NHS Digital Data Release Register - reformatted

Northwest Ehealth Limited projects

132 data files in total were disseminated unsafely (information about files used safely is missing for TRE/"system access" projects).

VICTORION-Spirit: Phase IIIb, multicentre, randomised controlled study to evaluate the implementation of inclisiran sodium in participants with, or at risk of, Atherosclerotic Cardiovascular Disease and elevated Low Density Lipoprotein Cholesterol using a vaccine model in an NHS primary care setting — DARS-NIC-421602-N3B0X

Type of data: information not disclosed for TRE projects

Opt outs honoured: Identifiable, No (Consent (Reasonable Expectation))

Legal basis: Health and Social Care Act 2012 – s261(2)(c)

Purposes: Yes (Agency/Public Body)

Sensitive: Non-Sensitive

When:DSA runs 2022-12-09 — 2025-12-08 2023.02 — 2023.03.

Access method: One-Off

Data-controller type: NOVARTIS PHARMACEUTICALS UK LIMITED

Sublicensing allowed: No

Datasets:

  1. Emergency Care Data Set (ECDS)
  2. Hospital Episode Statistics Accident and Emergency (HES A and E)
  3. Hospital Episode Statistics Admitted Patient Care (HES APC)
  4. Hospital Episode Statistics Outpatients (HES OP)

Objectives:

Background
Elevated low-density lipoprotein associated cholesterol (LDL-C), is one of the major risk factors for coronary heart disease (CHD). Despite advances in treatment, atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death and disability worldwide. Despite the proven efficacy of statins, there is still a considerable variability in individuals to these drugs, even when being treated with a high intensity regime. Furthermore, not all people tolerate statins or are able to take statins at sufficient intensive doses. Therefore, there is a clear unmet medical need for additional options beyond current available oral treatments for the lowering of LDL-C.

Inclisiran is a medicine used to lower LDL-C. Raised LDL-C is generally accepted to be an independent risk factor for the development and progression of atherosclerotic cardiovascular disease. Novartis Pharmaceuticals UK Limited holds the UK marketing authorisation for Inclisiran and there is a collaboration agreement in place between Novartis and NHS England. In accordance with the collaboration agreement, it is aimed that 300,000 patients with raised LDL-C will be prescribed Inclisiran over three years so they may benefit from its LDL-C lowering effects. The SPIRIT study, sponsored and funded by Novartis, will inform the national roll out of Inclisiran within a UK primary care setting. While Novartis could benefit financially if Inclisiran is widely prescribed within the NHS, it is expected that this large number of patients will derive benefit in terms of LDL-C reduction.

Inclisiran is a treatment for elevated low-density lipoprotein associated cholesterol and can be given in primary care settings as a twice-yearly injection to people with high cholesterol who have already had a previous cardiovascular event to reduce the chances of them having another. It can be used on its own or alongside statins or other cholesterol lowering drugs. Inclisiran works in a new way. It is the first of a new type of cholesterol-lowering treatment which uses ribonucleic acid (RNA) interference (RNAi) to boost the liver’s ability to remove harmful cholesterol from the blood. Ribonucleic acid is a nucleic acid present in all living cells. RNAi refers to a phenomenon where small pieces of RNA can shut down protein translation by binding to and causing the destruction of messenger RNAs that code for those proteins.

The efficacy of inclisiran has already been evaluated in three phase III studies (ORION-9, -10, and -11; conducted between November 2017 and September 2019 by The Medicines Company, which was subsequently acquired by Novartis Pharmaceuticals) in patients with ASCVD or ASCVD risk equivalents (e.g. type 2 diabetes mellitus) and/or familial hypercholesterolaemia. These preliminary observations are consistent with the general concept that however LDL-C is lowered, it is thought to result in reduced risk of future cardiovascular events. The overall safety and tolerability profile was generally similar between the inclisiran and placebo groups.
However, it is acknowledged that randomised clinical trials, by definition, are highly controlled and enrol a more select patient population than is expected to be prescribed the medicine post-approval. The impact of a new treatment on patient healthcare seeking behaviour and utilisation of local healthcare services is hard to measure from clinical studies with their own schedule of defined visits and procedures, whereby the clinician and patient are following a prescriptive protocol rather than the usual clinical practice. This study seeks to study the effectiveness of inclisiran in a real-world setting, rather than just the efficacy as measured in the previous phase III studies.

Study Design
This is an implementation research study, the aim of which is to evaluate the practicality and acceptability of administering inclisiran subcutaneously (via injection) in GP practices (in a vaccine-like programme) to consenting participants who have elevated LDL-C and are on established lipid lowering medication or have been recommended lipid lowering therapy by their healthcare provider but are unable to tolerate treatment. 805 participants were randomised onto the trial between July 2021 and March 2022 within the Greater Manchester Area. Recruitment is complete. Participants are split evenly per treatment group into the 3 groups described below at up to 30 primary care centres will be recruited.
For clarity, implementation research is commonly defined as the study of methods and strategies to promote the uptake of interventions that have proven effective into routine practice, with the aim of improving population health; how to organise, deliver and maintain an innovative treatment for ASCVD in a primary care setting in a sustainable way. Implementation research seeks to understand and work within real world conditions and is especially concerned with the users of the research and not purely the production of knowledge. In the case of this study, the users are patients and healthcare providers who are, respectively, receiving and administering inclisiran (or managing the administration thereof) within GP practices.
The study is based on the following principles:
- It is run in the setting where inclisiran is intended to be implemented in clinical practice, with the intention of understanding the effects of innovations within the real-world conditions of everyday clinical practice
- Inclusion / exclusion criteria reflect the patient population for whom inclisiran is intended to be used, rather than selecting patients who are suitable for a standard clinical trial
- Health delivery context: taking account of institutional and health system contexts – including the viewpoints of various stakeholder including commissioners, system managers and clinicians

This study will be conducted using North West E Health’s (NWEH’s) ConneXon clinical trials platform which integrates patient level electronic healthcare record data from primary care, secondary care, and national data sources, to support the integration of ‘real-world evidence’ from individually consented participants. ConneXon has been validated for use in clinical studies.

