RESEARCH Open Access

Development of a pilot rare diseaseregistry: a focus group study of initial stepstowards the establishment of a rare diseaseecosystem in SloveniaDalibor Stanimirovic1* , Eva Murko1, Tadej Battelino2,3 and Urh Groselj2

Abstract

Background: According to rough estimates, there are approximately 150,000 rare disease patients in Slovenia (outof a total population of 2 million). Despite the absence of accurate epidemiological data on their status, thesefigures reveal the great importance of this area for the Slovenian healthcare system. Consistent monitoring in thefield of rare diseases facilitates evidence-informed healthcare policies, comprehensive observation of rare diseasepatients, and consequently serves increasingly demanding medical and statistical needs. This paper initially exploresthe current situation concerning rare diseases and identifies related challenges for the planned development of anational rare disease registry in Slovenia. Based on the research findings, the paper outlines the construction of thepilot rare disease registry and conceptualizes the establishment of a rare disease ecosystem in Slovenia.

Methods: The research is based on a case study design, where focus group sessions were used as the main datacollection technique. Structured discussions were conducted with 24 eminent experts affiliated with the leadinginstitutions in the field of rare diseases in Slovenia. Analysis and interpretations of the data obtained were carried bymeans of conventional content analysis. A subsequent course of action for developing the pilot rare disease registryand conceptualizing the rare disease ecosystem was formulated in collaboration with the experts participating inthe focus groups.

Results: The research results indicate that the effective development of the national rare disease registry, followedby the establishment of the rare disease ecosystem in Slovenia, requires a broad approach that entails a wholeseries of systemic changes and considerations. Moreover, well-orchestrated and well-funded efforts to achieve thisgoal should involve the coordinated action of all stakeholders, including the amendment of the regulatoryframework, quality design, and enactment of a general rare disease policy, as well as the alignment of medical,organizational, and technological aspects in accordance with the long-term public healthcare objectives.

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© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

* Correspondence: dalibor.stanimirovic@nijz.si1National Institute of Public Health, Trubarjeva Street 2, 1000 Ljubljana,SloveniaFull list of author information is available at the end of the article

Stanimirovic et al. Orphanet Journal of Rare Diseases (2019) 14:172 https://doi.org/10.1186/s13023-019-1146-x

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Conclusions: The establishment of a rare disease ecosystem in Slovenia and probably elsewhere, including a nationalrare disease registry, would represent an important improvement for patients, as it could significantly contribute tomore coordinated healthcare treatment and enable comprehensive monitoring of the treatment process and results. Awell-organized rare disease ecosystem could bring considerable benefits to healthcare system managers by providinga useful platform for estimating the required resources, evidence-informed policymaking, technological innovation, andorganizational restructuring. This research provides valuable insight into the background of the issues that manycountries face in the field of rare diseases, and ultimately provides practical recommendations for the development ofnational rare disease registries. However, ensuring effective healthcare delivery in this intricate field is criticallydependent on the harmonization of digital solutions with other systemic factors and the adaptation of the rare diseaseecosystem to the patients’ needs and the specifics of the healthcare environment.

Keywords: Rare diseases, Pilot rare disease registry, National rare disease registry, Rare disease ecosystem, Case study,Focus group, Slovenia

BackgroundAccording to rough estimates, there are approximately150,000 rare disease (RD) patients in Slovenia [1, 2].Despite the absence of accurate epidemiological data onthe status of RDs, the above-mentioned numbers showthat this area is of great importance for the Slovenianhealthcare system. Besides the general lack of knowledgeand resources in this field, RDs have specific and oftenintricate characteristics, which further increase theseverity of this challenge for the healthcare system [3].The problems in detecting and treating RDs includelengthy and arduous diagnostic procedures, oftenaccompanied by difficulty choosing the most appropriatetreatment method. The treatment approaches in thefield are frequently underdeveloped and are often notsupported by either empirical evidence (only trial treat-ments) or the existence of adequate medications. Fromthe normative point of view, however, problems arisemainly from the necessity to provide an explicit legalbasis for the monitoring of patients with RDs. Compre-hensive monitoring of patients with RDs, coordinationof their treatment, execution of screening, diagnosis, andmeticulous reporting of identified new cases fall underthe scope of organizational challenges, which often re-main unresolved due to their inherent complexity andother systemic circumstances [2]. And then there is theinformation and communication technology (ICT) infra-structure, which should provide effective and user-friendly support to all stakeholders in the field of RD.Properly designed ICT solutions could be a very import-ant tool for healthcare professionals in their clinicalwork with patients, for communication between stake-holders, as well as for healthcare management and thepolicymakers who direct the work of the entire health-care system. However, regrettably, this field has beenmuch neglected in terms of specialized ICT solutionsand general ICT support.

RD registries in this sense represent one of the funda-mental instruments of unbiased data collection, themonitoring of RDs, and epidemiological and clinical re-search, and can greatly contribute to improving health-care planning and the treatment of patients [4].Therefore, they are considered to be essential ICT com-ponents, as they aid in the collection, storage, analysis,and reporting of pertinent data on RDs to all stake-holders in the RD ecosystem. This ecosystem is consid-ered to be a functional environment that incorporates allstakeholders and mechanisms for coordinated andcomprehensive patient treatment. It should include thenormative framework, the regulatory and policymakingbodies, clinical institutions for treatment and rehabilita-tion, patients and associations, ICT solutions (thenational RD registry) and platforms (the national contactpoint for rare diseases; NCP), national and internationalRD organizations, statistical agencies and the researchcommunity, existing national and international datasources, and the precisely defined rules of operation andwork processes between these entities [1]. As one of themain elements of the RD ecosystem, a RD registry intechnological terms basically denotes a database of iden-tifiable individuals containing a clearly defined set ofhealth and demographic data collected for a specificpublic healthcare purpose [5]. Registration, on the otherhand, could be defined as the process of the continuoussystematic collection of data on the occurrence andcharacteristics of the related healthcare phenomenon.Moreover, RD registries facilitate comprehensive surveil-lance of the prevalence and incidence of RDs, and enablethe well-founded evaluation of different aspects ofhealthcare procedures and outcomes [6]. Quality RDregistries ipso facto provide a beneficial and applicableplatform in all stages of evidence-informed healthcarepolicymaking, and may contribute to significantadvancement in the management of RDs in general. For

