advisory Committee (IPAC) and other NICE programmes. NICE have not formally commissioned the EAG to complete the analysis outlined in this research, however have provided a letter of support for this work, and a commissioner letter for the External Assessment Group within NMPCE to support this agreement, which extends to 2027.

Wider project:

This work is an initial pilot, to determine whether Real-World Evidence (RWE) from routinely collected NHS England datasets can support development of future NICE guidance in place of, or as an adjunct to, costly trial data which may not reflect NHS practice. The methodologies developed within the context of this project may support future Cancer Drug Fund (CDF) topics, and could be adapted and applied to other programmes within NICE (Diagnostics, Interventional Procedures, and Medical Technologies) to incorporate Real-World Evidence within national guidance production.

The key objective for processing data within this agreement is to use a linked dataset (cohort identified from Systemic Anti-Cancer (SACT) and Cancer Registry, longitudinally followed across SACT, Cancer Registry, Radiotherapy (RTDS) and Hospital Episode Statistics Admissions (HES APC) datasets to track outcomes of four specific cohorts of patients receiving chemotherapies which have exited the Cancer Drug Fund; where differences between SACT data and trial data were noted in the published Technology Appraisal.

There are 4 main objectives to this analysis:

1) To compare demographics and outcomes with the SACT data reported in the published technology appraisals as a form of validation that the studies have similar cohort identification,

2) to compare the demographics and outcomes with trial data, and explore reasons for differences between the two (accounting for covariates);

3) to determine whether outcomes are different when additional follow-up (using the latest data available across all datasets) is considered;

4) to determine uptake of the treatments post-guidance, and determine whether the outcomes are different in patients receiving the treatment in routine practice post-technology appraisal publication compared with trial data, or whether the same trends are observed.

In the absence of Blueteq data (unavailable to external researchers to request), a comprehensive cohort of CDF patients can be implied through the intersection of the SACT dataset (recording chemotherapy delivered), and the Cancer Registry or SACT dataset (recording the indication of interest). The pseudonymised cohort can then be followed using a common patient ID (TOKEN_PERSON_ID) across multiple national datasets:

To achieve this the following NHS England Data will be accessed:

• NDRS Cancer Registrations to identify cancer recurrence, development of secondary cancers, and mortality status.

• NDRS National Radiotherapy Dataset (RTDS) to identify any subsequent radiotherapy treatments a patient receives

• NDRS Linked HES APC to identify subsequent surgery and hospital resource usage (length of stay)

• NDRS SACT to identify subsequent chemotherapies for the specified cancer of interest (as well as secondary cancers);

Pseudonymised data is required to ensure robust longitudinal follow-up for each included patient, use of TOKEN_PERSON_ID means that identifiable information is not required.

The Data will be minimised as follows

Limited to a study cohort of adults aged 18 and over at diagnosis (the 4 chemotherapies have NICE recommendations which state “in adults” so this would indicate the use age at diagnosis and application of a threshold of 18 years and over only). All sexes. All ethnicities treated at an NHS hospital in England between 2017-latest available, identified by NHS England as meeting the following criteria: 4 chemotherapies which have exited the Cancer Drug Fund and have published NICE Technology Appraisal guidance. Treatment regimens will be defined by the first drug stated for each technology appraisal (TA):

1) TA870 Ixazomib with Ienalidomide and dexamethasone for relapsed or refractory multiple myeloma (published 2023);

2) TA766 Pembrolizumab for adjuvant treatment of completely resected stage 3 melanoma with lymph node involvement (published 2021);

3) TA795 Ibrutinib for Waldenstrom's macroglobulinae (published 2022);

4) TA780 Nivolumab and Ipilimumab for untreated advanced renal cell carcinoma (published 2022).

The data is limited to the geographic areas of England only (to ensure generalisability of results).

The time period of interest is 2017 onwards (when the 4 shortlisted chemotherapies were added to the CDF). To maximise follow up the latest data available from all datasets will be requested; this should enable up to 5 years follow-up. Additional covariate analysis (patient history, prior treatment) requires retrospective analysis (2 years prior, 2015-2017) to explore whether patient history is prognostic of outcome. No time restrictions are applied to capture cancer incidence.