Most of the study data will be extracted directly from the patient electronic medical record (EMR) in order to minimise direct participant contact and maximise the outcomes of interest related to implementation (patients consent to data from their GP and hospital records to be collected). Some study specific data not routinely collected will also be reported by the investigator or delegate in an integrated Electronic Case Report Form (e-CRF) for accuracy and in compliance with regulatory standards.
The study is divided into three elements:
1. A prospective phase IIIb intervention with 3 groups of patients:
a. Group 1: Participants will continue to receive their existing lipid lowering therapy plus behavioural support
b. Group 2: Participants will continue to receive their existing lipid lowering therapy, plus inclisiran injection
c. Group 3: Participants will continue to receive their existing lipid lowering therapy, plus inclisiran injection, plus behavioural support. (Behavioural support consists of a regular support telephone call to motivate patients to make effective choices for self-management including behavioural change, goal setting, and empowerment)
2. An observational data assessment utilising the EMR held in primary and secondary care, and analysing data collected within these records during normal clinical practice to examine ongoing healthcare resource utilisation (HRU) and outcomes in the patient cohort
3. A process evaluation that will ascertain the views of patients and healthcare providers about the service they have received or provided and its potential for wider use across the NHS

Objective for Processing
The primary objective of this study is to demonstrate superiority of inclisiran +/- behavioural support compared to the patient’s usual lipid lowering drugs + behavioural support in a primary care setting (i.e. the 3 groups of patients described in point 1 above), in reducing the percentage change in LDL-C from baseline to Day 270 in adults with elevated LDL-C.
The secondary objectives of this study are to evaluate user satisfaction/experience and process evaluation for the 3 groups of patients by means of:
- Validated questionnaires to measure patient satisfaction, patient activation and empowerment, and patient adherence to cardiovascular disease self-management
- A process evaluation conducted using the Consolidated Framework for Implementation Research (CFIR) which will explore inclisiran delivery at three levels
- Feasibility and acceptability of delivery models for inclisiran to patients
- Feasibility and acceptability of delivery models for inclisiran to providers
- Wider use of the proposed delivery models across the NHS (outer setting)
- The service costs of each delivery model
- The acceptability and perceived sustainability of patient identification and referral routes
- Serious adverse event profile

NB. Patient activation is a measure of a person's knowledge, skills, and confidence to manage their own health and wellbeing. Patient empowerment is a process through which people gain greater control over decisions and actions affecting their health.
The exploratory objectives of this study are to compare the 3 groups of patients on the following assessments:
- Total lipid profile (total cholesterol, HDL-C, triglycerides), blood pressure, weight, BMI from baseline to end of study visit.
- Healthcare resource utilisation during the period of the study taken from the primary and secondary care EMR e.g. number of outpatient visits, number of hospital admissions, number of A&E visits, number of primary care visits.
- Assessments of treatment simplicity, resources used for treatment, and treatment impact will be made from bespoke questionnaires based on standard questionnaires used in the assessment of diabetes treatments.

Secondary care data from HES is crucial for the complete analysis of the service costs of each model, Healthcare Resource Utilisation (HRU) analysis, and serious adverse event profile for all patients participating in the study.

Legal Bases
Processing of the data is justified under the following UK GDPR Articles:
9(2)(j)– Scientific research. Also, improvement in public health due to increased uptake of inclisiran is in the public interest
6(1)(f) – It is a legitimate interest of Novartis to investigate means of most effectively delivering a proven therapy. The outcome of a Legitimate Interest Assessment conducted by Novartis: The processing may be within the public interest, as it assists with achieving the clinical study aim of providing new and innovative medicines to patients and improving population health. All parties involved in the processing have an interest in this aim.

Novartis are a pharmaceutical company who have an interest in developing therapies for treating and preventing coronary heart disease. Novartis are interested in understanding how best to deliver their proven therapy for lowering LDL-C in a way that increases uptake and improves public health. Access to primary care data from GP EMR systems and secondary care data from HES data sets will allow for a full statistical analysis of HRU. This analysis will a) inform the evaluation of the superiority of inclisiran when delivered using the described model and, hence, support the primary objective of the study, and b) allow evaluation of the service costs of each delivery model and, hence, support this aspect of the secondary objectives of the study.

All participating patients have given informed consent and the study has been approved by an independent Research Ethics Committee. This study does not present any harm to the public.

Data Requested
Emergency Care DataSet (ECDS), Hospital Episode Statistics (HES) Outpatients, Admitted Patient Care, and A+E data is requested so that the patient’s journey across the whole secondary care setting can be analysed. This information, along with primary care data from GPs, will be used to compare the total primary and secondary healthcare resources used by the three patient cohorts and establish if inclisiran and/or behavioural support reduces HRU.

Record level data is required, but no identifiable or sensitive data are being requested. The data requested is minimised to only that of participating patients based on basic demographics (e.g. month and year of birth – to cross reference to primary care data), appointments/attendance/admissions/discharges/periods of care, treatment, diagnoses, and healthcare resource groups. A significant number of events for patients with ASCVD which occur in secondary care are not coded in primary care. These data are required for the calculation of HRU; without secondary care data the full HRU analysis could not be performed.

To address the UK GDPR principle of minimisation, only data for the period 5 years prior to the patient’s date of consent and throughout the course of the study (i.e. up to the end of December 2022) will be required. The first patient was recruited onto the study in July 2021, so HES data sets back to 2016/17 have been selected in this application to accommodate this (i.e. back to at least July 2016). Date of consent will be provided to NHS Digital, only 5-years of ‘pre-consent’ data for each patient can be delivered. This option is requested in the interest of further data minimisation.

