MR806: BSPAR Enbrel Cohort Study (BSPAR EN) (Formerly: BSPAR, BNDR (Biologics and New Drugs Registry) for Juvenile Idiopathic Arthritis ( JIA ) patients)

The University of Manchester have received data from NHS Digital in order to enhance the safety data already captured by the British Society for Paediatric and Adolescent Rheumatology (BSPAR) Etanercept Cohort Study (BSPAR ETN). This is a long-term prospective observational cohort study to monitor the safety of the biologic drug etanercept and its biosimilars (trade names Enbrel, Benepali and Erelzi all come under the generic name Etanercept) in the treatment of juvenile idiopathic arthritis (JIA) in routine healthcare, specifically to understand if these drugs increase the risk of developing cancer or premature death, above that of what would be expected in a population with similar disease characteristics, not receiving these therapies.

Detailed and fully adjusted analysis of the full dataset will take place in the University of Manchester Data Safe Haven where BSPAR ETN data will be combined with the NHS Digital data on cancer and mortality to see if there is any increased risk of cancer and premature death due to these drugs. The study already captures extensive healthcare data on consented study participants via the NHS paediatric, adolescent and occasionally, adult rheumatology hospital teams. This includes the capture of special category data (namely health data and ethnicity). Data from NHS Digital on the occurrence of key outcomes of interest (specifically cancer and death) will ensure that the study has robust and complete data on these important outcomes.

The University of Manchester has determined the lawful basis for processing research data under Article 6 of UK GDPR for these data is “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” (Art 6; 1. e.): For sensitive information under Article 9 of UK GDPR, the legal reason is: “the processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes… 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”. (Art 9; 2, j.).

All personal data from research participants is processed by The University of Manchester only.

Data will be held securely, and the amount of personal data processed will be minimised to ensure safeguarding of the data. Published results from the full analysis will be in the form of aggregated datasets and individual personal data will not be shared outside of the study team and only where appropriate legal agreements are in place. NHS Digital data will not be shared with any third parties.

The primary objective of the study is to compare the risk of key safety outcomes (including cancer and death) between UK patients with JIA starting any etanercept therapy with an appropriate comparator cohort of patients with JIA starting the standard therapy, methotrexate, already established in the BSPAR ETN. The data requested will allow the study team to link the hospital and treatment data already captured under the study consent with national cancer and death data on study participants to ensure the register has no missing data on these two major outcomes. This will then allow the study to understand whether there is any increased risk of cancer and death in patients receiving these drugs.

Over the past decade, biologic medicines (which are made from living organisms using biotechnology methods) have become increasingly used as therapy in patients with Juvenile Idiopathic Arthritis (JIA). A UK-wide study looking at the long-term safety of one of these treatments, Enbrel, was established in 2004, initially at the University of Birmingham, and then moving to the University of Manchester in 2012. The study continues today with nearly 2,000 participants registered by paediatric and adolescent rheumatology departments at NHS hospitals across the UK. Continuous monitoring and analysis of the BSPAR EN data from participants in this study over the years has, and continues to be, a valuable resource for policymakers such as the National Institute for Health and Clinical Excellence (NICE) in its consideration of biologic drugs, as well as providing important safety information to healthcare professionals, patients, product manufacturers and medicines regulatory agencies such as the European Medicines Agency (EMA). Data from the study to date have provided doctors and patients with reassurance regarding the short to medium-term (5-10 years) safety of Enbrel.

Information is currently collected by regular clinical questionnaires which are sent to the hospitals asking about what drugs the patient is receiving and how severe their disease is. The University of Manchester also ask doctors and nurses to report side effects but the University of Manchester don’t always get to know about these for a number of reasons.

It could be that the patients were treated for a medical event at a completely different hospital and the paediatric rheumatologist was not aware of this. This linkage to NHS Digital will provide an invaluable additional source of information about both long-term outcomes, such as rare diseases like cancer which may not developed until years after the diagnosis of JIA, as well as additional information about other illnesses that develop in children, young people and also young adults with this condition, such as infection and the need for surgery. Through this linkage the University of Manchester will enhance the data the University of Manchester have available on the development of other important morbidities and thus can study which aspects of the disease or its treatment are associated with these outcomes.

Common to most research studies, this linkage may not immediately benefit the participants in the study currently, but better understanding course of the illness will help in choosing the best treatment for people with JIA in the future.

