Clinical and economic burden of graft versus host disease in allogeneic stem cell transplant recipients in England – A retrospective cohort study

LA-SER EUROPE LIMITED (a Certara company) requires access to NHS England data for the purpose of the following research project: Clinical and economic burden of graft versus host disease in allogeneic stem cell transplant recipients in England – A retrospective cohort study.

The following is a summary of the aims of the research project provided by LA-SER EUROPE LIMITED (a Certara company):

Purpose: The primary objective is to describe the healthcare resource utilisation and cost burden of graft-versus-host disease (GVHD) among haematological cancer patients undergoing allogenic hematopoietic stem cell transplantation (allo-HSCT) by processing this data. It is critical to evaluate the health and economic burden of GVHD to establish the existing unmet need for payers and decision makers. For this reason, a real-world analysis of the clinical and economic burden of patients developing GVHD following allo-HSCT is proposed to be conducted in England. These findings will add to previous studies which examined the clinical and economic burden of GVHD in France and Germany.

Necessity: There is a significant paucity of data relating to the implications of GVHD in haematological cancer patients who underwent allo-HSCT in England. Additional data are required to identify unmet needs and facilitate planning and resource allocation to improve patient outcomes. By acquiring data from this large database, it will be possible to identify a sufficiently large population of haematological cancer patients who underwent allo-HSCT during the study period to enable a population-based comprehensive description of clinical and economic outcomes of GVHD.

Benefit: This study will benefit all the people who are involved in the care of haematological patients who undergo allo-HSCT, particularly those that develop GVHD by leading to potential improvements in the treatment and management of the disease based upon evidence generated by the proposed study.

LA-SER EUROPE LIMITED (a Certara company) will ask NHS England to provide the data based on the eligibility criteria outlined above. LA-SER EUROPE LIMITED (a Certara company) does not require any identifiers, such as names, NHS numbers, or addresses, for this study. As the cohort will be extracted by NHS England, Certara France will only receive a pseudonymised version of this cohort. As this study does not require any identifiable data, the risk of intrusion or personal detriment is low. In addition to it, the number of patients under 5 will not be presented in the analysis. Necessary appropriate measures will be taken to minimise the risk of patients being re-identified from the study.

Primary objectives:

• To estimate the excess healthcare resource utilization (HRU, for hospital in- and outpatient visits) and costs due to GVHD following an allo-HSCT (allogenic-hematopoietic stem cell transplantation) in adult (≥18 years) patients

Secondary objectives:

• To estimate the incidence, and time to onset of GVHD (graft-versus-host disease) among adult patients following an allo-HSCT

• To estimate the excess mortality due to GVHD following an allo-HSCT

• To estimate the rate of severe infections (by type – bacterial, fungal, viral, other) due to GVHD following an allo-HSCT.

Exploratory objectives:

• To assess the main drivers of resource use and costs among adult patients with and without GVHD following an allo-HSCT.

• To estimate the rate of relapse of the underlying malignancy among adult patients with and without GVHD following an allo-HSCT.

• Subject to data availability, to conduct stratified analyses to assess healthcare resource utilization, mortality, severe infections, and relapse rate according to type of GVHD (acute GVHD vs. no GVHD / chronic GVHD vs. no GVHD / acute and chronic GVHD vs. no GVHD).

The following NHS England data will be accessed:

• Hospital Episode Statistics Admitted Patient Care (HES APC), Hospital Episode Statistics Accident & Emergency (HESAE), Hospital Episode Statistics Outpatients (HESOP) – necessary to enable the identification of patients who underwent allo-HSCT and patients who subsequently developed GVHD and complications such as severe infections. Access to this data is also important to track healthcare resource utilisation to address the primary objectives of the study.

• Cancer Registration – necessary to identify patients with haematological cancers and to describe their demographic and clinical characteristics.

• Systemic Anti-Cancer Therapy Dataset (SACT) – necessary to enable the identification of treatments such as preparative regimens and prophylaxis prior to allo-HSCT. These data will also be used to describe relapses and healthcare resource utilisation.

