Hospital Treatment Insights

IQVIA Ltd is an information and technology company composed of a number of affiliates serving the health care industry. IQVIA Ltd produces a longitudinal research database, Hospital Treatment Insights (HTI). This database contains unique information on diagnosis, treatment and drug usage across secondary care in England and has been linked to primary care data in the past. It is IQVIA Ltd.’s understanding that HTI is currently the largest routinely collected population-based database available for monitoring the use and safety of medicines used in the secondary care setting.

NHS Digital has in the past acted as a Trusted Third Party and provided linkage services for HTI. NHS Digital has done this by providing record level pseudonymised, non-sensitive HES data (the “Data”) with a link to IQVIA’s Hospital Prescribing Audit data (HPA)- under this iteration of this Data Sharing Agreement no data is to be released while IQVIA addresses issues highlighted by NHS Digital and the Independent Group Advising on the Release of Data (IGARD). This Data Sharing Agreement permits retention of data, but no further processing of data released under this Agreement unless it is to support the secure retention of data already held.

Previously, direct identifiers flowed from the hospital to NHS Digital who then enabled the linkage of the two data types under Section 251 of the National Health Service Act 2006. All direct identifiers were then removed before the data is shared with IQVIA Ltd. Under this iteration of this Data Sharing Agreement NHS Digital will not be undertaking any linkage or releasing any data to IQVIA.

Under former iterations of this Data Sharing Agreement data was processed for the purposes of the legitimate interests pursued by the controller or by a third party, except where such interests are overridden by the interests or fundamental rights and freedoms of the data subject which require protection of personal data, in particular where the data subject is a child (covered by Article 6 (1)(F) of the GDPR). Under this iteration of this Agreement, IQVIA are not permitted to process any data disseminated by NHS Digital unless it is to support the secure retention of the data already held.

IQVIA Ltd is the Sole Data Controller.

Under this iteration of this Data Sharing Agreement, IQVIA are not permitted to further process the data already held unless it is to support the secure retention of the data, as such there are no new expected outputs.

Under this iteration of this Data Sharing Agreement, IQVIA are not permitted to further process the data already held unless it is to support the secure retention of the data, as such there are no new expected outputs. The below outlines the benefits that were yielded prior to the restriction on processing.

1. IQVIA Ltd have performed a number of studies on healthcare resource utilisation within patients prescribed high-cost drugs

Autoimmune conditions are complicated to manage and result in debilitating conditions for patients. Recent immunomodulating therapies such as anti TNF based drugs (all prescribed in secondary care) have been shown to provide considerable benefit to patients with a reduction in morbidity and improved quality of life. However, these drugs are expensive and the control and use within guidelines is important for NHS trusts with implications for those involved with commissioning fully funded pathways. According to The National Institute for Clinical Excellence (NICE) in the UK reports that a 26-week cycle of an anti-TNF alpha medicine (such as infliximab) for ulcerative colitis costs approximately £4,900-£5,500 for an adult, while other conventional treatments cost £50-£850 (https://www.nice.org.uk/guidance/ta329/resources/costing-statement-pdf-428356477). IQVIA Ltd has conducted a series of epidemiological studies in this therapy area to determine the dosing patterns, the indications for which the drugs are prescribed and the patient populations within which they are used.

It has been shown, IQVIA Ltd conducted a study which showed that biologics for treating inflammatory bowel disease high-cost drugs (anti-TNFs and biologics) are used more frequently in routine clinical practice than anticipated than recommended in the guidelines. This creates an additional cost burden to the NHS than planned for which has a direct consequence on services that hospitals are able to fund. Using HTI data, IQVIA Ltd showed that inflammatory bowel disease patients treated with high-cost drugs showed differences in the rates of hospitalisation and surgical interventions between different agents. In 2018 there were approximately 487,000 people living with IBD in the UK (Pasvol TJ, Horsfall L, Bloom S, et al, Incidence and prevalence of inflammatory bowel disease in UK primary care: a population-based cohort study, BMJ Open 2020;10:e036584. doi: 10.1136/bmjopen-2019-036584). The information from this study can be used to identify patient groups that would benefit most from these biologics high-cost drugs and allow resources to be allocated accordingly.

This piece of work has been disseminated at one of the leading European conferences, the United European Gastroenterology Week (UEG). Attendees at the UEG include leading specialists across gastroenterology, making it a key opportunity for knowledge sharing across the gastroenterology community. It has also been published via an open access journal PLOS One, this means that NHS staff are able to access this research for free via a standard literature search for evidence, meaning there is no paywall standing in the way of health professionals accessing this material (http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0149692).

2. Probability of hospitalisation

Intravenous iron therapy is not considered as first line treatment of for iron deficiency anaemia in the majority of patients. The IQVIA business conducted an epidemiological study in collaboration with a pharmaceutical company to show that the 30-day readmission rate in patients treated with oral iron therapy was 81% compared with 34% readmitted for those treated with IV iron therapy. Among those, patients treated with IV were significantly lower than those treated with oral therapies. Readmission to hospital is distressing for patients and identifying which patients would benefit from IV therapy could lead to a reduction of readmission and improved patient outcomes. Readmission but is also an inefficient use of NHS resources. In this study IQVIA Ltd selected 30-day readmission rates since is a key quality metric that is used to evaluate NHS Trusts. This study was presented at the Digestive Disorders Federation's annual scientific meeting and its inclusion was decided by a panel of gastrointestinal experts. This study has now been published in an open access journal this means that NHS staff are able to access this research for free via a standard literature search for evidence, meaning there is no paywall standing in the way of health professionals accessing this material (http://gut.bmj.com/content/64/Suppl_1/A18.2).

3. Adherence to medication

It is well known that nonadherence to medications can result in worsening clinical outcomes, including rehospitalisation, exacerbation of chronic medical conditions, increased healthcare costs and death. The IQVIA business conducted a feasibility study to investigate the % proportion of patients who continued treatment of anticoagulant therapy in primary care within 90 days of discharge from hospital. Anticoagulants are effective for prevention of strokes and heart attacks but adherence to medication is crucial for maximising treatment benefits. The HTI data which was linked to primary care data from CPRD showed that further anticoagulation therapy was continued in primary care in over half of hospitalisations discharged with these medications. This study was presented as a poster at the International Conference of Pharmacoepidemiology (ICPE) in 2016.

Prescribing across Primary and Secondary Care

In this study IQVIA Ltd collaborated with CPRD to conduct a feasibility study to investigate the proportion of patients who continued treatment of anticoagulant therapy in primary care within 90 days of discharge from hospital. From the HTI data we were able to determine which anticoagulant treatment had been prescribed to a patient on discharge from hospital. Leveraging the CPRD linkage IQVIA Ltd followed those patients to determine which anticoagulant treatment was prescribed by the GP. This study demonstrated that linking secondary and primary care prescribing data can be used to evaluate outcomes for patients associated with continuity of care across sectors.

4. Real world data on the use of Palivizumab in infants to prevent respiratory syncytial virus (RSV). RSV usually causes mild respiratory infection in adults and children, but it can be severe in infants who are at increased risk of acute lower respiratory tract infection. It is the most common cause of bronchiolitis in children aged under 2 years, a common cause of paediatric hospital admissions over the winter months. Palivizumab is a monoclonal antibody licensed for the prevention of RSV in children. Since this treatment is expensive it usually restricted to high-risk patients. There is limited evidence of the use of Palivizumab in routine clinical care. In this study researchers identified patients who would be considered ‘high risk’ and would benefit from treatment with Palivizumab using an algorithm. The proportion of those eligible and those who received the treatment was measured. The results have been submitted for publication. This is an important piece of research that will help to inform clinicians about the use of Palivizumab to prevent RSV and specifically, which patients would benefit from it. For patients, this research will ensure that those patients who are at high risk of RSV will receive Palivizumab as a preventative measure. This will reduce the burden on the NHS of these patients being hospitalised.

5. Antipsychotic use in HTI hospitals. IQVIA Ltd provides feedback to participating hospitals on the use of drugs within their trust. Each feedback report focuses on a different therapy area. The purpose of the reports is to provide independent analysis of the pharmacy data provided to IQVIA Ltd. Often, hospital pharmacists do not have the capacity or resources to conduct these analyses themselves. The reports provide the hospital with an overview of drug dispensing in their own hospital compared with HTI overall. The therapy areas are selected according to areas that may be of interest to chief pharmacists and are in-line with the priorities of NHSE in relation to their Medicines Value and Medicines Optimisation Programmes. In the most recent report, IQVIA Ltd reported the use of antipsychotic drugs within HTI hospitals. In recent years NICE has issued guidance around the appropriate use of antipsychotic drugs. The feedback IQVIA Ltd provided to hospitals outlined the use of these drugs within their hospital and the associated indications by ICD10 diagnosis. These reports will help chief pharmacists monitor the use of antipsychotics in line with NICE guidance in order to better manage care provided for these patients and improve use of NHS resources.

6. A feedback report to hospitals using data from the COVID-19 first and second wave periods was generated to show chief pharmacists of HTI hospitals which drugs were used within their hospitals to treat these patients. The report allowed chief pharmacists to benchmark their drug utilisation against all HTI hospitals and inform their medicines management.

IQVIA Ltd is an information and technology company composed of a number of affiliates serving the health care industry. IQVIA Ltd produces a longitudinal research database, Hospital Treatment Insights (HTI). This database contains unique information on diagnosis, treatment and drug usage across secondary care in England and has been linked to primary care data in the past. It is IQVIA Ltd.’s understanding that HTI is currently the largest routinely collected population-based database available for monitoring the use and safety of medicines used in the secondary care setting.

NHS Digital has in the past acted as a Trusted Third Party and provided linkage services for HTI. NHS Digital has done this by providing record level pseudonymised, non-sensitive HES data (the “Data”) with a link to IQVIA’s Hospital Prescribing Audit data (HPA)- under this iteration of this Data Sharing Agreement no data is to be released while IQVIA addresses issues highlighted by NHS Digital and the Independent Group Advising on the Release of Data (IGARD). This Data Sharing Agreement permits retention of data, but no further processing of data released under this Agreement unless it is to support the secure retention of data already held.

Previously, direct identifiers flowed from the hospital to NHS Digital who then enabled the linkage of the two data types under Section 251 of the National Health Service Act 2006. All direct identifiers were then removed before the data is shared with IQVIA Ltd. Under this iteration of this Data Sharing Agreement NHS Digital will not be undertaking any linkage or releasing any data to IQVIA.

Under former iterations of this Data Sharing Agreement data was processed for the purposes of the legitimate interests pursued by the controller or by a third party, except where such interests are overridden by the interests or fundamental rights and freedoms of the data subject which require protection of personal data, in particular where the data subject is a child (covered by Article 6 (1)(F) of the GDPR). Under this iteration of this Agreement, IQVIA are not permitted to process any data disseminated by NHS Digital unless it is to support the secure retention of the data already held.

IQVIA Ltd is the Sole Data Controller.

Under this iteration of this Data Sharing Agreement, IQVIA are not permitted to further process the data already held unless it is to support the secure retention of the data, as such there are no new expected outputs.

Under this iteration of this Data Sharing Agreement, IQVIA are not permitted to further process the data already held unless it is to support the secure retention of the data, as such there are no new expected outputs. The below outlines the benefits that were yielded prior to the restriction on processing.

1. IQVIA Ltd have performed a number of studies on healthcare resource utilisation within patients prescribed high-cost drugs

Autoimmune conditions are complicated to manage and result in debilitating conditions for patients. Recent immunomodulating therapies such as anti TNF based drugs (all prescribed in secondary care) have been shown to provide considerable benefit to patients with a reduction in morbidity and improved quality of life. However, these drugs are expensive and the control and use within guidelines is important for NHS trusts with implications for those involved with commissioning fully funded pathways. According to The National Institute for Clinical Excellence (NICE) in the UK reports that a 26-week cycle of an anti-TNF alpha medicine (such as infliximab) for ulcerative colitis costs approximately £4,900-£5,500 for an adult, while other conventional treatments cost £50-£850 (https://www.nice.org.uk/guidance/ta329/resources/costing-statement-pdf-428356477). IQVIA Ltd has conducted a series of epidemiological studies in this therapy area to determine the dosing patterns, the indications for which the drugs are prescribed and the patient populations within which they are used.

It has been shown, IQVIA Ltd conducted a study which showed that biologics for treating inflammatory bowel disease high-cost drugs (anti-TNFs and biologics) are used more frequently in routine clinical practice than anticipated than recommended in the guidelines. This creates an additional cost burden to the NHS than planned for which has a direct consequence on services that hospitals are able to fund. Using HTI data, IQVIA Ltd showed that inflammatory bowel disease patients treated with high-cost drugs showed differences in the rates of hospitalisation and surgical interventions between different agents. In 2018 there were approximately 487,000 people living with IBD in the UK (Pasvol TJ, Horsfall L, Bloom S, et al, Incidence and prevalence of inflammatory bowel disease in UK primary care: a population-based cohort study, BMJ Open 2020;10:e036584. doi: 10.1136/bmjopen-2019-036584). The information from this study can be used to identify patient groups that would benefit most from these biologics high-cost drugs and allow resources to be allocated accordingly.

This piece of work has been disseminated at one of the leading European conferences, the United European Gastroenterology Week (UEG). Attendees at the UEG include leading specialists across gastroenterology, making it a key opportunity for knowledge sharing across the gastroenterology community. It has also been published via an open access journal PLOS One, this means that NHS staff are able to access this research for free via a standard literature search for evidence, meaning there is no paywall standing in the way of health professionals accessing this material (http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0149692).

2. Probability of hospitalisation

Intravenous iron therapy is not considered as first line treatment of for iron deficiency anaemia in the majority of patients. The IQVIA business conducted an epidemiological study in collaboration with a pharmaceutical company to show that the 30-day readmission rate in patients treated with oral iron therapy was 81% compared with 34% readmitted for those treated with IV iron therapy. Among those, patients treated with IV were significantly lower than those treated with oral therapies. Readmission to hospital is distressing for patients and identifying which patients would benefit from IV therapy could lead to a reduction of readmission and improved patient outcomes. Readmission but is also an inefficient use of NHS resources. In this study IQVIA Ltd selected 30-day readmission rates since is a key quality metric that is used to evaluate NHS Trusts. This study was presented at the Digestive Disorders Federation's annual scientific meeting and its inclusion was decided by a panel of gastrointestinal experts. This study has now been published in an open access journal this means that NHS staff are able to access this research for free via a standard literature search for evidence, meaning there is no paywall standing in the way of health professionals accessing this material (http://gut.bmj.com/content/64/Suppl_1/A18.2).

3. Adherence to medication

It is well known that nonadherence to medications can result in worsening clinical outcomes, including rehospitalisation, exacerbation of chronic medical conditions, increased healthcare costs and death. The IQVIA business conducted a feasibility study to investigate the % proportion of patients who continued treatment of anticoagulant therapy in primary care within 90 days of discharge from hospital. Anticoagulants are effective for prevention of strokes and heart attacks but adherence to medication is crucial for maximising treatment benefits. The HTI data which was linked to primary care data from CPRD showed that further anticoagulation therapy was continued in primary care in over half of hospitalisations discharged with these medications. This study was presented as a poster at the International Conference of Pharmacoepidemiology (ICPE) in 2016.

Prescribing across Primary and Secondary Care

In this study IQVIA Ltd collaborated with CPRD to conduct a feasibility study to investigate the proportion of patients who continued treatment of anticoagulant therapy in primary care within 90 days of discharge from hospital. From the HTI data we were able to determine which anticoagulant treatment had been prescribed to a patient on discharge from hospital. Leveraging the CPRD linkage IQVIA Ltd followed those patients to determine which anticoagulant treatment was prescribed by the GP. This study demonstrated that linking secondary and primary care prescribing data can be used to evaluate outcomes for patients associated with continuity of care across sectors.

4. Real world data on the use of Palivizumab in infants to prevent respiratory syncytial virus (RSV). RSV usually causes mild respiratory infection in adults and children, but it can be severe in infants who are at increased risk of acute lower respiratory tract infection. It is the most common cause of bronchiolitis in children aged under 2 years, a common cause of paediatric hospital admissions over the winter months. Palivizumab is a monoclonal antibody licensed for the prevention of RSV in children. Since this treatment is expensive it usually restricted to high-risk patients. There is limited evidence of the use of Palivizumab in routine clinical care. In this study researchers identified patients who would be considered ‘high risk’ and would benefit from treatment with Palivizumab using an algorithm. The proportion of those eligible and those who received the treatment was measured. The results have been submitted for publication. This is an important piece of research that will help to inform clinicians about the use of Palivizumab to prevent RSV and specifically, which patients would benefit from it. For patients, this research will ensure that those patients who are at high risk of RSV will receive Palivizumab as a preventative measure. This will reduce the burden on the NHS of these patients being hospitalised.

5. Antipsychotic use in HTI hospitals. IQVIA Ltd provides feedback to participating hospitals on the use of drugs within their trust. Each feedback report focuses on a different therapy area. The purpose of the reports is to provide independent analysis of the pharmacy data provided to IQVIA Ltd. Often, hospital pharmacists do not have the capacity or resources to conduct these analyses themselves. The reports provide the hospital with an overview of drug dispensing in their own hospital compared with HTI overall. The therapy areas are selected according to areas that may be of interest to chief pharmacists and are in-line with the priorities of NHSE in relation to their Medicines Value and Medicines Optimisation Programmes. In the most recent report, IQVIA Ltd reported the use of antipsychotic drugs within HTI hospitals. In recent years NICE has issued guidance around the appropriate use of antipsychotic drugs. The feedback IQVIA Ltd provided to hospitals outlined the use of these drugs within their hospital and the associated indications by ICD10 diagnosis. These reports will help chief pharmacists monitor the use of antipsychotics in line with NICE guidance in order to better manage care provided for these patients and improve use of NHS resources.