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these reasons, the development of RD registries is one ofthe EU’s priorities in the field of the monitoring and con-trol of RDs [7]. This is evidenced by specific recommenda-tions and measures to support the development of suchregistries in different EU healthcare resolutions, strategicdocuments [8, 9], and EU-funded projects, including theRD-Connect (2012–2018) and EPIRARE (EuropeanPlatform for Rare Disease Registries, 2011–2014) projects.The RD-Connect project provided an integrated platform

connecting databases, registries, biobanks, and clinical bio-informatics for RD research. This multidisciplinary project,which later gave rise to the RD-Connect Community,united partners from the EU and beyond to create an inte-grated global infrastructure in the field of RDs [10]. TheEPIRARE project was focused on the conditions for theestablishment of the EU registries and databases on RDs,legal issues, the definition of a common data set and proce-dures for quality control, and agreement on the registryscope, governance, and long-term sustainability thereof[11]. In view of these projects and other initiatives, RDregistries in specific forms and of limited extent alreadyexist in France, Spain, Italy, Slovakia, and Belgium, whereasthose of Bulgaria and Sweden are in the process of beingprepared [12]. The development and introduction of a RDregistry in Slovenia is also one of the main concerns out-lined in the “Work plan in the field of rare diseases in theRepublic of Slovenia” from 2011 [1] and formulated in the“Resolution on the National Healthcare Plan 2016–2025”[13]. However, despite the unquestionable importance ofthe RD registry and initiatives from various internationaland supranational organizations, the legal basis for theestablishment of the national RD registry was adopted onlyrecently (19 April 2018). Consequently, Slovenia still doesnot have a functional RD registry. The RD registry wasincluded in the proposed amendment to the HealthcareDatabases Act [14], which was finally adopted after a longperiod of legislative gridlock.In view thereof, the aim of this paper is to explore the

existing state of affairs concerning RDs, outline thedevelopment of the pilot RD registry (PRDR), andpropose the establishment of a RD ecosystem inSlovenia. Accordingly, this paper primarily focuses onthe following interrelated research objectives:

� an analysis of the current situation and identificationof related systemic constraints and deficiencies inthe field of RDs in Slovenia;

� development of the PRDR and conceptualization ofthe RD ecosystem in Slovenia.

MethodsResearch designThis paper employs a case study design to investigatethe outlined research objectives concerning the current

situation in the field of RDs, the development of thePRDR and conceptualization of the RD ecosystem inSlovenia. Fourteen focus group sessions were used as themain data collection technique and conducted fromJanuary 2016 to February 2017. The selection of theresearch method was based on the particularities of theresearch problem [15, 16]. Since this study was largelyexploratory in nature, quantitative empirical methodscould not yield satisfactory results or provide a credibleassessment of the field. Namely, the complex field ofRDs in Slovenia is still in an early developmental stage,and it would be difficult to ensure the representativenessof the research sample. For this reason, the focus groupmethodology was considered the most favourable meth-odological approach to carrying out an in-depth analysisof the situation, the identification of the necessarysystemic changes, and shaping the preferred solutions inthis domain.

SampleThe selection of the focus group participants wasprimarily based on their experience and expertise in thearea of RDs, which was intended to ensure the credibil-ity of their views and facilitate constructive participationin the study. A non-random stratified sampling approachwas used to ensure a representative sample of thehealthcare experts that satisfied the required conditions.Assembling the focus groups was completed when thesaturation point was reached. The final sample sizecomprised 24 experts, who were affiliated with differentinstitutions: the National Institute of Public Health(NIPH) (3 participants), the University Medical CentreLjubljana (UMCL) (11 participants), the University ofMaribor Faculty of Medicine (6 participants), the SlovenjGradec General Hospital (2 participants), and ICT com-panies (2 participants). The participants were qualifiedhealthcare professionals specialized in microbiology andimmunology, human reproduction, the cardiovascularsystem, biochemistry and molecular biology, oncology,metabolic and hormonal disorders, ICT experts in com-plex systems and cybernetics from the healthcare andprivate sector (consultants and analysts), and experts inpublic health (methodologists and statisticians).

Data collectionThe final goals of the focus group sessions were revisedwith the participants in line with their comments andsuggestions, which helped to resolve some conceptualambiguities. The participation rate in the focus groupswas 100%; namely, all invited experts responded to theinvitation and ultimately participated in the focus groupsessions. The focus group sessions, which lastedapproximately 90 to 120 min, were held on the premisesof the UMCL. The directed and structured discussions

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were focused on the existing situation in the field of RDsin Slovenia and related problems, substantive, techno-logical and organizational issues concerning the develop-ment of the PRDR, and priority actions at the normativeand implementation levels. The participating experts hadto identify and outline the priority areas and critical factorsthat they deem to be crucial for the successful developmentof the PRDR (and potential subsequent development of thenational RD registry) and the establishment of the RDecosystem. The discussions and responses of the focusgroup participants were recorded in writing.

