THIN-HES IQVIA Solutions UK Ltd - IQVIA World Publications Ltd

IQVIA World Publications Ltd and IQVIA Solutions UK Ltd (referred to hereinafter as “IQVIA”) are specialists in the analysis of healthcare data to inform efficient allocation of medicines, understanding of safety and treatment pathways in a scientifically robust manner.

Background to The Health Improvement Network (THIN):

THIN (The Health Improvement Network) is a large UK database containing primary care records that were recorded during routine clinical practice. The unique nature of the UK’s NHS allows the life-long electronic health record (EMR) of a UK patient to be held by their GP practice.

THIN was set up by In Practice Systems (INPS) who provide Vision software to general practices in the UK. INPS collect pseudonymised patient data from practices that have chosen to join the THIN scheme. The data is collected from the practice's Vision clinical system on a regular basis without interruption to the running of the GP’s system and these data are collated to form the THIN database.

As of May 2018, the THIN database contains pseudonymised EMRs from over 17 million patients in the UK, 3.1 million of which are actively registered in a THIN contributing GP practice. The records collected for active patients are constantly updated and can be followed over time, whereas the records of patients no longer active will be included from the time they registered in the practice to the date they transferred out or when the practice stopped contributing to THIN.

Patients in the database are flagged for research quality which includes having a valid start date, which is the date when the patient was registered within the GP practice (adjusted for practice associated mortality recording dates) and an end date which is the earlier of the last practice collection or the date they transferred out of a practice. Patients that have been used in medical research have on average 9 years of follow up data recorded in THIN.

Both active and inactive research quality patients are included in THIN data because, as a combined population, these patients have been shown as representative of the UK population by age, gender, medical conditions and mortality rates adjusted for demographics and social deprivation. THIN Data represents approximately 5% of the UK population with almost 400 active practices in the UK. For comparison, there are over 10,000 UK primary care practices.

THIN data holds details of prescribed medication, symptoms, diagnoses, lab tests and additional information such as lifestyle factors, BMI and vaccinations.

The THIN database remains one of the UK’s largest and most utilised longitudinal primary care databases for medical research. IQVIA’s strategy is to continue making improvements to THIN’s core value to research.

Background to THIN-HES

GP practices in England who were contributing to THIN data in 2011 were invited to have their patients’ data linked with HES for the purposes of medical research. This linkage was carried out in collaboration with an Enhanced Trusted Third Party (eTTP) who had developed a secure encryption technology which enabled the THIN data linkage to take place without the need to export any patient identifiable data from the data providers (THIN practices and NHS Digital).

2.5 million patients from 158 practices in THIN were linked to HES. THIN-HES data can be used to support medical research studies investigating the relationship between primary and secondary care events. THIN-HES has details on diagnoses, emergency admissions, hospital procedures and length of stay and can be used to help validate diagnoses recorded in THIN data, confirm dates of hospital events and provide further details on hospital outcomes.

Although THIN data alone may contain data with a reference to a hospitalisation episode, it is only with THIN-HES linkage that other key information (such as hospital procedures, emergency admission, length of stay) may be determined.

The original THIN-HES linkage has never been refreshed or updated, and no new data linkage or data is being requested as part of this agreement

This agreement was originally put in place to sub-license to other organisations. The sub-licensing element of this agreement is now being removed as part of v7.

THIN data collection was approved by the NHS South East Multi-centre Research Ethics Committee (MREC) in 2003. Under the terms of this ethics approval, studies using pre-collected, pseudonymised data needed to undergo scientific review to help ensure appropriate analysis and interpretation of the data. REC has approved the THIN data collection scheme as a whole and also permitted the establishment of an Independent Scientific Review Committee to review THIN study protocols for scientific merit and feasibility.

IQVIA's objective is to process the data for medical research and studies will be carried out only by substantive employees or honorary contractors of IQVIA

THIN-HES data will be used for projects approved by ISEAC or analyses performed internally and to carry out basic feasibility counts for future projects. Basic feasibility counts involve a researcher running a query against data to see if the size of the patient group present in the data is sufficient for research to be meaningful. For example they may look at the number of patients with a particular ICD10 (diagnosis) code who have taken a particular medication. The output of a feasibility count will be a number of patients e.g. 2,567. Based on this number the researcher assesses if the research is likely to be statistically valid and therefore if a research study protocol should be submitted to the approvals committee (ISEAC) for consideration and approval.

The linked THIN-HES data will be used to answer focused scientific research questions with intrinsic scientific value. The governance process for approval of each individual study (see details of ISEAC below) will ensure that all studies conducted with THIN-HES data demonstrate a clear benefit to the provision of healthcare and/or the promotion of health.