6. A feedback report to hospitals using data from the COVID-19 first and second wave periods was generated to show chief pharmacists of HTI hospitals which drugs were used within their hospitals to treat these patients. The report allowed chief pharmacists to benchmark their drug utilisation against all HTI hospitals and inform their medicines management.

IQVIA Ltd is an information and technology company composed of a number of affiliates serving the health care industry. IQVIA Ltd produces a longitudinal research database, Hospital Treatment Insights (HTI). This database contains unique information on diagnosis, treatment and drug usage across secondary care in England and has been linked to primary care data in the past. It is IQVIA Ltd's understanding that HTI is currently the largest routinely collected population-based database available for monitoring the use and safety of medicines used in the secondary care setting. NHS Digital acts as a Trusted Third Party and provides linkage services for HTI. NHS Digital does this by providing record level pseudonymised, non-sensitive HES data (the “Data”) with a link to IQVIA’s Hospital Prescribing Audit data (HPA).

Direct identifiers flow from the hospital to NHS Digital who enable the link of the two data types under Section 251 of the National Health Service Act 2006. All direct identifiers are then removed before the data is shared with IQVIA Ltd.

The linkage requested is necessary for the purposes of the legitimate interests pursued by the controller or by a third party, except where such interests are overridden by the interests or fundamental rights and freedoms of the data subject which require protection of personal data, in particular where the data subject is a child (covered by Article 6 (1)(F) of the GDPR).

IQVIA Ltd requires access to health data to serve its purpose of serving the health care industry and populating the longitudinal research database.

The Legal basis for processing of personal data relating to patient health is under Article 9(2)(j)of the GDPR - Processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject. The data subjects’ interests and fundamental rights are protected through appropriate minimisation of fields; protection of the data in a secure environment and guaranteeing secure destruction at any stage at the request of NHS Digital or after a defined period on completion of the project.

IQVIA Ltd is the Sole Data Controller who also processes the data under this Agreement.

In order to link the different data sets, NHS Digital receives the identifiable pharmacy data (HPA) directly from NHS trusts and it then links that pharmacy data to the patient level HES data. A pseudonymised output of such linked HES Data is returned by NHS Digital to IQVIA Ltd. Identifiable data does not flow to IQVIA Ltd hereunder and IQVIA Ltd do not therefore, hold any identifiable data in this respect.

Currently there are more than 9 million patients in HTI data. This database is used for the benefit of healthcare across multiple studies in a variety of research disciplines.

1. Data will be used to undertake a programme of research studies, in two main areas, aimed at promoting public health which will include:

Advanced statistical analysis, such as:

• Epidemiology

• natural history of disease

• health economics and outcomes research

• drug exposures

• estimate the number of potential patients eligible for clinical research (including clinical trials)

Drug safety monitoring, such as:

• monitoring of adverse events for newly licenced drugs prescribed in secondary care

• pharmacovigilance

In all cases, purposes are restricted to those for the provision of health care or adult social care, or the promotion of health.

Potential users of the data are as follows:

1. Regulators such as the Medicines and Healthcare Products Regulatory Agency (MHRA) and the European Medicines Agency (EMA) can investigate potential adverse drug reactions (ADR) in marketed products. When new ADRs are discovered regulators can recommend actions to limit harm to patients exposed to the products. Responsiveness is key as products are already marketed meaning that further events could occur immediately. Therefore, it is crucial to have data, like HTI readily available that will allow direct investigation of ADR or evaluation of the likely public health impact should the potential ADR be established as a real effect.

Examples of regulatory use include:

Working with researchers who have a special interest in drug safety with a view to conducting a proof-of-concept drug safety study in HTI.

Regulators, such as the MHRA and EMA, have an interest in using data generated from HTI in their drug safety activities. They currently have access to primary care data. However, these regulators are also responsible for pharmacovigilance of products that are only used in a hospital setting and HTI is the only source of data on hospital drugs. Thus, access to HTI data has an important role in improving the use of medicines used in hospitals and could have a significant impact on public health. IQVIA has responded to a tender from the EMA for access to HTI to perform some of their regulatory work. There is currently an ongoing pre-pass study to assess the clinical risks and adverse events in patient with psoriasis. Should this project go ahead this DSA will be updated accordingly before the NHS Digital data is used for this purpose.

2. Arm’s Length Bodies (ALBs) involved in Health and Social Care. ALBs, such as NICE (National Institute for Clinical Excellence), can use HTI to monitor adherence to clinical guidance and decisions regarding uptake of innovative therapies, in order to reduce variation in the delivery of healthcare. ALBs concerned more directly with the provision of healthcare such as NHS England will be able to measure equity of access to treatments in the NHS using HTI and, therefore, reduce health inequality.

Examples of use by ALBs include:

• Uptake and utilisation of new and existing therapies

• Medical vs surgical treatment rates associated with specific pharmaceutical treatments

• Readmission rates associated with specific pharmaceutical treatments

• Rates of elective vs non elective admissions in patients following different treatment regimens

3. Medical researchers from academia and other types of organisations such as patient groups, charitable trusts and pharmaceutical companies.

Examples of use by medical researchers:

Research into disease management and outcomes to improve patient care, health economic studies, comparative effectiveness studies and drug utilisation studies. These studies support the long-term sustainability of the NHS by evaluating cost effectiveness. This will become increasingly important as drugs become more expensive, placing a higher financial burden on the health system. The topic of sustainability will be a focus area for researchers, particularly as 94% of new molecular entities will be for specialist care delivered within the hospital setting.

4. Estimate the number of potential patients eligible for clinical research

A typical use case of HTI for the purpose of clinical research is the estimation of the potential pool of patients that might be eligible for inclusion into a clinical trial. IQVIA would like to use HTI data to determine the proportion of patients diagnosed with a specific diagnosis or set of diagnoses (based on ICD-10 clinical coding as used in Hospital Episode Statistics data) who are then treated with a specific drug or set of drugs (based on IQVIA Hospital Pharmacy Audit data contained within HTI). This forms part of an attrition analysis, in which IQVIA Ltd will start with the number of patients in the population and estimate the number of patients with specific characteristics, by applying filters based on relevant characteristics of the population of interest, e.g. percentage IQVIA Ltd to estimate the percentage associated with drug treatment status to help determine the approximate size of a potential study population.

There are controls in place to ensure secure access to the data:

1. Researcher access - the HTI database contains pseudonymised data. All researchers accessing the data need to be substantive employees of IQVIA Ltd or access the data on IQVIA’s system via sub-licence. Honorary contracts must not be used to grant external access as an alternative to sublicensing arrangements.

All researchers accessing these data undertake training and sign additional confidentiality agreements with IQVIA Ltd. Researchers are informed that any misuse of data will result in formal disciplinary procedures. To enable research by medicines regulators, public health bodies and academic researchers the data must be accessible across all 4 countries within the UK. No row level data would leave the secure environment which is based in England.

IQVIA Ltd does not permit any access to pseudonymised patient record-level HTI Data from outside of the UK.

For the purpose of this short-term extension and renewal researchers are only permitted to access the NHS Digital data contained within the HTI Database for the two projects that were reviewed and approved by IQVIA’s independent review board, the Independent Scientific Ethical Advisory Committee (ISEAC). IQVIA are permitted to sub-licence data to UCL for the purpose of the following project only ‘Patterns of prescribing palivizumab in England’.

Within the subsequent iteration of this Agreement IQVIA will be required to outline details of all projects using HTI data and will no longer have delegated authority to approve projects on behalf on NHS Digital.

IQVIA Ltd understands the importance of data minimisation and ensures that records extracted from the database are limited to those absolutely necessary for conducting the particular study.

IQVIA is requesting access to the following data:

• HES records, either in an HTI trust or a non-HTI Trust, that can be linked to a pharmacy record

• All other HES records from HTI Trusts that cannot be linked to a pharmacy record. These records will only be used for data validation purposes to compare the percentage of linkage across different trusts and therapy areas.

Justification for historical data

Restricting back data for any database could potentially limit its usefulness for medical research, as historical information is used for cohort selection, bias adjustment, and prediction, among other things. To make database research robust and useful for making clinical decisions, the most comprehensive record of the patient's medical history must be included in each phase of the study. Since HTI is a database used for multiple studies of varying methodologies, it is not straightforward to know which studies would still be robust if the historic data period was reduced. ISEAC reviews protocols with data minimisation in mind and will ensure that researchers do not access data that would not be required for their study. Similarly, IQVIA’s internal processes for analysing and exporting data allow for the monitoring of data accessed for each study.

● IQVIA Ltd uses historical HES data (from 2005) in HTI studies in order to identify diagnosis prior to patients receiving a drug, to determine any other conditions in the patient’s medical history that might impact the patient’s response to a drug and to identify the date when a patient first had a secondary care visit for a particular diagnosis (index date). HTI has been used to conduct studies on drug treatment for chronic conditions including psoriasis, rheumatoid arthritis, multiple sclerosis and ulcerative colitis. Patients with chronic diseases have these conditions for life so it is important to have the maximum number of years of back data in order to conduct studies rigorously. IQVIA do not request data prior to 2005 due to NHS ID’s not being available to link datasets earlier than this.

● If historical HES data was not provided then researchers could miss important events which would then not be adjusted for in study results.

● In addition, the historical data may be used to detect rare, delayed adverse events. Researchers conducting regulatory studies need access to historical HES data in the HTI database in order to monitor drug safety, particularly of rare and delayed adverse events which may take many years to develop.

● Historic data is required to support Advanced Statistical Analysis projects and safety studies, as historical data allows robust analysis of trends over time.

● Historical data on patient contact with secondary care is important because the lead up to diagnosis of many conditions, particularly rare diseases, can be complex and lengthy. Evidence highlighted in the UK Strategy for Rare Diseases suggests that four in ten patients with rare diseases have “found it difficult to get the correct diagnosis” and that “25% of patients said that there was a gap of between 5 and 30 years between getting their first symptoms and a diagnosis”

● Historical data of patients with chronic conditions is needed to understand disease progression and can be used to investigate how the usage of different treatments impacts the typical time of disease progression

● Historical data is needed to understand previous and co-morbid conditions in order to adjust for these in the research study outcome. For example, a trust could be incorrectly identified as having poor outcomes or performance when they are in fact treating sicker or higher risk patients e.g. patients with previous cardiovascular and stroke events. This information in also needed to ensure the research outcome is correctly interpreted so that the medical professionals are able to provide the most appropriate care for patients e.g. a medication may be considered to have higher risk profile in a certain patient population

● Historical data provides extended longitudinal coverage to allow researchers to look at delayed adverse events or outcomes which have a long latency period from the time of exposure to manifestation.

Examples where historical data is important in conducting research:

1. HTI enables the study of hospital only medicines in a real world setting. This is very important because the patients receiving these medicines don’t always reflect those that the medicines are tested on . HTI studies are observational studies of the way in which drugs are used i.e. characterising the patients that receive them and then following those patients to see whether or not they benefit from the drug(s) in question. These studies are conducted over a specified study period i.e. a time frame over which the observation takes place. Setting the time period requires a starting point or ‘index’ date. This is usually the date at which a diagnosis has been made for which the drug being studied is a treatment. For chronic conditions diagnoses are made early in the patients’ history and the historic HES data enables an accurate index date to be set. Without the historic data, important information around the diagnosis of the disease would be missed.

2. HTI has been used to study the use of biologics in the treatment of autoimmune diseases such as ulcerative colitis and rheumatoid arthritis. These are expensive hospital only drugs and are not the first line of therapy for these diseases. The studies IQVIA have conducted have looked at healthcare resource use prior to the administration of these drugs i.e. the treatment pathway leading up to the administration of these drugs. Without the historic HES data, these studies would not be possible.

3. One very important use of HTI is in drug safety studies. These studies can sometimes involve identifying potential ‘signals’ or side effects of a drug. For these studies it is vital to access as much of a patient’s past medical history as possible. For example, some new drugs may have the potential to cause cardiovascular side effects; in order to evaluate these it would be important to know if a patient has suffered from cardiovascular problems in the past and to include as much detail as possible around those events into the analysis.

4. Some studies look at the difference in outcomes associated with different treatment options for a particular disease i.e. what are the characteristics of patients that respond better to one treatment over another. These studies are important because they can help doctors decide which treatment option would be more suitable for a patient. In order to conduct these studies with rigour and as much accuracy as possible, it is important to take into account every aspect the patient’s health state from their history because past medical history affects the decisions that doctors take for current and future drug therapy.

5. Large databases like HTI are often used to conduct observational epidemiological studies. The starting point of these studies requires building a cohort of study patients based on strict inclusion and exclusion criteria. Without access to the past medical history, it would be difficult to ensure that the patients included in the study are the ‘right’ patients and, as a result, the study results could be biased.

6. Evidence highlighted in the UK Strategy for Rare Diseases suggests that four in ten patients with rare diseases have “found it difficult to get the correct diagnosis” and that “25% of patients said that there was a gap of between 5 and 30 years between getting their first symptoms and a diagnosis”.

7. Past medical history often includes risk factors, co-morbidities and confounders that are important to adjust for when analysing data in order to ensure that conclusions drawn from the research are generalizable and robust.

There are no alternative or less intrusive ways of achieving the purpose of this programme of work.

There are no external funders' or commissioners involved in the data processing under this Data Sharing Agreement.

All HTI studies result in a scientific report structured along the lines of a scientific paper (e.g. Summary, Background, Methods, Results and Discussion). Interim tables of results (aggregated data with small number suppression in line with the HES analysis guide) may be circulated as interim results for discussion and appended to the study report. An exception would be made where the data is used for the purpose of estimating the number of potential patients eligible for clinical research (including clinical trials: here the analysis would support potential future clinical trials from which research will be produced, but the analysis itself would not result in a scientific report.

Further outputs include research publications in peer-reviewed journals and presentations at scientific conferences in addition to research included in Health Technology Assessments and Regulatory evidence. Researchers accessing HTI data for HTI studies are required to publish their findings or allow an anonymised (company and product blinded) version of the study to be included in the publicly available IQVIA Global bibliography. IQVIA Ltd will share these studies with participating trusts and healthcare stakeholders.

1. Participating NHS Trusts. IQVIA Ltd’s research team is working with NHS Trusts to assist in the production of information that will impact on improving patient care. An analytical team has been put in place for the purpose of generating a feedback report. The report delivered to each trust will contain aggregated, small number suppressed data across all trusts and will also contain trust-specific outputs which will only be shared with that trust. These findings will be sent to Chief Pharmacists at participating hospital Trusts.

2. Regulatory Authorities and Arm’s Length Bodies (ALBs) involved in Health and Social Care. The specific outputs expected for regulatory authorities include drug safety studies, signal detection and evaluation of adverse drug reactions of hospital prescribed therapies. ALBs such as NICE, NHS Digital and NHS England will be able to access the pseudonymised, non-sensitive record level database for conducting health technology assessments, monitoring adherence to guidance and to inform policy decisions.

3. Medical researchers from academia. Access to pseudonymised, non-sensitive record level data or delivery of aggregated tables for generation of research publications in peer-reviewed journals and presentations in scientific conferences. Information to be included in health technology assessments and evidence for regulators.

4. Pharmaceutical companies. Provision of aggregated, small number suppressed tables to answer research questions in two main areas, which will include:

Advanced statistical analysis, such as:

• epidemiology

• natural history of disease

• health economics and outcomes research

• drug exposures

• Estimate the number of potential patients eligible for clinical research (including clinical trials)

Drug safety monitoring, such as:

• monitoring of adverse events for newly licenced drugs prescribed in secondary care

• pharmacovigilance

Where possible, the outputs from these studies will be published in peer-reviewed journals and presented at scientific conferences, included in Health Technology Assessments or delivered to regulators. Pharmaceutical companies are required to publish their findings or allow an anonymised (company and product blinded) version of the study to be made available on the publicly available Global bibliography.

1. IQVIA Ltd have performed a number of studies on healthcare resource utilisation within patients prescribed high-cost drugs

Autoimmune conditions are complicated to manage and result in debilitating conditions for patients. Recent immunomodulating therapies such as anti TNF based drugs (all prescribed in secondary care) have been shown to provide considerable benefit to patients with a reduction in morbidity and improved quality of life. However, these drugs are expensive and the control and use within guidelines is important for NHS trusts with implications for those involved with commissioning fully funded pathways. According to The National Institute for Clinical Excellence (NICE) in the UK reports that a 26-week cycle of an anti-TNF alpha medicine (such as infliximab) for ulcerative colitis costs approximately £4,900-£5,500 for an adult, while other conventional treatments cost £50-£850 (https://www.nice.org.uk/guidance/ta329/resources/costing-statement-pdf-428356477). IQVIA Ltd has conducted a series of epidemiological studies in this therapy area to determine the dosing patterns, the indications for which the drugs are prescribed and the patient populations within which they are used.

