The Italian neuromuscular registry: a coordinated platform where patient organizations and clinicians collaborate for data collection and multiple usage

The Italian NMD Registry is under the responsibility of a dedicated legal entity (the ADR). A charter regulates its activities. The Italian NMD Registry is recorded in the Italian Data Protection Authority Register and is compliant with the Italian and European directives on data protection (EU GDPR 2016/279). The main governing body is the Executive Board, which includes a representative from each PO and Telethon; the President is always a PO representative, with a two-year mandate. When a new registry joins the NMD Registry, the referring Italian POs are invited to become members of the ADR and a representative joins the Executive Board. This has been the case for ACMT-Rete and this activity is now in progress for MGSD and TTR-FAP POs (Fig. 1).

ELAC is an independent board composed by five experts in ethical and legal issues, who advice the ADR on these matters. At the start of the initiative, the ELAC provided ADR with advice on the Italian and international legal requirements on data protection, validated the privacy design of the IT platform, the data management procedures and flowchart, and approved the Italian version of the Informed Consent for DMD and SMA registries. The ELAC also provided the Scientific Coordinator of the CMT Registry with advice on the Clinical Protocol and the patient Informed Consent before the submission of the documents for approval to the Institutional Review Board (IRB) of the coordinator and partners’ centres. The CMT registry was the first clinician-reported database hosted on the platform and the procedure developed for its implementation paved the way for the other disease-specific registries that followed. The ELAC also acted as independent consulting body for the evaluation of each request of data access addressed directly to the Italian NMD Registry. As described more in detail below, the ELAC model is now evolving into a new council defined “Access Board”.

A major implementation of the NMD Registry concerned the inclusion of registries collecting clinician-reported items (Table 1, Fig. 2). These registries, promoted by groups of interest from the Italian NMD clinical network, started as databases of observational studies with the explicit intention to maintain and re-use data as proper registries. Their scientific aims entail the collection of natural history data, validation of functional measures, studies on quality of life and care management, monitoring efficacy of available treatments in the real world (where applicable).

ADR made the IT platform available to these registry-based observational studies, with the scope of favouring the long-term maintenance, update and re-use of data. Dedicated Steering Committees, including the Scientific Coordinator, the principal investigator of each partner centre and other experts, are responsible for the strategic development and management of each registry. The IRBs of all clinical centres involved in data collection approved the protocols and the Informed Consent forms.

The increased complexity of the NMD Registry platform prompted the ADR Executive Board to revise the governance process, in order to include the different stakeholders’ roles and views. In the new management scheme, the Scientific Coordinators participate in the governance on behalf of their Steering Committees, and interact with the Executive Board (Fig. 1).

The Agreement describes the roles of POs, Telethon, AIM and ASNP, and of the independent experts that participate in the Access Board. It also illustrates the general principles that regulate the different phases of a registry’s life, namely: i) development of new registries; ii) management and use of data by participating centres (Coordinator and Steering Committee’s clinical members); iii) access policies by third parties (clinical researchers or other professionals who have interest in consulting the data and Industry); iv) dissemination of results; v) sustainability. Specific details on the registry management, which can slightly vary from one disease-specific registry to another, are then addressed in the respective protocols and are reflected in the legal contracts for data management that are co-signed by ADR and each participating centre.

The NMD Alliance may facilitate the establishment of a new registry; moreover, it supports the ADR in the definition of its strategic vision, in order to keep up with clinical research innovation in the NMD field.

When a request for consultation of the Italian DMD and SMA registries affiliated to TREAT-NMD is channelled through the international TREAT-NMD network, ADR relies on approval process of the International TREAT-NMD Global Database Oversight Committee [4, 24, 25], of which it is a member.

Up to now, for any other request that addresses specifically the Italian NMD Registry, the ADR asked ethical and legal advice to its ELAC. The increased complexity of the NMD Registry platform, however, meant that this model was no longer adequate and a new consultative board named “Access Board” is now replacing the ELAC, which includes proper expertise to better address the scientific issues that may arise regarding any enquiries. Therefore, the main remit of the Access Board is to evaluate any external requests, relying on the ethical, legal or scientific competences, and independence of its members. To avoid conflicts of interest, the clinical experts that are members of the Access Board should not participate in any disease-specific registry hosted on the NMD registry platform. In case of requests by third parties, both the Scientific Coordinator of the targeted registry and the referring PO’s representative participate in the discussion as informed persons, without voting rights. This model is the outcome of in depth discussion between ADR and the NMD Alliance, to which also the former ELAC members took part by helping ADR and clinicians to define clear roles for all stakeholders and, ultimately, designing a rigorous and transparent process that safeguards all rights.