Only pseudonymised data is being sought from NHS Digital, although NWEH supply NHS Digital with NHS number and date of birth to allow the correct patient cohort to be identified. No sensitive data is requested.
The population of 300 patients per arm of the study was chosen as this is the sample size necessary to detect statistically significant differences in outcomes between the three groups.
The geography of the study is already restricted to the Greater Manchester area. No further reduction in the data requested can be made based on geography.
Study participants are aged 18 years or older. To apply any further age restriction would undermine the real-world principles of the study.
Data from 5 years prior to enrolment on the study and up to the end of the study (end December 2022) is sought to allow a meaningful comparison of pre- and post-enrolment HRU. ECDS does not contain data for the full 5 years, so data from the HES A&E data set is being requested to provide this.
Only basic demographics (e.g. month and year of birth – to cross reference to primary care data), attendance, treatment, diagnoses, investigations, and conditions have been requested. The full range of these data are necessary for a complete HRU analysis.

The patients consented onto the study are from the Greater Manchester (GM) area and are registered with GPs in that area. Secondary care data is, therefore, likely to come from GM hospitals but could come from hospitals in other areas if, for example, patients had unscheduled visits while travelling or had to attend specialist clinics outside GM. Part of the rationale of using patient’s electronic records in a Real-World study such as this is to minimise interaction with patients and reduce any intrusion.

Organisations involved and their roles:

Novartis Pharmaceuticals UK Ltd
- Study Sponsor/funding body
- Data Controller
- Data Processor

NorthWest EHealth Limited (NWEH)*
- Data Processor

Northern Care Alliance NHS Foundation Trust (NCA)
- Data Processor
- Provide Azure cloud hosting service for NWEH

Microsoft Limited
- Data Processor
- Provide Azure cloud from NCA

Restore PLC
- Used for data storage / archiving

Wellbeing Ltd**
- Data Processor

NHS England (NHSE)
- There is an ongoing collaboration between Novartis and NHSE to improve lipid management in England. The funding for this study is coming from a budget agreed between Novartis and NHSE as part of the collaboration. For regulatory purposes Novartis is the study sponsor and responsible for setting the objectives and the conduct of the study. NHSE had no responsibility or accountability in the development of the study protocol and have had no involvement in the conduct of the study. However, as collaborators, NHSE will receive outputs of the study (e.g., publications, clinical study report and process evaluation reports).

*NWEH is wholly directed by Novartis on all aspects of data processing. The eCRF was developed by NWEH based on Novartis' study protocol. The data requested from NHS Digital and from GPs was that which will allow the objectives of the protocol to be fulfilled. NWEH will link data from the eCRF, HES, and GP systems and deliver it to Novartis in a format specified by Novartis for them to perform their own analysis.

**Wellbeing provides a 3rd party primary care data extraction service which extracts data from GP EMR systems and delivers it to NWEH. It does not process the GP data in any other way and will not process the data requested from NHS Digital in any way whatsoever.

Expected Benefits:

Inclisiran is already a proven therapy in lowering cholesterol and is being rolled out across England in a partnership between Novartis and NHS England. The first ‘population health agreement’ was announced in September 2021 between the NHS and Novartis (see https://www.england.nhs.uk/2021/09/nhs-cholesterol-busting-jab-to-save-thousands-of-lives/ and https://www.nice.org.uk/news/article/nice-approves-ground-breaking-cholesterol-lowering-drug-inclisiran ). This is expected to enable an estimated 300,000 patients with high cholesterol and a history of cardiovascular disease to benefit from the proven benefits of inclisiran over 3 years. It is expected that this figure could rise to almost 500,000 people beyond this period; this has the potential to prevent 55,000 heart attacks and strokes, saving 30,000 lives within the next decade.
However, Novartis seeks to explore improved ways of delivering inclisiran that may increase its uptake and, hence, effectiveness. This ground-breaking study is being delivered in a primary care setting using innovative technology to collect healthcare outcomes and safety data. Study intervention has been kept to a minimum to reduce the impact on patients and healthcare practitioners and helping to ensure the findings of the study are relevant in the real-world, everyday setting. The SPIRIT study seeks to investigate the lipid lowering properties of inclisiran +/- behavioural support compared to the patient’s usual lipid lowering drugs + behavioural support in a primary care setting, and to compare the cost to the NHS (across primary and secondary care) of patients from the three cohorts. This, along with the process evaluation, is intended to inform NHS England in the most effective and acceptable (to patients and healthcare professionals) way to progress the national programme in terms of inclisiran delivery.

Outputs:

There are several planned reports and publications from this study. The planned activities are outlined below:
- Documents shared by Novartis with NHS England and Academic Health Science Networks (AHSNs) - textual reports with no patient details
- Patient report #1: report on number of patients meeting broad ‘at risk’ criteria who may be eligible for treatment with inclisiran in the study. Completed January 2022
- Process evaluation #1: early insights report based on feed-back from commissioners, patients, and healthcare professionals. Completed January 2022
- Patient report #2: report on number of patients who meet the full inclusion criteria (i.e. are eligible for inclisiran in the study). Completed June 2022
(Note: the above reports haven't used NHS Digital data, but they do feed into the research as they add background to the research).
- Process evaluation #2: in-depth report based on feed-back from commissioners, patients, and healthcare professionals. Estimated Q2 2023
- Full Clinical Study Report: inclisiran efficacy, patient reported outcomes, safety outcomes, patient demographics, process evaluation summary, and HRU (cost) analysis across the delivery methods
- Peer reviewed publications - aggregate data with small numbers suppressed
- Patient Identification and SNOMED codes / national case findings. Submission to Cardiovascular Research estimated May 2023
- Study Methodology publication. Submission to British Medical Journal Open estimated May 2023

- Patient engagement: Prior to commencement of the trial a patient focus group was set up by NWEH (on behalf of Novartis) to involve patients at the development stage of the process, to help improve and inform the study, as well as providing an opportunity to gain a better understanding of the patient’s needs. In addition, it offered a chance for the protocol to be tested, issues to be identified, and problems to be resolved before a study opened for recruitment. The study concluded overwhelmingly that participants had a positive opinion about the study. In fact, all those interviewed stated they would be interested in taking part in the study if they were offered the opportunity. When discussed with the researcher, the vaccine like model was perceived as a good alternative to their current medications. From questioning, no participants had any major concerns regarding the study design or the drug administration. Novartis will also be sending participants a summary of findings at the conclusion of the study to keep study participants up to date with the study outcomes.