It has been shown, IQVIA Ltd conducted a study which showed that biologics for treating inflammatory bowel disease high-cost drugs (anti-TNFs and biologics) are used more frequently in routine clinical practice than anticipated than recommended in the guidelines. This creates an additional cost burden to the NHS than planned for which has a direct consequence on services that hospitals are able to fund. Using HTI data, IQVIA Ltd showed that inflammatory bowel disease patients treated with high-cost drugs showed differences in the rates of hospitalisation and surgical interventions between different agents. In 2018 there were approximately 487,000 people living with IBD in the UK (Pasvol TJ, Horsfall L, Bloom S, et al, Incidence and prevalence of inflammatory bowel disease in UK primary care: a population-based cohort study, BMJ Open 2020;10:e036584. doi: 10.1136/bmjopen-2019-036584). The information from this study can be used to identify patient groups that would benefit most from these biologics high-cost drugs and allow resources to be allocated accordingly.

This piece of work has been disseminated at one of the leading European conferences, the United European Gastroenterology Week (UEG). Attendees at the UEG include leading specialists across gastroenterology, making it a key opportunity for knowledge sharing across the gastroenterology community. It has also been published via an open access journal PLOS One, this means that NHS staff are able to access this research for free via a standard literature search for evidence, meaning there is no paywall standing in the way of health professionals accessing this material (http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0149692).

2. Probability of hospitalisation

Intravenous iron therapy is not considered as first line treatment of for iron deficiency anaemia in the majority of patients. The IQVIA business conducted an epidemiological study in collaboration with a pharmaceutical company to show that the 30-day readmission rate in patients treated with oral iron therapy was 81% compared with 34% readmitted for those treated with IV iron therapy. Among those, patients treated with IV were significantly lower than those treated with oral therapies. Readmission to hospital is distressing for patients and identifying which patients would benefit from IV therapy could lead to a reduction of readmission and improved patient outcomes. Readmission but is also an inefficient use of NHS resources. In this study IQVIA Ltd selected 30-day readmission rates since is a key quality metric that is used to evaluate NHS Trusts. This study was presented at the Digestive Disorders Federation's annual scientific meeting and its inclusion was decided by a panel of gastrointestinal experts. This study has now been published in an open access journal this means that NHS staff are able to access this research for free via a standard literature search for evidence, meaning there is no paywall standing in the way of health professionals accessing this material (http://gut.bmj.com/content/64/Suppl_1/A18.2).

3. Adherence to medication

It is well known that nonadherence to medications can result in worsening clinical outcomes, including rehospitalisation, exacerbation of chronic medical conditions, increased healthcare costs and death. The IQVIA business conducted a feasibility study to investigate the % proportion of patients who continued treatment of anticoagulant therapy in primary care within 90 days of discharge from hospital. Anticoagulants are effective for prevention of strokes and heart attacks but adherence to medication is crucial for maximising treatment benefits. The HTI data which was linked to primary care data from CPRD showed that further anticoagulation therapy was continued in primary care in over half of hospitalisations discharged with these medications. This study was presented as a poster at the International Conference of Pharmacoepidemiology (ICPE) in 2016.

Prescribing across Primary and Secondary Care

In this study IQVIA Ltd collaborated with CPRD to conduct a feasibility study to investigate the proportion of patients who continued treatment of anticoagulant therapy in primary care within 90 days of discharge from hospital. From the HTI data we were able to determine which anticoagulant treatment had been prescribed to a patient on discharge from hospital. Leveraging the CPRD linkage IQVIA Ltd followed those patients to determine which anticoagulant treatment was prescribed by the GP. This study demonstrated that linking secondary and primary care prescribing data can be used to evaluate outcomes for patients associated with continuity of care across sectors.

4. Real world data on the use of Palivizumab in infants to prevent respiratory syncytial virus (RSV). RSV usually causes mild respiratory infection in adults and children, but it can be severe in infants who are at increased risk of acute lower respiratory tract infection. It is the most common cause of bronchiolitis in children aged under 2 years, a common cause of paediatric hospital admissions over the winter months. Palivizumab is a monoclonal antibody licensed for the prevention of RSV in children. Since this treatment is expensive it usually restricted to high-risk patients. There is limited evidence of the use of Palivizumab in routine clinical care. In this study researchers identified patients who would be considered ‘high risk’ and would benefit from treatment with Palivizumab using an algorithm. The proportion of those eligible and those who received the treatment was measured. The results have been submitted for publication. This is an important piece of research that will help to inform clinicians about the use of Palivizumab to prevent RSV and specifically, which patients would benefit from it. For patients, this research will ensure that those patients who are at high risk of RSV will receive Palivizumab as a preventative measure. This will reduce the burden on the NHS of these patients being hospitalised.

5. Antipsychotic use in HTI hospitals. IQVIA Ltd provides feedback to participating hospitals on the use of drugs within their trust. Each feedback report focuses on a different therapy area. The purpose of the reports is to provide independent analysis of the pharmacy data provided to IQVIA Ltd. Often, hospital pharmacists do not have the capacity or resources to conduct these analyses themselves. The reports provide the hospital with an overview of drug dispensing in their own hospital compared with HTI overall. The therapy areas are selected according to areas that may be of interest to chief pharmacists and are in-line with the priorities of NHSE in relation to their Medicines Value and Medicines Optimisation Programmes. In the most recent report, IQVIA Ltd reported the use of antipsychotic drugs within HTI hospitals. In recent years NICE has issued guidance around the appropriate use of antipsychotic drugs. The feedback IQVIA Ltd provided to hospitals outlined the use of these drugs within their hospital and the associated indications by ICD10 diagnosis. These reports will help chief pharmacists monitor the use of antipsychotics in line with NICE guidance in order to better manage care provided for these patients and improve use of NHS resources.

IQVIA Ltd is an information and technology company composed of a number of affiliates serving the health care industry. IQVIA Ltd produces a longitudinal research database, Hospital Treatment Insights (HTI). This database contains unique information on diagnosis, treatment and drug usage across secondary care in England and has been linked to primary care data in the past. . It is IQVIA Ltd's understanding that HTI is currently the largest routinely collected population based database available for monitoring the use and safety of medicines used in the secondary care setting. NHS Digital acts as a Trusted Third Party and provides linkage services for HTI. NHS Digital does this by providing record level pseudonymised, non-sensitive HES data (the “Data”) with a link to IQVIA’s Hospital Prescribing Audit data (HPA).

Direct identifiers flow from the hospital to NHS Digital who enable the link of the two data types under Section 251 of the National Health Service Act 2006. All direct identifiers are then removed before the data is shared with IQVIA Ltd.

The linkage requested is necessary for the purposes of the legitimate interests pursued by the controller or by a third party, except where such interests are overridden by the interests or fundamental rights and freedoms of the data subject which require protection of personal data, in particular where the data subject is a child (covered by Article 6 (1)(F) of the GDPR). IQVIA Ltd requires access to health data to serve its purpose of serving the health care industry and populating the longitudinal research database.

The Legal basis for processing of personal data relating to patient health is under Article 9(2)(j)of the GDPR - Processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject. The data subjects’ interests and fundamental rights are protected through appropriate minimisation of fields; protection of the data in a secure environment, and guaranteeing secure destruction at any stage at the request of NHS Digital or after a defined period on completion of the project.

IQVIA Ltd is the Sole sole Data Controller who also processes the data under this Agreement. IQVIA Ltd is not permitted to grant access to the data to any third party.

In order to link the different data sets, NHS Digital receives the identifiable pharmacy data (HPA) directly from NHS trusts and it then links that pharmacy data to the patient level HES data. A pseudonymised output of such linked HES Data is returned by NHS Digital to IQVIA Ltd. Identifiable data does not flow to IQVIA Ltd hereunder and IQVIA Ltd do not therefore, hold any identifiable data in this respect.

Currently there are more than 9 million patients in HTI data. This database is used for the benefit of healthcare across multiple studies in a variety of research disciplines.

1. Data will be used to undertake a programme of research studies, in two main areas, aimed at promoting public health which will include:

Advanced statistical analysis, such as:

• Epidemiology

• natural history of disease

• health economics and outcomes research

• drug exposures

• estimate the number of potential patients eligible for clinical research (including clinical trials)

Drug safety monitoring, such as:

• monitoring of adverse events for newly licenced drugs prescribed in secondary care

• pharmacovigilance

In all cases, purposes are restricted to those for the provision of health care or adult social care, or the promotion of health.

Potential users of the data are as follows:

1. Regulatory Authorities. Regulators such as the Medicines and Healthcare Products Regulatory Agency (MHRA) and the European Medicines Agency (EMA) can investigate potential adverse drug reactions (ADR) in marketed products. When new ADRs are discovered regulators can recommend actions to limit harm to patients exposed to the products. Responsiveness is key as products are already marketed meaning that further events could occur immediately. Therefore it is crucial to have data, like HTI readily available that will allow direct investigation of ADR or evaluation of the likely public health impact should the potential ADR be established as a real effect.

Examples of regulatory use include:

Working with researchers who have a special interest in drug safety with a view to conducting a proof of concept drug safety study in HTI.

Regulators, such as the MHRA and EMA, have an interest in using data generated from HTI in their drug safety activities. They currently have access to primary care data. However, these regulators are also responsible for pharmacovigilance of products that are only used in a hospital setting and HTI is the only source of data on hospital drugs. Thus access to HTI data has an important role in improving the use of medicines used in hospitals and could have a significant impact on public health. IQVIA has responded to a tender from the EMA for access to HTI to perform some of their regulatory work. There is currently an ongoing pre-pass study to assess the clinical risks and adverse events in patient with psoriasis.

2. Arm’s Length Bodies (ALBs) involved in Health and Social Care. ALBs, such as NICE (National Institute for Clinical Excellence), can use HTI to monitor adherence to clinical guidance and decisions regarding uptake of innovative therapies, in order to reduce variation in the delivery of healthcare. ALBs concerned more directly with the provision of healthcare such as NHS England and Public Health England will be able to measure equity of access to treatments in the NHS using HTI and, therefore, reduce health inequality.

Examples of use by ALBs include:

• Uptake and utilisation of new and existing therapies

• Medical vs surgical treatment rates associated with specific pharmaceutical treatments

• Readmission rates associated with specific pharmaceutical treatments

• Rates of elective vs non elective admissions in patients following different treatment regimens

3. Medical researchers from academia and other types of organisations such as patient groups, charitable trusts and pharmaceutical companies.

Examples of use by medical researchers:

Research into disease management and outcomes to improve patient care, health economic studies, comparative effectiveness studies and drug utilisation studies. These studies support the long term sustainability of the NHS by evaluating cost effectiveness. This will become increasingly important as drugs become more expensive, placing a higher financial burden on the health system. The topic of sustainability will be a focus area for researchers, particularly as 94% of new molecular entities will be for specialist care delivered within the hospital setting.

4. Estimate the number of potential patients eligible for clinical research

A typical use case of HTI for the purpose of clinical research is the estimation of the potential pool of patients that might be eligible for inclusion into a clinical trial. IQVIA would like to use HTI data to determine the proportion of patients diagnosed with a specific diagnosis or set of diagnoses (based on ICD-10 clinical coding as used in Hospital Episode Statistics data) who are then treated with a specific drug or set of drugs (based on IQVIA Hospital Pharmacy Audit data contained within HTI). This forms part of an attrition analysis, in which IQVIA Ltd will start with the number of patients in the population and estimate the number of patients with specific characteristics, by applying filters based on relevant characteristics of the population of interest, e.g. percentage IQVIA Ltd to estimate the percentage associated with drug treatment status to help determine the approximate size of a potential study population.

There are controls in place to ensure secure access to the data:

1. Researcher access - the HTI database contains pseudonymised data. All researchers accessing the data need to be substantive employees of IQVIA Ltd or the must have an honorary contract with IQVIA Ltd and be acting under the direction and supervision of IQVIA Ltd. Honorary contracts must not be used to grant external access as an alternative to sublicensing arrangements. , alternatively, they must have an honorary contract with IQVIA Ltd in place. All researchers accessing these data undertake training and sign additional confidentiality agreements with IQVIA Ltd. Researchers are informed that any misuse of data will result in formal disciplinary procedures. To enable research by medicines regulators, public health bodies and academic researchers the data must be accessible across all 4 countries within the UK. No row level data would leave the secure environment which is based in England.

IQVIA Ltd does not permit any access to pseudonymised patient record-level HTI Data from outside of the UK.

2. Strong internal governance process - researchers only access the HTI data for single-study research projects that have received approval from IQVIA’s Independent Scientific Ethical Advisory Committee (ISEAC). This ensures that access is only granted to answer medical research questions and that for the purposes of data minimisation, only data required to answer the study question is extracted from the database. All additional studies, study modifications, or study extensions require further approval.

ISEAC approval requires advanced study planning for conducting observational research in the form of a detailed protocol and statistical analysis plan. IQVIA Ltd maintains an access control register and all usage of the database against an ISEAC approved protocol is logged and is auditable.

Under this Agreement, IQVIA Ltd is permitted to use the data for single-study research projects which received approval from ISEAC in line with the procedure described above and which were initiated prior to 30/06/2021.

IQVIA Ltd is not permitted to use the data for any purposes which were not approved and initiated prior to 30/06/2021.

Where appropriate, researchers accessing HTI data will be required to publish their findings or allow an anonymised (company and product blinded) version of the study to be included on the publicly available IQVIA global bibliography. IQVIA Ltd will share these findings with participating trusts. IQVIA Ltd will not make the outputs of safety studies publicly available to avoid generating undue public concern before guidance is issued by regulatory agencies.

IQVIA Ltd understands the importance of data minimisation and ensures that records extracted from the database are limited to those absolutely necessary for conducting the particular study.

IQVIA is requesting access to the following data:

• HES records, either in an HTI trust or a non-HTI Trust, that can be linked to a pharmacy record

• All other HES records from HTI Trusts that cannot be linked to a pharmacy record. These records will only be used for data validation purposes to compare the percentage of linkage across different trusts and therapy areas.

Justification for historical data

Restricting back data for any database could potentially limit its usefulness for medical research, as historical information is used for cohort selection, bias adjustment, and prediction, among other things. In order to make database research robust and useful for making clinical decisions, the most comprehensive record of the patient's medical history must be included in each phase of the study. Since HTI is a database used for multiple studies of varying methodologies, it is not straightforward to know which studies would still be robust if the historic data period was reduced. ISEAC reviews protocols with data minimisation in mind and will ensure that researchers do not access data that would not be required for their study. Similarly, IQVIA’s internal processes for analysing and exporting data allow for the monitoring of data accessed for each study.

● IQVIA Ltd uses historical HES data (from 2005) in HTI studies in order to identify diagnosis prior to patients receiving a drug, to determine any other conditions in the patient’s medical history that might impact the patient’s response to a drug and to identify the date when a patient first had a secondary care visit for a particular diagnosis (index date). HTI has been used to conduct studies on drug treatment for chronic conditions including psoriasis, rheumatoid arthritis, multiple sclerosis and ulcerative colitis. Patients with chronic diseases have these conditions for life so it is important to have the maximum number of years of back data in order to conduct studies rigorously. IQVIA do not request data prior to 2005 due to NHS ID’s not being available to link datasets earlier than this.

● If historical HES data was not provided then researchers could miss important events which would then not be adjusted for in study results.

● In addition, the historical data may be used to detect rare, delayed adverse events. Researchers conducting regulatory studies need access to historical HES data in the HTI database in order to monitor drug safety, particularly of rare and delayed adverse events which may take many years to develop.

● Historic data is required to support Advanced Statistical Analysis projects and safety studies, as historical data allows robust analysis of trends over time.

● Historical data on patient contact with secondary care is important because the lead up to diagnosis of many conditions, particularly rare diseases, can be complex and lengthy. Evidence highlighted in the UK Strategy for Rare Diseases suggests that four in ten patients with rare diseases have “found it difficult to get the correct diagnosis” and that “25% of patients said that there was a gap of between 5 and 30 years between getting their first symptoms and a diagnosis”

● Historical data of patients with chronic conditions is needed to understand disease progression and can be used to investigate how the usage of different treatments impacts the typical time of disease progression

● Historical data is needed to understand previous and co-morbid conditions in order to adjust for these in the research study outcome. For example, a trust could be incorrectly identified as having poor outcomes or performance when they are in fact treating sicker or higher risk patients e.g. patients with previous cardiovascular and stroke events. This information in also needed to ensure the research outcome is correctly interpreted so that the medical professionals are able to provide the most appropriate care for patients e.g. a medication may be considered to have higher risk profile in a certain patient population

● Historical data provides extended longitudinal coverage to allow researchers to look at delayed adverse events or outcomes which have a long latency period from the time of exposure to manifestation.

Examples where historical data is important in conducting research:

1. HTI enables the study of hospital only medicines in a real world setting. This is very important because the patients receiving these medicines don’t always reflect those that the medicines are tested on . HTI studies are observational studies of the way in which drugs are used i.e. characterising the patients that receive them and then following those patients to see whether or not they benefit from the drug(s) in question. These studies are conducted over a specified study period i.e. a time frame over which the observation takes place. Setting the time period requires a starting point or ‘index’ date. This is usually the date at which a diagnosis has been made for which the drug being studied is a treatment. For chronic conditions diagnoses are made early in the patients’ history and the historic HES data enables an accurate index date to be set. Without the historic data, important information around the diagnosis of the disease would be missed.

2. HTI has been used to study the use of biologics in the treatment of autoimmune diseases such as ulcerative colitis and rheumatoid arthritis. These are expensive hospital only drugs and are not the first line of therapy for these diseases. The studies IQVIA have conducted have looked at healthcare resource use prior to the administration of these drugs i.e. the treatment pathway leading up to the administration of these drugs. Without the historic HES data, these studies would not be possible.

