BILAG Biologics Prospective Cohort: The Use of Novel Biological Therapies in the Treatment of Systemic Lupus Erythematosus (SLE)

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Expected output

[2 paragraphs unchanged] To date, we have the University of Manchester has published 2 manuscripts in peer-reviewed journals (https://pubmed.ncbi.nlm.nih.gov/29216396/ and https://pubmed.ncbi.nlm.nih.gov/28431104/ see "Evidence" section for list). In addition, we the University of Manchester regularly present work coming out of the study at national and international [6 words unchanged] list). Outputs contain aggregated data and record level data are not reported. The study is funded until 2021, with on-going negotiations for funding past this beyond this. [8 paragraphs unchanged]

Benefits reported

As stated above, The BILAG BR has played a vital role in, [111 words unchanged] of the conditions being that patients were enrolled on the BILAG BR. It is likely that several more of these products will gain licences for use in SLE, or become part of clinical commissioning statements in the future and the presence of the BILAG BR is very important in this process. A major challenge for all research studies is the dissemination and implementation [38 words unchanged] consultants to generate ideas for new analyses based on clinically relevant questions. The majority of the research is presented at national and international conferences. Lay summaries are created to make the research more accessible to the patients and their families. [1 paragraph unchanged]

Unchanged: Objective for processing, Processing activities, Expected measurable benefits.

Text removed is struck through; text added is underlined. Unchanged paragraphs are summarised rather than repeated.

Datasets: + Cancer Registration Data; + Civil Registrations of Death; + Demographics · − MRIS - Personal Demographics Service; − MRIS - Scottish NHS / Registration

Objective for processing

This study will document use of biologic drugs in patients with Systemic Lupus Erythematosus (SLE) in order to assess their efficacy and safety during routine clinical use. 2 cohorts will be recruited: a cohort treated with biologic therapy and a biologically naïve group. The University of Manchester requires data from NHS Digital in order to enhance the safety data already captured by the BILAG Biologics Prospective Cohort. This is a long-term observational study to monitor the safety of new biologic and targeted therapies prescribed for Systemic Lupus Erythematosus (SLE) during routine healthcare, specifically to understand if these new drugs increase the risks of developing cancer or premature death above the expected risks in a population with similar disease characteristics not receiving these therapies. Detailed and fully adjusted analyses of the full dataset will take place in the University of Manchester Data Safe Haven where BILAG BR 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 rheumatology and nephrology 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 have robust and complete data on these important outcomes. The primary aim of establishing the BILAG Biologics Prospective Cohort is to ascertain whether using biologics in the routine treatment of SLE is associated with an increased risk of being hospitalised for infection, compared to SLE patients with similar disease activity receiving conventional therapies. The secondary purpose of the BILAG Biologics Prospective Cohort is to determine the long-term efficacy of biological therapies in the treatment of SLE. The University of Manchester’s justification for processing is for the public interest in the area of medical research to further scientific understanding of inflammatory diseases and therapeutic pathways. A further aim of the study is to collect biological samples from patients receiving biologic therapy in the UK to allow us to test whether there are variations in genes which can predict who will respond and who may get serious side effects. The risk of potential harm, in terms of moral or ethical issues, to the public by the dissemination of data from the study is minimal. Data will be held securely and the level 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. No NHS Digital data will be shared with any third parties including the participating pharmaceutical companies. The primary objective of the study is to compare the risk of key safety outcomes (including cancer and death) between UK patients with Systemic Lupus Erythematosus (SLE) starting any new biologic, biosimilar or other new targeted therapy with an appropriate comparator cohort already established in the BILAG BR. 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 The BILAG BR study started in 2009 (first participant recruited Sept 2010) at the University of Manchester with the aim to monitor the long-term safety of newer drugs prescribed in the NHS to treat patients with SLE. The BILAG BR has received unrestricted educational grant funding from Roche, LUPUS UK and GlaxoSmithKline (the company which manufactures the biologic Belimumab). Under the terms of this, the BILAG BR carries out reporting of serious adverse events to the pharmacovigilance team at GSK. No NHS Digital data are included in these reports, until they have been independently reported to the BILAG BR team by the centre on the CRF. However, the Chief Investigator and the BILAG BR team at the University have full academic independence when analysing the study data and are able to work independently of pharmaceutical industry influence. All decisions concerning analyses, interpretation and publication are made autonomously of any industrial contribution. Members of the BILAG BR University of Manchester team and staff complete an annual declaration in relation to conflicts of interest. With nearly 10 years of follow-up in some patients, the study continues to monitor for long-term risks of the original biologic therapies, whilst at the same time, monitoring the safety of newer drugs (including biosimilars) that have been used in the routine treatment of patients with SLE. The funders will have no scientific input into this study and no influence over the outputs. No NHS Digital data in any format will be transferred to the pharmaceutical companies. Aggregated NHS Digital data, analysed in the Data Safe Haven may be published and in the public domain in the form of aggregated data tables/manuscripts that have been accepted by scientific journals and accepted for publication. The source of all data will be acknowledged in the manuscript. 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 consultant 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 SLE, as well as additional information about other illnesses that develop in patients 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 SLE in the future. The data will only be used for the BILAG BR study 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 >5 years old, have a diagnosis of SLE, are under the care of a consultant at a participating centre, and are newly starting a biologic or one of the more recently developed biosimilars, or have started treatment in the last 12 months 2) Comparator cohort Patients are eligible for this cohort if they are >5 years old, have a diagnosis of SLE, are under the care of a consultant at a participating centre, have never been exposed to any biologic therapy (biologically naïve), and are newly starting a standard therapy such as mycophenolate mofetil, azathioprine or cyclophosphamide, or have started therapy in the last month Recruitment is coordinated at a national level. The study is based in England, Wales and Scotland. Due to the nature of the study, new biologics, targeted therapies and 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. Notifications for mortality and cancer data is required from where the study began with the 1st participant in 2010. The study has received some data from NHS Digital on these outcomes since the study started. 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 hospital 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. Under this Agreement, the University of Manchester is permitted to access data from participants recruited before 01/09/2020 as adults (aged 16 or over) using versions 3, 4, 5 or 6 of the Patient Information Sheet and Consent Form only. The University of Manchester is not permitted to retain or receive any data relating to participants recruited when aged under 16 on the basis of participant assent and parental consent. Only the minimum data required to identify patients will be used. The BILAG BR will supply the BILAG BR study ID, date of birth and NHS number to be flagged and the data received back will be the BILAG BR study ID and the cancer and death details. The BILAG BR does not require the patient identifiable fields such as NHS number and date of birth in the data file received and this will minimise the data required. The University of Manchester is the data controller for the study. The University of Manchester is the only organisation which processes the data NHS organisations are involved in the study as patients are recruited through hospital departments. Nurses and clinicians recruit participants to the study and provide routine clinical data into the BILAG BR database. They are not involved in the processing of study data.

