Haemophilia (2014), 20 (Suppl. 4), 121–129

DOI: 10.1111/hae.12406

REVIEW ARTICLE

Enhancing haemophilia care through registries G . D O L A N , * M . M A K R I S , † P . H . B . B O L T O N - M A G G S ‡ and J . A . R O W E L L § *Nottingham University Hospitals, Nottingham, UK; †Department of Cardiovascular Science, University of Sheffield and Sheffield Haemophilia and Thrombosis Centre, Sheffield, UK; ‡Serious Hazards of Transfusion Office, Manchester Blood Centre, Manchester, UK; and §Haemophilia Centre, Royal Brisbane and Women’s Hospital, Brisbane, Australia

Summary. Clinical registries or databases have an increasing role in the management of inherited bleeding disorders. Initially, research-based registries provided valuable data and now national databases are increasingly being developed with multiple stakeholders, including persons with haemophilia (PWH) and payers, to enable improvements and efficiencies in care.

Registries are extending to international collaborations to collect adverse event data and comparisons of national approaches to the management of haemophilia to improve the availability of product to PWH.

Introduction

impact on daily life. However, increasing data collection from individuals requires stringent adherence to security and privacy requirements to ensure that there is no impact on the PWH engaging in the registries. Descriptions of three types of registry illustrate their value: the UK Haemophilia Doctors’ Organisation (UKHCDO) National Haemophilia Database (NHD), a European approach to adverse event monitoring and the WFH compilation of information from national patient organizations, - all impact improving patient care.

Clinical registries have a clear role in the monitoring and benchmarking of quality of care and health outcomes in many areas of medicine. Registries can be disease or complication specific with a strong clinical or research focus, or a broad collection of data relating to a disease or condition – either based on geographic region or area of care, nationally or internationally. Clear recommendations for the establishment of national registries in haemophilia care are made by the World Federation of Haemophilia (WFH) [1] and leading professional groups in haemophilia [2], whereas registries in specific areas provide valuable information in rarer disorders, e.g. the rare bleeding disorders register [3]. National registries enable the documentation of clinical need with demographic information and the opportunity for planning of the resources and treatment product required. Strong clinical governance is required for national registries with input from key stakeholders – including clinicians, payers and persons with haemophilia (PWH). Advancing information technology allows engagement with PWH to input treatment and usage data, and allows either more real time data for outcomes of specific treatment or measures of quality of life and Correspondence: J.A Rowell, Haemophilia Centre, Royal Brisbane and Womens Hospital, Butterfield St., Herston, Brisbane, 4029, Australia. Tel.: +61 7 36468067; fax: +61 7 36461392; e-mail: [email protected] Accepted 24 February 2014 © 2014 John Wiley & Sons Ltd

Keywords: adverse event, haemophilia, registry, treatment

Patient registries for haemophilia and other bleeding disorders: the UK perspective (G Dolan) The National Patient Registry in the UK was established in 1968 in Oxford following the establishment of Haemophilia Centres by the Department of Health in the UK. The first annual report was delivered in 1969. Initially, the aims were modest and there were clear limitations on what data could be collected. The main questions were to determine how many PWH there were in the UK, where they were treated and how much treatment they needed. This data became essential in guiding production and distribution of therapeutic products in the UK. The early and continued success of the UK National Patient Registry or National Haemophilia Database (NHD) is due to strong governance by the leaders of haemophilia care in the UK, the unified healthcare system and the mandatory requirement that all haemophilia centres submit an annual return to the NHD. 121

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Rapid developments in information technology have facilitated the collection and recording of larger amounts of data and more sophisticated data. There are now many functions for modern patient registries (Table 1) and more stakeholders (Table 2) who have a key interest in the data derived from registries such as that in the UK.