3. One very important use of HTI is in drug safety studies. These studies can sometimes involve identifying potential ‘signals’ or side effects of a drug. For these studies it is vital to access as much of a patient’s past medical history as possible. For example, some new drugs may have the potential to cause cardiovascular side effects; in order to evaluate these it would be important to know if a patient has suffered from cardiovascular problems in the past and to include as much detail as possible around those events into the analysis.

4. Some studies look at the difference in outcomes associated with different treatment options for a particular disease i.e. what are the characteristics of patients that respond better to one treatment over another. These studies are important because they can help doctors decide which treatment option would be more suitable for a patient. In order to conduct these studies with rigour and as much accuracy as possible, it is important to take into account every aspect the patient’s health state from their history because past medical history affects the decisions that doctors take for current and future drug therapy.

5. Large databases like HTI are often used to conduct observational epidemiological studies. The starting point of these studies requires building a cohort of study patients based on strict inclusion and exclusion criteria. Without access to the past medical history, it would be difficult to ensure that the patients included in the study are the ‘right’ patients and, as a result, the study results could be biased.

6. Evidence highlighted in the UK Strategy for Rare Diseases suggests that four in ten patients with rare diseases have “found it difficult to get the correct diagnosis” and that “25% of patients said that there was a gap of between 5 and 30 years between getting their first symptoms and a diagnosis”.

7. Past medical history often includes risk factors, co-morbidities and confounders that are important to adjust for when analysing data in order to ensure that conclusions drawn from the research are generalizable and robust.

There are no alternative or less intrusive ways of achieving the purpose of this programme of work .

There are no external funders' or commissioners involved in the data processing under this Data Sharing Agreement.

All HTI studies result in a scientific report structured along the lines of a scientific paper (e.g. Summary, Background, Methods, Results and Discussion). Interim tables of results (aggregated data with small number suppression in line with the HES analysis guide) may be circulated as interim results for discussion and appended to the study report. An exception would be made where the data is used for the purpose of estimating the number of potential patients eligible for clinical research (including clinical trials: here the analysis would support potential future clinical trials from which research will be produced, but the analysis itself would not result in a scientific report.

Further outputs include research publications in peer-reviewed journals and presentations at scientific conferences in addition to research included in Health Technology Assessments and Regulatory evidence. Researchers accessing HTI data for HTI studies are required to publish their findings or allow an anonymised (company and product blinded) version of the study to be included in the publicly available IQVIA Global bibliography. IQVIA Ltd will share these studies with participating trusts and healthcare stakeholders.

1. Participating NHS Trusts. IQVIA Ltd’s research team is working with NHS Trusts to assist in the production of information that will impact on improving patient care. An analytical team has been put in place for the purpose of generating a feedback report. The report delivered to each trust will contain aggregated, small number suppressed data across all trusts and will also contain trust-specific outputs which will only be shared with that trust. These findings will be sent to Chief Pharmacists at participating hospital Trusts.

2. Regulatory Authorities and Arm’s Length Bodies (ALBs) involved in Health and Social Care. The specific outputs expected for regulatory authorities include drug safety studies, signal detection and evaluation of adverse drug reactions of hospital prescribed therapies. ALBs such as NICE, NHS Digital and NHS England will be able to access the pseudonymised, non-sensitive record level database for conducting health technology assessments, monitoring adherence to guidance and to inform policy decisions.

3. Medical researchers from academia. Access to pseudonymised, non-sensitive record level data or delivery of aggregated tables for generation of research publications in peer-reviewed journals and presentations in scientific conferences. Information to be included in health technology assessments and evidence for regulators.

4. Pharmaceutical companies. Provision of aggregated, small number suppressed tables to answer research questions in two main areas, which will include:

Advanced statistical analysis, such as:

• epidemiology

• natural history of disease

• health economics and outcomes research

• drug exposures

• Estimate the number of potential patients eligible for clinical research (including clinical trials)

Drug safety monitoring, such as:

• monitoring of adverse events for newly licenced drugs prescribed in secondary care

• pharmacovigilance

Where possible, the outputs from these studies will be published in peer-reviewed journals and presented at scientific conferences, included in Health Technology Assessments or delivered to regulators. Pharmaceutical companies are required to publish their findings or allow an anonymised (company and product blinded) version of the study to be made available on the publicly available Global bibliography.

1. IQVIA Ltd have performed a number of studies on healthcare resource utilisation within patients prescribed high-cost drugs

Autoimmune conditions are complicated to manage and result in debilitating conditions for patients. Recent immunomodulating therapies such as anti TNF based drugs (all prescribed in secondary care) have been shown to provide considerable benefit to patients with a reduction in morbidity and improved quality of life. However, these drugs are expensive and the control and use within guidelines is important for NHS trusts with implications for those involved with commissioning fully funded pathways. According to The National Institute for Clinical Excellence (NICE) in the UK reports that a 26 week cycle of a anti-TNF alpha medicine (such as infliximab) for ulcerative colitis costs approximately £4,900-£5,500 for an adult, while other conventional treatments cost £50-£850 (https://www.nice.org.uk/guidance/ta329/resources/costing-statement-pdf-428356477). IQVIA Ltd has conducted a series of epidemiological studies in this therapy area to determine the dosing patterns, the indications for which the drugs are prescribed and the patient populations within which they are used.

It has been shown, IQVIA Ltd conducted a study which showed that biologics for treating inflammatory bowel disease high cost drugs (anti-TNFs and biologics) are used more frequently in routine clinical practice than anticipated than recommended in the guidelines. This creates an additional cost burden to the NHS than planned for which has a direct consequence on services that hospitals are able to fund. Using HTI data, IQVIA Ltd showed that inflammatory bowel disease patients treated with high cost drugs showed differences in the rates of hospitalisation and surgical interventions between different agents. In 2018 there were approximately 487,000 people living with IBD in the UK (Pasvol TJ, Horsfall L, Bloom S, et al, Incidence and prevalence of inflammatory bowel disease in UK primary care: a population-based cohort study, BMJ Open 2020;10:e036584. doi: 10.1136/bmjopen-2019-036584).The information from this study can be used to identify patient groups that would benefit most from these biologics high-cost drugs and allow resources to be allocated accordingly.

This piece of work has been disseminated at one of the leading European conferences, the United European Gastroenterology Week (UEG). Attendees at the UEG include leading specialists across gastroenterology, making it a key opportunity for knowledge sharing across the gastroenterology community. It has also been published via an open access journal PLOS One, This means that NHS staff are able to access this research for free via a standard literature search for evidence, meaning there is no paywall standing in the way of health professionals accessing this material (http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0149692).

2. Probability of hospitalisation

Intravenous iron therapy is not considered as first line treatment of for iron deficiency anaemia in the majority of patients’. The IQVIA business conducted an epidemiological study in collaboration with a pharmaceutical company to show that the 30-day readmission rate in patients treated with oral iron therapy was 81% compared with 34% readmitted for those treated with IV iron therapy. Among those, patients treated with IV were significantly lower than those treated with oral therapies. Readmission to hospital is distressing for patients and identifying which patients would benefit from IV therapy could lead to a reduction of readmission and improved patient outcomes. Readmission but is also an inefficient use of NHS resources. In this study IQVIA Ltd selected 30 day readmission rates since is a key quality metric that is used to evaluate NHS Trusts. This study was presented at the Digestive Disorders Federation's annual scientific meeting and its inclusion was decided by a panel of gastrointestinal experts. This study has now been published in an open access journal this means that NHS staff are able to access this research for free via a standard literature search for evidence, meaning there is no paywall standing in the way of health professionals accessing this material (http://gut.bmj.com/content/64/Suppl_1/A18.2).

3. Adherence to medication

It is well known that nonadherence to medications can result in worsening clinical outcomes, including rehospitalisation, exacerbation of chronic medical conditions, increased healthcare costs and death. The IQVIA business conducted a feasibility study to investigate the % proportion of patients who continued treatment of anticoagulant therapy in primary care within 90 days of discharge from hospital. Anticoagulants are effective for prevention of strokes and heart attacks but adherence to medication is crucial for maximising treatment benefits. The HTI data which was linked to primary care data from CPRD showed that further anticoagulation therapy was continued in primary care in over half of hospitalisations discharged with these medications. This study was presented as a poster at the International Conference of Pharmacoepidemiology (ICPE) in 2016.

Prescribing across Primary and Secondary Care

In this study IQVIA Ltd collaborated with CPRD to conduct a feasibility study to investigate the proportion of patients who continued treatment of anticoagulant therapy in primary care within 90 days of discharge from hospital. From the HTI data we were able to determine which anticoagulant treatment had been prescribed to a patient on discharge from hospital. Leveraging the CPRD linkage IQVIA Ltd followed those patients to determine which anticoagulant treatment was prescribed by the GP. This study demonstrated that linking secondary and primary care prescribing data can be used to evaluate outcomes for patients associated with continuity of care across sectors.

4. Real world data on the use of Palivizumab in infants to prevent respiratory syncytial virus (RSV). RSV usually causes mild respiratory infection in adults and children, but it can be severe in infants who are at increased risk of acute lower respiratory tract infection. It is the most common cause of bronchiolitis in children aged under 2 years, a common cause of paediatric hospital admissions over the winter months. Palivizumab is an monoclonal antibody licensed for the prevention of RSV in children. Since this treatment is expensive it usually restricted to high risk patients. There is limited evidence of the use pof Palivizumab in routine clinical care. In this study researchers identified patients who would be considered ‘high risk’ and would benefit from treatment with Palivizumab using an algorithm. The proportion of those eligible and those who received the treatment was measured. The results have been submitted for publication. This is an important piece of research that will help to inform clinicians about the use of Palivizumab to prevent RSV and specifically, which patients would benefit from it. For patients, this research will ensure that those patients who are at high risk of RSV will receive Palivizumab as a preventative measure. This will reduce the burden on the NHS of these patients being hospitalised.

5. Antipsychotic use in HTI hospitals. IQVIA Ltd provides feedback to participating hospitals on the use of drugs within their trust. Each feedback report focuses on a different therapy area. The purpose of the reports is to provide independent analysis of the pharmacy data provided to IQVIA Ltd. Often, hospital pharmacists do not have the capacity or resources to conduct these analyses themselves. The reports provide the hospital with an overview of drug dispensing in their own hospital compared with HTI overall. The therapy areas are selected according to areas that may be of interest to chief pharmacists and are in-line with the priorities of NHSE in relation to their Medicines Value and Medicines Optimisation Programmes. In the most recent report, IQVIA Ltd reported the use of antipsychotic drugs within HTI hospitals. In recent years NICE has issued guidance around the appropriate use of antipsychotic drugs. The feedback IQVIA Ltd provided to hospitals outlined the use of these drugs within their hospital and the associated indications by ICD10 diagnosis. These reports will help chief pharmacists monitor the use of antipsychotics in line with NICE guidance in order to better manage care provided for these patients and improve use of NHS resources.

IQVIA is a business comprised of a number of legal entities which provide technology and services to healthcare.

IQVIA Ltd is an information and technology company serving the health care industry. IQVIA Ltd produces a longitudinal research database, Hospital Treatment Insights (HTI). This database contains unique information on diagnosis, treatment and drug usage across secondary care in England and has been linked to primary care data in the past. HTI is currently the only routinely collected population based database available for monitoring the safety of medicines used in the secondary care setting. NHS Digital acts as a Trusted Third Party and provides linkage services for HTI. NHS Digital does this by providing record level non-identified, non-sensitive HES data (the “Data”) with a link to IQVIA’s unique Hospital Prescribing Audit data (HPA).

Direct identifiers flow from the hospital to NHS Digital who enable the link of the two data types under Section 251 of the National Health Service Act 2006. All direct identifiers are then removed before the data is shared with IQVIA Ltd.

The linkage requested is necessary for the purposes of the legitimate interests pursued by the controller or by a third party, except where such interests are overridden by the interests or fundamental rights and freedoms of the data subject which require protection of personal data, in particular where the data subject is a child (covered by Article 6 (1)(F) of the GDPR). IQVIA Ltd requires access to health data to serve its purpose of serving the health care industry and populating the longitudinal research database.

The Legal basis for processing of personal data relating to patient health is under Article 9(2)(j)of the GDPR - Processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject. The data subjects’ interests and fundamental rights are protected through appropriate minimisation of fields; protection of the data in a secure environment, and guaranteeing secure destruction at any stage at the request of NHS Digital or after a defined period on completion of the project.

IQVIA Ltd is the Sole Controller who also process the data under this agreement.

In order to link the different data sets, NHS Digital receives the identifiable pharmacy data (HPA) directly from NHS trusts and it then links that pharmacy data to the patient level HES data. A non-identified output of such linked HES Data is returned by NHS Digital to IQVIA Ltd. Identifiable data does not flow to IQVIA Ltd hereunder and IQVIA Ltd do not therefore, hold any identifiable data in this respect.

Currently there are more than 6 million patients in HTI data. This database is used for the benefit of healthcare across multiple studies in a variety of research disciplines.

Researchers accessing these datasets will be (i) employees of IQVIA Ltd, or (ii) employees of other IQVIA entities, or external researchers, who have signed an NHS Digital approved honorary contract with IQVIA Ltd. Data aggregated in line with HES guidance may be made available to trained individuals in other organisations within the IQVIA group of companies worldwide and may also be made available worldwide to third parties.

1. Data will be used to undertake a programme of research studies, in two main areas, aimed at promoting public health which will include:

Advanced statistical analysis, such as:

• Epidemiology

• natural history of disease

• health economics and outcomes research

• drug exposures

• estimate the number of potential patients eligible for clinical research (including clinical trials)

Drug safety monitoring, such as:

• monitoring of adverse events for newly licenced drugs prescribed in secondary care

• pharmacovigilance

In all cases, purposes are restricted to those for the provision of health care or adult social care, or the promotion of health.

Potential users of the data are as follows:

1. Regulatory Authorities. Regulators such as the Medicines and Healthcare Products Regulatory Agency (MHRA) and the European Medicines Agency (EMA) can investigate potential adverse drug reactions (ADR) in marketed products. When new ADRs are discovered regulators can recommend actions to limit harm to patients exposed to the products. Responsiveness is key as products are already marketed meaning that further events could occur immediately. Therefore it is crucial to have data, like HTI readily available that will allow direct investigation of ADR or evaluation of the likely public health impact should the potential ADR be established as a real effect.

Examples of regulatory use include:

Working with researchers who have a special interest in drug safety with a view to conducting a proof of concept drug safety study in HTI.

Regulators, such as the MHRA and EMA, have an interest in using data generated from HTI in their drug safety activities. They currently have access to primary care data. However, these regulators are also responsible for pharmacovigilance of products that are only used in a hospital setting and HTI is the only source of data on hospital drugs. Thus access to HTI data has an important role in improving the use of medicines used in hospitals and could have a significant impact on public health.

2. Arm’s Length Bodies (ALBs) involved in Health and Social Care. ALBs, such as NICE (National Institute for Clinical Excellence), can use HTI to monitor adherence to clinical guidance and decisions regarding uptake of innovative therapies, in order to reduce variation in the delivery of healthcare. ALBs concerned more directly with the provision of healthcare such as NHS England and Public Health England will be able to measure equity of access to treatments in the NHS using HTI and, therefore, reduce health inequality.

Examples of use by ALBs include:

• Uptake and utilisation of new and existing therapies

• Medical vs surgical treatment rates associated with specific pharmaceutical treatments

• Readmission rates associated with specific pharmaceutical treatments

• Rates of elective vs non elective admissions in patients following different treatment regimens

3. Medical researchers from academia and other types of organisations such as patient groups, charitable trusts and pharmaceutical companies.

Examples of use by medical researchers:

Research into disease management and outcomes to improve patient care, health economic studies, comparative effectiveness studies and drug utilisation studies. These studies support the long term sustainability of the NHS by evaluating cost effectiveness. This will become increasingly important as drugs become more expensive, placing a higher financial burden on the health system. The topic of sustainability will be a focus area for researchers, particularly as 94% of new molecular entities will be for specialist care delivered within the hospital setting.

4. Estimate the number of potential patients eligible for clinical research

A typical use case of HTI for the purpose of clinical research is the estimation of the potential pool of patients that might be eligible for inclusion into a clinical trial. IQVIA would like to use HTI data to determine the proportion of patients diagnosed with a specific diagnosis or set of diagnoses (based on ICD-10 clinical coding as used in Hospital Episode Statistics data) who are then treated with a specific drug or set of drugs (based on IQVIA Hospital Pharmacy Audit data contained within HTI). This forms part of an attrition analysis, in which IQVIA Ltd will start with the number of patients in the population and estimate the number of patients with specific characteristics, by applying filters based on relevant characteristics of the population of interest, e.g. percentage IQVIA Ltd to estimate the percentage associated with drug treatment status to help determine the approximate size of a potential study population.

There are controls in place to ensure secure access to the data:

1. Researcher access - the HTI database contains non-identified data. All researchers accessing the data need to be employees of IQVIA Ltd or, alternatively, they must have an honorary contract with IQVIA Ltd in place. All researchers accessing these data undertake training and sign additional confidentiality agreements with IQVIA Ltd. Researchers are informed that any misuse of data will result in formal disciplinary procedures. To enable research by medicines regulators, public health bodies and academic researchers the data must be accessible across all 4 countries within the UK. No row level data would leave the secure environment which is based in England.

IQVIA Ltd does not permit any access to non-identified patient record-level HTI Data from outside of the UK.

