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.

This extension agreement is to allow NorthWest EHealth Limited to hold for archiving purposes, identifiable Hospital Episodes Statistics (HES) data (Admitted Patient Care and Outpatients) and Diagnostic Imaging Dataset (DIDs) that flowed under a previous version of this agreement. There are no further flows of data under this agreement.

The Study data as set out under this data sharing agreement (i.e., 5 years prior to diagnosis and 2 years post diagnosis) is being archived. All other data disseminated under this agreement has been securely destroyed.

This Data Sharing Agreement permits access to and use of Hospital Episode Statistics (HES) and Diagnostic Imaging Dataset (DIDS) data for the purpose of a retrospective data analysis of HES and DID data from patients with Refractory Chronic Cough (RCC).

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 Admitted Patient Care, HES Outpatient and DIDS data, linkage to the relevant cohort's GP data, and a comparison against an anonymised controlled cohort drawn from the Salford Integrated Record (SIR- owned by Salford CCG, and stored at Salford Royal NHS Foundation Trust).

Please note this Agreement 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 is not part of this Agreement with NHS Digital. NHS Digital are not providing the control group data.

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. 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) do not 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 its associated symptoms, such as gastroesophageal 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 remain 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.

For the purpose of this work HES APC, OP and DIDS data is required to enable NWEH to link with GP data to understand the healthcare utilization of patients across primary and secondary care. Specifically, for each data set, to determine the following (and associated costs):

• HES OP - the range of specialties that cough patients are referred to prior to RCC diagnosis

• HES APC – any admissions connected with RCC

• DIDS – diagnostic imaging procedures including those associated with cough (e.g. chest x-ray)

This is a stand-alone study commissioned by the sponsor Merck Sharp and Dohme (MSD), in collaboration with the Principal Investigator (PI) who is employed by Manchester University NHS Foundation Trust. 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.

To address the GDPR principle of minimisation the data requested under this Agreement is restricted to a cohort of ~ 200 individuals. 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 patients 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.

There are no alternative, less intrusive ways of achieving the purpose of this study. This was a minimally invasive study. It did not involve an investigational medicinal product. Patients consented to having their data extracted for analysis - no other participation was required from patients.

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 HES Analysis guidelines.

The sponsor has recently completed two Phase 3 clinical trials evaluating whether treatment with gefapixant reduced the primary outcome of cough frequency in participants with refractory chronic cough or unexplained chronic cough. These trials also included a secondary outcome of improvement in cough-related quality of life (as measured by the Leicester Cough Questionnaire)

Manchester Foundation Trust (MFT)

• Joint Data Controller

• MFT provide details of eligible patients

• MFT will receive no data (other than their own records) and will have sight of the final output report that is sent to MSD

North West E- Health (NWEH)

• 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 a Professor from Manchester Foundation Trust (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)

• Data Processor

• SIR data is hosted by SRFT, no further processing is done. Hosting facilities to the database are provided by SRFT.

• SRFT manages the Microsoft Azure platform on behalf of NWEH.

Microsoft

• 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.

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.

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. 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.

Only the outputs (aggregated with small numbers suppressed in line 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.

The sponsor of the study intends to publish the findings of these analyses in high impact journals. Any data contained within such articles will be aggregated with small numbers supressed in line with HES Analysis Guidance.

This was an exploratory study, with the primary purpose being 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 the participating patients, the findings will inform future work which could lead to patient benefits. The HRU analysis (based mainly on secondary care data) has shown that health care utilisation and associated costs reduces within 6 months of diagnosis of RCC. Early diagnosis of RCC is, therefore, of benefit to patients in reducing interaction with the health service (improved experience) and in reducing the cost to the NHS. Changes in clinical practice to facilitate earlier diagnosis are clearly desirable but were not the objective of this study. The main objective was to measure HRU before and after diagnosis - a crucial first step that had not hitherto been performed.

This Data Sharing Agreement permits access to and use of Hospital Episode Statistics (HES) and Diagnostic Imaging Dataset (DIDS) data for the purpose of a retrospective data analysis of HES and DID data from patients with Refractory Chronic Cough (RCC).

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 Admitted Patient Care, HES Outpatient and DIDS data, linkage to the relevant cohort's GP data, and a comparison against an anonymised controlled cohort drawn from the Salford Integrated Record (SIR- owned by Saflord CCG, and stored at Salford Royal NHS Foundation Trust).

Please note this Agreement 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 is not part of this Agreement with NHS Digital. NHS Digital are not providing the control group data.

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. 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) do not 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 its associated symptoms, such as gastroesophageal 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 remain 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.

For the purpose of this work HES APC, OP and DIDS data is required to enable NWEH to link with GP data to understand the healthcare utilization of patients across primary and secondary care. Specifically, for each data set, to determine the following (and associated costs):

• HES OP - the range of specialties that cough patients are referred to prior to RCC diagnosis

• HES APC – any admissions connected with RCC

• DIDS – diagnostic imaging procedures including those associated with cough (e.g. chest x-ray)

This is a stand-alone study commissioned by the sponsor Merck Sharp and Dohme (MSD), in collaboration with the Principal Investigator (PI) who is employed by Manchester University NHS Foundation Trust. 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.

To address the GDPR principle of minimisation the data requested under this Agreement is restricted to a cohort of ~ 200 individuals. 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 patients 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 HES Analysis 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.

The sponsor has recently completed two Phase 3 clinical trials evaluating whether treatment with gefapixant reduced the primary outcome of cough frequency in participants with refractory chronic cough or unexplained chronic cough. These trials also included a secondary outcome of improvement in cough-related quality of life (as measured by the Leicester Cough Questionnaire)

Manchester Foundation Trust (MFT)

• Joint Data Controller

• MFT provide details of eligible patients

• MFT will receive no data (other than their own records) and 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.

· WEH 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

• SIR 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.

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.

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 in line 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 2021 (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.

Further to this, the sponsor of the study intends to publish the findings of these analyses in high impact journals. Any data contained within such articles will be aggregated with small numbers supressed in line with HES Analysis Guidance.

There have been no yielded benefits because NorthWest EHealth have not yet received all the expected data required for these analyses.

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.

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.

Yielded Benefits is not a requirement for new applications.