The data will only be used for the BSPAR ETN and is not part of a wider project; The data subjects for this study consist of 2 types of cohorts

1) Exposed cohort

Patients are eligible for this cohort if they are <18 years old, have a diagnosis of Juvenile Idiopathic Arthritis (JIA), are under the care of a paediatric, adolescent or, occasionally, adult rheumatologist, and are newly starting the biologic Enbrel or one of the more recently of the generic etanercept biosimilars (including Benepali and Erelzi), or have started therapy in the last 6 months. For clarity in this Agreement, Etanercept is used to include both the biologic Enbrel and any biosimilars, such as Benepali and Erelzi.

2) Comparator cohort

Patients are eligible for this cohort if they are <18 years old, have a diagnosis of Juvenile Idiopathic Arthritis (JIA), are under the care of a paediatric, adolescent or, occasionally, adult rheumatologist, they have never been exposed to any biologic therapy (biologically naïve), and are newly starting the standard therapy methotrexate, or have started therapy in the last 6 months.

Recruitment is co-ordinated at a national level. The study is based in England, Wales and Scotland. Historically, patients with >6months therapy with Enbrel were included, but this has since been limited to those recruited within 6 months of their first exposure to Etanercept. Follow-up of these historic patients with increased pre-recruitment exposure continues. Due to the nature of the study, new Etanercept biosimilars will become eligible recruitment therapies as they are launched to market.

The purpose of the study is to obtain comprehensive long-term safety data on patients receiving these new therapies, and in particular with reference to NHS Digital data, to observe if participants receiving these new drugs are at a higher risk of cancer or premature death compared to patients with similar disease not receiving these drugs.

The study requires Civil Registration Mortality data and cancer data for the consented participants taking part in the study. The additional data from NHS Digital will allow the study to have full outcome data on cancer and death and will enhance the BSPAR ETN dataset.

Notifications for mortality and cancer data is required from where the study began with the 1st participant in 2004. Under previous iterations, the study has received some data from NHS Digital on these outcomes since the study started in 2004. The study currently holds ethical approval to continue the long-term follow of study participants until 2021 and the data over a long period will play an important part in order to understand the long-term safety of the drugs used.

Although the study will capture most cancer and death outcome data for the study via the NHS hospitals, there are occasions where the study will not be told that one of these events has occurred (i.e. the rheumatology team weren’t aware, the patient may have been treated in a different hospital) and therefore flagging with NHS Digital will allow complete data on these important outcomes. Complete data on this dataset can only be achieved with flagging with NHS Digital

Only the minimum data required to identify patients will be used. The BSPAR ETN will supply the BSPAR ETN study ID, date of birth, sex and NHS number to be flagged and the data received back will be the BSPAR ETN study ID and the cancer and death details. The BSPAR ETN does not require the patient identifiable fields such as sex and date of birth in the data file received and this will minimise the data required

The University of Manchester and the British Society of Rheumatology act as joint data controllers. The University of Manchester is the only organisation which processes the data.

NHS organisations are involved in the study as patients are recruited through paediatric, adolescent and occasionally adult rheumatology departments. Nurses and clinicians recruit participants to the study and provide routine clinical data into the BSPAR ETN database. They are not involved in the processing of study data. There are no finders/commissioners involved.

This Agreement permits continued retention of the data only. The Agreement does not permit any other processing of the data.

All organisations party to this agreement must comply with the Data Sharing Framework Contract requirements, including those regarding the use (and purposes of that use) by "Personnel" (as defined within the Data Sharing Framework Contract i.e.: employees, agents and contractors of the Data Recipient who may have access to that data).

The study team provides the following identifying details for BSPAR ETN study participants to NHS Digital to allow the flagging for mortality and cancer notifications to take place:

• BSPAR ETN Study Number;

• Date of birth;

• Sex;

• NHS number.

This will allow participants to be identified and flagged.

Participants’ patient entries are traced and flagged by the at NHS Digital. The the study team at the University of Manchester will receive back pseudonymised data from NHS Digital, which will include participants’ BSPAR ETN Study Number and cancer and death details, such as cause of death, ICD codes and date of death.

The data is stored at two locations, one owned by Equinix, the other owned by Digital Realty. University of Manchester simply rent the physical location of each site. All server, storage and network infrastructure used by University of Manchester within the data centre is owned by University of Manchester, operated and maintained by University of Manchester IT staff and is securely caged off from other Equinix / Digital Reality customers' equipment. Nothing is shared with 3rd parties. University of Manchester lease physically secure hosting space from Equinix. No Equinix or Digital Reality employees have access to the data. No shared services are consumed from Equinix.

