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.

BackgroundThe ASTERIX project developed a number of novel methods suited to study small populations. The objective of this exercise was to evaluate the applicability and added value of novel methods to improve drug development in small populations, using real world drug development programmes as reported in European Public Assessment Reports.MethodsThe applicability and added value of thirteen novel methods developed within ASTERIX were evaluated using data from 26 European Public Assessment Reports (EPARs) for orphan medicinal products, representative of rare medical conditions as predefined through six clusters. The novel methods included were ‘innovative trial designs’ (six methods), ‘level of evidence’ (one method), ‘study endpoints and statistical analysis’ (four methods), and ‘meta-analysis’ (two methods) and they were selected from the methods developed within ASTERIX based on their novelty; methods that discussed already available and applied strategies were not included for the purpose of this validation exercise. Pre-requisites for application in a study were systematized for each method, and for each main study in the selected EPARs it was assessed if all pre-requisites were met. This direct applicability using the actual study design was firstly assessed. Secondary, applicability and added value were explored allowing changes to study objectives and design, but without deviating from the context of the drug development plan. We evaluated whether differences in applicability and added value could be observed between the six predefined condition clusters.Results and discussionDirect applicability of novel methods appeared to be limited to specific selected cases. The applicability and added value of novel methods increased substantially when changes to the study setting within the context of drug development were allowed. In this setting, novel methods for extrapolation, sample size re-assessment, multi-armed trials, optimal sequential design for small sample sizes, Bayesian sample size re-estimation, dynamic borrowing through power priors and fall-back tests for co-primary endpoints showed most promise - applicable in more than 40% of evaluated EPARs in all clusters. Most of the novel methods were applicable to conditions in the cluster of chronic and progressive conditions, involving multiple systems/organs. Relatively fewer methods were applicable to acute conditions with single episodes. For the chronic clusters, Goal Attainment Scaling was found to be particularly applicable as opposed to other (non-chronic) clusters.ConclusionNovel methods as developed in ASTERIX can improve drug development programs. Achieving optimal added value of these novel methods often requires consideration of the entire drug development program, rather than reconsideration of methods for a specific trial. The novel methods tested were mostly applicable in chronic conditions, and acute conditions with recurrent episodes.Electronic supplementary materialThe online version of this article (10.1186/s13023-018-0925-0) contains...

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.

August 2015 e11−3.5 to 11.7; 26.8; CI, 17.6 to 36.8, respectively), a subjective visual analogue scale for alertness (−1.3; CI, −3.7 to 1.2; −2.5; CI, −4.8 to −0.2; −5.3; CI, −7.7 to −2.9, respectively) and saccadic peak velocity CI, 33.5 to 4.8;; CI, −29.0 to 7.1; −25.4 (CI, −44.2 to −6.6, respectively), a marker for sedation. Mecamylamine was well tolerated and had linear pharmacokinetics over the dose range tested. Conclusion: The pharmacological challenge model with mecamylamine 20 mg in healthy subjects leads to a reproducible pattern of cognitive disturbance that is nicotinic receptor specific. This model may be more suitable for proof of pharmacology and dose finding studies of nicotinic receptor agonists than the frequently used scopolamine model. Background: Vitamin K antagonists (VKA) are a major iatrogenic cause of haemorrhage and hospital admissions, but the incidence of bleeding during VKA exposure for atrial fibrillation (AF), as well as ischemic event, is not well established in real life and before introduction of direct oral anticoagulants (DOAC) for non-valvular AF (NVAF). Material and Methods: Cohort study of new VKA users between 2007 and 2011, with 2-year history and 3-year follow-up censored at end of 2012, was designed in the EGB, a 1/97 random sample of the French national health care claims and hospitalization database.The AF population was defined as patients with full coverage for AF, hospitalization, or probabilistic AF information in the database and the NVAF population as patients with AF diagnosis information (full coverage, hospitalization), without valvular disease history or other probable cause of VKA prescription. Outcomes were the first hospitalization for bleeding, arterial thrombotic event (ATE), acute coronary syndrome (ACS), and death. Incidence rate of outcomes was estimated during VKA exposure. Results: Among 8894 patients identified, 3530 were classified in AF population. Half were male (51%) with a mean age of 75 years, 87% had a CHA 2 DS 2 -VASc score ≥ 2, and 12% a HAS-BLED score > 3. The incidence rate of bleeding was 29 patients (95% CI, 24-34) for 1000 PY exposed to VKA, including 6 (95% CI, 4-8) cerebral, 10 (95% CI, 7-13) digestive, and 14 (95% CI, 10-17) other bleeds. Incidence rates were 16 (95% CI, 12-19) for ACS, 14 (95% CI, 11-18) for ATE, and 39 (95% CI, 33-45) deaths. Patient characteristics and incidence rates were very close for the 1 813 patients with NVAF population criteria. For this last population, incidence rates were 29 (95% CI, 23-34) for bleeding, 15 (95% CI, 11-19) for ACS, 14 (95% CI, 10-18) for ATE, and 37 (95% CI, 31-43) deaths. Conclusions:This study provides background reference for bleeding, ischemic events, and deaths before introduction of DOAC for NVAF with quite same frequency for AF and NVAF populations.