Survey by TEDDY European Network of Excellence for Paediatric Clinical Research demonstrates potential for Europe-wide trials.

AIM: The European Network of Excellence for Paediatric Clinical Research, known as the TEDDY Network, carried out a survey to determine the capacity and competence of paediatric centres to perform research studies. METHODS: A cross-sectional, web-based pilot survey was conducted from October 2016 to April 2017 with paediatric clinical research centres in 11 countries: Albania, Austria, Belgium, Denmark, Iceland, Ireland, Italy, Norway, Spain, Switzerland and the United Kingdom. All were registered with the TEDDY Network database. RESULTS: We approached 107 centres and 63 provided data on their experiences and expertise in paediatric clinical trials. Four groups of performance indicators were identified, referring to scientific experience, trial readiness, trial competence, regulatory issues, ethics and patients. Most centres were actively involved in paediatric clinical research: 53 centres (84.1%) had received funds for more than five paediatric studies in the last 5 years, and 42 (66.7%) had a specific clinical trial unit and dedicated study coordinators. We concluded that the European centres we studied had the capability and capacity to conduct paediatric trials, but there was still room for improvement, including enhanced collaboration. CONCLUSION: This pilot survey demonstrated that there is potential for performing paediatric trials across Europe, but improvements are possible.

The ethical framework for performing research with rare inherited neurometabolic disease patients.

The need for performing clinical trials to develop well-studied and appropriate medicines for inherited neurometabolic disease patients faces ethical concerns mainly raising from four aspects: the diseases are rare; include young and very young patients; the neurological impairment may compromise the capability to provide 'consent'; and the genetic nature of the disease leads to further ethical implications. This work is intended to identify the ethical provisions applicable to clinical research involving these patients and to evaluate if these cover the ethical issues. Three searches have been performed on the European regulatory/legal framework, the literature and European Union-funded projects. The European legal framework offers a number of ethical provisions ruling the clinical research on paediatric, rare, inherited diseases with neurological symptoms. In the literature, relevant publications deal with informed consent, newborn genetic screenings, gene therapy and rights/interests of research participants. Additional information raised from European projects on sharing patients' data from different countries, the need to fill the gap of the regulatory framework and to improve information to stakeholders and patients/families. CONCLUSION: Several recommendations and guidelines on ethical aspects are applicable to the inherited neurometabolic disease research in Europe, even though they suffer from the lack of a common ethical approach. What is Known: • When planning and conducting clinical trials, sponsors and researchers know that clinical trials are to be performed according to well-established ethical rules, and patients should be aware about their rights. • In the cases of paediatric patients, vulnerable patients unable to provide consent, genetic diseases' further rules apply. What is New: • This work discusses which ethical rules apply to ensure protection of patient's rights if all the above-mentioned features coexist. • This work shows available data and information on how these rules have been applied.

Paediatric clinical research in Europe: an insight on experts' needs and perspectives.

PedCRIN is a Horizon 2020 project aimed to develop a paediatric component of ECRIN (European Clinical Research Infrastructure Network) including tools supporting the conduct of neonatal and paediatric trials. A structured, cross-sectional, closed-ended questionnaire was electronically administered from April to May 2017 to stakeholders involved in paediatric clinical research to capture their needs to receive infrastructural support to cover specific research gaps. The questionnaire included 6 headings and 29 subheadings. Each item was evaluated using a Likert-scale. 147 questionnaires were returned (response rate of 24.6%). The application of innovative study design and the preparation of protocols for paediatric interventional clinical trials had the highest frequency of high need for support (123 and 117 respondents, respectively). Similarly, the identification and applications to relevant calls for funding was acknowledged as an area in which support is needed (123 respondents declaring high need). In 14 out of 29 activities, need for support was significantly higher in the respondents not being part of a Paediatric Research Network or Consortium (especially for regulatory expertise, pharmacovigilance and GCP training). Conclusions: These results document that the achievement of PedCRIN objectives would greatly advantage the paediatric research community.

The Italian multiregional thalassemia registry: Centers characteristics, services, and patients' population.