The establishment of the ADR legal entity entailed also the creation of a fund with equal contribution by all members. This fund was initially invested in the development of the IT structure according to the legal and technical requirements, the design of the web portal, and the creation of the first three disease-specific databases. The business plans of the registries developed more recently (muscle glycogenoses, SBMA, and TTR-FAP) were supported by a grant awarded to the Scientific Coordinators and partners by Telethon within a specific competitive call dedicated to NMD clinical studies. The allocated budget concerns the development of the database and part-time support to personnel engaged in data collection and processing, from data entry to validation. The clinical Host Institutions and the National Health System support the work carried out by clinicians to perform molecular diagnosis analyses and visit patients for the accurate data collection.

Telethon is now directly supporting costs for IT maintenance and general management activities. Alternative or complementary sustainability opportunities are being sought.

All databases entail that affected individuals, or their parents/legal guardians in case of minor or incapacitated subjects, start the registration process by creating their own account.

The IT platform hosts several databases with patient- and/or clinician-reported forms at different level of implementation (Table 1 and Fig. 3). The DMD and SMA registries are based on patient-reported forms. All other registries implemented a dual registration mode, with patients starting the process by filling in their personal data and indicating an expert clinician within a given list, who will record their clinical data collected through an accurate visit. In addition, patients may contribute their own information on the disease progression or daily life experience by filling in specific questionnaires, when foreseen by the registry design (Fig. 2). The molecular diagnosis reported for DMD and SMA registries is based on the Human Genome Variation Society nomenclature [26] and is validated by the Curator. The disease terminology used for the clinician-driven registries is based on the Online Mendelian Inheritance in Man (OMIM) codes [27] and the clinical classification on the Orphanet nomenclature [28].

As specifically detailed below for each registry, all clinical protocols of data collection derive from international consensus or include standardised disease-specific datasets (Table 1). Therefore, all registries can share metadata and are potentially interoperable with the respective international efforts.

Patient-reported forms are written in Italian, and their contents match to what implemented in different languages by the other registries participating in the TREAT-NMD Global Registry [24, 25]. The referring POs provide support to patients that need additional information or assistance through their call centers. The clinician-reported forms of dual registries are written directly in English, as they are filled in by physicians who are experts in the field and received ad hoc training for standardisation of this activity. Patients are informed about the items that will be collected during the consent talk and the clinical visit.

The DMD and SMA registries collect essential clinical information with mandatory and optional items on clinical status. The datasets were initially defined under the TREAT-NMD project and have recently been revised to take into account updates in standards of care and map novel treatments.

The DMD database collects mainly information on young adults with DMD and Becker muscular dystrophy (overall 161 individuals, mean age 26 years, range of age 4–79 years). The SMA database currently collects information of 560 patients with SMA types 1–4 (mean age 26 years, range of age 0–80 years).

Being part of the TREAT-NMD Global Registry, the two databases have been consulted several times to share aggregated data for feasibility enquires by pharmaceutical companies, inform suitable patients about upcoming trials and contribute information for analyses performed by the TREAT-NMD coordination team [24, 25]. The SMA registry has also been queried for a survey on respiratory care in Italy developed by the Italian SMA POs together with clinical experts [29]. Moreover, the Curator informed families of children with SMA1 when the Expanded Access Program supported by Biogen Idec of the new therapeutic product Spinraza became available [30, 31].

This registry is part of the CMT International Database (CMT-ID), which is based on national independent registries and is linked to the Inherited Neuropathy Consortium (INC), a network of 22 centres from US, UK, Italy, Belgium and Australia collecting data for a natural history study on CMT, with a centralised website based at the University of South Florida [32]. The forms derive from the consensus reached at the European NeuroMuscular Centre (ENMC) meeting held in 2009 [33]. Several other countries contribute to the CMT-ID, including South Korea, Brazil, Australia and New Zealand. Although the data of the Italian database are not directly transferred into the CMT-ID, the Italian CMT registry is potentially interoperable with the international CMT-ID. The Scientific coordinator is member of the INC and of the CMT-ID International Oversight Committee, and an ADR representative has recently joined the associated Patient Advocacy Group [34].