All research carried out under this service (Service 1) will be conducted by specialist researchers substantively employed by or on honorary contract to IQVIA Solutions, IQVIA LTD or IQVIA World Publications.

Example of previous research purposes (approved by NHS Digital) are as follows:

"Despite a decade of continuing decline in cardiovascular (CV) disease mortality, CV deaths remain the leading cause of mortality in the UK, accounting for approximately 31% of all deaths, with ischaemic heart disease and stroke representing the vast majority (17% and 10%, respectively). Lowering of low-density lippoprotein cholesterol (LDL-C), the bad cholesterol, with a statin has shown to reduce death rates, heart attacks, strokes and surgery such as heart bypass in certain groups of patients who previously had high levels of cholesterol. The high tolerability and safety of statins has also been established across these subgroups. Despite the demonstrated advantages of this treatment, appropriate statin use and atherogenic lipid level reduction remain suboptimal in clinical practice.

The authors have just published a study on the retrospective examination of lipid-lowering treatment patterns in a real-world high-risk cohort in the UK in 2014: comparison with the National Institute for Health and Care Excellence (NICE) 2014 lipid modification guidelines.

This study will analyse event rates of myocardial infarction, unstable angina and cardiac revascularisation in conjunction with a patients’ lipid levels and the intensity of lipid lowering (statin). The first phase of the study has utilised primary care data from The Health Improvement Network (THIN) to model subsequent CV risk in 2011 against patients’ treatment in 2010, treatment goals and unmet need (where lipid goals are not met in spite of treatment).

This study will refine the cardiovascular risk model so that hospital doctors can confidently assess the likely impact of prescribing first and second line medications on a patients serum lipids (LDL cholesterol) to reduce the risk of heart attacks, strokes and mortality. In summary the model is being designed to assess the risks of high lipids v the patient benefits of reducing lipids and the cost to the NHS of further lowering lipids.

The current analysis of primary care data has indicated that some “inpatient“ CV event episodes are missing from primary care data, leading to a potential underestimation of CV event rates and resultant underestimation of potential benefit to patients.

For the study detailed above, IQVIA will utilise the linked THIN-HES data to:

1. identify CV events missing from THIN to add into the CV event model

2. to identify CV diagnosis / procedure-related admissions around the date of death (using death event date present in THIN) and other admissions (=”non CV”) around death event date to estimate the CV-related death rate in this cohort of patients to be incorporated in the mortality part of the model"

IQVIA will only carry out research on behalf of the following groups:

Category A – Providers/commissioners of healthcare services: NHS Healthcare providers; Private secondary care providers; NHS England; Public Health England; Regulatory bodies

Category B – Academics: Universities

Category C – Life science industry: Pharmaceutical companies; Medical Device companies; Industry bodies

Category D - Other, limited to: Patient groups; health related charities

Use of the linked THIN-HES data for Service 1 is limited to the following areas of medical research: epidemiology, pharmacoepidemiology, drug safety, public health research (including clinical audit), drug utilisation studies (DUS), post authorisation safety studies (PASS), outcomes research, health economics research, resource utilisation.

The ISEAC committee will review all Service 1 requests. Further details on the ISEAC process is described in the processing activities section of this agreement.

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 requires access to health data to serve it's purpose of serving the health care industry.

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.

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

THIN-HES data linkage methodology

The linkage of THIN-HES data which took place in 2011 used the following methodology:

(1) The patient identifier was encrypted using NHS number in the both provider data sources to create an ‘encryption key’;

(2) The keys were uploaded to a secure website along with the pseudonymised THIN and HES patient IDs;

(3) The matching keys were linked using only the pseudonymised THIN and HES patient IDs;

(4) The pseudonymised THIN and HES ID is then used by the providers to extract the data for the linked patients.

Following a thorough review of the linkage methodology by the then National Information Governance Board for Health and Social Care (NIGB), the NIGB declared that no additional ethical approval is required, since THIN will only collect and link to pseudonymised data.

No new data linkage is requested as part of this version of the agreement. IQVIA may wish in future to carry out the above linkage on patients within the THIN data however any such linkage would be subject to a future application to NHS digital.

IQVIA World Publications Ltd and IQVIA Solutions UK Ltd and IQVIA Ltd have been listed as Joint Data Controllers for the purposes of this agreement. All organisations are responsible for determining the purpose and manner in which THIN-HES linked data are processed. In practice, this means that employees of all organisations may work together on the data (subject to an access control process which includes training and record keeping) as well as all organisations being responsible for designing the security and access control policy. It should be noted that the separation between the organisations is purely legal as all organisations report to the same individual. No other organisation within the IQVIA group will have access to the record level HES data or aggregate HES data containing small numbers.