Processing activities

This is an observational prospective cohort study to compare the risk of development initially over 3 years, of the endpoint in two cohorts: (i) a group of patients with SLE newly exposed to a biologic therapy and (ii) A comparison cohort of patients with SLE newly exposed to conventional, non-biologic therapy, with an equivalent disease severity. We intend to flag both the biologic cohort and the comparison cohort for notification of mortality and cancer registration. A copy of the death certificate will be required for those who die and a copy of the histology for those who develop a malignancy. This will enable us to monitor any adverse events in both cohorts The study team provides the following identifying details for BILAG BR study participants to NHS Digital to allow the flagging for mortality and cancer notifications to take place: • BILAG BR Study Number; • Date of birth; • NHS number. This will allow participants to be identified and flagged Participants’ patient entries are traced and flagged by the Medical Research Information Service at NHS Digital. The data the study team will receive back from NHS Digital will include participants’ BILAG BR Study Number and cancer and death details. Data obtained from NHS Digital data will be downloaded into the University of Manchester’s Data Safe Haven (DSH) for two purposes: Element 1 A flag (BILAG BR Study Number, occurrence of cancer/death – Yes/No) will be transferred from the DSH to the BILAG BR portal to show that the patient has had a cancer/death. No other patient level NHS Digital data will be transferred to the BILAG BR portal, just the fact that either of these events has been reported to NHS Digital. This will allow the study team to contact the hospital to obtain further details surrounding the event. Once the study team have this information confirmed by the hospital team, this is no longer classified as NHS Digital data, but BILAG BR 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 Data Safe Haven. When the BILAG BR 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 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 BILAG BR 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 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 Steering Committee. Only the University of Manchester will process the NHS Digital data under this Data Sharing Agreement. Data will not be matched to publicly available data and there will be no requirement/attempt 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 will only occur within the University of Manchester’s Data Safe Haven. The study data will not be linked with any other sources. All data processing is carried out by substantive employees of the University of Manchester and NHS Digital data access will only occur within the University of Manchester’s Data Safe Haven.

Expected output

Not stated in the previous version; added here.

The outputs for the BILAG BR study will include reports, submissions to peer reviewed journals and presentations and posters at relevant conferences. BILAG BR 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.

