A retrospective observational study of treatment patterns, resource use and outcomes in patients with early-stage Non-Small Cell Lung Cancer (NSCLC) in England

Adelphi Group Limited and Merck Sharp & Dohme (MSD) Medical Affairs UK requires access to NHS England data for the purpose of the following research project: A retrospective observational study of treatment patterns, resource use and outcomes in patients with early-stage Non-Small Cell Lung Cancer (NSCLC) in England

The following is a summary of the aims of the research project:

1. To describe the demographics and clinical characteristics of patients diagnosed with early stage or locally advanced NSCLC, stratified by stage at diagnosis and first-line treatment modality (exploratory).

2. To describe the pharmacological and other interventional (i.e. surgery, radiotherapy) treatment utilization patterns of patients diagnosed with early stage or locally advanced NSCLC, stratified by stage at diagnosis, first-line treatment modality (exploratory) and referral type.

3. To describe the all-cause and NSCLC-related healthcare resource utilisation and direct medical costs, for patients diagnosed with early stage or locally advanced NSCLC for different disease states, stratified by stage at diagnosis and first-line treatment modality (exploratory).

4. [Exploratory] To evaluate real-world effectiveness outcomes of patients diagnosed with early stage or locally advanced NSCLC including disease-free survival (DFS); event-free survival (EFS); progression-free survival (PFS); overall survival (OS); time from L/RP treatment to R/DM; time from L/RP treatment to death. Effectiveness outcomes will be stratified by stage at diagnosis and first-line treatment modality.

[Exploratory] Further stratifications may be applied to the final objective, e.g. deprivation quintile, referral type and performance status. Regression models may also be applied, attempting to control for explanatory variables, e.g., deprivation quintile, stage, CCI score, PS status.

This study will aim to help highlight treatment gaps and inform the use of new treatments that can improve outcomes for patients with early stage or locally advanced NSCLC. Specifically, results from the study may indicate that patients may benefit from immunotherapy as part of their treatment regimen. The study will provide evidence to support ongoing medical strategies, inform the implementation of future clinical trials and support the UK reimbursement process. The study will be using pseudonymised secondary care data, and only aggregated outputs reported across the overall cohort or broad categories (e.g. type of treatment plan). Adelphi Group Limited consulted with their internal GDPR and compliance team to clarify that the use of pseudonymised secondary data and aggregated outputs for reporting of results, ensures that there is a very low risk of potential harm to the public with no moral and ethical issues also.

To help achieve the study objectives the following NHS England data will be accessed:

- NDRS Hospital Episode Statistics (HES) – necessary to access information on hospital stays, outpatient appointments and A&E attendances with cancer and other specialists.

- NDRS HES Admitted Patient Care – necessary to assess healthcare resource utilisation (HCRU) of NSCLC patients, identify surgeries and disease progression following diagnosis of NSCLC.

- NDRS HES Accident & Emergency - necessary to assess HCRU of NSCLC patients

- NDRS HES Outpatients - necessary to assess HCRU and identify surgeries and disease progression following diagnosis of NSCLC.

- NDRS Diagnostic Imaging Dataset (DIDS) – necessary to report baseline characteristics (imaging events) and HCRU.

- NDRS Cancer Pathway – necessary to assess and confirm significant disease pathway events and timings of these.

- NDRS Cancer Waiting Times (Treatment (CWT) – necessary for assessing SACT and radiotherapy treatment patterns, as well as origin of referral.

- NDRS Cancer Registration – necessary to identify patients who have been diagnosed with stage I-III NSCLC, as well as report demographics and disease characteristics.

- NDRS Systemic Anti-Cancer Therapy Dataset (SACT) – necessary to obtain information on the chemotherapy treatments patients received after a diagnosis of NSCLC, for an understanding of treatment patterns.

- NDRS National Radiotherapy Dataset (RTDS) – necessary to obtain information on any radiotherapy treatment received after a diagnosis of NSCLC, for an understanding of treatment patterns.

The level of the data will be pseudonymised.

In the data request, Adelphi Group Limited and MSD Medical Affairs UK have limited the variables requested to only those that are necessary and essential for meeting the study objectives and limiting the granularity of the data requested.

NHS England at production level will apply the inclusion criteria (1, 3, 4, 5) and exclusion criteria defined below; Adelphi Group Limited will apply inclusion criteria 2 upon data delivery whilst morphology/histology codes are under review/subject to change. NHS England at production level will apply the staging inclusion criteria and the following minimisation to define the study cohort.

Inclusion Criteria defined by NHS England

• Limited to data between 01 April 2014 – 31 Dec 2019 (indexing period cohort)

• Limited to the following geographic areas: England;

• Limited to conditions relevant to the study identified by specific ICD-10 codes;

- ICD-10 code C34

- TNM staging criteria

i) T1a-b, N0-N2, M0

ii) T2a-b, N0-N2, M0

iii) T3, N0-N2, M0

iv) T4, N0-N2, M0

Or numbered stage I-III

- Patient is aged ≥18 years on the date of the first record of early stage/locally advanced NSCLC

The following is a full summary of the eligibility criteria and will be applied to the study population. All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to ensure that the subject qualifies for the study.

