title: The ethical framework for performing research with rare inherited neurometabolic disease patients.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Fondazione Per la Ricerca Farmacologica Gianni Benzi Onlus, Via Abate Eustasio 30, 70010, Valenzano, BA, Italy. vg@benzifoundation.org.
authors.forename: Viviana
authors.identifier: http://orcid.org/0000-0002-2534-6783
authors.initials: V
authors.lastname: Giannuzzi
authors.affiliation: Department of Development and Regeneration, University of Leuven, O&N IV Herestraat 49-box 805, 3000, Leuven, Belgium.
authors.forename: Hugo
authors.initials: H
authors.lastname: Devlieger
authors.affiliation: Department of Basic Medical Sciences, Neuroscience and Sense Organs, "Aldo Moro" University of Bari, Piazza Giulio Cesare 11, 70124, Bari, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Margari
authors.affiliation: Department of Obstetrics and Gynaecology, Uppsala Universitet, 751 85, Uppsala, SE, Sweden.
authors.forename: Viveca Lena
authors.initials: VL
authors.lastname: Odlind
authors.affiliation: Cairo University, Al Orman Guiza, Giza, 12613, Egypt.
authors.forename: Lamis
authors.initials: L
authors.lastname: Ragab
authors.affiliation: Brains for Brain Foundation - onlus, Padova, Italy.
authors.forename: Cinzia Maria
authors.initials: CM
authors.lastname: Bellettato
authors.affiliation: Brains for Brain Foundation - onlus, Padova, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: D'Avanzo
authors.affiliation: Brains for Brain Foundation - onlus, Padova, Italy.|Department of Pediatric and Adolescent Medicine, Centre for Rare Diseases, Horst Schmidt Klinik Wiesbaden, Wiesbaden, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Lampe
authors.affiliation: Neurology, Gastroenterology Pathology and Clinical Biochemistry Departments, IRP-HSJD and CIBERER, Barcelona, Spain.
authors.forename: Linda
authors.initials: L
authors.lastname: Cassis
authors.affiliation: Neurology, Gastroenterology Pathology and Clinical Biochemistry Departments, IRP-HSJD and CIBERER, Barcelona, Spain.
authors.forename: Elisenda
authors.initials: E
authors.lastname: Cortès-Saladelafont
authors.affiliation: Neurology, Gastroenterology Pathology and Clinical Biochemistry Departments, IRP-HSJD and CIBERER, Barcelona, Spain.
authors.forename: Ángels Garcia
authors.initials: ÁG
authors.lastname: Cazorla
authors.affiliation: University Hospital Centre Zagreb, Zagreb, Croatia.|School of Medicine, University of Zagreb, Zagreb, Croatia.
authors.forename: Ivo
authors.initials: I
authors.lastname: Barić
authors.affiliation: School of Medicine, University of Zagreb, Zagreb, Croatia.
authors.forename: Ljerka
authors.initials: L
authors.lastname: Cvitanović-Šojat
authors.affiliation: University Hospital Centre Zagreb, Zagreb, Croatia.
authors.forename: Ksenija
authors.initials: K
authors.lastname: Fumić
authors.affiliation: Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Christine I
authors.initials: CI
authors.lastname: Dali
authors.affiliation: Fondazione Per la Ricerca Farmacologica Gianni Benzi Onlus, Via Abate Eustasio 30, 70010, Valenzano, BA, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Bartoloni
authors.affiliation: Fondazione Per la Ricerca Farmacologica Gianni Benzi Onlus, Via Abate Eustasio 30, 70010, Valenzano, BA, Italy.
authors.forename: Fedele
authors.initials: F
authors.lastname: Bonifazi
authors.affiliation: Brains for Brain Foundation - onlus, Padova, Italy.|Department of Pediatric and Adolescent Medicine, Centre for Rare Diseases, Horst Schmidt Klinik Wiesbaden, Wiesbaden, Germany.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Scarpa
authors.affiliation: Fondazione Per la Ricerca Farmacologica Gianni Benzi Onlus, Via Abate Eustasio 30, 70010, Valenzano, BA, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Ceci
mesh_terms: D035843:Biomedical Research / Q000941:ethics*; D002648:Child; D002986:Clinical Trials as Topic / Q000941:ethics*; D005060:Europe; D005062:European Union; D006801:Humans; D007258:Informed Consent / Q000331:legislation & jurisprudence*; D008659:Metabolic Diseases; D009422:Nervous System Diseases; D035583:Rare Diseases
keywords: Clinical research; Ethics; Genetic disease; Paediatric; Rare