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Article History

Received: 16 January 2018

Accepted: 29 August 2018

First Online: 10 September 2018

Ethics approval and consent to participate

: All patients (or their legal representatives) provided written informed consent before enrolling in the TOSCA disease registry. The study was designed, implemented, and reported in accordance with the principles of Good Clinical Practice, Good Pharmacoepidemiology Practices of the International Society for Pharmacoepidemiology (ISPE 2008), the STROBE (Strengthening and Reporting of Observational Studies in Epidemiology) guidelines, and the ethical principles laid down in the Declaration of Helsinki, and all local regulations. The study protocol and all amendments were reviewed and approved (if applicable) by independent ethics committee/institutional review board for each center: National Hospital Organization Central Ethics Committee; Gazi University Clinical Research Ethics Committee; Independent Multidisciplinary Committee on Ethical Review of Clinical Trials; Peking Union Medical College Hospital; Commissie Medische Ethiek UZ Brussel; CNIL (Commission National de l’Informatique et des Libertés), CCTIRS (Comité Consultatif sur le traitement de l’information en matière de recherche dans le domaine de la santé); Comité Etico Investigación Clínica de Euskadi (CEIC-E); Consejeria de Salud y Bienestar Social, Dirección General de Calidad, Investigación, Desarrollo e Innovación, Comité Coordinador de Ética de la Investigación Biomédica de Andalucía; Research Ethics Committee of the University of Tartu (UT REC); Ethikkommission der Medizinischen Universität Graz; North Wales REC – West; Regionala Etikprövningsnämnden i Göteborg; REK – Regionale komiteer for medisinsk og helsefaglig forskningsetikk; Komisja Bioetyczna przy Instytucie “Pomnik Centrum Zdrowia Dziecka”; Ethikkommission bei der Ludwig-Maximilians-Universitat München; Hokkaido University Hospital Independent clinical research Institutional Ethics Committee; Medical Juntendo University Institutional Ethics Committee; National Center for Chile Health and Deveropment of IRB; Osaka University Hospital of IRB; Ethics Committee at Moscow Institute of Pediatrics and Pediatric Surgery; Peking University First Hospital; Sanbo Brain Hospital Capital Medical University; Tianjin Children’s Hospital; Childrens Hospital Of Fudan University; Zhongshan Hospital Fudan University; Fudan University Shanghai Cancer Center; The Second Affiliated Hospital of Guangzhou Medical University; The First Affiliated Hospital, Sun Yan-Sen University; The First Affiliated Hospital Of Guangzhou Medical University; Shenzhen Children’s Hospital; West China Hospital, Sichuan University; Xijing Hospital; Children’s Hospital of Chongqing Medical University; Wuhan Children’s Hospital; The second affiliated hospital of Xi’an jiaotong university; Guangdong 999 brain hospital; Seoul National University Hospital Institutional Review Board; National Taiwan University Hospital (NTUH) Research Ethics Committee (REC); Institutional Review Board of the Taichung Veterans General Hospital; Institutional Review Board of Chung Shan Medical University Hospital; Institutional Review Board, Tungs’ Taichung MetroHarbor Hospital; Institutional Review Board of National Cheng Kung University Hospital; Metro South Human Research Ethics Committee; Sydney Children’s Hospital Network Human Research Ethics Committee; St Vincents Hospital Human Research Ethics Committee; Royal Melbourne Hospital Human Research Ethics Committee; Siriraj Institutional Review Board; The Institutional Review board, Faculty of Medicine, Chulalongkorn University, 3rd Floor, Ananthamahidol Building, King Chulalongkorn Memorial Hospital; The committee on Human Rights Related to Research Involving Human Subjects; Institutional Review board, Royal Thai Army Medical Department IRB RTA, 5th Floor, Phramongkutklaowejvitya Building, Phramongkutklao College of Medicine; Research Ethics Committee, Faculty of Medicine, Chiang Mai University; Research and Development, Queen Sirikit National Institute of Child Health; Human Research Ethics Committee, Faculty of Health Sciences, University of Cape Town; Shaare Zedek Meidcla center Helsinki comittee; Sheba Medical center Helsinki comittee; Tel Aviv Sourasly Medical center Helsinki comittee; General University Hospital of Patras Ethics Committee; Pendeli Children’s Hospital Ethics Committee; General University Hospital of Athens “G. Gennimatas” Ethics Committee; Evaggelismos General Hospital Ethics Committee; General University Hospital of Thessaloniki “AHEPA” Ethics Committee; General University Hospital of Ionnina Ethics Committee; METC UMC Utrecht; Direcció General de Regulació, Planificació i Recursos Sanitaris; Comité Ético de Investigación Clínica del Hospital Universitario Vall d’Hebron de Barcelona, Generalitat de Catalunya.Departament de Salut; Comité Ético de Investigación Clínica Hospital Universitario La Paz; Dirección General de Ordenación e Inspección, Consejería de Sanidad Comunidad de Madrid, Servicios de Control Farmacéutico y Productos Sanitarios; Comité Etico Investigación Clínica del Hospital Universitario y Politécnico de La Fe; Dirección General de Farmàcia i Productes Sanitaris, Generalitat de Valencia; Comité de Ética de la Investigación de Centro de Granada; Instituto Aragonés de Ciencias de la Salud (IACS);; Comité Etico Investigación Clínica Regional del Principado de Asturias;; Comité Etico Investigación Clínica Hospital 12 de Octubre;, Comité Etico Investigación Clínica Hospital Universitario Virgen de la Arrixaca;; Sección de Ordenación e Inspección Farmacéutica Departamento de Salud; Comité Ético de Investigación Clínica del Hospital Universitario del Río Hortega de Valladolid;, Comissão de Ética para a Saúde (CES), Centro Hospitalar de Lisboa Ocidental, EPE; Comissão de Ética para a Saúde (CES), Centro Hospitalar do Porto, E.P.E; Comissão de Ética para a Saúde (CES), Centro Hospitalar Lisboa Central, EPE; Comissão de Ética para a Saúde (CES), Hospital Garcia de Orta, EPE; Comissão de Ética para a Saúde (CES), Centro Hospitalar de São João, EPE; Comissão de Ética para a Saúde (CES), Hospital Professor Doutor Fernando Fonseca, EPE; Comissão de Ética para a Saúde (CES), Centro Hospitalar do Algarve, EPE (Unidade de Faro); LUHS Kaunas Regional Biomedical Research Ethics Committee; Paula Stradiņa klīniskās universitātes slimnīcas, Attīstības biedrības Klīniskās izpētes Ētikas komiteja, Ethics Committee for Clinical Research; Komisija Republike Slovenije za medicinsko etiko; Comitato Etico Indipendente Presso La Fondazione Ptv Policlinico Tor Vergata Di Roma; Comitato Etico Regione Calabria Sezione Centro c/o A.O.U. Mater Domini Di Catanzaro; Comitato Etico Azienda Ospedaliera Universitaria Di Cagliari; Comitato Etico Cardarelli-Santobono c/o Ao Cardarelli; Comitato Etico Per La Sperimentazione Clinica Delle Province Di Verona E Rovigo, Presso Aoui Verona; Eticka Komise Fn Brno; Eticka Komisia Dfnsp Bratislava; Eticka Komisia Pri Dfn Kosice; Eticka Komisia Bratislavskeho Samospravneho Kraja; Comisia Națională de Bioetică a Medicamentului și a Dispozitivelor Medicale; Comitato Etico Milano area 1 c/o ASST FBF Sacco - P.O. L. Sacco; Comité de Ética de la Investigación de Centro Hospital Universitario Virgen del Rocío; Comité Ético de Investigación Clínica Fundació Sant Joan de Déu Generalitat de Catalunya. Departament de Salut; Comité Ético de Investigación Clínica Hospital Infantil Universitario Niño Jesús; Consejería de Sanidad Dirección General de Salus Pública Junta de Castilla León; Dirección General de Asistencia Sanitaria, Consejería de Sanidad Gobierno del Principado de Asturias; Dirección General de Planificación, Ordenación Sanitaria y Farmacéutica e Investigación, Consejeria de Sanidad y Política Social Región de Murcia; Ethics Committee at Moscow Institute of Pediatrics and Pediatric Surgery; Paula Stradiņa klīniskās universitātes slimnīcas, Attīstības biedrības Klīniskās izpētes Ētikas komiteja, Ethics Committee for Clinical Research; The First Affiliated Hospital of The Fourth Military Medical University; Zhongshan hospital fudan university.

