World bleeding disorders registry: The pilot study

The advancement of evidence-based care of haemophilia is limited by factors inherent to research in rare diseases: small sample sizes, geographical dispersion of patients and heterogeneity in the clinical course observed in patients.1 In addition, these factors diminish a study's statistical power, making the generation of high-quality evidence in clinical and treatment outcomes in rare disease challenging. This has given rise to a call for global rare-disease registries, with a goal of providing better evidence on all aspects of treatment and adverse events.2 Registries, with international collaboration between centres and countries, are an effective way to pool data in order to achieve a sufficient sample size to enable epidemiological and clinical research for rare disorders. Patient registries provide a real-world setting in which clinical therapies, drug safety and quality of care can be monitored. The observational component of a prospective, longitudinal clinical registry can facilitate multiple epidemiological, clinical and intervention studies. They also provide a cohort of patients from which subsequent clinical trials can rely upon for patient recruitment. Increasingly, regulatory bodies around the globe 3-6 are relying on supplemental real-world data, including patient registry data, to inform their regulatory and reimbursement decisions, health technology assessments and treatment guidelines. As part of the WFH's vision of treatment for all, collecting data and generating evidence is an essential activity in achieving this goal. In 2000, the WFH began collecting country-level data on the epidemiology of haemophilia and care around the world in the Annual Global Survey (AGS). Since then, the number of identified patients has increased from 78 629 to 187 183 and has shed light on the widely varying levels of care around the world.7 Several studies have been published utilizing AGS data, which have pointed to large disparities in both patient identification and treatment based upon a country's socioeconomic status.8, 9 These results have formed the basis for WFH resource allocation and humanitarian aid efforts. To meet the challenge of increasing the amount and type of data available on patients with bleeding disorders, the WFH is developing a World Bleeding Disorders Registry (WBDR), which will complement the AGS data by providing patient-level data from individual treatment centres. This registry is intended to collect real-world data on the patient clinical experience around the globe, allowing researchers to use patient data to generate evidence and build advocacy initiatives aimed at health policy decision-makers. With the ultimate aim of conducting a future large-scale WBDR, a pilot study was designed to assess the feasibility of conducting a patient registry in countries around the world with varying levels of economic development and experience in participating in research studies. Using methodology closely replicating that of the planned WBDR, the pilot study (US National Institutes of Health www.ClinicalTrials.gov Identifier NCT02776826) was an observational, non-interventional, multicentre, global registry of patients diagnosed with haemophilia A or B 10 (Figure 1). The web-based data system was developed by McMaster University, Ontario, Canada, and the pilot study protocol was approved by the institutional review board of McMaster University. Where required, HTCs obtained ethics approval at their centre and patients provided written informed consent before study participation. Forty HTCs were selected for invitation to participate, aiming for representation from all levels of World Bank's classification of countries by Gross National Income (GNI),11 and from regions around the globe. Patients diagnosed with haemophilia A or B who were registered at one of the participating HTCs were eligible for inclusion. The minimal data set was based on the Universal Case Report Form (U-CRF), designed to guide clinical practice and assess important outcomes.12 HTCs were asked to enrol at least 10 patients each, determined to be a sufficient sample to enable assessment of the completeness of data at each HTC. To assess the feasibility of conducting a large-scale patient registry, four performance measures were identified a priori on which the pilot was assessed (Table 1). These performance measures were believed to represent the important predictors of a successful registry. A minimum target level was assigned to each performance measure, used as a signal to indicate likelihood of success in the roll out of the WBDR around the world. As shown in Table 1, all pilot study performance measures met our defined targets. Thirty-one HTCs accepted our invitation, of which 26 obtained ethics approval. A total of 356 patients were entered in the database and 92% of data fields were complete. Overall interest in participating in the pilot study was high (78%), but varied by GNI category, ranging from 57% to 100%: interest was lowest among HTCs from high-income countries (57%), gradually increasing to 100% for HTCs from the lowest income countries. In total, 5 (16%) participating HTCs did not complete the pilot study: 3 from high-income countries (2 withdrew voluntarily prior to submitting for ethics approval, 1 received ethics approval after the close of the pilot), 1 from a lower middle-income country (not granted ethics approval) and 1 from a low-income country (not granted ethics approval). A total of 7 patients (2%) refused to participate: 5 from high-income GNI countries and 2 from upper middle-income GNI countries. The 26 participating HTCs were from 25 countries representing all GNI levels and geographical regions around the world: Algeria, Argentina, Australia, Belgium, Brazil, Cameroon, Canada, Egypt, Estonia, Ethiopia, India (n = 2), Indonesia, Jamaica, Kenya, Kyrgyzstan, Mali, Morocco, Philippines, Senegal, Slovenia, Sri Lanka, Switzerland, Thailand, Uganda, United Kingdom, Unites States, Uzbekistan, Venezuela, Vietnam and Zimbabwe. Although the number of patients enrolled from each HTC/country was small, the wide representation of GNI levels and geographical regions allowed us to identify key challenges that we will likely encounter with the full-scale global registry. The most important finding of this pilot study is that implementing a patient registry at HTCs around the world is feasible. The high level of interest in participating in the pilot study among HTCs (78%) and patients (98%), is encouraging with both surpassing the target goals of 50%. Although regulatory burden was cited as one of the primary challenges for HTCs in the pilot study, only 2 HTCs were refused ethics approval, indicating that obtaining ethics approval is achievable in countries around the world. Additionally, the pilot sites were able to obtain ethics approval fairly quickly (range 2-32 weeks), with