Inclusion criteria

1. Patient has a first diagnosis of a primary lung cancer (ICD-10 code C34) recorded within the Cancer Registry during the index period.

2. Patient has a confirmed histology of ͚non small cell carcinoma͛ or any subtype of NSCLC (see Appendix 1. Code lists in the protocol) of the primary lung tumour (ICD-O-3 code).

3. Patient has a record of early stage or locally advanced disease of the primary lung tumour within the indexing period defined as: a. TNM staging criteria: i) T1a-b, N0-N2, M0 ii) T2a-b, N0-N2, M0 iii) T3, N0-N2, M0 iv) T4, N0-N2, M0 b. Stage derived from imaging (numbered stage best): Stage I-IIIB

4. Patient is aged 18 years on the date of the first record of early stage/locally advanced NSCLC.

5. Patient has data linkage to HES datasets (necessary for deriving full assessment of treatment patterns, and associated HCRU /costs).

Exclusion Criteria

- Patient is diagnosed with and/or receiving treatment for other primary malignancies registered within the Cancer Registry prior to, including or during the index and/or follow up period.

- Patient has a record of newly diagnosed primary lung tumor at TNM: M1 or Stage IV.

- Patient is enrolled in a clinical trial for any line of systemic anti-cancer therapy treatment relating to their NSCLC diagnosis, identified by the clinical trial indicator in SACT (or any other of the NCRAS datasets).

- Patient has been treated with any immunotherapy in the neoadjuvant or adjuvant setting

- Patient who has not received surgery or undergone resection regardless of stage at diagnosis.

Patients who receive immunotherapy at any time will not be included in the assessment of outcomes (e.g. treatment patterns, HCRU and effectiveness outcomes), but the numbers of patients meeting this characteristic will be described. This is likely to be a small percentage of the overall cohort.

MSD Medical Affairs UK has commissioned Adelphi Group Limited to undertake this work and has determined the purpose of processing. Adelphi Group Limited, in the form of their subsidiary Adelphi Real World, make decisions about the means of processing and is therefore considered a joint controller with MSD Medical Affairs UK.

The objectives described above are the only intended use for the requested data and were designed in collaboration with MSD Medical Affairs UK. MSD Medical Affairs UK 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 Adelphi Group Limited.

Adelphi Group Limited will act as the Data Processor for this project.

Adelphi Group Limited and MSD Medical Affairs UK both rely on Article 6(1)(f) of the General Data Protection Regulation (GDPR) as the lawful basis of processing - "processing is necessary for the purposes of the legitimate interests pursued by the controller or by a third party”. It is in Adelphi Real World’s legitimate interest to add value to data through the application of epidemiological methods and expertise. Adelphi Real World will provide MSD Medical Affairs UK with aggregated data, with small numbers suppressed and will help them to interpret these outputs for wider dissemination to the scientific and public community as outlined in the study outputs. MSD Medical Affairs UK has determined the processing is necessary for its legitimate interests in being able to inform and raise awareness of the care pathway for patients.

The lawful basis for processing special category data under the UK GDPR cited by Adelphi Group Limited and MSD Medical Affairs UK 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.

This is justified as the project aims to drive improvements in the quality and safety of care and to improve outcomes for patients with lung cancer. To protect the data subjects interests and fundamental rights, appropriate data minimisation has been applied, data will be stored and processed in a secure environment and Adelphi Group Limited guarantee secure destruction of data after a defined period on completion of the project.

The funding is provided by MSD Medical Affairs UK and is specifically for the project described. MSD Medical Affairs UK will have no ability to suppress or otherwise limit the publication of findings.

The data is being used to describe the current treatment patterns and outcomes for the patient group to increase general understanding and increase awareness for multiple scientific and public groups including clinicians, researchers, the patient community, and the general public. Adelphi Group Limited will not be investigating the effectiveness of any specific treatments (including MSD’s treatments). MSD do manufacture pembrolizumab (Keytruda) which is approved for use in the UK for several indications, including NSCLC. The study will not evaluate or capture the outcomes of any specific treatments (including MSD’s treatments). Results for this study will be used to inform wider medical plans on activities that should be prioritised, such as further data generation studies. Results may also be used to supplement health technology assessment (HTA) reimbursement proposals (such as NICE) in which Marketing Authorisation Application (MAA) has been submitted. This may contribute to commercial gain for Merck Sharpe and Dohme. The potential commercial benefit to Merck Sharp & Dohme Limited of better understanding this care pathway is proportionate to the potential public benefits of increased understanding of this area of care.