Epidemiology and medical care The NHD has had an important role in studying the natural history of haemophilia and has facilitated the analysis of life expectancy in haemophilia in the UK. Improvements in care and the improved safety of therapeutic products have had a positive impact on life expectancy. It is clear that this will be useful in planning services and resource allocation for the increasing population of PWH, including the impact of the emerging population of older individuals with haemophilia The NHD has also highlighted the issue of the migration to the UK of PWH from other countries through economic migration, migration to secure better medical care or through refugee status. The key demographics of the patients registered in the UK may also be used to help patient care directly by guiding investigations in extended family members, e.g. molecular diagnosis and facilitated extended Table 1. Uses of patient registries. Epidemiology and Clinical Care Number and distribution of patients Natural history Complications Advocacy for bleeding disorders Directing policy Surveillance and Safety Transfusion-transmitted infection Inhibitors Other safety issues Quality of Care Assess clinical practice and variation in practice Assess clinical outcomes – effectiveness and safety Assess quality of care and quality of life Research ‘Real-life’ evidence Observational data to compliment randomized controlled studies (RCTs) Generate data where RCTs not feasible or unethical Pharmacovigilance Real-life efficacy and safety of therapeutic products Large numbers of patients Contracting for Therapeutic Products Establishing and monitoring national or regional contracts

Table 2. Stakeholders for patient registries. Clinicians and Multidisciplinary Hemophilia Clinical Team National Hemophilia Organisations Commissioners/Payers/Health Insurers Regulatory Authorities Patients Pharmaceutical Organisations

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communication between centres in liaison and in treatment.

Surveillance and safety The NHD provided important data on the transmission and natural history of the hepatitis B and hepatitis C viruses (HBV and HCV), and HIV in the haemophilia population, and demonstrated that there have not been any transmissions of HCV or HIV through factor concentrates after the introduction of effective virucidal treatment and recombinant technology. However, the emergence of variant CreutzfeldtJakob disease (vCJD) in the UK in the 1990s and the subsequent evidence that it could potentially be transmitted through blood products caused major alarm in the haemophilia community and the public health organizations in the UK. The detailed information on the treatment histories of all registered patients, where these patients had been treated and where they were currently being treated, meant that the UK centres could respond quickly to inform patients and institute public health safety measures to reduce the potential risk of transmission of infection [4].

Quality of care With increasing pressure to demonstrate that haemophilia care is cost effective as well as clinically effective, a major review in the UK has been mandated to examine what data is collected as well as its quality and timely analysis. Thus, each commissioning region (healthcare region) in the UK knows the number of patients, and the average use of factor concentrates by patients, in each region and in each haemophilia centre in the UK. These data have not only been essential for managing resources for each commissioning region, but have also enabled a form of benchmarking between regions (Fig. 1) and centres (Figs 2 and 3). These data raise important questions and suggest evaluations of the quality of care between centres as well as the cost effectiveness of care between centres. The challenge for the haemophilia community is to agree on a set of outcome measures by which quality of care can be assessed and the high costs of haemophilia care can be justified. These parameters should be agreed upon internationally so that higher quality data can be obtained by increasing the sample size of this relatively rare population with bleeding disorders, and by collecting through existing or new patient registries. Key to meeting the challenge to determine and collect informative outcomes is obtaining individual data from patients. In recent years, the NHD team has developed a patient-held, on-line or mobile, system to collect key data on issues such as prophylaxis, breakthrough bleeds, bleed treatment, causes and reso© 2014 John Wiley & Sons Ltd

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Fig. 1. Factor VII usage (including inhibitor) divided by number of severe haemophilia A patients by commissioning region.

lution of bleeds. This process requires significant input from the national registry team and haemophilia centres, and support from local and national patient organizations. It is crucial to ensure that PWH understand the importance of their participation (Fig. 4).

Research and pharmacovigilance Through the governance of UKHCDO, much research was initiated using the registry as a resource with important publications [5,6], including inhibitor development in PWH. [7]. The climate of hierarchy of clinical studies has been changing in recent years. While the randomized controlled study (RCT) retains its position as the highest quality study, it is increasingly recognized that observational data, obtained from registries such as the NHD, are very valuable in areas where RCTs will never be feasible due to small patient numbers, or where randomized studies may not be ethical [8]. © 2014 John Wiley & Sons Ltd

A recent example of an observational study is the UK ‘Switching Study’ where previously treated patients (PTPs) who switched therapeutic products were assessed for inhibitor development. The regulatory authorities have imposed challenging requirements on manufacturers of therapeutic products in recent years. These include the requirement to include more subgroups of patients, e.g. previously untreated patients (PUPs), and the inclusion of post-marketing surveillance studies as a condition of licensing. It is increasingly recognized that registries may be used to meet some of these requirements, and the NHD has conducted several such studies in partnership with individual pharmaceutical companies.