One change in this agreement is that IQVIA Ltd will be added as a controller and processor in addition to the existing controllers and processors, which include IQVIA World Publications Ltd - this is because, it is intended at some point during the term of this agreement, that IQVIA will be further simplifying the number of trading legal entities it has in the UK by transferring the business and assets (including the assignment of contracts) from IQVIA World Publications Ltd into IQVIA Ltd. Once this transfer is complete, IQVIA will apply to remove IQVIA World Publications Ltd from this agreement. Both IQVIA World Publications Ltd and IQVIA Ltd will, as a result of this change, be listed as controllers and processors to ensure that this agreement does not need to be reissued at the point that the transfer occurs (which is intended to take place at the end of a financial quarter to simplify the financial record keeping requirements). NHS Digital will be informed in advance of the exact date when this will occur.

IQVIA Ltd is the legacy Quintiles part of the IQVIA business that runs the clinical trials.

The purpose of this transfer is to reduce the number of trading legal entities and to simplify the IQVIA UK legal structure: although the head office of IQVIA Ltd (and its registered office) the locations of the data, the controls around it, the purposes it is used for (as defined in the agreement), the customer base and the analysts will not be changing.

Data is stored at two locations only - IQVIA and also within the IQVIA Health 'Cage'. The Cage is hosted by Sungard Availability Services (UK) Ltd. This is the historical storage solution following on from CSDMR UK. Sungard do not process the data, they provide a 'bricks and mortar' location. Sungard can physically access the server but not the data held on it.

Data can only be accessed by those on the THIN-HES access control list which is managed by IQVIA World Publications Ltd and audited by IQVIA Solutions UKLtd. Access is via the IQVIA infrastructure only using IQVIA provided equipment only.

IQVIA will store the linked THIN-HES data for the following purposes:

• Retaining data previously used to produce published findings, in line with recommendations set out by the NHS, the Medical Research Council (MRC) and legislated by EU law, to ensure reanalysis of the original dataset can feasibly be undertaken if required, subject to additional approval from NHS Digital.

• The unique encrypted HESIDs need to be retained for use in future HES linkages. Without these, it would not be possible for NHS Digital to provide further linkage to the THIN data held by IQVIA.

Data Minimisation

All previously held HES data which are not linked to THIN has been securely destroyed and destruction certificates completed and provided to NHS Digital.

Justification for number of HES data years held

IQVIA holds THIN-HES data from 1997/98 to 2017/18 . There are numerous scientific and medical reasons why so many years of data are required.

1) In order for real world evidence studies in patient data to be scientifically sound, all information relating to a patient’s past medical events should be considered as this will influence their doctor’s decision and affect their current care. 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”. Previous IQVIA work in pulmonary arterial hypertension (PAH) suggests that patients can experience delays of on average between 1 to 4 years from onset of the first symptoms to reaching a confirmed diagnosis. Patients are often seen by multiple physicians and receive incorrect diagnoses before a confirmed diagnosis of PAH is made. In order to analyse the full patient journey IQVIA require historical data, dating back to when initial symptoms arose until the patient was cured or died.

2) Real world data can play a very important role in understanding disease incidence in prevalence. It is paramount to have a patient’s entire history from birth to understand incidence of disease, especially within real world data sources. If the amount of available data was reduced this would decrease the number of patients forming birth cohorts which could impact understanding of disease incidence and progression. This is particularly important in cases of rare diseases as a larger number years’ increases the likelihood of having a statistically valid number of patients within the study cohort. A rare disease is defined in the EU as affecting less than 5 in 10,000 of the general population. Fewer data years would therefore mean that patients with risk factors associated with a particular rare disease or individuals with historical diagnosis are missed.

3) IQVIA conducts studies looking at chronic disease progression, in long term conditions that may be present across a large portion of the patient’s life. It is therefore a requirement to utilise all historical data to fully understand the disease progression.

Justification for data retention

Data retention is the current standard in medical research and part of recommendations set out by the NHS, the Medical Research Council (MRC) and legislated by EU law.

IQVIA employees who access the event level THIN-HES data for:

• Recorded on an access control register ensuring that it is possible to identify everyone with access to patient level information.

• Before being given access to the THIN-HES data, employees receive information security awareness training which covers how to log incidents and how the IQVIA information security management system operates.