the majority (N = 18, 69%) receiving approval within 16 weeks. Meeting the predefined target of 90% has provided a degree of confidence around the regulatory challenges that will come up during the course of the full-scale WBDR. Importantly, WFH did not pay expenses for ethics approvals, and in most instances, fees were waived based on WFH being a non-profit entity. The results from the pilot study also demonstrate that entering complete patient data, a necessary component of a successful registry, is achievable. The accuracy of data entered was not verified beyond the automated edit checks used in the database; therefore, the quality was based solely on having no missing data fields that were determined to be mandatory. Gross national income, known to be strongly correlated to national factor use,9 was used as an indicator of the level of care available to patients in each country. In exploratory analyses, participation in the pilot was inversely associated with GNI, with only 57% of HTCs in high GNI level countries participating, gradually increasing to 100% participation rate among the lowest GNI countries. Reasons provided for not participating included ‘not enough time’, and ‘already participating in another patient registry’, thus, diminishing motivation to participate in an additional registry. Most higher-income countries already have some form of a patient registry.2, 13 A recent survey of 45 European countries confirmed that 78% of the respondent countries (n = 29/37) reported having a national registry.13 In contrast, patient disease registries in low-income settings are lacking,14 with the unfortunate consequence of making patients with bleeding disorders invisible to public health authorities.15 This finding in the pilot confirms the importance of not only prioritizing enrolment to countries without an existing registry, but also of pursuing a database linkage program, allowing data from existing patient registries to be shared directly with the WBDR. Linking registries at the patient level will allow us to optimize the available data on patients with bleeding disorders from around the world and permit comparison of data from unique countries and socioeconomic levels. To this end, harmonization of common data elements and methods of measurement with larger registries are currently underway in an effort to simplify a future data-sharing program. Despite the numerous registries that exist for patients with bleeding disorders, most are regional, country or HTC specific with the exception of a few international registries.2, 13, 14 They are predominantly found in high-income settings 13, 14 where patients have access to high quality of care, and are heterogeneous in terms of patients included, data collected and outcomes measured,2, 14 limiting the ability to merge or link data between registries. Additionally, evidence stemming from registry data is lacking. Authors of a recent scoping study concluded that translation of data into evidence on treatment outcomes was rare,14 with only 11 registries, all from high-income countries, having published on treatment outcomes. The limited dissemination of data and evidence from current registries and the concentration of registries in high-income countries, where quality and access to care are not representative of the global environment, may be leading to a biased understanding of the global haemophilia experience. These factors underscore the necessity expressed by many authors 2, 12, 14 of a global registry that collects uniform and standardized individual patient data with systematic documentation of care that people with haemophilia receive around the world. Only through a robust and global registry can we generate enough data to answer important clinical questions on quality and access to care for all patients.2 As a global organization with access to a network of 134 national member organizations (NMO), more than 1000 HTCs and numerous patients in countries with varying levels of access to care, the WFH is uniquely positioned to develop such a registry. The strong collaborative relationships built over the past 5 decades between the WFH, the NMOs and HTCs, are essential to the success of unifying data collection methods around the world. This registry will not only provide the bleeding disorders community with a pooled data source for comparing treatments and clinical outcomes, and for answering persistent epidemiological research questions, it will also provide physicians a mechanism to track individual, longitudinal patient data to assist clinical management. HTCs will be able to compare their current practice and patient outcomes with peer HTCs and with other countries. This comparative data will be useful for benchmarking their current practice, which in turn may support the development of better quality of care and resource planning. It will also be invaluable for the development of advocacy initiatives aimed at governments and ministries of health. Combined with the aggregate data reported through the WFH AGS, patient-level data reported in the WBDR will be a valuable resource for all stakeholders, to elevate treatment practices, patient outcomes and advocacy initiatives based on population-wide evidence-based medicine, around the world. The World Bleeding Disorders Registry will be implemented in the latter half of 2017 with a 5-year goal of enrolling 200 HTCs, representing 50 countries and 10 000 people with haemophilia. The WFH would like to thank the participating haemophilia treatment centres for their support in the pilot study of the WBDR. Alfonso Iorio's Institution has received project-based funding via research or service agreements with Bayer, Biogen Idec, Grifols, Novo Nordisk, Octapharma, Pfizer and Shire (formerly Baxter and Baxalta). Donna Coffin worked as a consultant to the WFH in 2015 & 2016. Glenn F. Pierce, Board of Directors, World Federation of Hemophilia. Saliou Diop, Board of Directors, World Federation of Hemophilia. The WFH would like to thank the participating haemophilia treatment centres for their support in the pilot study of the WBDR. Donna Coffin worked as a consultant to the WFH in 2015 and 2016.Glenn F. Pierce is a member of the Board of Directors, World Federation of Hemophilia. Saliou Diop is a member of the Board of Directors, World Federation of Hemophilia Alfonso Iorio’s Institution has received project based funding with Bayer, Biogen Idec, Grifols, NovoNordisk, Octapharma, Pfizer and Shire (formerly Baxter and Baxalta). All members contributed to the design of the research study; DC, CH + AI performed the data acquisition; DC, GP +AI analysed and interpreted the data; DC wrote the first draft of the manuscript; and all authors contributed to the critical revisions of the draft. The work was carried out at WFH, 1425 boul. Rene-Levesque O., Bureau 1010, Montreal, Quebec, Canada.

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