- Data output: Northwest EHealth will produce a dataset of linked data from the eCRF, GP EMR systems, and the HES datasets. This data will be transformed into the standard format required for submission to regulatory authorities for analysis by Novartis. The data will be patient level and pseudonymised but Novartis will not have access to the pseudonymization key or identifiers and cannot re-identify the patients (see ‘Linked data’ under ‘Processing Activities’). This linked data is necessary for the subsequent production of the Full Clinical Report by Novartis (including HRU analysis) for dissemination to NHS England.

Processing:

There will be no data linkage undertaken with NHS Digital data provided under this agreement that is not already noted in the agreement.

The VICTORION-Spirit: Phase IIIb, multicentre, randomised controlled study is a collaboration between Novartis and NorthWest EHealth; Novartis operate at a more strategic level and ultimately make the decisions about the means and manner of data processing for the purpose of this application. NWEH provide clinical operations and data acquisition/processing services. Specifically:

Clinical
- GP liaison
- GP Site set-up
- Patient recruitment and consent
- Patient consultation and administering the investigational product (inclisiran) by NWEH nurses

Data acquisition/processing
- Liaison with 3rd parties (including GP system vendors) to secure primary care data
- Application to NHS Digital to secure secondary care data
- Data quality checks
- Linking data and formatting ready for Novartis to analyse

Processing of the data will be made secure, as detailed below:

> Patient data is entered into the electronic Case Report Form (eCRF) by research nurses. This is a Web application and is part of NWEH's ConneXon platform. Connexon has been fully validated to host patient data from clinical studies).
> Data from GP systems is transferred to NWEH (ConneXon) by Wellbeing via secure File Transfer Protocol (FTP)
> HES data from NHS Digital is transferred to NWEH (ConneXon) via the SEFT mechanism
> ConneXon is hosted within the NHS and benefits from the security that this affords
> Data is transferred to and from Novartis via their validated Intralinks Web Connect System
> All organisations processing the data are on the Data Protection register and have either ISO27001 accreditation, Data Security and Protection Toolkit accreditation, or have provided NHS Digital with acceptable security documentation.

Electronic Case Report Form (eCRF) data: When a patient is consented on to the study, data including basic demographics (e.g. NHS number, age, sex, race/ethnicity) is entered into the study eCRF by a NWEH Research Nurse. The eCRF data is held in the NWEH subscription within the NCA Microsoft Azure tenancy. Each patient is allocated a unique, internal participant identifier (PID). Data from the eCRF is loaded into a study specific database in ConneXon (the trial delivery platform). A list of NHS number study ID's is sent from ConneXon to a staging server within the same secure environment. This list forms the basis of the files (‘consent manifests’) sent to Wellbeing and NHS Digital for primary care data and secondary care data, respectively.

GP data: A consent manifest containing patient’s NHS number, PID, and GP practice code is sent to Wellbeing via Secure File Transfer Protocol (sFTP) daily. Wellbeing use the NHS number and GP practice code to identify the patients and extract their clinical record. In addition to the patients providing informed consent, practices participating in the study also must sign a Wellbeing consent form and activate an electronic agreement within the GP EMR system before any patient data can be extracted from the practice. Wellbeing returns the full clinical record along with the PID (not NHS number) to the NWEH staging server. This data is subsequently loaded into the study database in ConneXon.

HES data: A consent manifest containing patient’s NHS number and PID will be sent to NHS Digital via the Secure Electronic File Transfer (SEFT) portal. NHS Digital will use NHS number and date of birth, to identify the cohort of patients who have consented within the HES datasets (APC, OP, and AE) and make requested clinical data and the PID (again, not NHS number) available within the SEFT portal where it will be picked up by NWEH and loaded onto their staging server. From there it will be loaded into the study database in ConneXon.

Linked data: Under instruction from Novartis, NWEH Database Administrators (DBAs) will link data from the eCRF, GP EMR systems (via Wellbeing), and the HES datasets by PID in ConneXon. NWEH analysts will transform the linked data into the standard format required for submission to regulatory authorities (Study Data Tabulation Model, ‘SDTM’). This dataset will be sent to Novartis analytics division in Switzerland via the Novartis validated Intralinks Web Connect System (IWC) for analysis. Novartis do not require to re-identify patients. The data will be pseudonymised and Novartis will not have access to the pseudonymization key or identifiers and cannot re-identify the patients. It is this linked primary and secondary care data that is necessary to achieve two of the secondary objectives of the study:
- Serious adverse event (which could involve hospitalisation) profile
- Service cost (HRU) of each delivery model across primary and secondary care

Data handling and personnel: data processing is only carried out by substantive employees of the data processor(s) and or data controller(s) who have been appropriately trained in data protection and confidentiality required. Within NWEH and Novartis, the DBAs and analysts who will handle the data undergo mandatory training in data protection and confidentiality. The Novartis Information Management Policy that has been supplied states that "All information management activities must be conducted in accordance with applicable laws, regulations and industry codes, which may be more stringent than the requirements outlined in this Policy." ." Switzerland is subject to an ‘adequacy decision’ by the United Kingdom Government and so is considered to have a suitable level of data protection, equivalent to UK GDPR.