Data analysisAnalysis of the data obtained and the interpretationthereof were carried out by means of conventionalcontent analysis [17, 18], while the platform for thedevelopment of the PRDR and the conceptualization ofthe RD ecosystem in Slovenia were derived from thefocus group discussions and literature review. The con-tent analysis was based on codifying the key statementsrelated to each construct highlighted by the participatingexperts (priority areas and critical factors). The codingcategories were derived from the focus group discus-sions. In order to increase the objectivity and credibilityof the findings obtained, a final content analysis was car-ried out independently by several coders (the authors).Following the data analysis, the development of thePRDR and the subsequent conceptualization of the RDecosystem were conducted in collaboration with theparticipating experts, who played a constructive rolethroughout all phases of the study. After an extensive re-view of the literature and investigation of primary andsecondary sources containing RD-related content [1, 2,4, 8, 9, 12, 13], the current situation concerning RDs inSlovenia was systematically analysed. In this phase, theresearch was especially focused on the imminent chal-lenges in the field, in an effort to provide a feasible plat-form for the planned development of the PRDR andconceptualization of the RD ecosystem in Slovenia. Therole of the participating experts within the proposedstudy was twofold. First, they had to participate in theanalysis of the existing situation in the field of RDs. Andsecond, drawing from their own experience and know-ledge in the field, they had to provide their vision of thedevelopment of the PRDR (including its ensuing trans-formation into the operative national RD registry) andconceptualization of the RD ecosystem in Slovenia.

ResultsThe experts participating in the focus groups outlinedthe state of affairs in the field and highlighted the prior-ity areas and critical factors that need to be carefullyconsidered in order to successfully implement the PRDR

(and subsequently also the national RD registry) and es-tablish a functional RD ecosystem (Table 1).The listed priority areas and related critical factors

(Table 1) were thoroughly discussed and scrutinized inthe subsequent phases of the study. A general analysis ofthe current situation in the field, including the identifiedsystemic constraints and deficiencies concerning theoutlined priority areas and critical factors are presentedin the following sections.

Analysis of the current situation and identification ofrelated systemic constraints and deficiencies in the fieldof RDs in SloveniaClinical work and the patient treatment perspectiveThe focus group participants initially identified and elabo-rated different issues regarding clinical work in the fieldand the patient treatment perspective. These two priorityareas cover a large number of critical factors that are crucialfor the overall situation in the field. The results presentedbelow are derived from the focus group discussions.For the classification and codification of RDs, health-

care professionals in Slovenia currently use the updatedAustralian modification of the 10th revision of the Inter-national Statistical Classification of Diseases and RelatedHealth Problems (ICD-10-AM, version 6) proposed bythe World Health Organization (WHO) [19]. Since thereis only a narrow range of specific codes for around 6000existing RDs contained in the ICD-10-AM, clinical prac-tice in the field is rather diverse and inconsistent [2]. Aslegally required, the NIPH keeps records of the hospitaltreatment of patients whereby the main diagnoses andsupplementary diagnoses are recorded [20]. The Insti-tute of Oncology records the incidence of rare cancersin Slovenia as part of the Pan-European RARECAREproject [21].The Healthcare Databases Act, which represents the

main legal basis, defines the types of databases and stip-ulates the conditions required for data processing [14].Annex 1 to the Healthcare Databases Act defines thecontent of specific healthcare databases, their purpose,periodic reports, the manner of reporting, and dataretention periods. The RD registry was only recentlyincluded in the Act. However, the Act had already con-tained five registries of diseases that are either rare orpertain to RDs. Of these five registries, which were pre-viously listed in Annex 1 to the aforementioned Act,there are only three registries implemented in practicethat include RDs, namely the Registry of CongenitalAnomalies, the Registry of Children at Risk, and theRegistry of Blood Clotting Disorders. In contrast, thereare several clinical RD registries in Slovenia (Table 2)that lack legitimate status and an appropriate legal basisin the Act. Notwithstanding this, some of them already

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report data to the European registries (e.g. the Fabry’sDisease Registry, the Cystic Fibrosis Registry, etc.).Even though the RD registry was only recently in-

cluded in the Healthcare Databases Act [14], it is ratherobvious that the establishment of such a registry is anessential prerequisite for the comprehensive monitoringand management of RDs in Slovenia, and certainlyrepresents one of the priorities in the field [22, 23]. Con-sidering the needs of stakeholders in the field of RDs inSlovenia and international experience [12, 19], a well-designed and efficiently managed RD registry could

provide many opportunities for improvements in thefield, since it could be very instrumental in:

� monitoring prevalence and incidence and theconsequent signalling of early warning signs;

� providing information for the development ofsuitable services at the national level and thedevelopment of suitable clinical pathways for the useof specialist services abroad;

� revealing the natural course of the disease – thecharacteristics of the disease, management, andoutcomes with or without treatment;

� monitoring the safety of newly introduced orexperimental treatments;

� evaluation of the clinical efficacy of newinterventions;

� monitoring the results/outcomes of treatment andenabling a comparison with European andinternational standards;

� creating a list of patients that can be contacted forclinical trials or participation in multicentre studies;

� providing information on the economic evaluationof healthcare, such as disease costs and analyses ofcost-effectiveness.