• National Radiotherapy Dataset (RTDS) – necessary to enable the identification of preparative treatments. These data will also be used to describe relapses and healthcare resource utilisation.

The level of the data will be pseudonymised.

The data will be minimised by NDRS as follows:

• Limited to data between 01/01/2010 (baseline period starts on 01/01/2010) to 31/12/2023 (or latest available data available); - Adult patients at time of allo-HSCT (18 years old and above)

•Limited to conditions relevant to the study identified by specific ICD or OPCS codes;

PREVALENT HAEMATOLOGICAL CANCER CASES:

• Diagnosis of haematological cancer between 01/01/1995 and 31/12/2010, identified using following codes: o For pre-2013 diagnoses use ICD10 codes (‘C81’,’C82’,’C83’,’C84’,’C85’,’C86’,’C88’,’C90’,’C91’,’C92’,’C93’,’C94’,’C95’,’C96’,’D45’,’D46’,’D47’)

o Excluding morphology codes (‘8000’,’8765’) to remove poorly coded malignancies and MGUS tumours.

o For 2013 onwards use ICDO3 morphology and behaviour from analysishanhualiu.gdo_morph_haem

• For all years, exclude transformation events for all tumours (https://www.cancerdata.nhs.uk/getdataout/GDO_0031/Counting%20Haematological%20Cases%20SOP%202.0.pdf). AND Allo-HSCT between 01/01/2011 and 31/12/2023 (or latest available date) using the following codes

• ICD-10 codes (Z94.8, Z94.9, T86.0) or OPCS-4 codes (W34.2, W34.3, W34.4, W34.5, W34.6, W34.8, W34.9, W99.1, W99.8, W99.9, X33.6 or X33.8) in the NDRS Cancer registry, NDRS Linked HES APC, or NDRS Linked HES Outpatient

INCIDENT HAEMATOLOGICAL CANCER CASES:

Diagnosis of haematological cancer between 01/01/2011 and 31/12/2020 (or latest available date), identified using following codes:

o For pre-2013 diagnoses use ICD10 codes (‘C81’,’C82’,’C83’,’C84’,’C85’,’C86’,’C88’,’C90’,’C91’,’C92’,’C93’,’C94’,’C95’,’C96’,’D45’,’D46’,’D47’)

o Excluding morphology codes (‘8000’,’8765’) to remove poorly coded malignancies and MGUS tumours. o For 2013 onwards use ICDO3 morphology and behaviour from analysishanhualiu.gdo_morph_haem

For all years, exclude transformation events for all tumours (https://www.cancerdata.nhs.uk/getdataout/GDO_0031/Counting%20Haematological%20Cases%20SOP%202.0.pdf). AND Allo-HSCT between 01/01/2011 and 31/12/2023 (or latest available date) using the following codes.

o ICD-10 codes (Z94.8, Z94.9, T86.0) or OPCS-4 codes (W34.2, W34.3, W34.4, W34.5, W34.6, W34.8, W34.9, W99.1, W99.8, W99.9, X33.6 or X33.8) in the NDRS Cancer registry, NDRS Linked HES APC, or NDRS Linked HES Outpatient

The exclusion criteria below will be applied by the data recipient on receipt of data, not NHS England

- Patients without a history of any type of GVHD prior to the first allo-HSCT during baseline or between 01/01/2011 and 31/12/2023 (or latest available date)

- Patients without multiple allo-HSCT during study period (1st January 2011 to latest available)

- Patients without evidence of previous solid organ transplant (subject to data) during baseline period;

CSL Behring Incorporated is the Sponsor of this study. LA-SER EUROPE LIMITED (a Certara company) is the data controller and defined the study objectives, methods and processing to be implemented to address study objectives.

The lawful basis for processing personal data under the UK GDPR is: Article 6(1)(f) - the processing is necessary for your legitimate interests or the legitimate interests of a third party, unless there is a good reason to protect the individual’s personal data which overrides those legitimate interests.