Retrospective data analysis of HES and DID data from patients with Refractory Chronic Cough (RCC) who have given consent for their electronic healthcare records to be used in the analysis of healthcare resource utilisation. — DARS-NIC-290527-P5C0Y

Type of data: information not disclosed for TRE projects

Opt outs honoured: No - consent provided by participants of research study, Identifiable, Anonymised - ICO Code Compliant, No (Consent (Reasonable Expectation))

Legal basis: Health and Social Care Act 2012 – s261(2)(c), Health and Social Care Act 2012 – s261(2)(c)

Purposes: Yes (Agency/Public Body)

Sensitive: Non Sensitive, and Non-Sensitive

When:DSA runs 2020-06-11 — 2021-06-10 2020.11 — 2021.12.

Access method: One-Off

Data-controller type: MANCHESTER UNIVERSITY NHS FOUNDATION TRUST, MERCK SHARP & DOHME LIMITED (MSD)

Sublicensing allowed: No

Datasets:

  1. Diagnostic Imaging Dataset
  2. Hospital Episode Statistics Admitted Patient Care
  3. Hospital Episode Statistics Outpatients
  4. Bridge file: Hospital Episode Statistics to Diagnostic Imaging Dataset
  5. HES-ID to MPS-ID HES Admitted Patient Care
  6. HES-ID to MPS-ID HES Outpatients
  7. Diagnostic Imaging Data Set (DID)
  8. Hospital Episode Statistics Admitted Patient Care (HES APC)
  9. Hospital Episode Statistics Outpatients (HES OP)

Objectives:

The study will aim to increase the understanding of the profile and characteristics of patients with unexplained Refractory Chronic Cough (RCC) by understanding the healthcare resource utilisation (HRU) and treatment patterns of these patients. The rationale for the study is to analyse the cost of the healthcare resource utilisation (e.g. how much and what healthcare services are used) by patients with RCC and better understand the burden (e.g. the cost in both money and time) of managing patients diagnosed with RCC to the greater health care system.

The primary objective of the initial work is to determine the outpatient and primary care healthcare costs in the 5-years prior to a diagnosis of RCC, compared to a control cohort, matched by demographics and smoking status. This will be achieved through a linkage to NHS Digital HES and DIDS data, linkage to the relevant cohort's GP data, and a comparison against an anonymised controlled cohort.

Please note this application relates to the consented patient cohort and not the control group and that the second part of the project that will compare the consented patient data to a control group in not part of this application to NHS Digital. NHS Digital are not providing the control group data data the control cohort data will be provided by the Salford Integrated Record (SIR) directly to the study.

Background:
This is a retrospective data study to assess the HRU and treatment patterns of patients with RCC. RCC is an unremitting (e.g. where symptoms are continuous) symptom leading to a marked decrease in quality of life like that seen in patients with Chronic Obstructive Pulmonary Disease (COPD). RCC is defined as a cough persisting for longer than 8 weeks and that remains unexplained after investigation despite guideline-based treatment – e.g. where a doctor has provided treatment as per defined NHS guidance (Morice, McGarvey, Pavord, 2006). The condition poses a real challenge for clinicians since treatment of the underlying cause does not always provide adequate relief, an obvious cause is difficult to establish, and current antitussives (medicines to supress a cough) don’t always work and can have undesirable side-effects (Chung, McGarvey, Mazzone 2013). A systematic approach to diagnosis and treatment remains the most effective way to manage RCC, the most recent guidance being the CHEST Guidelines and Expert Panel Report (Gibson et al, 2016). RCC is thought to be a common symptom in the general population but the prevalence (commonness) and severity in the community is uncertain and poorly understood. RCC is a condition which is notoriously difficult to diagnose as it's associated symptoms, such as gastrooesophageal reflux, heartburn, and regurgitation, can easily be attributed to other conditions.

RCC is a common condition that has a significant adverse impact on the individual patient affected. Prior to diagnosis, patients may have frequent healthcare consultations and investigations, before being referred to a specialist clinic, which can take up to 10 years. For this reason, patients with undiagnosed RCC frequently languish in the health system for years, moving between referrals to different specialisms before being correctly diagnosed. Along with the delays in referral and diagnosis patients attending specialist clinics routinely have investigations duplicated with financial costs to both the health service and the patient.

It is evident from the literature that more research is needed to better understand the impact of RCC to the greater health care system, and provide important information for clinicians, healthcare providers, payers, and patients when considering the use of new therapeutic agents (medicines). Therapies for RCC are in development, creating an urgency to document the current cost of care. Such cost data can also inform economic models for emerging therapies. Therefore, the objective of this study is to better understand the care pathway and subsequent healthcare resource utilisation, in patients diagnosed with RCC compared to a control cohort supplied by Salford Integrated Record (SIR) , which will be matched by demographics and smoking status.
This study will have two components, firstly a consented cohort of patients recruited from a specialist clinic (in Wythenshawe Hospital - part of Manchester University NHS Foundation Trust), to determine the cost of outpatient and primary care utilisation prior to diagnosis of RCC.

The second part will be comparing the consented patient data to an anonymized control cohort supplied by Salford Integrated Record (SIR), which will be matched for demographics (age, sex) and smoking history. The proposed study will be conducted with NorthWest EHealth (NWEH), specialists in delivering Electronic Records (EHR) driven clinical trials. NWEH will extract the data from primary care, secondary care and national datasets for statistical analysis.
By working with NorthWest EHealth (NWEH) and the NHS in Greater Manchester, MerckSharp & Dohme Limited (MSD), the study Sponsors are interested in understanding the profile and characteristics of patients with unexplained RCC.

