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BackgroundTo 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.MethodsA 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.Results88% (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.ConclusionsThe 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.Electronic supplementary materialThe online version of this article (10.1186/s13023-018-0926-z) contains supplementary material, which is available to authorized users.

The internal systems for quality assure are being introduced in the health care environment, and especially in hospitals. The Clinical Pharmacology Service (CPS) at a University Hospital has implemented a quality management system, consistently with ISO 9001:2008 requirements and subjected to external audits by AENOR. The CPS defined 6 processes representing its activity in the hospital, and within each of those processes defined a number of indicators of the performance and its quality (process/n indicators): Clinical consultations (6), Safety of medicines and pharmacovigilance (7), Therapeutic Drug Monitoring (3), Policy and medicines selection (5), Clinical trials (4) and Clinical research (2). Three of the indicators were satisfaction surveys. The implantation period lasted 10 months. In a first phase (4 months), the design and documentation of the processes were developed; 24 procedures, 9 work instructions and 67 forms (or records) were documented and incorporated into the management system. In a second phase (6 months) the system was implemented. The internal and the external audits valued the performance and gave the higher standards to the CPS. The certification improved the activity of the CPS by using a structured process, analyzing the results, and introducing improvements. Furthermore the activity of the CPS was clearly visible for the rest of the Hospital and especially for the head physician team. The extra bureaucratic work pays off for the results obtained.

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