Evidence supporting regulatory-decision making on orphan medicinal products authorisation in Europe : methodological uncertainties
Pontes García, Caridad (Parc Taulí Hospital Universitari. Institut d'Investigació i Innovació Parc Taulí (I3PT))
Fontanet Sacristán, Juan Manuel (Institut d'Investigació Biomèdica Sant Pau)
Vives, Roser (Parc Taulí Hospital Universitari. Institut d'Investigació i Innovació Parc Taulí (I3PT))
Sancho López, Aranzazu (Instituto de Investigación Sanitaria Puerta de Hierro - Segovia de Arana)
Gómez-Valent, Mònica (Parc Taulí Hospital Universitari. Institut d'Investigació i Innovació Parc Taulí (I3PT))
Ríos, José (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Morros, Rosa (Institut Universitari d'Investigació en Atenció Primària Jordi Gol)
Martinalbo, Jorge (Universitat Autònoma de Barcelona. Departament de Farmacologia, de Terapèutica i de Toxicologia)
Posch, Martin (Medical University of Vienna)
Koch, Armin (Hannover Medical School)
Roes, Kit (University of Utrecht, Utrecht, The Netherlands)
Rengerink, Katrien Oude (University of Utrecht, Heidelberglaan, CX Utrecht, The Netherlands)
Torrent-Farnell, Josep (Institut d'Investigació Biomèdica Sant Pau)
Torres, Ferran (Institut d'Investigacions Biomèdiques August Pi i Sunyer)

Date:	2018
Abstract:	To assess uncertainty in regulatory decision-making for orphan medicinal products (OMP), a summary of the current basis for approval is required; a systematic grouping of medical conditions may be useful in summarizing information and issuing recommendations for practice. A grouping of medical conditions with similar characteristics regarding the potential applicability of methods and designs was created using a consensus approach. The 125 dossiers for authorised OMP published between 1999 and 2014 on the EMA webpage were grouped accordingly and data was extracted from European Public Assessment Reports (EPARs) to assess the extent and robustness of the pivotal evidence supporting regulatory decisions. 88% (110/125) of OMP authorizations were based on clinical trials, with 35% (38/110) including replicated pivotal trials. The mean (SD) number of pivotal trials per indication was 1. 4 (0. 7), and the EPARs included a median of three additional non-pivotal supportive studies. 10% of OMPs (13/125) were authorised despite only negative pivotal trials. One-third of trials (53/159) did not include a control arm, one-third (50/159) did not use randomisation, half the trials (75/159) were open-label and 75% (119/159) used intermediate or surrogate variables as the main outcome. Chronic progressive conditions led by multiple system/organs, conditions with single acute episodes and progressive conditions led by one organ/system were the groups where the evidence deviated most from conventional standards. Conditions with recurrent acute episodes had the most robust datasets. The overall size of the exposed population at the time of authorisation of OMP - mean(SD) 190. 5 (202. 5) - was lower than that required for the qualification of clinically-relevant adverse reactions. The regulatory evidence supporting OMP authorization showed substantial uncertainties, including weak protection against errors, substantial use of designs unsuited for conclusions on causality, use of intermediate variables, lack of a priorism and insufficient safety data to quantify risks of relevant magnitude. Grouping medical conditions based on clinical features and their methodological requirements may facilitate specific methodological and regulatory recommendations for the study of OMP to strengthen the evidence base. The online version of this article (10. 1186/s13023-018-0926-z) contains supplementary material, which is available to authorized users.
Grants:	European Commission 603160
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Orphan drug production ; Rare diseases ; Research design/methods ; Research design/standards ; Clinical trials as topic ; Drug approval
Published in:	Orphanet journal of rare diseases, Vol. 13 (november 2018) , ISSN 1750-1172

DOI: 10.1186/s13023-018-0926-z
PMID: 30442155

15 p, 807.5 KB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Parc Taulí Research and Innovation Institute (I3PT
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Recerca Sant Pau
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Articles > Published articles