Table 1 Priority areas and critical factors in the RD field highlighted by the experts

Priority area Critical factor

Clinical work - Envisaged benefits and potentials of RD registries for clinical workwith patients, designing standards, and research

-Monitoring the effects of patient treatment and planning furtherprocedures

-Effective work and access to all relevant patient information in one place

Patient treatment perspective - Better coordination and monitoring of the treatment process

- Higher quality, safer medical treatment and better treatment results(better quality of life)

-An effective communication channel and secure exchange of information

- Evidence-based allocation of resources for patients with rare diseases

ICT infrastructure and solutions - Effective and user-friendly ICT solutions (RD registry)

- Ensuring interoperability despite the heterogenity of the information systems

- Definition of the rules of operation, information flows, and organizationalprocesses

-The role of eHealth (the Central Registry of Patient Data (CRPD))

Normative framework - Adequate legal basis

-Protection of personal data (application of the safe-by-design principle)

-Personal Data Protection Act / General Data Protection Regulation (GDPR)

Development of the PRDR andconceptualization of the RDecosystem in Slovenia

- Strategic documents and development directions

-Research and pilot projects

-Adequate funding, engagement of stakeholders, and healthcare policy support

-Selection of the appropriate approach for the development of the PRDR(and subsequently the national RD registry) and the establishment of the RDecosystem in Slovenia

Table 2 The list of existing clinical RD registries

Registry name

Registry of Patients with Cystic Fibrosis

Registry of Patients with Inborn Errors of Metabolism

National Registry of Patients with Fabry’s Disease

Registry of People with Blood Clotting Disorders

Registry of Patients with Renal Failure

Registry of Patients with Neuromuscular Diseases

Slovenian National Registry of Patients with Primary Immune Deficiency

Registry of Congenital Anomalies

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The coding of diseases by healthcare providers iscurrently adapted to the prevailing national practicesand existing sectoral specifics. Subsequently, diagnosesof RDs can be coded according to different nomencla-tures and terminologies, such as Orphanet, Online Men-delian Inheritance in Man (OMIM), or the SystematizedNomenclature of Medicine – Clinical Terms (SNOMEDCT), depending on the context and the desired granular-ity of coding [24]. The 11th revision of the ICD with,thus far, approximately 5400 codes for RDs was releasedon 18 June 2018 [25, 26]. It is expected that this versionwith modifications will also be adopted by the Republicof Slovenia, but the process of adoption can take severalyears to complete. The data on hospital treatments is animportant source of information for healthcare manage-ment and the assessment of the health status of thepopulation. These sources of information are also usedfor reporting to the EU, the WHO, and other supra-national and international organizations. In 2013, a uni-form system for monitoring hospital treatments (namedeTransfer) was implemented. This system significantlyimproves the monitoring of diagnosis-related groups(DRGs) and individual occurences within the DRGs [27].Taking into account the planned adoption of the ICD-11, it should be considered whether the standard inter-national coding of RDs should be implemented in allhospital information systems (the use of codes from theOrphanet nomenclature of RDs). Some countries (e.g.Germany and France) have already adapted the ICD-10by applying extensions for the specific coding of RDs[19]. Furthermore, considering the anticipated require-ments of the national RD registry, hospital informationsystems should certainly support the appropriate stan-dardized coding of RDs and enable the transfer ofhealthcare data into the RD registry. Namely, patientswith RDs are in most cases treated at four institutions inSlovenia – the UMCL, the Golnik University Clinic ofRespiratory and Allergic Diseases, the Slovenj GradecGeneral Hospital, and the Valdoltra OrthopaedicHospital. The rehabilitation of patients is carried out atthe Soča University Rehabilitation Institute. The Centrefor Undiagnosed Rare Diseases at the Clinical Instituteof Medical Genetics of the UMCL is the first specializedunit for such diseases in the region [22].

ICT infrastructure and solutionsConcerning the broader field of ICT, the focus group par-ticipants pointed out various issues, ranging from typicallytechnological to management (and policy) aspects, whichconcern the long-term planning of healthcare informatics,human resources, organization and operational processes,and sustainable funding. The presented findings are basedon the focus group discussions.

When designing long-term ICT projects, an applicablemodel of management and sustainable funding must beconsidered in the early planning stages. It often happensin Slovenia that only start-up and pilot project funds areensured in the planning stage. Only afterwards are ques-tions about long-term management, the role of specificstakeholders, and the organization of their work oftenraised, although these issues should have been includedin the development activities from the very beginning.This also relates to the provision of funds for ensuringthe financial sustainability of the project, as well asmaintaining, upgrading, and developing the ICT solutionin the future. Ensuring suitable resources is a key pre-requisite for the effective development of the nationalRD registry and its successful implementation in thecomplex healthcare environment. Moreover, the useful-ness of the planned national RD registry will largely de-pend on the resources (financial, human, informational,organizational) available for its day-to-day managementand continued operation. In accordance with thestrategic documents for the regulation of this field andthe establishment of the national RD registry in Slovenia,some important steps have been taken in the past fewyears. These are reflected in a more serious approach tothis issue and the launching of the NCP for RDs. How-ever, questions regarding the institutional management,vertical and horizontal organization, and long-termfunding of the RD registry still remain largely unre-solved. Since the implementation of the RD registry isone of the essential measures for successfully dealingwith this important public health problem, the field ofRDs is indeed not systemically regulated.In addition, the ICT in the Slovenian healthcare is ex-

tremely heterogeneous, in the sense of both the differentdegrees of digitalization of particular healthcare servicesand the numerous different ICT solutions. Consequently,there have been many interoperability problems detectedin the past, which partially still occur today, although toa much more limited extent. With the introduction ofthe eHealth solutions and the use of uniform infrastruc-ture and data exchange standards, these problems havebeen largely eliminated. However, it must be emphasizedthat not all healthcare providers use the eHealth solu-tions and that some healthcare providers do not usethem to their full extent. In the context of the plannedestablishment of the national RD registry, special consid-eration should be devoted to the Central Registry ofPatient Data (CRPD). The CRPD contains a summary ofpatient healthcare data and patients’ medical records.The CRPD allows healthcare providers in Slovenia toaccess and exchange patient healthcare data to ensurehigh-quality patient treatment. For technical or otherreasons, not all public healthcare providers in Sloveniasend patient healthcare data to the CRPD, even though

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the central infrastructure has been operative for quitesome time. Conventional healthcare data standards en-sure a high level of interoperability and have improvedthe general quality of healthare data in the registries. Inorder to overcome the problems associated with inter-operability between the local healthcare information sys-tems and the national RD registry, the use of healthcaredata standards must be planned in the early phases ofthe development of the RD registry. In addition, only ad-equately structured and standardized healthcare data canbe transferred into the electronic records of the patientsand subsequently used for various purposes (planninghealthcare treatment, epidemiological and other publichealth studies, the preparation of public healthcarepolicies/programmes, etc.) [24].