2. Strong internal governance process - researchers only access the HTI data for single-study research projects that have received approval from IQVIA’s Independent Scientific Ethical Advisory Committee (ISEAC). This ensures that access is only granted to answer medical research questions and that for the purposes of data minimisation, only data required to answer the study question is extracted from the database. All additional studies, study modifications, or study extensions require further approval.

ISEAC approval requires advanced study planning for conducting observational research in the form of a detailed protocol and statistical analysis plan. IQVIA Ltd maintains an access control register and all usage of the database against an ISEAC approved protocol is logged and is auditable.

Where appropriate, researchers accessing HTI data will be required to publish their findings or allow an anonymised (company and product blinded) version of the study to be included on the publicly available IQVIA global bibliography. IQVIA Ltd will share these findings with participating trusts. IQVIA Ltd will not make the outputs of safety studies publicly available to avoid generating undue public concern before guidance is issued by regulatory agencies.

IQVIA Ltd understands the importance of data minimisation and has taken steps to reduce the number of HES records requested and on a study by study basis, IQVIA Ltd ensures that the minimum dataset is extracted.

IQVIA is requesting access to the following data:

• HES records, either in an HTI trust or a non-HTI Trust, that can be linked to a pharmacy record

• All other HES records from HTI Trusts that cannot be linked to a pharmacy record. These records will only be used for data validation purposes to compare the percentage of linkage across different trusts and therapy areas. These records will only be accessible to researchers for data validation purposes and will be used to indicate whether the data is high quality enough for medical research studies.

Justification for historical data

● IQVIA Ltd uses historical HES data (from 2005) in HTI studies in order to identify diagnosis prior to patients receiving a drug, to determine any other conditions in the patient’s medical history that might impact the patient’s response to a drug and to identify the date when a patient first had a secondary care visit for a particular diagnosis (index date). HTI has been used to conduct studies on drug treatment for chronic conditions including psoriasis, rheumatoid arthritis, multiple sclerosis and ulcerative colitis. Patients with chronic diseases have these conditions for life so it is important to have the maximum number of years of back data in order to conduct studies rigorously.

● If historical HES data was not provided then researchers could miss important events which would then not be adjusted for in study results.

● In addition, the historical data may be used to detect rare, delayed adverse events. Researchers conducting regulatory studies need access to historical HES data in the HTI database in order to monitor drug safety, particularly of rare and delayed adverse events which may take many years to develop.

● Historic data is required to support Advanced Statistical Analysis projects and safety studies, as historical data allows robust analysis of trends over time.

● Historical data on patient contact with secondary care is important because the lead up to diagnosis of many conditions, particularly rare diseases, can be complex and lengthy. Evidence highlighted in the UK Strategy for Rare Diseases suggests that four in ten patients with rare diseases have “found it difficult to get the correct diagnosis” and that “25% of patients said that there was a gap of between 5 and 30 years between getting their first symptoms and a diagnosis”

● Historical data of patients with chronic conditions is needed to understand disease progression and can be used to investigate how the usage of different treatments impacts the typical time of disease progression

● Historical data is needed to understand previous and co-morbid conditions in order to adjust for these in the research study outcome. For example, a trust could be incorrectly identified as having poor outcomes or performance when they are in fact treating sicker or higher risk patients e.g. patients with previous cardiovascular and stroke events. This information in also needed to ensure the research outcome is correctly interpreted so that the medical professionals are able to provide the most appropriate care for patients e.g. a medication may be considered to have higher risk profile in a certain patient population

● Historical data provides extended longitudinal coverage to allow researchers to look at delayed adverse events or outcomes which have a long latency period from the time of exposure to manifestation.

Examples where historical data is important in conducting research:

1. HTI is unique in that it enables the study of hospital only medicines in a real world setting. This is very important because the patients receiving these medicines don’t always reflect those that the medicines are tested on . Many HTI studies are observational studies of the way in which drugs are used i.e. characterising the patients that receive them and then following those patients to see whether or not they benefit from the drug(s) in question. These studies are conducted over a specified study period i.e. a time frame over which the observation takes place. Setting the time period requires a starting point or ‘index’ date. This is usually the date at which a diagnosis has been made for which the drug being studied is a treatment. For chronic conditions diagnoses are made early in the patients’ history and the historic HES data enables an accurate index date to be set. Without the historic data, important information around the diagnosis of the disease would be missed.

2. HTI has been used to study the use of biologics in the treatment of autoimmune diseases such as ulcerative colitis and rheumatoid arthritis. These are expensive hospital only drugs and are not the first line of therapy for these diseases. The studies we have conducted have looked at healthcare resource use prior to the administration of these drugs i.e. the treatment pathway leading up to the administration of these drugs. Without the historic HES data, these studies would not be possible.

3. One very important use of HTI is in drug safety studies. These studies can sometimes involve identifying potential ‘signals’ or side effects of a drug. For these studies it is vital to access as much of a patient’s past medical history as possible. For example, some new drugs may have the potential to cause cardiovascular side effects; in order to evaluate these it would be important to know if a patient has suffered from cardiovascular problems in the past and to include as much detail as possible around those events into the analysis.

4. Some studies look at the difference in outcomes associated with different treatment options for a particular disease i.e. what are the characteristics of patients that respond better to one treatment over another. These studies are important because they can help doctors decide which treatment option would be more suitable for a patient. In order to conduct these studies with rigour and as much accuracy as possible, it is important to take into account every aspect the patient’s health state from their history because past medical history affects the decisions that doctors take for current and future drug therapy.

5. Large databases like HTI are often used to conduct observational epidemiological studies. The starting point of these studies requires building a cohort of study patients based on strict inclusion and exclusion criteria. Without access to the past medical history, it would be difficult to ensure that the patients included in the study are the ‘right’ patients and, as a result, the study results could be biased.

6. For the study of chronic and rare diseases and delayed side effects of medicines, a long past medical history is important because the lead up to diagnosis of such conditions can be complex and lengthy.

7. Evidence highlighted in the UK Strategy for Rare Diseases suggests that four in ten patients with rare diseases have “found it difficult to get the correct diagnosis” and that “25% of patients said that there was a gap of between 5 and 30 years between getting their first symptoms and a diagnosis”.

8. Past medical history often includes risk factors, co-morbidities and confounders that are important to adjust for when analysing data in order to ensure that conclusions drawn from the research are generalizable and robust.

There are no alternative or less intrusive ways of achieving the purpose of this programme of work .

There are no external funders' or commissioners involved in the data processing under this Data Sharing Agreement.

All HTI studies result in a scientific report structured along the lines of a scientific paper (e.g. Summary, Background, Methods, Results and Discussion). Interim tables of results (aggregated data with small number suppression in line with the HES analysis guide) may be circulated as interim results for discussion and appended to the study report. An exception would be made where the data is used for the purpose of estimating the number of potential patients eligible for clinical research (including clinical trials: here the analysis would support potential future clinical trials from which research will be produced, but the analysis itself would not result in a scientific report.

Further outputs include research publications in peer-reviewed journals and presentations at scientific conferences in addition to research included in Health Technology Assessments and Regulatory evidence. Researchers accessing HTI data for HTI studies are required to publish their findings or allow an anonymised (company and product blinded) version of the study to be included in the publicly available IQVIA Global bibliography. IQVIA Ltd will share these studies with participating trusts and healthcare stakeholders.

1. Participating NHS Trusts. IQVIA Ltd’s research team is working with NHS Trusts to assist in the production of information that will impact on improving patient care. An analytical team has been put in place for the purpose of generating a feedback report. The report delivered to each trust will contain aggregated, small number suppressed data across all trusts and will also contain trust-specific outputs which will only be shared with that trust. These findings will be sent to Chief Pharmacists at participating hospital Trusts.

2. Regulatory Authorities and Arm’s Length Bodies (ALBs) involved in Health and Social Care. The specific outputs expected for regulatory authorities include drug safety studies, signal detection and evaluation of adverse drug reactions of hospital prescribed therapies. ALBs such as NICE, NHS Digital and NHS England will be able to access the non-identified, non-sensitive record level database for conducting health technology assessments, monitoring adherence to guidance and to inform policy decisions.

3. Medical researchers from academia. Access to non-identified, non-sensitive record level data or delivery of aggregated tables for generation of research publications in peer-reviewed journals and presentations in scientific conferences. Information to be included in health technology assessments and evidence for regulators.

4. Pharmaceutical companies. Provision of aggregated, small number suppressed tables to answer research questions in two main areas, which will include:

Advanced statistical analysis, such as:

• epidemiology

• natural history of disease

• health economics and outcomes research

• drug exposures

• Estimate the number of potential patients eligible for clinical research (including clinical trials)

Drug safety monitoring, such as:

• monitoring of adverse events for newly licenced drugs prescribed in secondary care

• pharmacovigilance

Where possible, the outputs from these studies will be published in peer-reviewed journals and presented at scientific conferences, included in Health Technology Assessments or delivered to regulators. Pharmaceutical companies are required to publish their findings or allow an anonymised (company and product blinded) version of the study to be made available on the publicly available Global bibliography.

1. Post Authorisation Safety Study to understand the risk of major cardiovascular events in patients with moderate to severe psoriasis. There is limited literature on the classification of disease severity in patients diagnosed with psoriatic diseases that can be applied to real world data. Most studies recommend the administration of anti TNF factor drugs or hospitalisation to identify patients with severe disease. In England, these drugs are usually initiated under the care of a specialist and, therefore, data are not available outside of the hospital setting. The use of HTI for this study has enabled the research team to observe the rate of serious cardiovascular events associated with the treatment of patients with severe disease. Most importantly, this study will inform clinicians about the characteristics of those patients that experience adverse events so that these can be taken into consideration when making treatment choices for this patient group.

2. Real world data on the use of Palivizumab in infants to prevent respiratory syncytial virus (RSV). RSV usually causes mild respiratory infection in adults and children, but it can be severe in infants who are at increased risk of acute lower respiratory tract infection. It is the most common cause of bronchiolitis in children aged under 2 years, a common cause of paediatric hospital admissions over the winter months. Palivizumab is an monoclonal antibody licensed for the prevention of RSV in children. Since this treatment is expensive it usually restricted to high risk patients. There is limited evidence of the use pf Palivizumab in routine clinical care. In this study researchers identified patients who would be considered ‘high risk’ and would benefit from treatment with Palivizumab using an algorithm. The proportion of those eligible and those who received the treatment was measured. The results have been submitted for publication. This is an important piece of research that will help to inform clinicians about the use of Palivizumab to prevent RSV and specifically, which patients would benefit from it. For patients, this research will ensure that those patients who are at high risk of RSV will receive Palivizumab as a preventative measure.

3. Antipsychotic use in HTI hospitals. IQVIA provides feedback to participating hospitals on the use of drugs within their trust. Each feedback report focuses on a different therapy area. The purpose of the reports is to provide independent analysis of the pharmacy data provided to us. Often, hospital pharmacists do not have the capacity or resources to conduct these analyses themselves. The reports provide the hospital with an overview of drug dispensing in their own hospital compared with HTI overall. The therapy areas are selected according to areas that may be of interest to chief pharmacists and are in-line with the priorities of NHSE in relation to their Medicines Value and Medicines Optimisation Programmes. In the most recent report, IQVIA reported the use of antipsychotic drugs within HTI hospitals. In recent years NICE has issued guidance around the appropriate use of antipsychotic drugs. The feedback IQVIA provided to hospitals outlined the use of these drugs within their hospital and the associated indications by ICD10 diagnosis. These reports will help chief pharmacists monitor the use of antipsychotics in line with NICE guidance.

4. Studies planned for commencement in the next three months;

4. Switching between biosimilar and originator molecule. Authors of the study have reported anecdotally that within their clinical practice patients who are switched to biosimilar for cost saving reasons may not always tolerate the product as well as the originator and often have to revert to treatment with the originator. They consider that the reverse may also be true i.e. patients started on biosimilar will not tolerate a switch to originator. The research team will investigate this using HTI in order to confirm or deny the anecdotally reported hypothesis that patients respond better to stabilised therapy with biologic drugs. The results of this study will help hospitals manage costs associated with biologic use and improve the experience of patients treated with these drugs.

5. A feedback report to hospitals using data from the COVID-19 first and second wave period to show pharmacists which drugs were used within their hospitals to treat these patients. IQVIA will endeavour to help them identify COVID related drug management.

Examples of other feedback reports provided to HTI Trusts contributing to improvements in patient care:

• Biosimilar switch data. IQVIA feedback on each individual trust but also compare with peer-matched trusts across the UK and nationally. This is primarily a cost-saving initiative however, by reducing cost, it allows the NHS to treat more patients with MABs thereby improving treatment and outcomes. By comparing, it also enables Chief Pharmacists to share best practice to improve uptake for their own local population.

• Antibiotic usage trending reports (local, regional and national). This is in line with the UK and the WHO (aWare) Antibiotic Stewardship Programmes. It allows Chief Pharmacists to monitor antibiotic usage identifying areas of poor practice. This leads to guideline/protocol development, prescriber education and change management initiatives to stimulate appropriate prescribing and improved treatment for the benefit of the patient but also in line with the strategy for reducing antibiotic resistance.

• Opioid usage reports. The aim is to limit the use of strong opioids when weak opioids or alternative analgesics can be used as an alternative. This reduces the likelihood of long-term strong opioid use and the potential for tolerance and dependence in the patient population. These reports provide Chief Pharmacists with a comparison of weak vs strong opioid use locally and regionally allowing anomalies to be identified and actions to be taken to minimise overuse (auditing opportunities, clinical guideline development, prescribing guidance etc).

About IQVIA

IQVIA is a business comprised of a number of legal entities which provide technology and services to healthcare.

IQVIA Ltd is an information and technology company serving the health care industry. IQVIA Ltd produces a longitudinal research database, Hospital Treatment Insights (HTI). This database contains unique information on diagnosis, treatment and drug usage across secondary care in England and has been linked to primary care data in the past. HTI is currently the only routinely collected population based database available for monitoring the safety of medicines used in the secondary care setting. NHS Digital acts as a Trusted Third Party and provides linkage services for HTI. NHS Digital does this by providing record level non-identified, non-sensitive HES data (the “Data”) with a link to IQVIA’s unique Hospital Prescribing Audit data (HPA).

Direct identifiers flow from the hospital to NHS Digital who enable the link of the two data types under Section 251 of the National Health Service Act 2006. All direct identifiers are then removed before the data is shared with IQVIA Ltd.

The linkage requested is necessary for the purposes of the legitimate interests pursued by the controller or by a third party, except where such interests are overridden by the interests or fundamental rights and freedoms of the data subject which require protection of personal data, in particular where the data subject is a child (covered by Article 6 (1)(F) of the GDPR). IQVIA Ltd requires access to health data to serve its purpose of serving the health care industry and populating the longitudinal research database.

The Legal basis for processing of personal data relating to patient health is under Article 9(2)(j)of the GDPR - Processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject. The data subjects’ interests and fundamental rights are protected through appropriate minimisation of fields; protection of the data in a secure environment, and guaranteeing secure destruction at any stage at the request of NHS Digital or after a defined period on completion of the project.

IQVIA Ltd is the Sole Controller under this agreement. The Data Processors are IQVIA Ltd and The Bunker Secure Hosting Ltd.

In order to link the different data sets, NHS Digital receives the identifiable pharmacy data (HPA) directly from NHS trusts and it then links that pharmacy data to the patient level HES data. A non-identified output of such linked HES Data is returned by NHS Digital to IQVIA Ltd. Identifiable data does not flow to IQVIA Ltd hereunder and IQVIA Ltd and its processors do not, therefore, hold any identifiable data in this respect.

Currently there are more than 6 million patients in HTI data. This database is used for the benefit of healthcare across multiple studies in a variety of research disciplines.

Researchers accessing these datasets will be (i) employees of IQVIA Ltd, or (ii) employees of other IQVIA entities, or external researchers, who have signed an NHS Digital approved honorary contract with IQVIA Ltd. Data aggregated in line with HES guidance may be made available to trained individuals in other organisations within the IQVIA group of companies worldwide and may also be made available worldwide to third parties.

1. Data will be used to undertake a programme of research studies, in two main areas, aimed at promoting public health which will include:

Advanced statistical analysis, such as:

• Epidemiology

• natural history of disease

• health economics and outcomes research

• drug exposures

• estimate the number of potential patients eligible for clinical research (including clinical trials)

Drug safety monitoring, such as:

• monitoring of adverse events for newly licenced drugs prescribed in secondary care

• pharmacovigilance

In all cases, purposes are restricted to those for the provision of health care or adult social care, or the promotion of health.

Potential users of the data are as follows:

1. Regulatory Authorities. Regulators such as the Medicines and Healthcare Products Regulatory Agency (MHRA) and the European Medicines Agency (EMA) can investigate potential adverse drug reactions (ADR) in marketed products. When new ADRs are discovered regulators can recommend actions to limit harm to patients exposed to the products. Responsiveness is key as products are already marketed meaning that further events could occur immediately. Therefore it is crucial to have data, like HTI readily available that will allow direct investigation of ADR or evaluation of the likely public health impact should the potential ADR be established as a real effect.

Examples of regulatory use include:

Working with researchers who have a special interest in drug safety with a view to conducting a proof of concept drug safety study in HTI.

Regulators, such as the MHRA and EMA, have an interest in using data generated from HTI in their drug safety activities. They currently have access to primary care data. However, these regulators are also responsible for pharmacovigilance of products that are only used in a hospital setting and HTI is the only source of data on hospital drugs. Thus access to HTI data has an important role in improving the use of medicines used in hospitals and could have a significant impact on public health.