This is a stand-alone study commissioned by the study Sponsor in collaboration with the Principal Investigator (PI). The focus of this work will be on understanding the HRU and treatment patterns of these patients. The patient cohort has been identified by the clinical team of the Principal Investigator (PI) who runs a cough clinic in Manchester University NHS Foundation Trust (MFT). A cohort of 200 patients have been diagnosed with RCC and have given their informed consent for their full clinical record to be used in this study.

The patient cohort is restricted to those who were diagnosed from 2015 onwards. To create a patient profile, the data needs to be from 5 years pre-diagnosis to 2 years post-diagnosis (if available). Data is requested from 2010 onwards to ensure that this period is complete for all patients. Only the Inpatients, Outpatients, and Diagnostic Imaging (scan e.g. x-ray, MRI etc) data sets are requested.

The PI's clinic is one of only a few of its' kind in the country. Therefore, although the patient cohort is mainly from the North West, a wider geographical distribution can be expected in part of the cohort.

The data requested is date of birth, gender, ethnicity, specialisms, diagnoses, treatments and procedures and associated costs (to produce the patient profile).

As the data has identifiable elements it has been necessary to obtain patients consent. This has been done by an invitation letter and a follow up call. Other than if the patents have questions, this is the only contact made with patients - the study is minimally intrusive.

The secondary objectives of the study are;
To determine the following for both the RCC cohort and the control cohort in the 5 years prior to diagnosis/index date:
• Total number of GP visits
• Total number of outpatient visits
• Total number of visits related to investigations required for RCC
• Total number of respiratory outpatient visits
• Total number of ENT outpatient visits
• Total number of gastroenterology outpatient visits
• Total number of Urology outpatient visits
• Total number of gynaecology outpatient visits
• To attach costs to each of the above items
• To determine the total healthcare cost in at least two 6-month intervals post-diagnosis of RCC
• To determine the number of SALT (Speech and Language Therapists) visits post-diagnosis of RCC
• To calculate the Charlson Comorbidity Index for patients with RCC and the control cohort
• To assess the severity and duration of RCC at the time of diagnosis (baseline) using the cough severity Visual Analog Scale (VAS) and Leicester Cough Questionnaire
• To examine the correlation, if any, between VAS score and costs
• To determine the costed care pathway for all patients identified with RCC
• To conduct a sensitivity analysis to examine the effects of including inpatient costs

The study has received full ethical approval from the Health Research Authority (HRA) and Health and Care Research Wales (HCRW). Patients participating in the study have been fully informed and have given written consent.

The organisations involved in the study and their roles are:

Merck Sharp and Dohme (MSD)
• Study sponsor
• Joint Data controller
• MSD will receive no data but will have sight of any final output report. The report will contain aggregate numbers with small number suppression (no personally identifiable information) in line with NHS Digital guidelines.
• MSD may require source data verification (SDV) although this requirement has not been finalised. These monitors will have access to full, identifiable, paper hospital (MFT only) records and access to the electronic Case File Record (eCRF) for a small subset of the consented patients for the purpose of monitoring the quality of data input. This will happen on site at MFT. This data will not be transmitted to MSD. These MSD monitors will not have access to any other data including that provided to NWEH by NHS Digital.

Manchester Foundation Trust (MFT)
• Joint Data Controller
• MFT provide details of eligible patients
• MFT will receive no data (other than their own records) but will have sight of the final output report that is sent to MSD

North West E- Health (NWEH)
• Joint Data Processor
• NWEH is a Clinical Research Organisation (CRO) which specialises in using electronic clinical records to offer a range of services to the pharmaceutical industry. For this study NWEH will manage the procurement (collecting) and analysis of consented patient clinical data from primary and secondary care sources and produce the final report of all the work which NWEH carry out for the study will be under the direction of the data controllers.
• Certain substantive employees of NWEH will have access to personally identifiable information (PII) for consented patients. The purpose of this is for patient recruitment, GP recruitment and entry of data onto the eCRF. All such employees will have honorary contracts with MFT and access to PII will be on MFT premises or by email between NHS.net accounts.

NWEH are a data processor for the purpose of this application because;

· NWEH are following instructions from the Joint Data Controllers (MSD and MFT) regarding the processing of personal data.

· NWEH did not decide to collect personal data from individuals. The criteria for eligibility was determined by the Joint Data Controllers and MFT staff working under Prof. Smith (or staff working under honorary contracts to MFT) have determined which patients fit this criteria.

· NWEH have been instructed which data to collect in order to provide sufficient data for analysis to satisfy the study endpoints.

· NWEH do make some decisions in relation to how the data is processed, but these decisions are implemented under a contract with MSD and MFT.

· The legal basis for processing of the data has been determined by the Joint Data Controllers. NWEH does not determine what purposes the data will be used for.

· NWEH is bound by confidentiality and security requirements as part of the contract and regulatory requirements, and does not determine whether to disclose the data, or to whom.

· Decisions regarding retention of the data have been determined by the Joint Data Controllers in accordance with Good Pharmacoepidemiology Practice.

· NWEH have no interest in the end result of the processing - reports containing aggregated data will be produced by NWEH and shared with MSD and MFT.

Salford Royal Foundation Trust (SRFT)
• Joint Data Processor
• Data is hosted by SRFT, no further processing is done. Hosting facilities to the database are provided by SRFT.

Microsoft
• Joint Data Processor
• Providers of Azure Cloud
• No further processing of the data is permitted by Microsoft - other than cloud-based hosting activities.

GP practices of participating patients
• Permit the extraction and linkage of GP data to the cohort.

Apollo Medical
• Joint Data Processor
• Extract data from GP systems.
• Apollo are a third-party specialist data extraction organisation. Beyond extraction, no further data processing is done by Apollo.