: All patients were informed that the reason for enrolling in the study was to collect natural history data for scientific analysis and publication (an obligation mandated by the Good Clinical Practice guidelines) and they signed consent forms with that understanding.

: P.J.dV., E.B., T.C., V.C., P.C., G.B.d’A., J.C.K., J.C.F., M.F., C.F., C.H., S.J., R.N., F.O’C, J.Q., M.S., R.T., M.D., J.A.L., A.M., S.Y., M.P.B., B.Z. and A.C.J. received honoraria and support for the travels from Novartis. V.C. received personal fees for consulting, lecture fees and travel from Actelion, Bayer, Biogen Idec, Boehringer Ingelheim, Gilead, GSK, MSD, Novartis, Pfizer, Roche, Sanofi; grants from Actelion, Boehringer Ingelheim, GSK, Pfizer, Roche; personal fees for developing educational material from Boehringer Ingelheim and Roche. P.J.dV. has been on the study steering group of the EXIST-1, 2 and 3 studies sponsored by Novartis, and co-PI on two investigator-initiated studies part-funded by Novartis. RN received grant support, paid to her institution, from Eisai and lectures fees from Nutricia, Eisai, Advicenne and GW Pharma. Y.T. received personal fee from Novartis for lecture and for copyright of referential figures from the journals, and received grant from Japanese government for intractable epilepsy research. S.J. was partly financed by the EC Seventh Framework Programme (FP7/2007–2013; EPISTOP, grant agreement no. 602391), the Polish Ministerial funds for science (years 2013–2018) for the implementation of international cofinanced project and the grant EPIMARKER of the Polish National Center for Research and Development No STRATEGMED3/306306/4/2016. J.C.K., P.C., C.H., J.A.L., and J.Q. received research grant from Novartis. R.M., L.D’A. and S.S. are employees of Novartis. V.S. reported no competing interest. This study was funded by Novartis Pharma AG. All authors approved the final version of the manuscript prior to submission.

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