Normative frameworkThe following results concerning the normative frame-work are largely based on a review of the documents(legal acts of the EU and the Republic of Slovenia). Onlya small part of the results concerning the identificationof neccesary changes in the Slovenian legal environmentupon the enactment of General Data Protection Regula-tion is derived from the focus group discussions.The valid Healthcare Databases Act provided a legal

basis for the collection of data on patients with RDs onlyat the end of April 2018 [14]. The preparation of theamended Act was included in the regulatory workprogramme of the Government of the Republic ofSlovenia for 2016, but since its adoption was notmandatory, all related activities were delayed [28]. How-ever, based on the current momentum in the field of RDsand the tremendous efforts of the authors of this paper,the amended Act was adopted before the end of that term,namely in June 2018. The adoption of an appropriate Actis crucial to this end, as it provides the required legal basisfor the collection of data on patients with RDs and theestablishment of the national RD registry.Directive 95/46/EC of the European Parliament and of

the Council of 24 October 1995 on the protection ofindividuals with regard to the processing of personaldata and on the free movement of such data providesthe legal framework for personal data protection in theEU [29]. The Directive provides rules on the lawfulprocessing and protection of personal data, and on thenecessity of suitable control mechanisms concerning theprotection of personal data. The Directive introduces thenotion of individual consent and the prior notification ofindividuals regarding the processing of their data. InSlovenia, this area is regulated by the Personal Data Pro-tection Act [30], which transposes the provisions of theDirective into the Slovenian legislation. On 25 January2012, the European Commission published a proposalfor the in-depth reform of the EU legislation regarding

personal data protection. The aim of the reform was toprotect personal data within the EU, increase citizens’control over their own data, and decrease costs for com-panies. The new General Data Protection Regulation(GDPR) (EU) 2016/679 of the European Parliament andof the Council of 27 April 2016 on the protection of nat-ural persons with regard to the processing of personaldata, and repealing Directive 95/46/EC entered intoforce in May 2018 [31]. Since the Slovenian regulationand the Personal Data Protection Act [30] are very re-strictive in terms of the protection of personal data, theintroduction of specific systemic changes or other mea-sures was not necessary. The only significant change wasrelated to the establishment of a data protection officerin all organizations where sensitive personal data areprocessed. The legislation provides a binding frameworkthat needs to be respected in the design, implementa-tion, and use of the national RD registry. Furthermore,throughout the process of developing the national RDregistry it is necessary to follow the software engineeringprinciple of safe by design. This principle stipulates thatspecial attention should be devoted to the safety of theproduct and the security of users during the entire plan-ning, development, and implementation process.

Development of the PRDR and conceptualization of theRD ecosystem in SloveniaThe results related to the development of the PRDR andthe conceptualization of the RD ecosystem in Sloveniaare generally derived from the focus groups and litera-ture review. Each important paragraph in this sectioncontains an explanation of which data the presentedfindings are based on.Focus group participants outlined recent activities and

projects in the field related to the potential developmentof the national RD registry. Unfortunately, an up-to-datestrategic document and action plan in the field of RDsdo not exist. Based on the strategic guidelines of the“Work plan in the field of rare diseases in the Republicof Slovenia” [1], the two-year research project “Analysisand development in the field of rare diseases in Slovenia”was launched in October 2015. The scope of the projectincludes a detailed sectoral analysis, the design of a na-tional system for monitoring RDs, and the developmentof the PRDR [2]. In 2015, the Ministry of Health alsolaunched a project for the creation of a website of theNCP for RDs, led by the Division of Paediatrics at theUMCL. The NCP was successfully established in 2016.The goal of the NCP is to create a network of stake-holders and to provide patients and experts access tohigh-quality information on the treatment of RDs isSlovenia [23]. The same stakeholders will provide themain data sources for the national RD registry upon itsestablishment in the future. The long-term goal, based

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on continuing to raise awareness of RDs, is to offer pa-tients the option to self-register through the NCP.Planning the development of the PRDR and conceptu-

alizing the RD ecosystem was based on a distinctivemethodological approach proposed by the focus groupexperts and already well-established formal steps fromthe literature [2]:

The registry’s main purposes

– The primary objectives of the PRDR were to addressseveral of the traditionally unanswered issuesregarding RDs that are important for the broaderaim of improving the treatment of patients withRDs. Among these, we wanted to generate robustdata on the incidence and prevalence of RDs inSlovenia, on the natural histories and diagnosticcharacteristics of RDs, and the management thereofat institutional and clinical levels. On that basis, weenvisaged the PRDR as a means to improve not onlythe treatment of individual patients with a RD, butalso to improve the RD ecosystem as a whole.Another important aim of the PRDR was also toensure interoperability within the Slovenian eHealthsystem and to facilitate international data exchange.

Key stakeholders and the feasibility of the registry

– The PRDR was developed as a collaborativenationwide project by the institutions that are mainstakeholders in the areas of RD clinical management,public health and epidemiology, and healthcareinformatics. In addition, with the help of governmentrepresentatives, we envisaged the appropriateregulatory framework for the national RD registry,including sufficient resources (i.e. we prepared aspecific legislative proposal that was laterincorporated into the Healthcare Databases Act [14]).