Physical access to the data centre is strictly limited to University of Manchester Data Centre staff and a limited number of authorised IT Services staff. The Data Centre is protected by physical and electronic access security systems, swipe card access in and out of the data centre and CCTV coverage. The data centre is locked down out of hours and access is discouraged, but can be arranged by prior agreement with the University Infrastructure Manager.

The data is stored and processed on the University of Manchester virtual machine (VM) service which has encrypted at rest storage. The VM Service is hosted across both data centres for resilience and sustainability. Only those researchers on the research team who have been trained and are authorised to access the data have access to the VM provided by the service.

A valid Active Directory account and relevant security group membership is required to login to the VM and access specific project data. Account credentials are unique to each member of staff and only the account owner knows the password. Access is also protected by two-factor authentication.

Data obtained from NHS Digital data will be downloaded into the University of Manchester’s Data Safe Haven (DSH) for two purposes:

NB. All data received from NHS Digital will be held in the DSH and will not leave as per the agreement between the existing organisational agreement between the UoM and NHS Digital. All analyses will take place at the UoM-by-UoM researchers, within the Data Safe Haven. All analyses will be carried out on aggregated data, which will contain no personal sensitive data i.e. all identifiers will be removed. Only aggregated data tables will extracted from the Data Safe Haven.

Element 1

A flag (BSPAR ETN Study Number, occurrence of cancer/death – Yes/No) will be transferred from the DSH to the BSPAR ETN portal to show that the patient has had a cancer/death. No other patient level NHS Digital data will be transferred to the BSPAR ETN portal, just the fact that either of these events has been reported to NHS Digital. The study would never share individual patient level data derived or as provided solely from NHS Digital. T flag will allow the study team at the University of Manchester to contact the hospital to obtain further details surrounding the event, such as what the event was, when it occurred and any discharge summary. Once the study team have this information provided by and confirmed by the hospital team, this is no longer classified as NHS Digital data, because it has been sent to the study team, independently by the NHS, but BSPAR ETN study data which can be used to enhance the safety data captured in the study.

Element 2

The full NHS Digital dataset will be stored in the University of Manchester Data Safe Haven (DSH). When the BSPAR ETN study reaches a sufficient size, usually at pre-determined points based on the number of patients recruited to the study and the length of exposures to their treatments, a pre-specified analysis will be undertaken by researchers at the University of Manchester, against the primary objectives of the study. Prior to starting this analysis, a more detailed analysis plan will be prepared by the statistician.

A copy of the BSPAR ETN dataset will be transferred into the Data Safe Haven and, when required according to the analysis plan, the full NHS Digital data on deaths and cancers will be linked to the BSPAR ETN Dataset in order to perform statistical analyses of the larger combined dataset to allow the University of Manchester to undertake the specified analysis. Only aggregated data in the form of summary data tables will be exported out of the Data Safe Haven to allow the University of Manchester to publish the results of the study which will help inform clinicians, patients, regulators and policy makers on the long-term safety of these drugs. An updated research plan, devised by the University of Manchester, is shared annually with the BSR.

Only the University of Manchester will process the NHS Digital data under this Data Sharing Agreement and there will be no attempt or requirement to re-identify individuals. The Data processing is only carried out by substantive employees of the University of Manchester who, as part of their employment, carry out regular mandatory training in data protection. Processing and NHS Digital data access will only occur within the University of Manchester’s Data Safe Haven. The study data will not be linked with any other sources. There are organisational agreements between the University of Manchester and NHS Digital that cover this.

The outputs for the BSPAR ETN study may include reports, submissions to peer reviewed journals, such as paediatric journals, including Rheumatology, to reach a paediatric audience, and presentations and posters at relevant conferences, such as the British Society for Paediatric and Adolescent Rheumatology (BSPAR) at the British Society for Rheumatology (BSR) and the Annual European Congress of Rheumatology. Target journals include Lancet Rheumatology, Rheumatology, Archives of Disease in Childhood, Arthritis and Rheumatology and other similar publications. BSPAR ETN study data will be combined with NHS Digital data to maximise data available and used in outputs.