Contracting for therapeutic products In the UK, as in other countries such as Canada and Australia, a national organization and a national database are essential components in the tendering for large volHaemophilia (2014), 20 (Suppl. 4), 121--129

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Fig. 2. Annual FVIII usage 2012/13 in severe haemophilia A patients aged under 18 years with no current inhibitor, by centre, ranked by median usage.

Fig. 3. Annual FVIII usage per kilogram body weight 2012/13 in severe haemophilia A patients aged under 18 years with no current inhibitor, by centre, ranked by median usage per kilogram.

umes of factor concentrates at competitive prices. The UK has conducted three such contracts to date and has been successful in containing the overall costs of haemoHaemophilia (2014), 20 (Suppl. 4), 121--129

philia therapy by using accurate data on the consumption of concentrates and the distribution of patients, and through the ability to monitor the adherence to any new © 2014 John Wiley & Sons Ltd

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Fig. 4. National IT Strategy Map.

contracts. This may be an attractive option for other registries to explore as financial constraints continue to be imposed on healthcare in many countries.

European haemophilia safety surveillance (EUHASS) (M Makris) At registration, medicines have to be shown to be efficacious and safe. Mandated regulatory studies, however, tend to be small and are likely to identify only frequent adverse events. No other patient community has suffered as much as that of haemophilia patients in terms of treatment adverse events. Before 1985, a single exposure to clotting factor concentrate had an almost 100% chance of transmitting the hepatitis C virus (HCV) to the recipient. It is obvious, therefore, that effective pharmacovigilance is critical to this community. Systems for reporting adverse events are available in many countries but, unfortunately, they are often not used for many reasons including lack of time to undertake reporting, belief that the event is already well known, uncertainty about the relationship of the event to treatment, and delaying until the treating clinician has published their own report on the case(s). EUHASS is a simple prospective adverse event reporting system set up in Europe with support from the © 2014 John Wiley & Sons Ltd

European Commission and the pharmaceutical industry [9]. The system started on 1 October 2008, and 75 sentinel haemophilia centres from 26 European countries participated in the first 4 years of the project. The adverse events reported by the centres are as follows:

• • • • • • • •

Allergic or acute reactions Transfusion transmitted infections Inhibitors Thromboses New malignancies Deaths Unexpected poor efficacy (since 2012) Any other possible adverse event (since 2012).

The EUHASS system is a secure web based system and patient details are reported anonymously. Events are reported at the time they occur or, at a minimum, at the end of each 3 month period. Centres not having any events to report still have to confirm this by signing off each quarter. Participating centres also have to provide, annually, the number of patients with bleeding disorders registered in their centre and how many of these received treatment with clotting factor concentrate or platelet transfusions (for inherited platelet disorders), in the preceding 12 month period. Furthermore, annually, centres provide information on how many patients in their centre received each clotting Haemophilia (2014), 20 (Suppl. 4), 121--129

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Table 3. Total number of events during first 4 years of surveillance. Event

Total number reported

Acute or allergic reaction Transfusion transmitted infections New inhibitors Thromboses New malignancies Deaths Total

101 0 205 104 208 324 942

factor concentrate and how many of these individuals had a severe bleeding disorder. The patients included in the surveillance are as follows:



• •

All individuals with inherited deficiencies of factors I, II, V, VII, VIII, IX, X, XI, XIII; antiplasmin; combined factors V and VIII; combined factors II, VII, IX, X, PC and PS; female carriers with low levels (

Enhancing haemophilia care through registries.

Clinical registries or databases have an increasing role in the management of inherited bleeding disorders. Initially, research-based registries provi...
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