• Employees also receive training on THIN; on IQVIA ethical and contractual obligations around the data, and on best practices for processing. The training has been updated to include THIN- HES which is completed by all employees before being given access to the THIN-HES.

• Finally a THIN-HES Confidentiality Agreement is signed by each employee which enables them to gain access to event level information. This document contains information on best practice and rules which must be abided by.

• Only substantive employees of IQVIA Solutions UK Ltd and IQVIA World Publications Ltd who have completed the above and have been recorded on the Access Control Register will be given permission to access the THIN-HES data.

• Any other researchers with a requirement to access the row level will need to sign an honorary contract (the content of which has been agreed with NHS Digital).

Any employees found to be in breach of confidentiality guidelines would be managed in accordance with the main substantive terms and conditions of their employment. All employees who work for IQVIA World Publications Ltd or IQVIA Solutions UK Ltd are employed under the same terms and conditions of employment with the same disciplinary and confidentiality policies in place.

Analytical software packages are used to analyse the patient event level data. Prior to external presentation, the data are aggregated and small numbers suppressed in line with the HES Analysis Guide. Any results that are shared externally are also subject to secondary suppression which means that additional (non-small) cells in a table (or categories in a chart) may be suppressed to avoid reverse engineering of the small number.

Independent Scientific Ethical Advisory Committee (ISEAC) from June 2017

IQVIA World Publications and IQVIA Solutions UK Ltd have updated the ISEAC review process for proposed THIN-HES studies following guidance from DAAG and NHS Digital. From June 2017, all new medical research studies conducted using HES data linked to THIN will be submitted to ISEAC for approval.

ISEAC terms of reference and composition have been reviewed and revised in line with NHS Digital requirements. ISEAC membership now includes patient representatives in the updated committee ISEAC meeting minutes are not publicly available since protocols are reviewed electronically.

1. Researcher access - All researchers accessing the THIN-HES data need to be a substantive employee of IQVIA Solutions UKLtd or IQVIA World Publications Ltd or must have an honorary contract with either in place. All researchers accessing these data undertake training and sign additional confidentiality agreements. Researchers are informed that any misuse of data will result in formal disciplinary procedures.

2. Strong governance process - researchers only access the data for carrying research projects and for feasibility counts as described previously. Any research projects will have received approval from IQVIA’s Independent Scientific Ethical Advisory Committee (ISEAC) for THIN-HES. This ensures that access is only granted to answer medical research questions and that only data required to answer the study question is extracted from the database. All additional studies, study modifications, or study extensions require further approval.

3. Advanced study planning - further safeguards include the standard IQVIA Solutions UK Ltd and IQVIA World Publications Ltd procedures for conducting observational research which require pre-registration of study objectives and procedures in the form of a detailed protocol. IQVIA World Publications Ltd maintains an access control register. All protocols with SRC and/or ISEAC approval are logged.

Transparency:

IQVIA posts summaries of THIN-HES published studies on the organisation’s online bibliography, which is publicly available via in the internet. For studies that aren’t published IQVIA World Publications Ltd will include the following wording in the summary section: ‘This study was conducted using the THIN-HES data and is recorded on the IQVIA Global Bibliography for awareness’.

The summaries take the form of abstracts or links to published articles, conference abstracts/posters or white papers. All summaries contain only data that is aggregated with small numbers suppressed in line with the HES Protocol Guidance.

IQVIA will not approve or otherwise authorise the use of the data supplied by NHS Digital for any additional purposes other than those described in this agreement.

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

The expected outputs from the results of analyses performed using the linked data are in the format of small number suppressed, aggregated outputs e.g. presentations, spreadsheets, word documents and other formal documentation. The data are also used to create conference posters, white papers and scientific peer reviewed publications. Specific examples of the type of analyses that IQVIA have performed using the linked database are given in the section below. All outputs will contain only data that is aggregated with small numbers suppressed in line with the HES Analysis Guide

IQVIA works with researchers to facilitate studies in THIN-HES data. Requests for collaboration are received on an ongoing basis. Current studies in progress include (1) CV risk model – underreporting of CV hospitalisations in THIN (2) 5-ASA use in Inflammatory Bowel Disease (3) The burden of illness of Pulmonary Arterial Hypertension.

In addition IQVIA supplied this data to the University of Birmingham ( under sub-licesnsing arrangements under a previous iteration of this agreement - but under a now under a separate data sharing agreement) and their studies include:

(i) An epidemiological study exploring novel risk factors and long-term health effects of Postpartum Haemorrhage

(ii) Long term impact of giving antibiotics before skin incision versus after cord clamping on children born by caesarean section: longitudinal study based on UK electronic health records

The THIN data is extensively used by researchers to undertake population based medical research studies. There have been over 600 publications utilising THIN data, including publications in numerous peer-reviewed journals including; British Journal of General Practice, The Lancet, British Medical Journal (BMJ), Pharmacoepidemiology Drug Safety among others.