The Newcastle upon Tyne Hospitals NHS Foundation Trust (NuTH) is the controller as the organisation responsible for ensuring that the Data will only be processed for the purpose described above. Only substantively employed NuTH and Newcastle University staff will process the data for this purpose. Clinical experts, and database managers within NuTH will be consulted to ensure the cleaning and analysis does not introduce bias. NICE have provided a letter of support for this work, however NICE have not directly commissioned the EAG to conduct this work. NICE does not specify what data are required to deliver the work nor how the data shall be processed to achieve that purpose. Such decisions are taken by NuTH as sole data controller and the research sponsor 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 under the UK 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;

NuTH are a public authority conducting transparent observational research and publication of healthcare outcomes from healthcare interventions in the NHS. NHS providers have administrative systems which feed into HES; therefore this represents the only national routine dataset of NHS activity in secondary and tertiary care.

The lawful basis for processing special category data under the UK GDPR is:

Article 9(2)(j) - processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes 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 public interest justification for public health purposes is that NMPCE outcomes research programme includes processing for reasons of public health, including adoption of medical technologies and outcomes of interventional procedures, to ensure high standards of quality and safety, as described in this research.

Local funding has been provided by NMPCE (NuTH). The funder(s) will have no ability to suppress or otherwise limit the publication of findings. Additional funding will be sought to secure data analyst time when the data application has been approved.

NuTH is the sole data controller and joint processor with Newcastle University. Only NuTH and Newcastle University staff will provide data analysis and statistical support in data processing.

NICE will not access the data, however will be acting as part of an oversight group as all 4 chemotherapies have undergone NICE Technology Appraisal. Only high-level summaries with small number suppression applied (in line with HES analysis guide) will be shared externally by NuTH and University of Newcastle.

A Public and Patient Involvement and Engagement group helped refine the purpose of the research.

Patient and public involvement (PPI) has been incorporated in the NICE technology appraisal for each of the 4 chemotherapies, with lay member representation on the committee (TA870, TA766, TA795, TA780). The group supported the collection of the data for the purposes described above.

When considering general methodologies of analysing routinely available data, moral and ethical issues and risk of potential harm to the public from the data processing methods, have been considered through active engagement with patient and public involvement (PPI) groups in the Trust and NuTH. Patients and their representatives have told NuTH that they positively endorse and demand such use of their data to benefit medical research and the NHS, as described in this agreement

In line with the national data opt-out policy, opt-outs are not applied because the data is not Confidential Patient Information as defined in section 251(10) and section 251(11) of the National Health Service Act 2006.

Where individuals have opted out of disease registration by the National Disease Registration Service (NDRS), their data has been permanently removed from the registry and therefore will not be disseminated under this Data Sharing Agreement (DSA). https://digital.nhs.uk/ndrs/patients/opting-out

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

NHS England will provide the relevant records from the NDRS SACT, NDRS RTDS, NDRS RTDS NDRS HES APC and NDRS cancer registrations to NuTH. The data will contain no direct identifying data items. The Data will be pseudonymised and individuals cannot be reidentified through linkage with other data in the possession of the recipient.

The Data will not be transferred to any other location. Only high-level summaries will be shared externally (following small number suppression rules and HES analysis guide).

All data received from NHS England are stored on NuTH premises, securely within the NuTH IT network which is access protected in accordance with NuTH Network Security & Access Control Policy. Access to the server room requires special permission, as it has its own access restrictions.

Data are backed up to tape, which is held in a secure area in a different fire zone in the Freeman Hospital (hospital within NuTH) Grounds.

The Data will remain on the servers at NuTH at all times and accessed via remote access where:

- Remote access will only be from secure locations situated within the territory of use (as further restricted elsewhere within the DSA if so done) stated within this DSA;

- Access controls granting users the minimum level of access required are in place;

- Remote access is only via secure connections (e.g., VPNs or secure protocols) to protect data;

- Multifactor authentication (MFA) is required for remote access;

- Device security, including up-to-date software and operating systems, antivirus software, and enabled firewalls are utilised for the remote access;

- All remote access is undertaken within the scope of the organisation’s DSPT (or other security arrangements as per this agreement) and complies with the organisation’s remote access policy.

The Data will not leave England at any time.

Access is restricted to employees of NuTH and Newcastle University who have authorisation from the Principal Investigator, EAG Director and Head of NMPCE department. NICE is not permitted to access the Data.

All personnel accessing the Data have been appropriately trained in data protection and confidentiality.

The Data will not be linked with any other data. there will be no requirement and no attempt to reidentify individuals when using the Data.

Analysts/researchers from the External Assessment Groups (EAG) at the NuTH and University of Newcastle will process/analyse the Data for the purposes described above. The processors will be used across both sites (NuTH and University of Newcastle) to ensure capacity to analyse the data, QA and provide statistical oversight. Specific to this data extract NuTH and Newcastle University are analysing 4 cohorts each with a different chemotherapy for a different cancer. Having both teams will ensure that the data are analysed to a high quality, checked and reported in a transparent and reproducible manner, and reported within the stated timeframes.