Dissemination and communication of results to stakeholders includes regular review by BILAG BR project boards, including the BILAG BR Steering Committee and BILAG BR Data Monitoring and Ethics Committees. The study also has a comprehensive study website (https://sites.manchester.ac.uk/bilag) which has areas aimed at Hospitals/Sites participating, study participants and researchers.

To date, we have published 2 manuscripts in peer-reviewed journals (https://pubmed.ncbi.nlm.nih.gov/29216396/ and https://pubmed.ncbi.nlm.nih.gov/28431104/ see "Evidence" section for list). In addition, we regularly present work coming out of the study at national and international scientific meetings/conferences (see "Evidence" section for list). Outputs contain aggregated data and record level data are not reported.

The study is funded until 2021, with on-going negotiations for funding past this

The BILAG BR 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.

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?

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

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

The first patient was enrolled into BILAG BR in 2010, with the study having been set up in 2009. Therefore, over the next few years the study team will start to observe patients who have been receiving biologic therapies for 10+ years. This is an unexplored area in this patient group. Hence, the BILAG BR can and will give unique insight into the very long-term use of biologics, 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 originator biologics to 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 biosimilar use with 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 BILAG BR 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.

Expected measurable benefits

There have been very few major advances in the treatment of Systemic Lupus Erythematosus (SLE) over the past 35 years. In the past 5 years however, there has been an explosion of interest in developing new molecules for the treatment of SLE. A number of approaches have been proposed and are currently in various stages of development including B-cell depleting therapies, IL6 and IL10 blockade as well as inhibition of co-stimulatory molecules, TNF-blockade and lymphodepletion. As these drugs become available for diseases such as RA, off-licence use in SLE is already underway and it is likely that several of these products will gain licences for use in SLE over the next 5 years. However, clinical trials are limited by patient numbers and study duration and therefore are under powered to study potentially important adverse events. In addition, clinical trials tend to exclude patients who have been exposed to other biological therapies in the past and therefore the potential medium-term interactions between various therapeutic approaches cannot be adequately studied. It was therefore decided to establish the BILAG Biologics Prospective Cohort to monitor the long-term safety and efficacy of these new biologic treatments in patients with SLE 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 BILAG BR has many stakeholders, not only clinicians and patients, and each of these is considered in turn. 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 himself. The fact that these safety queries can be discussed with the team will be advertised more widely through newsletters and websites (BILAG BR). The pharmacoepidemiological research programme within the BILAG BR will be further driven by knowledge gaps identified in systematic reviews, such as during guideline development. Patients: The study team have developed a relationship with LUPUS UK, one of the previous funders of the study, which also provides insight into the questions patients have about these therapies. The study has a website www.sites.manchester.ac.uk/bilag 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. Regulators: The BILAG BR has played a vital role in, and had a significant influence on obtaining access to the biologic therapies, rituximab and belimumab for SLE patients. In 2013 an Interim Clinical Commissioning Statement was published by NHS England, which specified that they would fund the use of Rituximab in SLE patients, as long as a number of conditions were fulfilled, including that the patients were registered with the BILAG BR, to allow for effective monitoring and follow-up. This was followed in 2016, by NICE guidelines allowing access to the licenced drug Belimumab for SLE patients, once again with one of the conditions being that patients were enrolled on the BILAG BR. It is likely that several more of these products will gain licences for use in SLE, or become part of clinical commissioning statements in the future and the presence of the BILAG BR is very important in this process 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.

Benefits reported

Yielded Benefits is not a requirement for new applications. As stated above, The BILAG BR has played a vital role in, and had a significant influence on obtaining access to the biologic therapies, rituximab and belimumab for SLE patients. In 2013 an Interim Clinical Commissioning Statement was published by NHS England, which specified that they would fund the use of Rituximab in SLE patients, as long as a number of conditions were fulfilled, including that the patients, with their consent should be registered with the National BILAG Biologics Register or UK Juvenile SLE (JSLE) Cohort Study until their transition to the adult service, to allow for effective monitoring and follow-up. This was followed in 2016, by NICE guidelines allowing access to the licenced drug Belimumab for SLE patients, once again with one of the conditions being that patients were enrolled on the BILAG BR. It is likely that several more of these products will gain licences for use in SLE, or become part of clinical commissioning statements in the future and the presence of the BILAG BR is very important in this process. A major challenge for all research studies is the dissemination and implementation of results. The close collaboration with the lupus community, through BILAG, and its 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 consultants to generate ideas for new analyses based on clinically relevant questions. The majority of the research is presented at national and international conferences. Lay summaries are created to make the research more accessible to the patients and their families. 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 SLE in the future as well as allowing them access to therapies otherwise not approved.