MSD are carrying out this project in line with Article 6 (1)(f) of the GDPR - to meet their legitimate interests.
MSD are a pharmaceutical company who have an interest in developing therapies for cough. MSD are interested in understanding the profile and characteristics of patients with unexplained RCC. Identifying the cost burden (e.g. the cost in money and time) of RCC patients 5 years prior to diagnosis and up to 2 years after diagnosis will help MSD to understand the potential market for an effective drug to treat RCC. This study will not inform a specific drug development at this point but, depending on the results, could provide the evidence needed to justify future research and/or clinical trials.
The resulting report will give MSD insight into the current treatment pathway of patients with RCC. This intelligence may be of use in future research or in business decisions.

MFT are carrying out this project in line with the conditions set out in Article 6 (1)(e) of the GDPR. The collection of data from NHS Digital is essential to provide evidence to fully understand the patients journey through primary and secondary care providers. This is in the public interest as: (1) results from study will advance academic and clinical knowledge regarding healthcare utilisation in patients with RCC (2) allow better understanding of the burden (e.g. the cost in money and time) of RCC which ultimately could save the healthcare system money and (3) results from the study may lead to either further clinical studies or direct change in clinical service provision with the aim of improving patient care.
The PI runs one of the few chronic cough clinics in the UK at Manchester University NHS Foundation Trust (MFT). The study patients will be recruited by the PI and team. This is the first time this type of data has been collected in a robust, systematic way for Chronic Cough, the Health Resource Utilisation analysis and subsequent publications could lead onto further research being funded in this field and, ultimately, to improvements patient’s treatment and experience.

The study is also in line with the requirements to process special category data as stated in Article 9(2)(j) of the GDPR - Public interest, scientific or historical research purposes or statistical purposes. Statistical analysis of clinical records of known RCC patients will allow an HRU profile to be developed which will improve the understanding of the patient journey of this poorly understood cohort.

Data will be minimised (e.g. only the necessary data items will be used) to the cohort of consented patients. For the HES data the study will exclude critical care, geographical, maternity, organisation, psychiatric and socioeconomic records, and data will be limited to over 16's. For the DIDs data the study will exclude people under 16 years of age, organisational, locational, provider and referrer records.

Expected Benefits:

People with RCC frequently remain undiagnosed for years. Symptoms of RCC can be similar to those of other conditions such as gastrointestinal disease and heart disease, leading patients to languish in the care system being referred to, potentially, multiple inappropriate specialisms. This results in prolonged suffering for the patient and unnecessary expense for the NHS.

This is the first time this type of data has been collected in a robust, systematic way for Chronic Cough, the Health Resource Utilisation analysis and subsequent publications could lead onto further research being funded in this field.

RCC is a debilitating condition similar in severity to Chronic Obstructive Pulmonary Disease (COPD). There may be great benefit to patients who would otherwise not have been identified as having RCC is, potentially, a greatly reduced journey to correct diagnosis and, hence, treatment.

The study will allow MSD and Manchester University NHS FT to understand how much an undiagnosed RCC condition costs the health service and, hence, the possible financial benefit should a future MSD therapy be adopted. This may help to develop a business case leading to funding of further research into RCC therapies by MSD and/ or clinical trials.

The ability to correctly diagnose RCC earlier on in a patient care pathway means that they can be treated appropriately in a timely manner, reducing suffering and disease cost. Understanding the patient pathway and HRU is key to understanding where early clinical interventions can be made in the future.

Enhancing general understanding of the treatment pathway of the specific patient cohort in this study may allow improvement/ acceleration in the treatment of patients not yet diagnosed with RCC.

It must be stressed that this is an exploratory study, and its primary purpose is to understand the Health Resource Utilisation of patients who are diagnosed with RCC. Even though the results of this study will not yield direct benefits to patients, the findings will inform future work which could lead to benefiting patients. If the HRU identifies clear points of failure in the treatment of patients with RCC, it may inform changes in clinical practice which could improve patient͛s treatment and experience, and cut costs.

Conference presentations and peer reviewed papers aim to educate health professionals, researchers and NHS decision makers about the negative experiences of patients with this condition and the condition burden (e.g. cost in time and money) on health care services, a key benefit of this study will be increasing the likelihood of further research being funded in this field and leading to changes in clinical practice that will improve the care of patients.

Outputs:

NWEH will not share any record level data with the study Sponsor or the Principal Investigator (although the PI has access to patient data from MFT as they are under the PI's direct care).

A final report created by NWEH will be shared with the Sponsor and the PI. The reports will be the property of the Sponsor and will only contain aggregate data with small numbers suppressed (in line with the HES Analysis Guide).

The contents of the reports will not be used for sales and marketing purposes.

The beneficial outcomes of this study are not guaranteed. This is a preliminary study which may form the basis of other research. The specific purpose of the study is to find out what patients with RCC cost the health service.

Decisions on future work, be it drug development or further research, cannot be made without first understanding these costs. However, if the HRU analysis shows clear differences in treatment between:
a) pre- and post-diagnosis data for RCC patients
and
b) RCC patient and control data,

a key outcome from the feasibility study will be the publication of research papers by both the Sponsors and the PI. One possible route for further research which this feasibility study may create is comparisons between costs incurred to the UK health service in the management of the RCC disease versus those in the US and/or Europe.

Only the outputs (aggregated with small numbers suppressed inline with HES analysis guide) of this feasibility project would be used for this type of follow on research, not source data. A method of comparing HRU and costs across different regions would need to be defined as part of the further research.

It is the intention of the Sponsor that the outputs of this study will be presented at the European Respiratory Society International Congress in September-October 2020 (https://www.ersnet.org/). This, along with the research papers will raise the profile of this serious condition as an important clinical problem both to researchers and clinical teams in Primary and Secondary care worldwide.

All outputs will contain only data that is aggregated with small numbers suppressed in line with the HES Analysis Guide.

Processing:

All organisations party to this agreement 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).