2. Arm’s Length Bodies (ALBs) involved in Health and Social Care. ALBs, such as NICE (National Institute for Clinical Excellence), can use HTI to monitor adherence to clinical guidance and decisions regarding uptake of innovative therapies, in order to reduce variation in the delivery of healthcare. ALBs concerned more directly with the provision of healthcare such as NHS England and Public Health England will be able to measure equity of access to treatments in the NHS using HTI and, therefore, reduce health inequality.

Examples of use by ALBs include:

• Uptake and utilisation of new and existing therapies

• Medical vs surgical treatment rates associated with specific pharmaceutical treatments

• Readmission rates associated with specific pharmaceutical treatments

• Rates of elective vs non elective admissions in patients following different treatment regimens

3. Medical researchers from academia and other types of organisations such as patient groups, charitable trusts and pharmaceutical companies.

Examples of use by medical researchers:

Research into disease management and outcomes to improve patient care, health economic studies, comparative effectiveness studies and drug utilisation studies. These studies support the long term sustainability of the NHS by evaluating cost effectiveness. This will become increasingly important as drugs become more expensive, placing a higher financial burden on the health system. The topic of sustainability will be a focus area for researchers, particularly as 94% of new molecular entities will be for specialist care delivered within the hospital setting.

4. Estimate the number of potential patients eligible for clinical research

A typical use case of HTI for the purpose of clinical research is the estimation of the potential pool of patients that might be eligible for inclusion into a clinical trial. IQVIA would like to use HTI data to determine the proportion of patients diagnosed with a specific diagnosis or set of diagnoses (based on ICD-10 clinical coding as used in Hospital Episode Statistics data) who are then treated with a specific drug or set of drugs (based on IQVIA Hospital Pharmacy Audit data contained within HTI). This forms part of an attrition analysis, in which IQVIA Ltd will start with the number of patients in the population and estimate the number of patients with specific characteristics, by applying filters based on relevant characteristics of the population of interest, e.g. percentage IQVIA Ltd to estimate the percentage associated with drug treatment status to help determine the approximate size of a potential study population.

There are controls in place to ensure secure access to the data:

1. Researcher access - the HTI database contains non-identified data. All researchers accessing the data need to be employees of IQVIA Ltd or, alternatively, they must have an honorary contract with IQVIA Ltd in place. All researchers accessing these data undertake training and sign additional confidentiality agreements with IQVIA Ltd. Researchers are informed that any misuse of data will result in formal disciplinary procedures. IQVIA Ltd does not permit any access to non-identified patient record-level HTI Data from outside of the UK.

2. Strong internal governance process - researchers only access the HTI data for single-study research projects that have received approval from IQVIA’s Independent Scientific Ethical Advisory Committee (ISEAC). This ensures that access is only granted to answer medical research questions and that for the purposes of data minimisation, only data required to answer the study question is extracted from the database. All additional studies, study modifications, or study extensions require further approval.

ISEAC approval requires advanced study planning for conducting observational research in the form of a detailed protocol and statistical analysis plan. IQVIA Ltd maintains an access control register and all usage of the database against an ISEAC approved protocol is logged and is auditable.

Where appropriate, researchers accessing HTI data will be required to publish their findings or allow an anonymised (company and product blinded) version of the study to be included on the publicly available IQVIA global bibliography. IQVIA Ltd will share these findings with participating trusts. IQVIA Ltd will not make the outputs of safety studies publicly available to avoid generating undue public concern before guidance is issued by regulatory agencies.

IQVIA Ltd understand the importance of data minimisation and have taken steps to reduce the number of HES records requested and on a study by study basis, IQVIA Ltd ensures that the minimum dataset is extracted.

IQVIA is requesting access to the following data:

• HES records, either in an HTI trust or a non-HTI Trust, that can be linked to a pharmacy record

• All other HES records from HTI Trusts that can't be linked to a pharmacy record. These records will only be used for data validation purposes to compare the percentage of linkage across different trusts and therapy areas. These records will only be accessible to researchers for data validation purposes and will be used to indicate whether the data is high quality enough for medical research studies.

Justification for historical data

● IQVIA Ltd uses historical HES data (from 2005) in HTI studies in order to identify diagnosis prior to patients receiving a drug, to determine any other conditions in the patient’s medical history that might impact the patient’s response to a drug and to identify the date when a patient first had a secondary care visit for a particular diagnosis (index date). HTI has been used to conduct studies on drug treatment for chronic conditions including psoriasis, rheumatoid arthritis, multiple sclerosis and ulcerative colitis. Patients with chronic diseases have these conditions for life so it is important to have the maximum number of years of back data in order to conduct studies rigorously.

● If historical HES data was not provided then researchers could miss important events which would then not be adjusted for in study results.

● In addition, the historical data may be used to detect rare, delayed adverse events. Researchers conducting regulatory studies need access to historical HES data in the HTI database in order to monitor drug safety, particularly of rare and delayed adverse events which may take many years to develop.

● Historic data is required to support Advanced Statistical Analysis projects and safety studies, as historical data allows robust analysis of trends over time.

● Historical data on patient contact with secondary care is important because the lead up to diagnosis of many conditions, particularly rare diseases, can be complex and lengthy. Evidence highlighted in the UK Strategy for Rare Diseases suggests that four in ten patients with rare diseases have “found it difficult to get the correct diagnosis” and that “25% of patients said that there was a gap of between 5 and 30 years between getting their first symptoms and a diagnosis”

● Historical data of patients with chronic conditions is needed to understand disease progression and can be used to investigate how the usage of different treatments impacts the typical time of disease progression

● Historical data is needed to understand previous and co-morbid conditions in order to adjust for these in the research study outcome. For example, a trust could be incorrectly identified as having poor outcomes or performance when they are in fact treating sicker or higher risk patients e.g. patients with previous cardiovascular and stroke events. This information in also needed to ensure the research outcome is correctly interpreted so that the medical professionals are able to provide the most appropriate care for patients e.g. a medication may be considered to have higher risk profile in a certain patient population

● Historical data provides extended longitudinal coverage to allow researchers to look at delayed adverse events or outcomes which have a long latency period from the time of exposure to manifestation.

Examples where historical data is important in conducting research:

1. HTI is unique in that it enables the study of hospital only medicines in a real world setting. This is very important because the patients receiving these medicines don’t always reflect those that the medicines are tested on . Many HTI studies are observational studies of the way in which drugs are used i.e. characterising the patients that receive them and then following those patients to see whether or not they benefit from the drug(s) in question. These studies are conducted over a specified study period i.e. a time frame over which the observation takes place. Setting the time period requires a starting point or ‘index’ date. This is usually the date at which a diagnosis has been made for which the drug being studied is a treatment. For chronic conditions diagnoses are made early in the patients’ history and the historic HES data enables an accurate index date to be set. Without the historic data, important information around the diagnosis of the disease would be missed.

2. HTI has been used to study the use of biologics in the treatment of autoimmune diseases such as ulcerative colitis and rheumatoid arthritis. These are expensive hospital only drugs and are not the first line of therapy for these diseases. The studies we have conducted have looked at healthcare resource use prior to the administration of these drugs i.e. the treatment pathway leading up to the administration of these drugs. Without the historic HES data, these studies would not be possible.

3. One very important use of HTI is in drug safety studies. These studies can sometimes involve identifying potential ‘signals’ or side effects of a drug. For these studies it is vital to access as much of a patient’s past medical history as possible. For example, some new drugs may have the potential to cause cardiovascular side effects; in order to evaluate these it would be important to know if a patient has suffered from cardiovascular problems in the past and to include as much detail as possible around those events into the analysis.

4. Some studies look at the difference in outcomes associated with different treatment options for a particular disease i.e. what are the characteristics of patients that respond better to one treatment over another. These studies are important because they can help doctors decide which treatment option would be more suitable for a patient. In order to conduct these studies with rigour and as much accuracy as possible, it is important to take into account every aspect the patient’s health state from their history because past medical history affects the decisions that doctors take for current and future drug therapy.

5. Large databases like HTI are often used to conduct observational epidemiological studies. The starting point of these studies requires building a cohort of study patients based on strict inclusion and exclusion criteria. Without access to the past medical history, it would be difficult to ensure that the patients included in the study are the ‘right’ patients and, as a result, the study results could be biased.

6. For the study of chronic and rare diseases and delayed side effects of medicines, a long past medical history is important because the lead up to diagnosis of such conditions can be complex and lengthy.

7. Evidence highlighted in the UK Strategy for Rare Diseases suggests that four in ten patients with rare diseases have “found it difficult to get the correct diagnosis” and that “25% of patients said that there was a gap of between 5 and 30 years between getting their first symptoms and a diagnosis”.

8. Past medical history often includes risk factors, co-morbidities and confounders that are important to adjust for when analysing data in order to ensure that conclusions drawn from the research are generalizable and robust.

There are no alternative or less intrusive ways of achieving the purpose of this programme of work .

There are no external funders' or commissioners involved in either Data Controller or Data Processor capacity.

All HTI studies result in a scientific report structured along the lines of a scientific paper (e.g. Summary, Background, Methods, Results and Discussion). Interim tables of results (aggregated data with small number suppression in line with the HES analysis guide) may be circulated as interim results for discussion and appended to the study report. An exception would be made where the data is used for the purpose of estimating the number of potential patients eligible for clinical research (including clinical trials: here the analysis would support potential future clinical trials from which research will be produced, but the analysis itself would not result in a scientific report.

Further outputs include research publications in peer-reviewed journals and presentations at scientific conferences in addition to research included in Health Technology Assessments and Regulatory evidence. Researchers accessing HTI data for HTI studies are required to publish their findings or allow an anonymised (company and product blinded) version of the study to be included in the publicly available IQVIA Global bibliography. IQVIA Ltd will share these studies with participating trusts and healthcare stakeholders.

1. Participating NHS Trusts. IQVIA Ltd’s research team is working with NHS Trusts to assist in the production of information that will impact on improving patient care. An analytical team has been put in place for the purpose of generating a feedback report. The report delivered to each trust will contain aggregated, small number suppressed data across all trusts and will also contain trust-specific outputs which will only be shared with that trust. These findings will be sent to Chief Pharmacists at participating hospital Trusts.

2. Regulatory Authorities and Arm’s Length Bodies (ALBs) involved in Health and Social Care. The specific outputs expected for regulatory authorities include drug safety studies, signal detection and evaluation of adverse drug reactions of hospital prescribed therapies. ALBs such as NICE, NHS Digital and NHS England will be able to access the non-identified, non-sensitive record level database for conducting health technology assessments, monitoring adherence to guidance and to inform policy decisions.

3. Medical researchers from academia. Access to non-identified, non-sensitive record level data or delivery of aggregated tables for generation of research publications in peer-reviewed journals and presentations in scientific conferences. Information to be included in health technology assessments and evidence for regulators.

4. Pharmaceutical companies. Provision of aggregated, small number suppressed tables to answer research questions in two main areas, which will include:

Advanced statistical analysis, such as:

• epidemiology

• natural history of disease

• health economics and outcomes research

• drug exposures

• Estimate the number of potential patients eligible for clinical research (including clinical trials)

Drug safety monitoring, such as:

• monitoring of adverse events for newly licenced drugs prescribed in secondary care

• pharmacovigilance

Where possible, the outputs from these studies will be published in peer-reviewed journals and presented at scientific conferences, included in Health Technology Assessments or delivered to regulators. Pharmaceutical companies are required to publish their findings or allow an anonymised (company and product blinded) version of the study to be made available on the publicly available Global bibliography.

HTI studies to date:

Multiple papers have been published in scientific journals and several posters have been published. Some examples are included below:

Antibiotic use

There has been a focus on stewardship programmes to curb inappropriate antibiotic prescribing and reduce antimicrobial resistance. In-hospital, patient-level prescribing linked to indication is needed to support surveillance, evaluation of stewardship initiatives, as well as other antibiotic research. IQVIA evaluated whether a novel dataset linking hospital pharmacy records to Hospital Episode Statistics (HES) data can be used for antibiotic research:

Linking individual-level data on diagnoses and dispensing for research on antibiotic use: Evaluation of a novel data source from English secondary care Patrick Rockenschaub, David Ansell, Laura Shallcross Pharmacoepidemiology and Drug Safety 2018, 27 (2): 206-212

Iron Deficiency

Iron deficiency anaemia (IDA) is the most common micronutrient deficiency worldwide, and is a major cause of referral to secondary care. Orally administered iron may inadequately control symptoms of IDA, particularly in those with underlying gastrointestinal (GI) conditions that impair iron absorption or cause bleeding. Inadequate treatment of IDA may increase the risk of hospital treatment and associated costs. In this study, the potential relationship of oral and intravenously administered iron with hospitalization is examined in a retrospective cohort.

Treating iron deficiency in patients with gastrointestinal disease: Risk of re-attendance in secondary care: Tomkins, Susannah & Chapman, Callum & Myland, Melissa & Tham, Rachel & de Nobrega, Rachael & Jackson, Brinley & Keshav, Satish. (2017).. PLOS ONE. 12. e0189952. 10.1371/journal.pone.0189952.

Dose Escalation in Colitis

The objectives of this study were to provide insights into the disease management and estimate the proportion of UC patients administered adalimumab who dose escalate (doubling dose or increasing dose frequency [100%]), the time to dose escalation and any subsequent de-escalation, and the proportion who de-escalate.

Dose Escalation And Healthcare Resource Use Among Ulcerative Colitis Patients Treated With Adalimumab In England: C. M. Black1, E. McCann2, E. Yu3, M. Nixon3, S. Kachroo1 1Merck, Whitehouse Station, United States, 2Merck, Hoddesdon, 3IMS Health, London, United Kingdom

PLOS ONE | DOI:10.1371 2016

The IQVIA business has conducted two important safety studies in the HTI database and intends to carry out more.

The IQVIA business were engaged by a drug’s marketing authorisation holder to conduct a three year post-authorisation safety study (PASS), a requirement for the marketing approval for this drug set out by the European Medicines Agency (EMA) on patients in England. The EMA requested the reason for administering the drug and the mode of administration be monitored using HTI in order to determine any off-label use. The mode of administration was monitored since some applications of the drug could result in harm.

In the case of off-label usage, a marketing authorisation holder would need to include the possible harm of such usage in their risk management plan to prevent recurrence and to prevent patient harm. This should be of significant interest to the NHS due to the possible implication for preventable harm.

A second study looked at the use of a marketed medicine which is known to have harmful effects in specific subpopulations of cancer patients. The regulator requested monitoring of exposure to the drug within these populations. This research has assisted in protecting patients from receiving drugs which are contraindicated for them. The results of the study were submitted to the European Medicines Agency in support of a risk management plan (RMP) which helped to characterise the overall benefit risk profile the drug and ensures that it is used as safely as possible. Safety information which is included in the summary of product characteristics and on the drug’s package leaflet in based on the RMP so findings and guidance from this study are directly available to healthcare professionals and patients.

Due to data quality issues during the past 12 months it has not been possible to produce further research. With these issues now resolved it is anticipated that within the next 6 months new research will have been conducted and will have produced scientific reports. NHS Digital will be updated with information regarding these publications

About IQVIA

IQVIA is a business comprised of a number of legal entities which provide technology and services to healthcare.

This agreement is a request to amend the agreement currently in place to include an additional data controller IQVIA Ltd. The IQVIA UK group is consolidating the majority of its UK business within IQVIA Ltd. IQVIA will be transferring the business and assets (including contracts) of IQVIA Solutions UK Limited into IQVIA Ltd. Throughout this agreement IQVIA Solutions UK Limited, and IQVIA Ltd . will be referred to collectively as IQVIA.

IQVIA Solutions UK Limited is an information and technology company serving the health care industry. IQVIA Solutions UK Limited produces a longitudinal research database, Hospital Treatment Insights (HTI). This database contains unique information on diagnosis, treatment and drug usage across secondary care in England and has been linked to primary care data in the past. HTI is currently the only routinely collected population based database available for monitoring the safety of medicines used in the secondary care setting. NHS Digital acts as a Trusted Third Party and provides linkage services for HTI. NHS Digital does this by providing record level non-identified, non-sensitive HES data (the “Data”) with a link to IQVIA’s unique Hospital Prescribing Audit data (HPA).

Direct identifiers flow from the hospital to NHS Digital who enable the link of the two data types under Section 251 of the National Health Service Act 2006. All direct identifiers are then removed before the data is shared with IQVIA.

The linkage requested is necessary for the purposes of the legitimate interests pursued by the controller or by a third party, except where such interests are overridden by the interests or fundamental rights and freedoms of the data subject which require protection of personal data, in particular where the data subject is a child (covered by Article 6 (1)(F) of the GDPR). IQVIA Solutions UK Limited is an information and technology company serving the health care industry. IQVIA Solutions UK Limited produces a longitudinal research database, Hospital Treatment Insights (HTI) - and requires access to health data to serve it's purpose of serving the health care industry and populating the longitudinal research database.

The Legal basis for processing of personal data relating to patient health is under Article 9(2)(j)of the GDPR - Processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject. The data subjects interests and fundamental rights are protected through appropriate minimisation of fields; protection of the data in a secure environment, and guaranteeing secure destruction at any stage at the request of NHS Digital or after a defined period on completion of the project.

IQVIA Solutions UK Limited and IQVIA Ltd are joint Data Controllers under this agreement. The Data Processors are IQVIA Solutions UK Limited, IQVIA Ltd and The Bunker Secure Hosting Ltd.