Registry team

– The PRDR preparatory team comprised aninterdisciplinary group of professionals withbackgrounds in clinical medicine, ICT/bioinformatics, genetics, and public health/epidemiology, thus representing all the main areasthat need to be addressed in PRDR development andimplementation. For practical implementation, itwas also planned that the PRDR team would includeadministrators, coders, and an oversight body thatincludes patient representative(s).

Registry scope and data set

– It was proposed that the PRDR would include allpatients diagnosed with a non-malignant RD and thepertaining OrphaCODE when diagnosed (all malig-nant RDs are subject to the national cancer registry).The proposed data set for the PRDR is presented inTable 3. For each patient, certain data sets (personaldata, vital status) are to be generated from theCentral Register of the Population of the Republic ofSlovenia, while the remainder would be provided bythe reporting physician on a standard reportingform. Importantly, the PRDR data set wasadditionally modified to ensure compatibility andinteroperability with the recently proposed “Set ofCommon Data Elements for RD Registration” of theEuropean Commission’s Joint Research Centre, inorder to ensure international data exchange.

The technical/technological part of the PRDR develop-ment process was structurally based on recommenda-tions from the literature [4, 11, 12, 32], andmethodologically on the suggestions of the focus groupparticipants. The whole technical/technological part ofthe project was carried out in parallel with the abovesteps and in accordance with the content outputs thatwere generated within each of the listed phases. ThePRDR was designed as a web application that allows thecompetent subspecialized healthcare providers to reportdata on diagnosed RDs. Five reporting institutionscollaborated on the project by participating in both the

Table 3 Proposed data set for the Slovenian PRDR

Data set categories and their content

1. Personal data: UMCN; name/surname; gender; place of birth

2. Vital status: alive (Y/N); date and time of death

3. Healthcare institution (of registration): name; department; dateof first contact; date of registration; name of physician

4. Diagnostic codes (main diagnosis): OrphaCODE; ICD-10 code

5. Characteristics (main diagnosis): description of the diagnosis;date of diagnosis; confirmed (Y/N); age at diagnosis; time offirst signs/symptoms (year/antenatal/at birth/ND)

6. Other diagnoses (all to be listed): ICD-10 code; description

7. Genetic characteristics and biological material: HGNC code;HGVS code; OMIM number; type of biological materialavailable; biobank name

8. Functionality/Disability scores: result according to the ICFclassification

9. Therapeutic data: any orphan drugs (according to the EMA list)

List of abbreviations: EMA European medicines agency, HGNC The HUGO GeneNomenclature Committee, HGVS Human Genome Variation Society, ICD-10International Classification of Diseases 10th Revision, ICF Internationalclassification of functioning, diseases and health, N No, ND Not determined,OMIM Online Mendelian Inheritance in Man, UMCN Unique Master CitizenNumber, Y Yes

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design of the PRDR itself and in its testing and finaloptimization. The construction of the PRDR was basedon the open electronic health records (OpenEHR) meth-odology, which has become widely used to achievesemantic interoperability in healthcare and which wasalso used to create some analogous registries (e.g. theendoprosthetics registry) in Slovenia. This approach is“open” in terms of data, and the modelling and subse-quent translation thereof into electronic form. TheOpenEHR registry development methodology is basedon the separate treatment of the clinical content and theICT solution used for content management itself. Theclinical content was planned, designed, and structuredseparately from the rest of the ICT solution developmentprocess. The point of this concept was that the clinicalcontent preparation is done by clinical specialists, allow-ing the ICT analysts and developers to focus on thetechnical/technological aspects of the solution.Arising from the analysis of the current situation, pri-

ority areas, and identification of the critical factors in

the field of RDs, we conceptualized the preferred RDecosystem in Slovenia (Fig. 1) based on the recommen-dations of the focus group participants.The national RD registry is envisaged as one of the

central points of the RD ecosystem, providing a meansfor improving the treatment of patients with RDs. Onthe practical level, the national RD registry should beable to interconnect stakeholders to ensure the collec-tion of relevant data (i.e. on RD incidence and preva-lence, natural histories, and diagnostic characteristics,and their management at institutional and clinicallevels), and also foster international data exchange. Onthe institutional level, the national RD should become apoint of reference for RDs, systematically connecting thealready existing but very fragmented infrastructure (e.g.the NCP for RDs, the existing RD registries), patients’organizations, healthcare and academic institutions, andrelevant governmental bodies. The reporting system forthe national RD registry should be based on well-organized and reliable data sources, whereas standardized

Data sources

Clinical institutions (hospitals,

laboratories)

GURS – The Surveying and

Mapping Authority of the

Republic of Slovenia

CRP – Central Register of the

Population

Existing registries / national health databases, death

registry, etc.

International registries

(international health databases,

etc.)

National rare disease registry

Electronic health record

International / supranational rare disease platforms

National contact point for rare diseases

Patient treatment

Patients

Rehabilitation institutions

Population studies

Associations (patient and professional)

Healthcare policymaking bodies

National statistics and health databases

Government regulatory bodies

Therapy (orphan drugs, clinical trials, biobanks)

Defined and coordinated work

processes

Data standards and formats

Input methodology and

protocols

Security and authorized access

Sustainable funding(human resources,

maintenance,development, etc.)

Rules of operation

Fig. 1 The proposed model of the RD ecosystem in Slovenia. Structure and organization of the proposed model of the RD ecosystem in Slovenia,including the national RD registry and all relevant entities in the field of RDs

Stanimirovic et al. Orphanet Journal of Rare Diseases (2019) 14:172 Page 9 of 13

data transfers should be performed and controlled withinthe framework of precise and clearly defined rules of oper-ation. In order to provide tangible benefits to all stake-holders, the analysis demonstrated that the operation ofall entities in the RD ecosystem must be process- andoutcome-oriented, as well as adequately technologicallyand normatively supported.