The Italian CMT registry is a dual registry, as CMT comprehends a heterogeneous group of disorders with a complex classification and reporting of clinical, electrophysiological and genetic information needs to be accomplished by the attending clinician (Fig. 2). The minimal dataset contains important clinical information about: disease onset; sensory, motor and skeletal manifestations; ability to walk and use of upper limbs; additional features such as optic atrophy and hearing loss; surgical intervention for foot deformities and other skeletal abnormalities; need for shoe inserts, ankle foot orthoses and other devices; electrophysiology; nerve biopsy availability; precise diagnosis, DNA testing results [33]. In addition, clinicians administer the CMT Neuropathy Score/Examination Score version 2 (CMTNS/CMTES) [35] for adults, or the CMT Pediatric Score (CMT PedS) scale [36] for children. These are internationally validated scales and evaluate disability and impairment. Aims of the Registry are to collect information about: 1) epidemiology of CMT in Italy regarding the relative distribution of CMT subtypes, and the mutation frequency for the main CMT genes; 2) natural history course for the main CMT subtypes, as patients are asked to be evaluated every year. Important objectives are also to facilitate recruitment for forthcoming clinical trials and to assist the national and international networks of experts in the development of standard of diagnosis and care.

By June 2018, 721 CMT patients (mean age 46 years, range 5–88 years) had registered and chosen one of the nine reference centres; up to now clinical information has been entered in the Registry for 584 of them.

Registered patients had also the chance to participate in a linked study that required to fill in online self-reported questionnaires related to five important domains: disease course and complications during pregnancy; use, efficacy and tolerability of orthotics and assistive devices; outcome of surgery for skeletal deformities; safety of anaesthesia; occurrence of sleep disorders (including evaluation of fatigue, anxiety and depression). Control individuals also filled in online the questionnaires for pregnancy, anaesthesia, and sleep, and were recruited among friends and unaffected relatives of CMT participants, matched as much as possible for age and sex. By the end of the study (30 November 2017), 306 patients (161 females) and 66 relatives/friends (as healthy controls) had filled in the questionnaires. A huge amount of data have been collected, which will be very important for improving knowledge and giving advice to patients about pregnancy, orthotics, surgery, anaesthesia, sleep and fatigue in CMT, as well as for defining needs, disease burden and standards of care in CMT. Data analysis is under way.

The registry capitalized on the CMT experience for its development. International experts reached an agreement on the items to be collected during the 210th ENMC workshop [12, 37]. Like the CMT Registry, this is a dual registry. The plan is to register about 200 patients, implementing the network of Italian referral centres for SBMA and extending the collaboration to foreign centres of the SBMA European Consortium. The registry is designed to become the basis for an International Registry, being ready for other country to join it. Main scopes are: to test novel outcome measures such as the SBMA Functional Rating Scale (SBMAFRS) [38, 39] and (in selected cases) the quantitative muscle Magnetic Resonance Imaging (MRI) [40]; to perform a natural history study; to build and maintain an SBMA biorepository with collection of biological material; to help defining epidemiology of SBMA in Italy (all main centres that follow these patients are engaged in the registry); to prepare the pathway to clinical trials in Italy. The minimal dataset collects a series of information on comorbidities, current medication, participation to clinical trials, genetic data, family history, age at onset of symptoms, age of loss of fundamental activities of daily life milestones, a complete clinical evaluation, gynecomastia, erectile dysfunction, SBMAFRS, nerve conduction studies/electromyography, availability of biological material. At June 2018, 119 male patients have already registered (mean age 59 years, range 30–81 years), and clinical information has been entered for 91 of them.

The purpose of this registry is to collect uniform clinical and laboratory data of patients with MGSD. The Italian Registry is aligned with the international criteria on the molecular and clinical classification of individuals with MGSD [41, 42]. In fact, patients inclusion need to be sustained by appropriate clinical and laboratory clues as: 1) clinical features observed in the two main forms, namely a) “dynamic form” with exercise intolerance, contractures, hyperCKemia, rhabdomyolisis, myalgia, myoglobinuria and transient weakness and b) “fixed form” with progressive muscle weakness; 2) functional tests (forearm or exercise tests to evaluate lactic acid levels); 3) neurophysiological examinations, 4) neuroimaging features, 5) morphological aspects mainly from muscle biopsy (i.e., presence of vacuoles and/or glycogen accumulation); 6) biochemical findings (residual enzyme activity causing deficiency of glycolytic or glycogenolytic enzymes); 7) molecular genetic changes in the related genes.