There will be no data linkage undertaken with NHS Digital data provided under this agreement that is not already noted in the agreement.

For this study, Merck Sharp and Dohme (MSD) and Manchester University NHS Foundation Trust (MFT) are jointly the data controllers and NWEH will act as the main data processor.
The Principle Investigator (PI) for the study has identified potential patients based on attendees to their Refractory Chronic Cough Clinic.

The PI has a close relationship with the patients and believes them to be very engaged and keen to be involved in research into their condition.

The HRA have produced guidelines for research organisations to advise them on their legal basis for processing data. In line with this MSD has a valid and legal reason to have the patient’s personal data processed under 'legitimate interests'. To support this decision, a Legitimate Interests Assessment (LIA) assessment has been performed by the Sponsor in line with ICO guidance.
Details about the purpose of the processing are explained in detail in the patient information sheet (PIL) and each participant has consented to share their data for the study.

Patients are made aware (PIL and consent form) that they can withdraw from the study at any time but, if their data has been extracted to NWEH, then it will not be deleted as it is required for the purposes of analysis and in line with research guidelines. This approach has been approved by an ethics committee, the Health Research Authority (HRA) and Health and Care Research Wales (HCRW).

The data is required to enable the study endpoints to be met and maintain the scientific integrity of the study. The identifiable data will be restricted to NHS number. This is the minimum amount of information to reliably identify the patients in the NHS Digital data sets and link to their primary care data (the consented patients GP is contacted to authorise the extraction of their data). Subsequent analysis of the patient’s clinical record will be performed on pseudonymised data.

The purpose of processing the data is to understand the profile and characteristics of patients with RCC in terms of healthcare resource utilisation and treatment pattern. The health resource utilisation information is currently held in disparate data sets, therefore analysis of the full patient journey will not be possible without linking of datasets to facilitate analysis.

The data will be collected retrospectively directly from the patients’ medical records following consent. The amount of clinical data (5 years pre-diagnosis and 2 years post diagnosis) is the minimum required to facilitate appropriate analysis. Nothing further is required of the patient. The process is not intrusive and does not impact on patient care in any adverse way.

All processing will be compliant with GDPR, DPA 2018 and ISO/IEC 27001:2013 controls. A DPIA checklist has been performed in line with GDPR regulations and ICO recommendations. No data relating to children will be collected.

The wider benefits to processing this data is that it may lead to improvement/acceleration in the treatment of patients that are currently being treated but have not yet received the diagnosis of RCC. This is important because RCC is a debilitating condition, similar in severity to Chronic Obstructive Pulmonary Disorder (COPD). Therefore, earlier diagnosis and appropriate treatment would be of great benefit to sufferers.

As this project is a non-interventional data study, it is not in scope for Good Clinical Practice (GCP). We will comply with Good Pharmacoepidemiology Practice (GPP).
Patient data will only be accessed and processed by substantive employees of NorthWest EHealth Limited and potentially by MSD employees for the purposes of monitoring. The study monitors working for MSD (on MFT premises) will have access to the consented patients paper clinical records from the cough clinic. A small subset of these will be used to check that the data entered into the eCRF by the Research Nurse has been done so correctly. The study monitors do not have access to NHS Digital or GP derived data. All such staff (NWEH and MSD) will have honorary contracts with MFT. Data will not be accessed or processed by any other third parties not mentioned in this agreement. SRFT and Microsoft Azure will process data for the purposes of data base storage and database back up only.

For all consented patients Name, NHS number and date of birth will be entered into an electronic Case Report Form (eCRF) by a Research Nurse at MFT. This data is loaded into the study database hosted by SRFT. The NWEH Research Nurses and other NWEH staff working at MFT have honorary contracts with MFT. These honorary contract holders will not have access to NHS Digital or GP data.
NWEH will send Participant IDs and NHS numbers to NHS Digital to allow identification of study patients within the Hospital Episode Statistics Admitted Patient Care, Outpatients and Diagnostic Imaging databases (DID).

The data requested from NHS Digital using Participant ID will allow linkage to primary care data sets obtained by a third party (Apollo Medical Ltd). Point for clarification: the protocol says that EMIS or 'some other specialist company' will extract the GP data. At the time of writing the protocol it was hoped that there would be enough patients in EMIS practices that the project could use just those practices. It subsequently became clear that this would not be the case and it would be necessary to use a specialist company which could extract data from a range of GP systems. Apollo is the specialist company that was chosen to work with.

Data from all GP practices will contain the patients full medical record from 5 years pre-diagnosis to 2 years post-diagnosis with RCC. The only identifiable data will be date of birth, date of death, ethnicity and gender.

Apollo Medical only extracts the data, no further processing is performed by them. They do not store or access the data. Apollo software is installed on the GP system and facilitates a direct transfer of data from the GP practice to an agreed endpoint in NWEH's subscription within the SRFT Azure tenancy. All data are transmitted over a secure network. The NWEH Database Administrator (DBA) team will link the GP data to the HES and DID data using Participant ID. The HRU analysis will be done by the NWEH Statistics team who will only have access to the de-identified (no NHS number) data. The analysis does not require any knowledge of the individual patients͛ identity (name or address). At no point will the NHS Digital data be linked to any other data source which could identify patients. The NWEH DBA and Statistics teams all have honorary NHS contracts with SRFT and work in accordance with SRFT Information Governance policies. All NWEH staff undergo annual NHS Information Governance training through SRFT.

A pseudonymised data set from the Salford Integrated Record (SIR) will provide the control group. As it is pseudonymous, this data will not be linked to GP records or any NHS Digital data set. No data will flow to NHS Digital from this control data set. SIR is owned by Salford CCG and hosted by SRFT. The SIR Governance Board has given approval for the use of this data.

Data analysis will be carried out according to a pre-determined statistical analysis plan.