Only aggregated data will be included in any study outputs and data will be safeguarded by ensuring that results which include small numbers which could identify study participants will be excluded, in line with the HES analysis guide. These outputs will be produced when the study has sufficient person-years follow-up to answer the original hypotheses, but is likely to be after June 2022

Dissemination and communication of results to stakeholders includes regular review by BSPAR ETN project boards, including the BSPAR ETN Steering Committee and BSPAR ETN Data Monitoring and Ethics Committees. The study also has a comprehensive study website (https://sites.manchester.ac.uk/bcrdbspar/) which has areas aimed at Hospitals/Sites participating, study participants and researchers. In terms of exploitation of the results/outputs, the British Society for Rheumatology also has links back to the BSPAR ETN study site, in addition to details and the process of applying to access study data for research purposes (https://www.rheumatology.org.uk/practice-quality/registers).

Publications:

Kearsley-Fleet et al. (2020) “Frequency of biologic switching and the outcomes of switching in children and young people with juvenile idiopathic arthritis: a national cohort study”. Lancet Rheumatology; 2(4):e217

Davies et al (2020) “The risk of uveitis in patients with JIA receiving etanercept: the challenges of analysing real-world data”. Rheumatology; 59(6):1391.

Kearsley-Fleet et al. (2019) “Methotrexate persistence and adverse drug reactions in patients with juvenile idiopathic arthritis”. Rheumatology; 58(8):1453.

Kearsley-Fleet et al. (2016) “Factors associated with choice of biologic among children with Juvenile Idiopathic Arthritis: results from two UK paediatric biologic registers”. Rheumatology; 55(9):1556.

Kearsley-Fleet et al. (2016) “Factors associated with improvement in disease activity following initiation of etanercept in children and young people with Juvenile Idiopathic Arthritis: results from the British Society for Paediatric and Adolescent Rheumatology Etanercept Cohort Study”. Rheumatology; 55(5):840.

Kearsley-Fleet et al. (2015) “Growth in Children and Adolescents with JIA after 2 years of treatment with Etanercept: Results from the BSPAR Etanercept Cohort Study”. Rheumatology; 54(7):1279.

Davies et al. (2016) “Mortality rates are increased in patients with severe juvenile idiopathic arthritis (JIA): Results from the BSPAR Etanercept Cohort Study (BSPAR-ETN)”. Archives of disease in childhood; 102(2):206.

Davies et al. (2015) “Medically Significant Infections are Increased in Patients with Juvenile Idiopathic Arthritis Treated with Etanercept: Results from the British Society for Paediatric and Adolescent Rheumatology Etanercept Cohort Study”. Arthritis & Rheumatology; 67(9):2487.

Southwood et al. (2011) “Duration of etanercept treatment and reasons for discontinuation in a cohort of juvenile idiopathic arthritis patients”. Rheumatlogy; 50(1):189.

Conferences attended for posters and presentations:

British Society for Paediatric and Adolescent Rheumatology Annual Conference: 2012, 2013, 2014, 2015, 2017, 2018, 2019

American College for Rheumatology Annual Conference: 2013, 2014, 2017, 2018

British Society for Rheumatology Annual Conference: 2013, 2014, 2015, 2018, 2019

European Alliance of Associations for Rheumatology, (EULAR) Conference: 2014, 2018, 2019

Paediatric Rheumatology European Society Congress: 2014, 2019

The BSPAR ETN study releases occasional newsletters which can be accessed via the study website which describes the progress of the study and latest study findings in language targeted at study participants or individuals from a hospital site.

A major challenge for all research studies is the dissemination and implementation of results. The close collaboration with BSR representatives has ensured that study data are disseminated as widely as possible, including to policy makers such as NICE. The study team also work with rheumatologists to generate ideas for new analyses based on clinically relevant questions. The majority of the research is presented at national and international conferences. The study has also established an ongoing and mutually beneficial collaboration with “JIA at NRAS” (National Rheumatoid Arthritis Society; a patient-led organisation) as one route of dissemination. Lay summaries are created to make the research more accessible to the patients and their families.

Planned future analysis/output will focus on two related and equally important research questions:

(1) What is the long term risk of exposure to established biologic therapies?

The first patient was enrolled into BSPAR ETN in 2004. Therefore, over the next few years the study team will start to observe who has been receiving etanercept therapy for over 10 years. This is an unexplored area due to the very nature of when this drug was introduced. Hence, the BSPAR ETN can and will give unique insight into the very long-term use of etanercept, including treatment persistence and long-term safety, such as late occurrence of malignancies. The presence of equally long follow-up in an untreated comparison cohort will add to these analyses.

(2) What is the absolute and relative effectiveness and risk of new biologic therapies?