The relevant legitimate interests pursued are to perform research in the area of health. More specifically, the objectives for this study are hoped to generate real-world evidence regarding the clinical burden of GVHD, to further establish the existing unmet need of this complication of allo-HSCT. It is hoped this study will benefit all the stakeholders involved in the care of haematological cancer patients who undergo allo-HSCT, thus leading to potential improvements in the treatment and management of the disease based upon evidence generated by the proposed study.

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 right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject.

The processing of this data falls under article 9(2)(j) so that research can be conducted to generate much required evidence to assist clinicians, patients, and the pharmaceutical industry to better understand the disease and develop treatment strategies to manage GVHD patients in allo-HSCT.

The funding is provided by CSL Behring Incorporated. The funding is specifically for the study described. Funding is in place until 31st October 2023. The funders will have no ability to suppress or otherwise limit the publication of findings

Certara France S.A.R.L is a data processor acting under the instructions of LA-SER EUROPE LIMITED (a Certara company). Certara France S.A.R.L is the branch in France and is the same organisation as LA-SER EUROPE LIMITED (a Certara company).

Microsoft Limited (Microsoft SharePoint Online) provides IT hosting services to LA-SER EUROPE LIMITED (a Certara company) and will store the data as contracted by LA-SER EUROPE LIMITED (a Certara company).

Neither the funder (CSL Behring Incorporated) nor any other party outside of Certara France S.A.R.L will be permitted to access or process the data.

LA-SER EUROPE LIMITED (a Certara company) and Certara France S.A.R.L maintain appropriate access controls and governance. Only authorised users, permanent employees from Certara France S.A.R.L will have access to the data.

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 (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 Agreement.

NHS England data will provide the relevant records from the Cancer Registry, SACT, RTDS, HES A&E, HES APC and HES OP datasets to Certara France S.A.R.L. The data will contain no direct identifying data items but will contain a unique person ID which can be used to link the data within each of the datasets.

The data will be pseudonymised. The applicant does not hold any cohort identifiers and all linkage will take place by NHS England's NDRS Team. The data is not permitted to be re-identified.

The data will not be transferred to any other location.

The data will be processed by analysts at Certara France S.A.R.L . The analysts at are based in France a country listed by the Information Commissioners Office (ICO) with suitable adequacy regulations which confirm an adequate data protection regime to protect personal data. The data will be stored on servers at Microsoft Limited (Microsoft SharePoint Online) located in England.

Certara France S.A.R.L stores data on the Cloud provided by Microsoft Limited (Microsoft SharePoint Online).

The data will be stored on servers at Microsoft Limited (Microsoft SharePoint Online) located in England.

Certara France S.A.R.L stores data on the Cloud provided by Microsoft Limited (Microsoft SharePoint Online).

The data will be accessed by authorised personnel via remote access.

The data will be stored on a UK based secured cloud server. Data will be accessed in the UK and France as the programming software and statisticians at Certara France S.A.R.L are located in France (a country listed by the UK’s Information Commissioners Office (ICO) with suitable adequacy regulations which confirm an adequate data protection regime to protect personal data).

Personnel are prohibited from downloading or copying data to local devices.

The data will be stored in England and Wales and will not leave the EEA at any time.

Access is restricted to epidemiologists, statisticians, and data analysts within Certara France S.A.R.L who have authorisation from the Principal Investigator. All such individuals are substantive employees of Certara France S.A.R.L

Microsoft Limited (Microsoft SharePoint Online) and CSL Behring Incorporated are not permitted to access the data.

Only substantive staff (epidemiologists, statisticians, and data analysts) with training in data protection at Certara France S.A.R.L have access to the data for the purpose of conducting the study.

The data will not be linked with any other data.

No efforts to re-identify individuals will be undertaken.

Epidemiologists, statisticians, and data analysts from Certara France S.A.R.L are based in France and will analyse the data for the purposes described above.

To optimise the potential public benefits from the use of the data, study findings will be disseminated in the form of conference abstracts and peer-reviewed publications. The conferences to which abstracts will be considered for submission will include the European Society for Blood and Marrow Transplantation (EBMT) annual meeting which is open to patients and includes a “Patient, family and donor day” thereby providing opportunities to disseminate findings to a wider audience.