OBJECTIVES: The prognosis of beta-Thalassemia major and other congenital hemoglobinopathies has profoundly changed over the last decades. Moreover, only few countries in Europe provide dedicated services and the description of the measures for patients monitoring and treatment is overall very scarce. The HTA-Thal project is aimed to identify the services available in Italy and to collect epidemiological and clinical data on the thalassemic population (HTA-Thal Registry). METHODS: A map of the existing centers was created and two electronic questionnaires were completed with information on the services and patients. RESULTS: On 182 centers identified, 60 completed the two questionnaires. Centers resulted to be extremely heterogeneous in terms of size, age of patients in care, and services availability. The transition of pediatric patients to adult centers was not guaranteed. Thousand eight hundred and seventy-three beta-Thalassemia major patients (of which 259 pediatrics), regularly transfused, were registered. Deferasirox is the most used chelator as monotherapy (616 patients) and its use prevails in younger patients. A higher number of patients (847 patients) use Deferoxamine, either alone (448 patients) or in combination with DFP (399 patients), while 782 patients use Deferiprone alone (383 patients) or in combination (399 patients). 31.6 and 66.6% of centers were not equipped for specialized visits or local MRI, respectively. Centers with 30-80 patients show the high percentage of patients appropriately monitored when compared to smaller or bigger centers. CONCLUSIONS: This analysis confirms the importance of patients' registries for the collection of large datasets and the need for dedicated 'specialized centers' equipped to provide the best standard treatment to patients.

Review and evaluation of the methodological quality of the existing guidelines and recommendations for inherited neurometabolic disorders.

BACKGROUND: Inherited neurometabolic disorders (iNMDs) represent a group of almost seven hundred rare diseases whose common manifestations are clinical neurologic or cognitive symptoms that can appear at any time, in the first months/years of age or even later in adulthood. Early diagnosis and timely treatments are often pivotal for the favorable course of the disease. Thus, the elaboration of new evidence-based recommendations for iNMD diagnosis and management is increasingly requested by health care professionals and patients, even though the methodological quality of existing guidelines is largely unclear. InNerMeD-I-Network is the first European network on iNMDs that was created with the aim of sharing and increasing validated information about diagnosis and management of neurometabolic disorders. One of the goals of the project was to determine the number and the methodological quality of existing guidelines and recommendations for iNMDs. METHODS: We performed a systematic search on PubMed, the National Guideline Clearinghouse (NGC), the Guidelines International Network (G-I-N), the Scottish Intercollegiate Guideline Network (SIGN) and the National Institute for Health and Care Excellence (NICE) to identify all the published guidelines and recommendations for iNMDs from January 2000 to June 2015. The methodological quality of the selected documents was determined using the AGREE II instrument, an appraisal tool composed of 6 domains covering 23 key items. RESULTS: A total of 55 records met the inclusion criteria, 11 % were about groups of disorders, whereas the majority encompassed only one disorder. Lysosomal disorders, and in particular Fabry, Gaucher disease and mucopolysaccharidoses where the most studied. The overall methodological quality of the recommendation was acceptable and increased over time, with 25 % of the identified guidelines strongly recommended by the appraisers, 64 % recommended, and 11 % not recommended. However, heterogeneity in the obtained scores for each domain was observed among documents covering different groups of disorders and some domains like 'stakeholder involvement' and 'applicability' were generally scarcely addressed. CONCLUSIONS: Greater efforts should be devoted to improve the methodological quality of guidelines and recommendations for iNMDs and AGREE II instrument seems advisable for new guideline development. The elaboration of new guidelines encompassing still uncovered disorders is badly needed.

The management of iron chelation therapy: preliminary data from a national registry of thalassaemic patients.

Thalassaemia and other haemoglobinopathies constitute an important health problem in Mediterranean countries, placing a tremendous emotional, psychological, and economic burden on their National Health systems. The development of new chelators in the most recent years had a major impact on the treatment of thalassaemia and on the quality of life of thalassaemic patients. A new initiative was promoted by the Italian Ministry of Health, establishing a Registry for thalassaemic patients to serve as a tool for the development of cost-effective diagnostic and therapeutic approaches and for the definition of guidelines supporting the most appropriate management of the iron-chelating therapy and a correct use of the available iron-chelating agents. This study represents the analysis of the preliminary data collected for the evaluation of current status of the iron chelation practice in the Italian thalassaemic population and describes how therapeutic interventions can widely differ in the different patients' age groups.