The research team believe there may be intangible commercial gain when findings are presented at international congresses or published in peer reviewed journals because Adelphi Group Limited and MSD Medical Affairs UK employees will be listed as the authors. The primary rationale for carrying out these studies is that there is limited data on the patient pathway and outcomes for these patients. As such, Adelphi Group Limited will evaluate the real-world clinical characteristics, treatment patterns, patient outcomes and healthcare resource utilisation (HCRU) for patients with early-stage NSCLC. The insights are hoped to lead to better clinical outcomes for a significant number of patients and ultimately improve survival outcomes.

No data will flow to NHS England for the purposes of this Agreement.

NHS England data will provide the relevant records from the NDRS HESAPC, NDRS HESAE, NDRS HESOP, NDRS DID, NDRS CWT, NDRS SACT, NDRS RTDS, NDRS Cancer Registry and NDRS Cancer Pathway datasets to Adelphi Group Limited. The data will contain no direct identifying data items but will contain a unique person ID.

The data will not be transferred to any other location.

Data will be securely stored and hosted on servers operated by Adelphi Group Ltd.

Access to the study file is restricted to only the immediate project team. Access is restricted by Adelphi Group Limited’s central IT services department whereby a request must be submitted and authorised through a chain of command, upon receipt of a detailed, valid rationale e.g. onboarding of an additional member of the study team. Access will only be granted for the purposes described in this application.

The data will be stored on the servers at Adelphi Group Ltd.

The data will be accessed by authorised personnel via remote access

- 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 or Wales at any time.

Only substantive employees of Adelphi Group Limited who have received appropriate training in data protection and confidentiality will have access to and process the data. All employees of Adelphi Group Limited are contractually obliged to remain current with data protection and confidentiality training.

MSD Medical Affairs UK and other subsidiaries that fall under Adelphi Group Limited are not permitted to access or view any data released under this Agreement that is not aggregated with small numbers suppressed.

The data will not be linked with any other data outside of the scope of the agreement.

There will be no requirement to re-identify individuals from the de-personalised data disseminated in this agreement.

Analysts from Adelphi Group Limited will only analyse the data for the purposes described above.

The expected outputs of the processing will be:

• A report detailing the study rationale, design, methods, aggregated results (in the form of graphs and tables, with small numbers suppressed) and conclusions. This is an internal document that Adelphi Group Limited develop for MSD Medical Affairs UK. The report is used as a basis for manuscript development for submission to peer reviewed journals, as well as abstracts/posters submitted to international conferences.

• Submissions to peer reviewed journals.

• Posters and abstracts at European Society for Medical Oncology [ESMO] or American Society of Clinical Oncology [ASCO], (to be decided).

The target date for dissemination of the first draft internal study report is 18 months post-receipt of the data, after which publication will be considered where time scales are likely to be 6-12 months post completion of the report, depending on target conferences for abstracts/posters.

The outputs will not contain NHS England data and will only contain aggregated data with small number suppression applied where as appropriate, in line with the relevant disclosure rules for the datasets from which the information was derived.

The outputs may be communicated to relevant recipients through the following dissemination channels:

• Journals

• Conferences

The study is not looking at specific treatments and direct outcomes and no safety data will be generated as a result of this study.

The data collected within this study is hoped will contribute to the improvement of health and social care planning, as the objectives are hoped will provide:

• A better understanding of the clinical characteristics of patients with stage I-III NSCLC

• Treatment patterns and observed pathways for patients diagnosed with stage I-III NSCLC

• An understanding of gaps in the treatment of stage I-III NSCLC, and highlight where the introduction of immunotherapy and other medical strategies may benefit patient outcomes and improve survival rates.

Lung cancer is the leading cause of cancer mortality with more than 1.7 million deaths worldwide in 2018 (18.4% of total cancer deaths worldwide). It is the third most common cancer in the United Kingdom (UK), with around 48,500 new cases every year. Patients with lung cancer have a poor prognosis; over half of people diagnosed with lung cancer die within one year of diagnosis and the 5-year survival is less than 18%. These statistics highlight that the study results could help highlight gaps in the care of stage I-III NSCLC patients and improve the lives of large proportion of cancer patients in the UK, including the majority of lung cancer patients.

The dissemination strategy is hoped to provide evidence to support clinicians in the treatment of stage I-III NSCLC, inform ongoing standard of care improvement strategies in the use of new and emerging treatments, and appraise the implementation of future clinical trials in line with the overall aim to improve patient outcomes.

The data collected within this study is hoped to contribute to the improvement of health and social care planning, as the objectives will provide an understanding of the burden of stage I-III NSCLC on both patients and the NHS by assessing the real-world effectiveness outcomes (e.g. survival and progression rates), as well as healthcare resource use and costs incurred to the NHS.

Analysis outputs are yet to be finalised and so published.