The expected outputs of the processing will be:

• Presentations at appropriate conferences that include EBMT (European bone marrow transplant) annual meeting, BMT Tandem Meetings (ASTCT & CIBMTR)

• Abstracts and posters

• Submissions to peer reviewed journals by early 2025

The study findings will be published in an open access peer-reviewed journal by early 2025. As such, the manuscript will be accessible to members of the public for free through the journal’s website.

• A report of findings to the study sponsor, CSL Behring Incorporated, at the end of the study in May/June 2024

• A secondary report of findings to the study sponsor, CSL Behring Incorporated, at the end of the study in late 2024

CSL Behring Incorporated are developing drugs in this area and may use the report findings to aid with initial reviews to highlight the unmet need for the drug or how to position it into the market if it proves to be successful in clinical trials (but would typically not be the only data on GvHD burden, as information needs to be provided from many countries), however the outputs, including the report and peer-reviewed publications will primarily be used to increase awareness of the entire scientific community, physicians and decision makers, regarding this disease.

CSL Behring Incorporated will only receive aggregated data as per the protocol and SAP the study develops, similar to aggregated data that will be presented in tabular format for scientific communications.

Only data relating to the study objectives will be presented in both the study report and published abstracts and manuscripts. All outputs will contain aggregated data only, with small numbers suppressed as per HES Analysis guide. Therefore, no individual level data will be presented in any publication and any findings for less than 10 patients will be suppressed to safeguard any possibility of identifying the subjects who contributed to this data.

This study is hoped to provide useful real-world background information on GVHD and its subtypes (acute and chronic) to anyone with an interest in this disease area.

In addition, this study is hoped to contribute considerable benefits to researchers, clinicians, policy makers and payers in England and elsewhere by providing:

• A better understanding of the natural history and epidemiology of GVHD following allo-HSCT therefore identifying unmet needs and identifying opportunities for improving treatment. Such evidence may contribute to the revision of clinical guidelines and the development of novel therapies. Ultimately this will benefit patients by reducing morbidity and mortality associated with GVHD.

• A better understanding of the burden of GVHD on the healthcare system, thereby providing benchmark data for the possible benefits of future GVHD treatments on the healthcare system. It is anticipated that these findings will particularly benefit payers including the NHS by improving the understanding of GVHD and thereby facilitating effective and efficient planning and resource allocation. This information may therefore ultimately lead to potential cost savings.

• A better understanding of the clinical outcomes of GVHD and its subtypes, thereby improving the overall understanding of this complication and providing clinical data to which the benefits of novel GVHD therapies may be compared.

In addition, this study is hoped to contribute considerable benefits to patients by providing:

• A better understanding of the natural history and epidemiology of GVHD following allo-HSCT therefore identifying unmet needs and identifying opportunities for improving treatment. Such evidence may contribute to the revision of clinical guidelines and the development of novel therapies. Ultimately this will benefit patients by reducing morbidity and mortality associated with GVHD.

LA-SER EUROPE LIMITED (a Certara company) and CSL Behring Incorporated have a documented history of collaborative scientific publication and dissemination of evidence relating to GVHD in France and Germany. The findings from the present study will add to this body of work by providing evidence relating to the clinical and economic burden of GVHD in England.

The purpose of this study is to evaluate patient characteristics (demographic and clinical), clinical outcomes, treatment patterns, and healthcare resource utilisation in haematological cancer patients who underwent allo-HSCT in England according to whether they developed GVHD. This complication is under-studied, particularly in England and as such contemporary data relating to the clinical and economic implications of GVHD are required to fill this evidence gap.

In addition, the project will involve key opinion leaders, including those involved in important organisations such as the EBMT and other learned societies. The EBMT in particular generate guidelines and handbooks related to the management of allo-HSCT recipients and therefore by involving these key opinion leaders will facilitate the translation of these findings to real-world public benefits.

Not stated in the register.