The most challenging analysis will be to study the risks of biosimilar therapies. There has been a noticeable switch in some patients from etanercept originator Enbrel to etanercept biosimilar products in the UK, despite a lack of supporting evidence about the safety of switching. The study team’s analyses in this area will include a comparison of first-line etanercept biosimilar use with etanercept originator, using recent historical originator data as a comparison, as well as the safety of a switch programme. An analysis of outcomes after switching needs careful consideration due to inherent selection bias (patients who switch between originator and biosimilar have usually experienced a response to the originator and by definition, have not experienced a treatment limiting adverse event). This selection bias will have to be considered when changes in disease activity and occurrence of adverse events following a switch are analysed and the rich historical data within the BSPAR ETN should allow for this. Additional study data collection forms are in place to ensure as much data as possible is captured regarding disease activity data at the point of switching.

Ensuring output achieves maximum benefit for both clinicians and patients:

For any research project to achieve maximum benefit for all stakeholders it is essential to understand the needs of each stakeholder, all the while asking the “so what?” question. Capturing data without a specific purpose will lead to disinterest and disinvestment from the people the study team want to benefit the most. The BSPAR ETN has many stakeholders, not only clinicians and patients, and each of these is considered in turn.

Patients:

The study team have developed a strong relationship with JIA-at-NRAS which also provides insight into the questions patients have about these therapies. The study has a website www.sites.manchester.ac.uk/bcrdbspar with a dedicated section for study participants. This is regularly updated with information about the study, with lay summaries of all work being of particular importance.

Clinicians:

The study will continue a programme of outputs to address questions related to key safety concerns of biologic therapies based on email queries, discussions at conferences (locally, nationally and internationally) and other communications as well as the clinical practice of the Chief Investigator herself. The fact that these safety queries can be discussed with the team will be advertised more widely through newsletters and websites (BSR and BSPAR ETN). The pharmacoepidemiological research programme within the BSPAR ETN will be further driven by knowledge gaps identified in systematic reviews, such as during guideline development.

Regulators:

The study team do not report safety events directly to the EMA and/or the UK Medicines and Healthcare products Regulatory Agency (MHRA). However, increasingly, the study’s relationship with the regulators has become more direct and the regulators have recognised the value of embedding pharmacovigilance within patient registers (as opposed to independent pharmaceutical company sponsored observational research). The study will continue to provide a vehicle for risk management as new products come to market.

British Society for Rheumatology:

The British Society for Rheumatology (BSR formerly BSPAR) and UoM have worked closely together on the BSPAR ETN since the transition of the study to UoM in 2012 and the study team share the pride of the BSR in its ongoing success. The team at UoM continually strives to maintain the highest standards of this study in part to contribute to the global profile and reputation of the BSR. The study is committed to this ongoing partnership and there is representative from BSR at the bi-annual face to face Steering Committee Meetings. The study will continue to present both study and scientific updates at the annual Paediatric and Adolescent Rheumatology autumn conference and work with the BSR to explore even greater ways to disseminate findings, support recruitment and data collection, and to promote the study.

Information from the BSPAR ETN has had significant influence on the clinical practice in the UK and more widely. Evidence emerging from the BSPAR ETN has influenced National Institute for Health and Care Excellence (NICE) technology appraisals (TA), UK and other clinical practice guidelines, and patient information sheets. Particularly regarding the NHS England Clinical Commissioning Policy Statement “Biologic Therapies for the treatment of Juvenile Idiopathic Arthritis (JIA)” published in 2015. These influences have resulted in more consistent prescribing across the country. In addition, the NHS England Statement has included a paragraph encouraging registration into the register: “All children who commence treatment with a Biologic should be offered the option of enrolling in the appropriate long-term national Registries. These Registries are designed to provide long-term safety data for all these drugs and enrolment of data to the Registries is strongly recommended.”

To date, 8 original papers have been published on the BSPAR ETN data since the study moved to the University of Manchester in 2012 (and one prior to the move). The research outputs from the BSPAR ETN study have contributed to a recent request from the Data Monitoring and Ethics Committee (DMEC) for the Steering committee to review the biologics and cancer risk statement, used by paediatric rheumatologists and specialist nurses when counselling families, to potentially provide further reassurance. The Committee decided not to amend it currently, but to re-confirm the position, with further cancer data provided (on the additional patients in the BSPAR ETN) the University of Manchester could be a position to fully review this statement should DMEC raise an updated request.