In order to link the different data sets, NHS Digital receives the identifiable pharmacy data (HPA) directly from NHS trusts and it then links that pharmacy data to the patient level HES data on behalf of IQVIA Solutions UK Limited. A non-identified output of such linked HES Data is returned by NHS Digital to IQVIA Solutions UK Limited. Identifiable data does not flow to IQVIA Solutions UK Limited hereunder and IQVIA Solutions UK Limited and its processors do not, therefore, hold any identifiable data in this respect.

Currently there are more than 6 million patients in HTI data. This database is used for the benefit of healthcare across multiple studies in a variety of research disciplines.

Researchers accessing these datasets will be (i) employees of IQVIA Solutions UK Limited or IQVIA Ltd, or (ii) employees of other IQVIA entities , or external researchers, who have signed an NHS Digital approved honorary contract with IQVIA Solutions UK Limited. Data aggregated in line with HES guidance maybe made available to trained individuals in other organisations within the IQVIA group of companies and may also be made available worldwide to third parties.

1. Data will be used to undertake a programme of research studies, in two main areas, aimed at promoting public health which will include:

Advanced statistical analysis, such as:

• Epidemiology

• natural history of disease

• health economics and outcomes research

• drug exposures

Drug safety monitoring, such as:

• monitoring of adverse events for newly licenced drugs prescribed in secondary care

• pharmacovigilance

In all cases, purposes are restricted to those for the provision of health care or adult social care, or the promotion of health.

Potential users of the data are as follows:

1. Regulatory Authorities. Regulators such as the Medicines and Healthcare Products Regulatory Agency (MHRA) and the European Medicines Agency (EMA) can investigate potential adverse drug reactions (ADR) in marketed products. When new ADRs are discovered regulators can recommend actions to limit harm to patients exposed to the products. Responsiveness is key as products are already marketed meaning that further events could occur immediately. Therefore it is crucial to have data, like HTI readily available that will allow direct investigation of ADR or evaluation of the likely public health impact should the potential ADR be established as a real effect.

Examples of regulatory use include:

Working with researchers who have a special interest in drug safety with a view to conducting a proof of concept drug safety study in HTI.

Regulators, such as the MHRA and EMA, have an interest in using data generated from HTI in their drug safety activities. They currently have access to primary care data. However, these regulators are also responsible for pharmacovigilance of products that are only used in a hospital setting and HTI is the only source of data on hospital drugs. Thus access to HTI data has an important role in improving the use of medicines used in hospitals and could have a significant impact on public health.

2. Arm’s Length Bodies (ALBs) involved in Health and Social Care. ALBs, such as NICE (National Institute for Clinical Excellence), can use HTI to monitor adherence to clinical guidance and decisions regarding uptake of innovative therapies, in order to reduce variation in the delivery of healthcare. ALBs concerned more directly with the provision of healthcare such as NHS England and Public Health England will be able to measure equity of access to treatments in the NHS using HTI and, therefore, reduce health inequality.

Examples of use by ALBs include:

• Uptake and utilisation of new and existing therapies

• Medical vs surgical treatment rates associated with specific pharmaceutical treatments

• Readmission rates associated with specific pharmaceutical treatments

• Rates of elective vs non elective admissions in patients following different treatment regimens

3. Medical researchers from academia and other types of organisations such as patient groups, charitable trusts and pharmaceutical companies.

Examples of use by medical researchers:

Research into disease management and outcomes to improve patient care, health economic studies, comparative effectiveness studies and drug utilisation studies. These studies support the long term sustainability of the NHS by evaluating cost effectiveness. This will become increasingly important as drugs become more expensive placing a higher financial burden on the health system. The topic of sustainability will be a focus area for researchers, particularly as 94% of new molecular entities will be for specialist care delivered within the hospital setting.

There are controls in place to ensure secure access to the data:

1. Researcher access - the HTI database contains non-identified data. All researchers accessing the data need to be employees of IQVIA Solutions UK Limited or IQVIA Ltd or, alternatively, they must have an honorary contract with IQVIA Solutions UK Limited in place. All researchers accessing these data undertake training and sign additional confidentiality agreements with IQVIA Solutions UK Limited. Researchers are informed that any misuse of data will result in formal disciplinary procedures. IQVIA Solutions UK Limited does not permit any access to non-identified patient record-level HTI Data from outside of the UK.

2. Strong internal governance process - researchers only access the HTI data for single-study research projects that have received approval from IQVIA’s Independent Scientific Ethical Advisory Committee (ISEAC). This ensures that access is only granted to answer medical research questions and that for the purposes of data minimisation, only data required to answer the study question is extracted from the database. All additional studies, study modifications, or study extensions require further approval.

ISEAC approval requires advanced study planning for conducting observational research in the form of a detailed protocol and statistical analysis plan. IQVIA Solutions UK Limited maintains an access control register and all usage of the database against an ISEAC approved protocol is logged and is auditable.

Where appropriate, researchers accessing HTI data will be required to publish their findings or allow an anonymised (company and product blinded) version of the study to be included on the publicly available IQVIA global bibliography. IQVIA Solutions UK Limited will share these findings with participating trusts. IQVIA Solutions UK Limited will not make the outputs of safety studies publicly available to avoid generating undue public concern before guidance is issued by regulatory agencies.

Note on Data minimisation

IQVIA Solutions UK Limited understand the importance of data minimisation and have taken steps to reduce the number of HES records requested and on a study by study basis, IQVIA Solutions UK Limited ensures that the minimum dataset is extracted.

IQVIA is requesting access to the following data:

• HES records, either in an HTI trust or a non-HTI Trust, that can be linked to a pharmacy record

• All other HES records from HTI Trusts that can't be linked to a pharmacy record. These records will only be used for data validation purposes to compare the % of linkage across different trusts and therapy areas. These records will only be accessible to researchers for data validation purposes and will be used to indicate whether the data is high quality enough for medical research studies.

Justification for historical data

● IQVIA Solutions UK Limited uses historical HES data (from 2005) in HTI studies in order to identify diagnosis prior to patients receiving a drug, to determine any other conditions in the patient’s medical history that might impact the patient’s response to a drug and to identify the date when a patient first had a secondary care visit for a particular diagnosis (index date). HTI has been used to conduct studies on drug treatment for chronic conditions including psoriasis, rheumatoid arthritis, multiple sclerosis and ulcerative colitis. Patients with chronic diseases have these conditions for life so it is important to have the maximum number of years of back data in order to conduct studies rigorously.

● If historical HES data was not provided then researchers could miss important events which would then not be adjusted for in study results.

● In addition, the historical data may be used to detect rare, delayed adverse events. Researchers conducting regulatory studies need access to historical HES data in the HTI database in order to monitor drug safety, particularly of rare and delayed adverse events which may take many years to develop.

● Historic data is required to support Advanced Statistical Analysis projects and safety studies, as historical data allows robust analysis of trends over time.

● Historical data on patient contact with secondary care is important because the lead up to diagnosis of many conditions, particularly rare diseases, can be complex and lengthy. Evidence highlighted in the UK Strategy for Rare Diseases suggests that four in ten patients with rare diseases have “found it difficult to get the correct diagnosis” and that “25% of patients said that there was a gap of between 5 and 30 years between getting their first symptoms and a diagnosis”

● Historical data of patients with chronic conditions is needed to understand disease progression and can be used to investigate how the usage of different treatments impacts the typical time of disease progression

● Historical data is needed to understand previous and co-morbid conditions in order to adjust for these in the research study outcome. For example a trust could be incorrectly identified as having poor outcomes or performance when they are in fact treating sicker or higher risk patients e.g. patients with previous cardiovascular and stroke events. This information in also needed to ensure the research outcome is correctly interpreted so that the medical professionals are able to provide the most appropriate care for patients e.g. a medication may be considered to have higher risk profile in a certain patient population

● Historical data provides extended longitudinal coverage to allow researchers to look at delayed adverse events or outcomes which have a long latency period from the time of exposure to manifestation.

Examples where historical data is important in conducting research:

1. HTI is unique in that it enables the study of hospital only medicines in a real world setting. This is very important because the patients receiving these medicines don’t always reflect those that the medicines are tested in. Many HTI studies are observational studies of the way in which drugs are used i.e. characterising the patients that receive them and then following those patients to see whether or not they benefit from the drug(s) in question. These studies are conducted over a specified study period i.e. a time frame over which the observation takes place. Setting the time period requires a starting point or ‘index’ date. This is usually the date at which a diagnosis has been made for which the drug being studied is a treatment. For chronic conditions diagnoses are made early in the patients’ history and the historic HES data enables an accurate index date to be set. Without the historic data, important information around the diagnosis of the disease would be missed.

2. HTI has been used to study the use of biologics in the treatment of autoimmune diseases such as ulcerative colitis and rheumatoid arthritis. These are expensive hospital only drugs and are not the first line of therapy for these diseases. The studies we have conducted have looked at healthcare resource use prior to the administration of these drugs i.e. the treatment pathway leading up to the administration of these drugs. Without the historic HES data, these studies would not be possible.

3. One very important use of HTI is in drug safety studies. These studies can sometimes involve identifying potential ‘signals’ or side effects of a drug. For these studies it is vital to access as much of a patient’s past medical history as possible. For example, some new drugs may have the potential to cause cardiovascular side effects; in order to evaluate these it would be important to know if a patient has suffered from cardiovascular problems in the past and to include as much detail as possible around those events into the analysis.

4. Some studies look at the difference in outcomes associated with different treatment options for a particular disease i.e. what are the characteristics of patients that respond better to one treatment over another. These studies are important because they can help doctors decide which treatment option would be more suitable for a patient. In order to conduct these studies with rigour and as much accuracy as possible, it is important to take into account every aspect the patient’s health state from their history because past medical history affects the decisions that doctors take for current and future drug therapy.

5. Large databases like HTI are often used to conduct observational epidemiological studies. The starting point of these studies requires building a cohort of study patients based on strict inclusion and exclusion criteria. Without access to the past medical history, it would be difficult to ensure that the patients included in the study are the ‘right’ patients and, as a result, the study results could be biased.

6. For the study of chronic and rare diseases and delayed side effects of medicines, a long past medical history is important because the lead up to diagnosis of such conditions can be complex and lengthy.

7. Evidence highlighted in the UK Strategy for Rare Diseases suggests that four in ten patients with rare diseases have “found it difficult to get the correct diagnosis” and that “25% of patients said that there was a gap of between 5 and 30 years between getting their first symptoms and a diagnosis”

8. Past medical history often includes risk factors, co-morbidities and confounders that are important to adjust for when analysing data in order to ensure that conclusions drawn from the research are generalizable and robust.

There are no alternative or less intrusive ways of achieving the purpose of this programme of work .

There are no external funders' or commissioners involved in either Data Controller or Data Processor capacity.

All HTI studies result in a scientific report structured along the lines of a scientific paper (e.g. Summary, Background, Methods, Results and Discussion). Interim tables of results (aggregated data with small number suppression in line with the HES analysis guide) may be circulated as interim results for discussion and appended to the study report.

Further outputs include research publications in peer-reviewed journals and presentations at scientific conferences in addition to research included in Health Technology Assessments and Regulatory evidence. Researchers accessing HTI data are required to publish their findings or allow an anonymised (company and product blinded) version of the study to be included in the publicly available IQVIA Global bibliography. IQVIA Solutions UK Limited will share these studies with participating trusts and healthcare stakeholders..

1. Participating NHS Trusts. IQVIA Solutions UK Limited’s research team is working with NHS Trusts to assist in the production of information that will impact on improving patient care. An analytical team has been put in place for the purpose of generating a feedback report. The report delivered to each trust will contain aggregated, small number suppressed data across all trusts and will also contain trust-specific outputs which will only be shared with that trust. These findings will be sent to Chief Pharmacists at participating hospital Trusts.

2. Regulatory Authorities and Arm’s Length Bodies (ALBs) involved in Health and Social Care. The specific outputs expected for regulatory authorities include drug safety studies, signal detection and evaluation of adverse drug reactions of hospital prescribed therapies. ALBs such as NICE, NHS Digital and NHS England will be able to access the non-identified, non-sensitive record level database for conducting health technology assessments, monitoring adherence to guidance and to inform policy decisions.

3. Medical researchers from academia. Access to non-identified, non-sensitive record level data or delivery of aggregated tables for generation of research publications in peer-reviewed journals and presentations in scientific conferences. Information to be included in health technology assessments and evidence for regulators.

4. Pharmaceutical companies. Provision of aggregated, small number suppressed tables to answer research questions in two main areas, which will include:

Advanced statistical analysis, such as:

• epidemiology

• natural history of disease

• health economics and outcomes research

• drug exposures

Drug safety monitoring, such as:

• monitoring of adverse events for newly licenced drugs prescribed in secondary care

• pharmacovigilance

Where possible, the outputs from these studies will be published in peer-reviewed journals and presented at scientific conferences, included in Health Technology Assessments or delivered to regulators. Pharmaceutical companies are required to publish their findings or allow an anonymised (company and product blinded) version of the study to be made available on the publicly available Global bibliography.

HTI studies to date:

Multiple papers have been published in scientific journals and several posters have been published. Some examples are included below:

Antibiotic use

There has been a focus on stewardship programmes to curb inappropriate antibiotic prescribing and reduce antimicrobial resistance. In-hospital, patient-level prescribing linked to indication is needed to support surveillance, evaluation of stewardship initiatives, as well as other antibiotic research. IQVIA evaluated whether a novel dataset linking hospital pharmacy records to Hospital Episode Statistics (HES) data can be used for antibiotic research:

Linking individual-level data on diagnoses and dispensing for research on antibiotic use: Evaluation of a novel data source from English secondary care Patrick Rockenschaub, David Ansell, Laura Shallcross Pharmacoepidemiology and Drug Safety 2018, 27 (2): 206-212

Iron Deficiency

Iron deficiency anaemia (IDA) is the most common micronutrient deficiency worldwide, and is a major cause of referral to secondary care. Orally administered iron may inadequately control symptoms of IDA, particularly in those with underlying gastrointestinal (GI) conditions that impair iron absorption or cause bleeding. Inadequate treatment of IDA may increase the risk of hospital treatment and associated costs. In this study, the potential relationship of oral and intravenously administered iron with hospitalization is examined in a retrospective cohort.

Treating iron deficiency in patients with gastrointestinal disease: Risk of re-attendance in secondary care: Tomkins, Susannah & Chapman, Callum & Myland, Melissa & Tham, Rachel & de Nobrega, Rachael & Jackson, Brinley & Keshav, Satish. (2017).. PLOS ONE. 12. e0189952. 10.1371/journal.pone.0189952.

Dose Escalation in Colitis

The objectives of this study were to provide insights into the disease management and estimate the proportion of UC patients administered adalimumab who dose escalate (doubling dose or increasing dose frequency [100%]), the time to dose escalation and any subsequent de-escalation, and the proportion who de-escalate.

Dose Escalation And Healthcare Resource Use Among Ulcerative Colitis Patients Treated With Adalimumab In England: C. M. Black1, E. McCann2, E. Yu3, M. Nixon3, S. Kachroo1 1Merck, Whitehouse Station, United States, 2Merck, Hoddesdon, 3IMS Health, London, United Kingdom

PLOS ONE | DOI:10.1371 2016

IQVIA Solutions UK Limited has conducted two important safety studies in the HTI database and intends to carry out more.

IQVIA Solutions UK Limited were engaged by a drug’s marketing authorisation holder to conduct a three year post-authorisation safety study (PASS), a requirement for the marketing approval for this drug set out by the European Medicines Agency (EMA) on patients in England. The EMA requested the reason for administering the drug and the mode of administration be monitored using HTI in order to determine any off-label use. The mode of administration was monitored since some applications of the drug could result in harm.

In the case of off-label usage, a marketing authorisation holder would need to include the possible harm of such usage in their risk management plan to prevent recurrence and to prevent patient harm. This should be of significant interest to the NHS due to the possible implication for preventable harm. .

A second study looked at the use of a marketed medicine which is known to have harmful effects in specific subpopulations of cancer patients. The regulator requested monitoring of exposure to the drug within these populations. This research has assisted in protecting patients from receiving drugs which are contraindicated for them. The results of the study were submitted to the European Medicines Agency in support of a risk management plan (RMP) which helped to characterise the overall benefit risk profile the drug and ensures that it is used as safely as possible. Safety information which is included in the summary of product characteristics and on the drug’s package leaflet in based on the RMP so findings and guidance from this study are directly available to healthcare professionals and patients.

IQVIA Solutions UK Limited is an information and technology company serving the health care industry. IQVIA Solutions UK Limited produces a longitudinal research database, Hospital Treatment Insights (HTI). This database contains unique information on diagnosis, treatment and drug usage across secondary care in England and has been linked to primary care data in the past. HTI is currently the only routinely collected population based database available for monitoring the safety of medicines used in the secondary care setting. NHS Digital acts as a Trusted Third Party and provides linkage services for HTI. NHS Digital does this by providing record level non-identified, non-sensitive HES data (the “Data”) with a link to IQVIA’s unique Hospital Prescribing Audit data (HPA).

Direct identifiers flow from the hospital to NHS Digital who enable the link of the two data types under Section 251 of the National Health Service Act 2006. All direct identifiers are then removed before the data is shared with IQVIA.

The linkage requested is necessary for the purposes of the legitimate interests pursued by the controller or by a third party, except where such interests are overridden by the interests or fundamental rights and freedoms of the data subject which require protection of personal data, in particular where the data subject is a child (covered by Article 6 (1)(F) of the GDPR). IQVIA Solutions UK Limited is an information and technology company serving the health care industry. IQVIA Solutions UK Limited produces a longitudinal research database, Hospital Treatment Insights (HTI) - and requires access to health data to serve it's purpose of serving the health care industry and populating the longitudinal research database.