By June 2018, 260 individuals (mean age 45 years, range 2–88 years) have been registered. Preliminary results of the clinical observations were disseminated in Italian (AIM; Italian Society of Neurology) and European (European Academy of Neurology) congresses by the Coordinator and some of the other clinicians involved in the registry.

The TTR-FAP Registry has been planned by tertiary clinical centres for peripheral neuropathies, most of which are also members of the Italian CMT network and reference centres for acquired and genetic amyloidosis according to the guidelines of the already active French TTR-FAP Network CORNAMYL [43, 44]. The rationale for developing this registry was based on preliminary results obtained by the Scientific Coordinator and partners indicating that Italy has a peculiar TTR variants geographical distribution with less than one fourth of the patients carrying the common Val30Met mutation with early and late onset cases [44‐46]. The only Italian epidemiological investigation of TTR-FAP highlighted a prevalence of 8.8/1,000,000 in Sicily, suggesting that Italy may be an endemic area and favouring the creation of the national registry [46].

This is a dual registry where patients register themselves and choose the centre where they want to be evaluated for the data collection. A collaborating academic centre was also included in the working group for the specific expertise on the psycho-social burden of patients with chronic diseases and their caregivers. Main aims are: to improve understanding of genotype-phenotype relationships, differences in disease presentation, diagnosis and course including inter- and intra-mutation variability; to identify most sensitive outcome measures in a one-year period; to collect information about quality of life, standards of care, psychosocial burden, professional support; to compare the Italian data with other European countries. The minimal dataset collects a series of information on demography, comorbidities, current medication, participation to clinical trials, genetic data, family history, symptoms at onset. The clinical data include neurological, autonomic and cardiologic evaluation, and neurophysiology, echocardiography, cardiac magnetic resonance imaging and scintigraphy. Asymptomatic carriers of TTR mutations are also enrolled in the registry.

At June 2018, 206 individuals have registered (148 symptomatic patients, mean age 62 years, range 29–90 years; 58 asymptomatic carriers, mean age 61 years, range 31–73 years). Other four Italian centres have recently asked to be involved in the registry and have obtained ethical approval by their respective IRBs.

A bias in the population selection may derive from a different exposure of patients and families to communication regarding the registry existence and scopes. Those who are regularly followed by centre of expertise or are members of the POs of interest are in general better informed. Moreover, given that POs typically direct families and patients towards their referring experts where possible, it is reasonable to expect that these patients are also followed according to the most updated standards of care, thus affecting the information on adopted standards of care that can be inferred from the registry.

Collecting medical information directly from patients has a number of advantages. First, it captures the direct experience of individuals with a specific condition, it offers a fresh perspective on the quality of life and needs, and engages the family in a responsible way, favouring empowerment and participation. Importantly, it can help reducing the burden on clinicians regarding the workload of data entry. This type of collection proved its usefulness to design clinical trials and helped patient recruitment into trials [6, 24, 25, 58] or, at least, promoted the identification of those that fulfilled the main criteria for a first screening (a clinical trial may have additional inclusion/exclusion criteria that are not identifiable through the registry). Nevertheless, the validity of patient-reported data is exposed to several risks that cannot be underestimated. First of all, the different participants may not uniformly record data and diagnoses. Although clinicians should not revise data inputted by patients [15], at least their validation of the genetic and clinical diagnosis should be ensured [60]. To this regard, if clinical data are required for purposes such as accurate natural history or post-marketing validation of a treatment, clinician-driven registries should be preferred. Another issue concerns patient retention. Filling in the registry forms and keeping data updated may not be a priority for affected individuals and their families or caregivers, especially when the health status of the patient worsens and the disease burden becomes high. Automatic reminders can favour the update of forms, but the support of the referring physician or the registry Curator can be very relevant to guarantee that the registry’s content is correctly updated.