Many studies using the data have advanced medical knowledge and understanding in both disease management and in public health, capturing the attention of prescribers, payers and key opinion leaders within the medical communities as well as helping patients better understand their medical conditions. The link to HES data adds valuable detail to the hospital related activity associated with patients in the database. It also broadens the research objectives which can be studied.

Going forward the team wish to maximise the research potential of the data by securely augmenting the existing primary care coverage with increasingly useful de-identified secondary care data, in order to perform studies that are beneficial to health and social care in a similar manner to the case studies described above.

The additional CV risk model project will benefit patients by indicating to doctors and patients how much a further reduction in serum lipids (LDL cholesterol) could potentially reduce heart attacks, strokes and mortality. A reduction in rates of myocardial infarction and stroke will improve patient well-being and reduce use of in-hospital resource.

Examples of previously published studies utilising the data linked to HES include a study looking at smoking cessation in which the findings suggested that delivering smoking cessation as a routine component of hospital care, as recommended by recent National Institute for Health and Care Excellence guidance, could achieve marked reductions in the prevalence of smoking and improve the cost-effectiveness of NHS hospitals.

The study was published in BMJ Thorax and has subsequently featured on the South East Coast Respiratory Programme NHS network website as well as being the subject of a NICE press release.

In reference to the study, the Director of Public Health at NICE commented: “It is absurd that smoking is still being passively encouraged within hospitals. We need to end the terrible spectacle of people on drips in hospital gowns smoking outside hospital entrances… As this study highlights, there is a huge opportunity for clinicians to offer support to over 1 million smokers who present to hospital each year. By using NICE guidance, they can help make NHS secondary care an exemplar for promoting healthy behaviour.”

A British Thoracic Society spokesman commented: "Smokers who are admitted to hospital include some of the poorest members of our society. This study shows that the NHS is missing regular opportunities to transform their lives through simple yet highly cost-effective measures to help them stop smoking… The health services regulators (CQC and Monitor) need to hold hospital chief executives to account and stop them ignoring the NICE recommendations to help people admitted to hospital to quit smoking."

~ Prevalence of smoking among patients treated in NHS hospitals in England in 2010/2011: a national audit. Szatkowski L1, Murray R1, Hubbard R1, Agrawal S2, Huang Y1, Britton J1. Thorax doi:10.1136/thoraxjnl-2014-206285

The above study is an example of the real world benefit to health and/or social care of using the linked data. It reinforced the importance for Hospitals to implement the latest NICE guidance on this subject as well as raising awareness amongst clinicians, instigating important debate on the matter as well as informing patients.

Another study utilised the linked data in the development and validation of a frailty index (developed by Birmingham University) resulted in the index being recommended for use by NICE. The researchers won an industry award (EHI 2016 award for Healthcare IT Product Innovation) and the index has been recommended in the latest NICE NG56 guidelines for Multimorbidity: clinical assessment and management (https://www.nice.org.uk/guidance/ng56). An extract from that guideline reads as follows (NG56, section 1.3.2): “Consider using a validated tool such as eFI, PEONY or QAdmissions, if available in primary care electronic health records, to identify adults with multimorbidity who are at risk of adverse events such as unplanned hospital admission or admission to care homes.”

~ Development and validation of an electronic frailty index using routine primary care electronic health record data. A Clegg, C Bates, J Young, R Ryan, L Nicols, E Teale, M Mohammed, J Parry, T Marshall. http://ageing.oxfordjournals.org/content/45/3/353.full?sid=b5104b50-3c53-49c8-8cdc-f7f2e4d06653

Another study found that by utilising the linked data, the completeness of maternity data in the primary care data could greatly be improved.

~ Assessing the completeness of maternity data in UK primary and secondary care: a study in The Health Improvement Network (THIN) and Hospital Episode Statistics (HES). S Man , I Petersen, I Nazareth, A Bourke, M Thompson. https://www.ucl.ac.uk/pcph/research-groups-themes/thin-pub/research_presentations/ISPOR-shukli-2012-HES_THIN

THIN-HES linked data has supported these drug safety studies which are necessary for monitoring patient safety of new medicines, and have helped assess rates of serious adverse events (e.g. liver failure, stroke, myocardial infarction, neurological paralysis) that require secondary care.