DiscussionThe literature reveals that national RD registries havecomplex and multidimensional effects on the entire fieldof RDs. There is general consensus that the constructionof a comprehensive national RD registry presents one ofthe foundations for the systemic regulation of RDs inthe country [33]. Based on the literature and focus groupfindings, a suitable RD registry could considerablycontribute to more effective monitoring of RDs [34], im-proved patient treatments [32, 35], reduced inequality,and provide better support for evidence-informedpolicymaking [10, 11, 36]. In addition, based on thefocus group findings, a well-coordinated RD ecosystemcould bring considerable benefits to all healthcare man-agers, providing a useful platform for the estimation ofthe required resources, technological innovation, andorganizational restructuring. However, it is clear that theimplementation of an effective RD registry and theestablishment of a comprehensive RD ecosystem requireprofound systemic changes and extensive efforts by thestakeholders, supported by targeted policy measures andsufficient funding.This research provided an in-depth analysis of the

current situation regarding RDs in Slovenia and enabledthe identification of the most significant systemic con-straints and deficiencies in the field. In addition, the paperpresented a practical process for developing the PRDRand proposed a conceptual framework for the construc-tion of the RD ecosystem. The systemic constraints anddeficiencies in Slovenia identified by the focus groupparticipants mainly concern the following matters:

� varying and inappropriate clinical practice in someparts of the coding process;

� regulatory shortcomings and non-compliance withlegislation in the field of RDs;

� fragmented, non-interoperable, and inefficient ICTsupport;

� a lack of material and immaterial resources(financial, human, informational, organizational;

� institutional and project management,organizational, and operational process issues arestill largely unsettled;

� the nonexistence of an up-to-date strategicdocument, action plan, evaluation framework, andwell-defined measurable objectives (concerning the

general issues in the field as well as the national RDregistry and RD ecosystem);

� specific challenges related to the development,introduction, and utilization of the national RDregistry and the RD ecosystem are difficult topredict at this stage.

The above-mentioned systemic constraints and defi-ciencies have an overarching impact on the priority areasand critical factors in the field of RDs highlighted by thefocus group experts. Moving forward, these issues willhave decisive implications for the successful futuredevelopment of the RD registry and the construction ofa functional RD ecosystem.The development the PRDR has proven to be a very

demanding task, since the entire process had to beconducted in a complex healthcare environment, and alldevelopmental activities were critically dependant on theclinical, ICT, organizational, regulatory, and other im-portant factors in the field of RDs. The forthcomingprocess of developing the national RD registry will haveto be based on a feasible project plan that preciselydefines the instutitonal organization and operationalprocesses related to data flows. The material conditionsfor the management and long-term sustainability of thenational RD registry will have to be ensured before theactual start of the project [36]. Similar principles willhave to apply to the potential construction of the pro-posed RD ecosystem. However, due to its size and thenumber of entities involved, it will require even moreeffective cooperation, adherence to the rules, and thestrong commitment of all stakeholders. The proposedmodel of the RD ecosystem does not seek to suggest a‘one-size-fits-all’ solution to the numerous issues relatedto the establishment of the RD ecosystem. However, thepresented study provides valuable insight into the back-ground of RDs in Slovenia, and may provide the ground-work for further advances in this area.

Practical recommendationsThe experience of some EU countries and examples ofgood practice confirm that the successful establishmentof the national RD registry demands a methodical devel-opment approach that includes the support of healthcarepolicies and the good collaboration of the stakeholders.Although there are no universal guidelines, some prac-tical recommendations can be deduced from the litera-ture [4, 5, 9, 11, 12, 35], which may be of assistance insimilar projects focused on the development of nationalRD registries:

� Ensure political support from the highest level andestablish an appropriate normative framework:

Stanimirovic et al. Orphanet Journal of Rare Diseases (2019) 14:172 Page 10 of 13

� bring together all stakeholders and vendors fromthe private sector;

� ensure the necessary funds and human and otherresources;

� prepare credible and viable strategy documents,feasibility studies, and action plans;

� promote international collaboration and provideevidence-based projections for future benefits.

� Mobilize all stakeholders to ensure commitment andmaterial and moral support, and to encourage theiractive participation and constructive criticism:� promote collaboration between policymakers,

healthcare professionals, government officials,and ICT professionals;

� provide an inclusive plan for communicationwithin the project team and between the projectteam and all stakeholders.

� Establish an organizational and technologicalframework for the development of the RD registry:

� Define the main purpose of the registry, identify thekey stakeholders and their assignments, organize aninterdisciplinary team that consists of experiencedindividuals from the field, and define the registryscope and data set in accordance with your nationalneeds and international guidelines;

� Choose a reliable and flexible technological platformthat enables integration with other standardizedinformation systems.

In addition to the recommendations from the litera-ture, we formulated some more specific guidelines basedon the focus groups in this study:

� Promote legislative amendments and adoptnecessary regulations concerning theimplementation of the RD registry and theestablishment of the RD ecosystem.

� Establish a robust evaluation framework, including theobjectives of evaluation, benchmarks and evaluationmetrics, and define strategic and operative measures.

� Select a top manager and a quality project teamwith experience in complex ICT projects, and forma steering committee that includes diverse experts.

� Ensure adequate resources before the start of eachproject phase and make realistic plans in bothtemporal and financial terms, define milestones, andanalyse operating and total costs.

� Perform constant supervision and strict control ofalready executed project tasks with respect tosubstantive and temporal objectives, and ensure theclose monitoring of tasks that are in the executionphase.

� Improve or build a comprehensive ICTinfrastructure (assess the current ICT infrastructure,

interoperability issues, broadband connections,operating systems, network protocols, and datastandards).