The Legal basis for processing of personal data relating to patient health is under Article 9(2)(j)of the GDPR - Processing is necessary for archiving purposes in the public interest, scientific or historical research purposes or statistical purposes in accordance with Article 89(1) based on Union or Member State law which shall be proportionate to the aim pursued, respect the essence of the right to data protection and provide for suitable and specific measures to safeguard the fundamental rights and the interests of the data subject. The data subjects interests and fundamental rights are protected through appropriate minimisation of fields; protection of the data in a secure environment, and guaranteeing secure destruction at any stage at the request of NHS Digital or after a defined period on completion of the project.

IQVIA Solutions UK Limited are the sole Data Controller under this agreement. The Data Processors are IQVIA Solutions UK Limited, IQVIA Ltd and The Bunker Secure Hosting Ltd.

In order to link the different data sets, NHS Digital receives the identifiable pharmacy data (HPA) directly from NHS trusts and it then links that pharmacy data to the patient level HES data on behalf of IQVIA Solutions UK Limited. A non-identified output of such linked HES Data is returned by NHS Digital to IQVIA Solutions UK Limited. Identifiable data does not flow to IQVIA Solutions UK Limited hereunder and IQVIA Solutions UK Limited and its processors do not, therefore, hold any identifiable data in this respect.

Currently there are more than 6 million patients in HTI data. This database is used for the benefit of healthcare across multiple studies in a variety of research disciplines.

Researchers accessing these datasets will be (i) employees of IQVIA Solutions UK Limited or IQVIA Ltd, or (ii) employees of other IQVIA entities , or external researchers, who have signed an NHS Digital approved honorary contract with IQVIA Solutions UK Limited. Data aggregated in line with HES guidance maybe made available to trained individuals in other organisations within the IQVIA group of companies and may also be made available worldwide to third parties.

1. Data will be used to undertake a programme of research studies, in two main areas, aimed at promoting public health which will include:

Advanced statistical analysis, such as:

• Epidemiology

• natural history of disease

• health economics and outcomes research

• drug exposures

Drug safety monitoring, such as:

• monitoring of adverse events for newly licenced drugs prescribed in secondary care

• pharmacovigilance

In all cases, purposes are restricted to those for the provision of health care or adult social care, or the promotion of health.

Potential users of the data are as follows:

1. Regulatory Authorities. Regulators such as the Medicines and Healthcare Products Regulatory Agency (MHRA) and the European Medicines Agency (EMA) can investigate potential adverse drug reactions (ADR) in marketed products. When new ADRs are discovered regulators can recommend actions to limit harm to patients exposed to the products. Responsiveness is key as products are already marketed meaning that further events could occur immediately. Therefore it is crucial to have data, like HTI readily available that will allow direct investigation of ADR or evaluation of the likely public health impact should the potential ADR be established as a real effect.

Examples of regulatory use include:

Working with researchers who have a special interest in drug safety with a view to conducting a proof of concept drug safety study in HTI.

Regulators, such as the MHRA and EMA, have an interest in using data generated from HTI in their drug safety activities. They currently have access to primary care data. However, these regulators are also responsible for pharmacovigilance of products that are only used in a hospital setting and HTI is the only source of data on hospital drugs. Thus access to HTI data has an important role in improving the use of medicines used in hospitals and could have a significant impact on public health.

2. Arm’s Length Bodies (ALBs) involved in Health and Social Care. ALBs, such as NICE (National Institute for Clinical Excellence), can use HTI to monitor adherence to clinical guidance and decisions regarding uptake of innovative therapies, in order to reduce variation in the delivery of healthcare. ALBs concerned more directly with the provision of healthcare such as NHS England and Public Health England will be able to measure equity of access to treatments in the NHS using HTI and, therefore, reduce health inequality.

Examples of use by ALBs include:

• Uptake and utilisation of new and existing therapies

• Medical vs surgical treatment rates associated with specific pharmaceutical treatments

• Readmission rates associated with specific pharmaceutical treatments

• Rates of elective vs non elective admissions in patients following different treatment regimens

3. Medical researchers from academia and other types of organisations such as patient groups, charitable trusts and pharmaceutical companies.

Examples of use by medical researchers:

Research into disease management and outcomes to improve patient care, health economic studies, comparative effectiveness studies and drug utilisation studies. These studies support the long term sustainability of the NHS by evaluating cost effectiveness. This will become increasingly important as drugs become more expensive placing a higher financial burden on the health system. The topic of sustainability will be a focus area for researchers, particularly as 94% of new molecular entities will be for specialist care delivered within the hospital setting.

There are controls in place to ensure secure access to the data:

1. Researcher access - the HTI database contains non-identified data. All researchers accessing the data need to be employees of IQVIA Solutions UK Limited or IQVIA Ltd or, alternatively, they must have an honorary contract with IQVIA Solutions UK Limited in place. All researchers accessing these data undertake training and sign additional confidentiality agreements with IQVIA Solutions UK Limited. Researchers are informed that any misuse of data will result in formal disciplinary procedures. IQVIA Solutions UK Limited does not permit any access to non-identified patient record-level HTI Data from outside of the UK.

2. Strong internal governance process - researchers only access the HTI data for single-study research projects that have received approval from IQVIA’s Independent Scientific Ethical Advisory Committee (ISEAC). This ensures that access is only granted to answer medical research questions and that for the purposes of data minimisation, only data required to answer the study question is extracted from the database. All additional studies, study modifications, or study extensions require further approval.

ISEAC approval requires advanced study planning for conducting observational research in the form of a detailed protocol and statistical analysis plan. IQVIA Solutions UK Limited maintains an access control register and all usage of the database against an ISEAC approved protocol is logged and is auditable.

Where appropriate, researchers accessing HTI data will be required to publish their findings or allow an anonymised (company and product blinded) version of the study to be included on the publicly available IQVIA global bibliography. IQVIA Solutions UK Limited will share these findings with participating trusts. IQVIA Solutions UK Limited will not make the outputs of safety studies publicly available to avoid generating undue public concern before guidance is issued by regulatory agencies.

Note on Data minimisation

IQVIA Solutions UK Limited understand the importance of data minimisation and have taken steps to reduce the number of HES records requested and on a study by study basis, IQVIA Solutions UK Limited ensures that the minimum dataset is extracted.

IQVIA is requesting access to the following data:

• HES records, either in an HTI trust or a non-HTI Trust, that can be linked to a pharmacy record

• All other HES records from HTI Trusts that can't be linked to a pharmacy record. These records will only be used for data validation purposes to compare the % of linkage across different trusts and therapy areas. These records will only be accessible to researchers for data validation purposes and will be used to indicate whether the data is high quality enough for medical research studies.

Justification for historical data

● IQVIA Solutions UK Limited uses historical HES data (from 2005) in HTI studies in order to identify diagnosis prior to patients receiving a drug, to determine any other conditions in the patient’s medical history that might impact the patient’s response to a drug and to identify the date when a patient first had a secondary care visit for a particular diagnosis (index date). HTI has been used to conduct studies on drug treatment for chronic conditions including psoriasis, rheumatoid arthritis, multiple sclerosis and ulcerative colitis. Patients with chronic diseases have these conditions for life so it is important to have the maximum number of years of back data in order to conduct studies rigorously.

● If historical HES data was not provided then researchers could miss important events which would then not be adjusted for in study results.

● In addition, the historical data may be used to detect rare, delayed adverse events. Researchers conducting regulatory studies need access to historical HES data in the HTI database in order to monitor drug safety, particularly of rare and delayed adverse events which may take many years to develop.

● Historic data is required to support Advanced Statistical Analysis projects and safety studies, as historical data allows robust analysis of trends over time.

● Historical data on patient contact with secondary care is important because the lead up to diagnosis of many conditions, particularly rare diseases, can be complex and lengthy. Evidence highlighted in the UK Strategy for Rare Diseases suggests that four in ten patients with rare diseases have “found it difficult to get the correct diagnosis” and that “25% of patients said that there was a gap of between 5 and 30 years between getting their first symptoms and a diagnosis”

● Historical data of patients with chronic conditions is needed to understand disease progression and can be used to investigate how the usage of different treatments impacts the typical time of disease progression

● Historical data is needed to understand previous and co-morbid conditions in order to adjust for these in the research study outcome. For example a trust could be incorrectly identified as having poor outcomes or performance when they are in fact treating sicker or higher risk patients e.g. patients with previous cardiovascular and stroke events. This information in also needed to ensure the research outcome is correctly interpreted so that the medical professionals are able to provide the most appropriate care for patients e.g. a medication may be considered to have higher risk profile in a certain patient population

● Historical data provides extended longitudinal coverage to allow researchers to look at delayed adverse events or outcomes which have a long latency period from the time of exposure to manifestation.

Examples where historical data is important in conducting research:

1. HTI is unique in that it enables the study of hospital only medicines in a real world setting. This is very important because the patients receiving these medicines don’t always reflect those that the medicines are tested in. Many HTI studies are observational studies of the way in which drugs are used i.e. characterising the patients that receive them and then following those patients to see whether or not they benefit from the drug(s) in question. These studies are conducted over a specified study period i.e. a time frame over which the observation takes place. Setting the time period requires a starting point or ‘index’ date. This is usually the date at which a diagnosis has been made for which the drug being studied is a treatment. For chronic conditions diagnoses are made early in the patients’ history and the historic HES data enables an accurate index date to be set. Without the historic data, important information around the diagnosis of the disease would be missed.

2. HTI has been used to study the use of biologics in the treatment of autoimmune diseases such as ulcerative colitis and rheumatoid arthritis. These are expensive hospital only drugs and are not the first line of therapy for these diseases. The studies we have conducted have looked at healthcare resource use prior to the administration of these drugs i.e. the treatment pathway leading up to the administration of these drugs. Without the historic HES data, these studies would not be possible.

3. One very important use of HTI is in drug safety studies. These studies can sometimes involve identifying potential ‘signals’ or side effects of a drug. For these studies it is vital to access as much of a patient’s past medical history as possible. For example, some new drugs may have the potential to cause cardiovascular side effects; in order to evaluate these it would be important to know if a patient has suffered from cardiovascular problems in the past and to include as much detail as possible around those events into the analysis.

4. Some studies look at the difference in outcomes associated with different treatment options for a particular disease i.e. what are the characteristics of patients that respond better to one treatment over another. These studies are important because they can help doctors decide which treatment option would be more suitable for a patient. In order to conduct these studies with rigour and as much accuracy as possible, it is important to take into account every aspect the patient’s health state from their history because past medical history affects the decisions that doctors take for current and future drug therapy.

5. Large databases like HTI are often used to conduct observational epidemiological studies. The starting point of these studies requires building a cohort of study patients based on strict inclusion and exclusion criteria. Without access to the past medical history, it would be difficult to ensure that the patients included in the study are the ‘right’ patients and, as a result, the study results could be biased.

6. For the study of chronic and rare diseases and delayed side effects of medicines, a long past medical history is important because the lead up to diagnosis of such conditions can be complex and lengthy.

7. Evidence highlighted in the UK Strategy for Rare Diseases suggests that four in ten patients with rare diseases have “found it difficult to get the correct diagnosis” and that “25% of patients said that there was a gap of between 5 and 30 years between getting their first symptoms and a diagnosis”

8. Past medical history often includes risk factors, co-morbidities and confounders that are important to adjust for when analysing data in order to ensure that conclusions drawn from the research are generalizable and robust.

There are no alternative or less intrusive ways of achieving the purpose of this programme of work .

There are no external funders' or commissioners involved in either Data Controller or Data Processor capacity.

All HTI studies result in a scientific report structured along the lines of a scientific paper (e.g. Summary, Background, Methods, Results and Discussion). Interim tables of results (aggregated data with small number suppression in line with the HES analysis guide) may be circulated as interim results for discussion and appended to the study report.

Further outputs include research publications in peer-reviewed journals and presentations at scientific conferences in addition to research included in Health Technology Assessments and Regulatory evidence. Researchers accessing HTI data are required to publish their findings or allow an anonymised (company and product blinded) version of the study to be included in the publicly available IQVIA Global bibliography. IQVIA Solutions UK Limited will share these studies with participating trusts and healthcare stakeholders..

1. Participating NHS Trusts. IQVIA Solutions UK Limited’s research team is working with NHS Trusts to assist in the production of information that will impact on improving patient care. An analytical team has been put in place for the purpose of generating a feedback report. The report delivered to each trust will contain aggregated, small number suppressed data across all trusts and will also contain trust-specific outputs which will only be shared with that trust. These findings will be sent to Chief Pharmacists at participating hospital Trusts.

2. Regulatory Authorities and Arm’s Length Bodies (ALBs) involved in Health and Social Care. The specific outputs expected for regulatory authorities include drug safety studies, signal detection and evaluation of adverse drug reactions of hospital prescribed therapies. ALBs such as NICE, NHS Digital and NHS England will be able to access the non-identified, non-sensitive record level database for conducting health technology assessments, monitoring adherence to guidance and to inform policy decisions.

3. Medical researchers from academia. Access to non-identified, non-sensitive record level data or delivery of aggregated tables for generation of research publications in peer-reviewed journals and presentations in scientific conferences. Information to be included in health technology assessments and evidence for regulators.

4. Pharmaceutical companies. Provision of aggregated, small number suppressed tables to answer research questions in two main areas, which will include:

Advanced statistical analysis, such as:

• epidemiology

• natural history of disease

• health economics and outcomes research

• drug exposures

Drug safety monitoring, such as:

• monitoring of adverse events for newly licenced drugs prescribed in secondary care

• pharmacovigilance

Where possible, the outputs from these studies will be published in peer-reviewed journals and presented at scientific conferences, included in Health Technology Assessments or delivered to regulators. Pharmaceutical companies are required to publish their findings or allow an anonymised (company and product blinded) version of the study to be made available on the publicly available Global bibliography.

HTI studies to date:

Multiple papers have been published in scientific journals and several posters have been published. Some examples are included below:

Antibiotic use

There has been a focus on stewardship programmes to curb inappropriate antibiotic prescribing and reduce antimicrobial resistance. In-hospital, patient-level prescribing linked to indication is needed to support surveillance, evaluation of stewardship initiatives, as well as other antibiotic research. IQVIA evaluated whether a novel dataset linking hospital pharmacy records to Hospital Episode Statistics (HES) data can be used for antibiotic research:

Linking individual-level data on diagnoses and dispensing for research on antibiotic use: Evaluation of a novel data source from English secondary care Patrick Rockenschaub, David Ansell, Laura Shallcross Pharmacoepidemiology and Drug Safety 2018, 27 (2): 206-212

Iron Deficiency

Iron deficiency anaemia (IDA) is the most common micronutrient deficiency worldwide, and is a major cause of referral to secondary care. Orally administered iron may inadequately control symptoms of IDA, particularly in those with underlying gastrointestinal (GI) conditions that impair iron absorption or cause bleeding. Inadequate treatment of IDA may increase the risk of hospital treatment and associated costs. In this study, the potential relationship of oral and intravenously administered iron with hospitalization is examined in a retrospective cohort.

Treating iron deficiency in patients with gastrointestinal disease: Risk of re-attendance in secondary care: Tomkins, Susannah & Chapman, Callum & Myland, Melissa & Tham, Rachel & de Nobrega, Rachael & Jackson, Brinley & Keshav, Satish. (2017).. PLOS ONE. 12. e0189952. 10.1371/journal.pone.0189952.

Dose Escalation in Colitis

The objectives of this study were to provide insights into the disease management and estimate the proportion of UC patients administered adalimumab who dose escalate (doubling dose or increasing dose frequency [100%]), the time to dose escalation and any subsequent de-escalation, and the proportion who de-escalate.

Dose Escalation And Healthcare Resource Use Among Ulcerative Colitis Patients Treated With Adalimumab In England: C. M. Black1, E. McCann2, E. Yu3, M. Nixon3, S. Kachroo1 1Merck, Whitehouse Station, United States, 2Merck, Hoddesdon, 3IMS Health, London, United Kingdom

PLOS ONE | DOI:10.1371 2016

IQVIA Solutions UK Limited has conducted two important safety studies in the HTI database and intends to carry out more.

IQVIA Solutions UK Limited were engaged by a drug’s marketing authorisation holder to conduct a three year post-authorisation safety study (PASS), a requirement for the marketing approval for this drug set out by the European Medicines Agency (EMA) on patients in England. The EMA requested the reason for administering the drug and the mode of administration be monitored using HTI in order to determine any off-label use. The mode of administration was monitored since some applications of the drug could result in harm.

In the case of off-label usage, a marketing authorisation holder would need to include the possible harm of such usage in their risk management plan to prevent recurrence and to prevent patient harm. This should be of significant interest to the NHS due to the possible implication for preventable harm. .

A second study looked at the use of a marketed medicine which is known to have harmful effects in specific subpopulations of cancer patients. The regulator requested monitoring of exposure to the drug within these populations. This research has assisted in protecting patients from receiving drugs which are contraindicated for them. The results of the study were submitted to the European Medicines Agency in support of a risk management plan (RMP) which helped to characterise the overall benefit risk profile the drug and ensures that it is used as safely as possible. Safety information which is included in the summary of product characteristics and on the drug’s package leaflet in based on the RMP so findings and guidance from this study are directly available to healthcare professionals and patients.