The expected outputs of the processing will be:

• A high-level report of findings to NICE

• Submissions to peer reviewed journals within 12 months of receipt of data.

• Presentations at appropriate conferences

Links to all publicly available information will be shared on the EAG

website (https://www.newcastle-hospitals.nhs.uk/services/medical-physics/nice-external-assessment-centre/), and reports contributing to NICE Technology Appraisals will be available on the NICE website.

The EAG engages with clinical coders in acute trusts across England prior to analysis of HES data, but also provides feedback to clinical coders to demonstrate the external uses of coded hospital data, with the aim to continually improve data quality at source. All publications using HES/mortality data will reference NHS England and cite a standardised copyright statement. The EAG strives to make all peer-reviewed publications available in open access form in order to maximise the availability of information to health care users, health care providers and general members of the public. For example, NuTH published the analysis code (written in R) which was used to analyse HES APC data to determine safety of mesh implants for stress urinary incontinence. Sharing methodology (not data) with the public will provide guidance to other researchers investigating other interventions in how to clean and analyse a large sample of HES data to identify complications; (Keltie et al. Complications following vaginal mesh procedures for stress urinary incontinence: an 8 year study of 92,246 women. Sci Rep. 2017; 7(1): 12015). The journal choice for any peer-reviewed publication will depend on the focus of the research question posed (e.g. methodology, patient safety, national policy or disease area).

The outputs will not contain NHS England Data and will 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.

Target date to produce outputs to NICE will be aligned to an instruction to proceed, which will include key milestones and timelines. Due to current uncertainty on when the requested data could be received from NHS England, the EAG currently estimates that the first topics could be analysed and reported within 6 months. Each shortlisted topic will then be addressed serially. The total DARS duration will enable analysis and publication of results, ensuring that the data is available to respond to reviewer comments. The EAG strives to share analytical code (where possible on Github, or journal permitting) for transparency and reproducibility purposes for future researchers.

The data requested will achieve the aim identified by collaborating with clinical experts (one for each topic), and writing up results to address the safety and efficacy of 4 specified chemotherapies which have exited the CDF, when used in current NHS practice. The outputs will include publication in open-access peer-reviewed journals, and presentation at appropriate conferences. Links to any outputs of this work will be publicised on the EAG website and on other social media.

The outputs of the programme are intended to inform national guidance updates for the 4 technologies and key decision-making. The analysis code will be made publically available (e.g. Github) so that external researchers and NHS England can apply this methodology across the NHS England datasets for future Cancer Drug Fund (CDF) topics.

This dissemination benefits the provision of health care or adult social care or the promotion of health in the following ways:

i) Contributing to national policy (e.g. update Technology Appraisal guidance issued nationally by NICE).

ii) Adding to the evidence base for specific chemotherapies to inform patients (e.g. via EAG website, NICE committee), as well as health care providers and professional societies (e.g. via open access peer-reviewed publications, conference presentations/posters).

iii) Documenting uptake of chemotherapies over time during CDF and following published Technology Appraisal guidance (active surveillance of key providers in HES over time) and data completeness of outcomes.

iv) Disseminating open-access peer-reviewed publications to inform local commissioners. For example describing associations between comorbidities, diagnoses and hospital resource usage.

v) Disseminating open-access peer-reviewed publications describing methodology used (including transparent publication of analysis code where used) to assist future researchers using NHS England data and to provide feedback to clinical coders to inform them of how coded administrative data submitted to NHS England is used which in turn improves clinical coding accuracy.

vi) Contributing to national audit (e.g. looking at patient outcomes, identifying any changes over time, investigating contributory factors and identifying areas for potential prospective research).

vii) Investigating population health/patient pathways (e.g. following cohorts of patients throughout their hospital care to determine hospital resources used).

Specific benefits to patients are expected as an outcome subject to the findings which include access to evidence-based chemotherapies, supported by NHS data on efficacy and safety.

It is hoped that through publication of findings in appropriate media, the findings of this research will add to the body of evidence that is considered by the bodies, organisations and individual care practitioners charged with making policy decisions for or within the NHS or treatment decisions in relation to specific patients. As each of the 4 chemotherapies included within this DARS was subject to NICE Technology Appraisal, the team will share high-level results with NICE and NHS England to inform future guidance updates/reviews.

Yielded Benefits is not a requirement for new applications.