� Test the applicability of the RD registry in pilotprojects and gradually implement individual ICTsolutions in healthcare institutions:� promote the application of the RD registry;� organize education and training, issue standard

practice guidelines.� Inform stakeholders promptly and report all

developments:� promote project achievements in order to

improve and expedite the acceptance of the RDregistry, facilitate comprehensive methodologicalexplanations, create a user manual and help desk,and gain support from the media, experts, andcitizens.

One should be aware that the listed recommendationsdepend on the current circumstances and severalsuccess factors, and cannot be easily transferred intopractice. All these collaborative activities must be com-bined into functional and well-coordinated action, whichis essentially the most challenging task of the projectmanagement team.

Limitations of the study and future research directionsThe research approach used in this paper has one clearmethodological limitation. Since Slovenia does not yethave a national RD registry, the notions of the RD eco-system including the national RD registry were hypothe-sized without concrete empirical validation in the actualhealthcare environment. Accordingly, the issues relatedto the projected implications of the national RD registryand conceptualization of the RD ecosystem may raisesome important questions of principle, while the re-search outcomes may therefore be disputable. Theseissues should be properly resolved in further researchaimed at comprehensive analysis of the long-term effectscaused by the establishment of the RD registry and theRD ecosystem. Future experiments should include de-tailed investigation of the applications and implicationsof the national RD registry, including its simulation andtesting in the actual healthcare environment. The envis-aged research goals should focus on facilitating therecommendations and operative guidelines for the estab-lishment of such structures in all countries where pa-tients are still not receiving adequate medical treatmentdue to systemic reasons and non-medical factors.Despite the outlined methodological limitation, the con-ducted research reveals the complex dynamics in thefield of RDs in Slovenia, as well as the critical role ofICT in establishing a much-needed RD ecosystem, andis expected to contribute to theory building in the field.

Stanimirovic et al. Orphanet Journal of Rare Diseases (2019) 14:172 Page 11 of 13

ConclusionEnsuring more effective healthcare delivery in thisspecific field is strongly related to successful implemen-tation of the national RD registry and its alignment withother systemic factors. The RD registry together withdata sources, rules of operation, and NCP for RDsshould form the ICT backbone of the RD ecosystem.The establishment of a comprehensive RD ecosystem,including the national RD registry, evidently requires themobilization of all stakeholders, substantial funding, andthe coordination of often conflicting interests within thehealthcare system. This could present a major challengefor the effective long-term regulation of the field of RDsin Slovenia. However, due to recent developments, in-cluding the launch of the PRDR, and particularly theadoption of the umbrella law in this field, the overallsituation concerning RDs looks more promising.Notwithstanding the identified intricacies, the estab-

lishment of the RD ecosystem in Slovenia, including thenational RD registry, undoubtedly represents a develop-ment opportunity that could efficiently connect differentstakeholders, improve utilization of the already existinginstitutional capacities, and contribute to the improvedhealthcare treatment for all patients with RDs.

AcknowledgementsNot applicable.

Authors’ contributionsDS contributed the methodological part, covered all technological aspects,and conceptualized the rare disease ecosystem. He was a major contributorin writing the manuscript. EM analyzed the current situation in the field ofrare diseases in Slovenia, including the system constraints and deficiencies,and provided a review of the developments on the EU level. UG elaboratedthe insights from the clinical environment, proposed a developmentalapproach, and provided a substantial part of the pilot rare disease registry(the registry structure and data set). TB outlined the content and frameworkof the manuscript, with a focus on the rare disease registry and rare diseaseecosystem, and set up the starting points for the discussion and conclusion.All authors read and approved the final manuscript.

Authors’ informationDS is head of the Centre for Healthcare Informatics at the National Instituteof public health of the Republic of Slovenia (NIPH). He is an assistantprofessor of informatics and his work has been published in leadinginternational academic journals. His general research interests include ICTpolicies and projects regarding healthcare and health information systemsEM is a medical doctor by education. She is currently a resident in publichealth working at the National Institute of Public Health of the Republic ofSlovenia (NIPH), and is involved in different projects and areas of work. Hergeneral interests include rare diseases, mental health, psychotherapy, alcoholabuse, and health promotion.UG is a metabolic pediatrician and researcher at the UMC – UniversityChildren’s Hospital Ljubljana. He is an assistant professor of pediatrics andhas published his research work in highly ranked scientific journals. His mainresearch interests include inborn errors of metabolism, dyslipidemias,medical ethics, and screening programs for children.TB is the Head of the Department of Endocrinology, Diabetes, andMetabolism at the UMC – University Children’s Hospital Ljubljana and theHead of the Department of Pediatrics at the Faculty of Medicine – Universityof Ljubljana. He is a full professor of pediatrics and has published hisresearch work in the highest-ranking scientific journals and presented it atleading conferences and seminars. His main research interests include dia-betes and pediatric endocrinology.

FundingThe manuscript was written within the project “Analysis and development ofthe rare diseases field in Slovenia”, Code V3–1505 (C), which was funded bythe Slovenian Research Agency (ARRS, included in the ARRS records) in theperiod 1 October 2015–30 September 2017. The project leader was TadejBattelino, ORCID ID; https://orcid.org/0000-0002-0273-4732.

Availability of data and materialsNot applicable.

Ethics approval and consent to participateNot applicable.

Consent for publicationNot applicable.

Competing interestsThe authors declare that they have no competing interests.

Author details1National Institute of Public Health, Trubarjeva Street 2, 1000 Ljubljana,Slovenia. 2Department of Endocrinology, Diabetes and Metabolism, UMC -University Children’s Hospital Ljubljana, 1000 Ljubljana, Slovenia. 3Faculty ofMedicine, University of Ljubljana, 1000 Ljubljana, Slovenia.

Received: 23 November 2018 Accepted: 26 June 2019

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