Dual Registries have ambitious aims, which include defining a well-characterized and properly diagnosed patient population, not only for recruitment in clinical trials, but also for natural history studies, validation of outcome measures, creation of biorepositories, epidemiological analyses (if feasible) or surveys. They guarantee both direct input of patients in the registry and the collection of accurate and validated clinical data that are recorded in a systematic and scientifically sound manner and can be rapidly analysed. Of course, to fulfil the above scopes, data need to be validated and of high quality. In our experience, the organisation of training sessions on the functional scales used to record patients’ performance, the implementation of standards of care by the involved centers, as well as the regular monitoring and solicitation of data entry by the registry’s Curator, contribute to implement the databases with data of good quality. These registries may have limitations too, which depend on the nature of the registry itself and, for instance, on the rarity of the diseases and their related clinical and molecular heterogeneity. There may be enrolment biases due to several reasons. One, again, relates to the fact that registration is on a voluntary basis. Participation in the registry is often stimulated by POs or Patient Advocacy Groups linked to clinical study networks and clinicians; therefore, patients are more likely to register if they are already engaged in the patients’ community, and have instruments and contacts to become aware of the registry. In other cases, registration depends on clinical and genetic characteristics; the most severely affected patients are more likely to attend tertiary centers, which in turn are more often involved in registries. Clinicians also may be more prone to encourage registration of patients with genetically defined disorders as compared with those without a precise genetic diagnosis. Upcoming treatments specific for certain disease subgroups may also be a reason for asymmetrical recruitment. Therefore, how much the registry population corresponds to the real world, and how valid the epidemiological inferences are remain open questions. To address and overcome such selection biases is rather difficult. One way is to try to enlarge the registration pathways as much as possible, by clearly defining and disseminating the objectives through the involvement of clinicians in promoting the registry, dedicating time to carefully explain the Informed Consent document, obtaining the agreement and endorsement from the scientific societies, developing the Patient Advocacy Groups’ role and the potentialities of the web. When the registry concerns ultra-rare patients, such as in the case of the MGSD, registration supported by the clinicians themselves may be more effective than waiting for spontaneous registration by affected individuals or their families.

Mapping individuals living with an ultra-rare NMD condition may be even more effective when this occurs directly through an international registry [6, 61, 62]. This could be the case also for the SBMA registry and discussion is ongoing to verify how this can be achieved [12]. In this case, the Italian registry hosted on the NMD registry platform could become an important reference model. Opening the platform to international direct interaction may imply also that the registry structure is fully interoperable. Continuing efforts are ongoing to adopt common data elements and implement ontologies such as the Human Phenome Ontology [59] in line with the international standards and guidelines [58].

Theoretically, registries should define: how many patients they plan to recruit based on a sample size estimation in relation to the aims; how frequently patients should be re-assessed; for how long the registry should last; which statistical analyses will be applied. A registry’s steering committee should include statisticians to deal with such aspects. Plans should be in place for recruiting a reasonable number of patients in a predetermined timeframe for the purposes of the registry, and a statistical analysis plan should be defined right in the registry project design [15].

The aims of the registries currently on the NMD platform are mainly of a descriptive nature and did not require preliminary sample size estimations per se. However, the Steering Committees that planned each database assessed their feasibility by careful evaluation of the expected number of individuals that the national registry could likely map, depending on the disease rarity and the patients’ cohorts of each participating center. The design of the registries was therefore based also on this knowledge, in addition to the international consensus on standardised items.

A very critical point that affects the timeframe and population size that allows the registry reaching statistical significance is its funding. This is particularly true when data collection puts a high burden on clinicians, because data items are numerous and/or patient population is relatively wide. In some cases, registries started as observational studies, with the declared intention of long-term maintenance, update and reuse of data. However, when the initial funding support ends it becomes more and more difficult for clinicians to keep the pace with data recording and updates. In order to overcome this problem, clinicians are encouraged to include fund request for structural sustainability and dedicated personnel in any grant application that entails using the registry as a tool.

Finally, a current limitation of the NMD registry platform is that, being owned by a private entity, it cannot merge data with public healthcare databases. This is clearly an obstacle when one considers the clinical burden in managing medical data and the missed opportunity to share individual biomedical information, which could already be available and complementary to the clinical data collected by the registry. All legally feasible efforts should be put in place to verify the possibilities of matching data with other systems, such as the regional or national healthcare registries [15] or the new NMD European Reference Network initiative [63].