An orphan disease is defined in the EU as a disorder affecting less than 1 in 2 000 individuals. The concept of ultra-orphan has been proposed for diseases with a prevalence of less than 1:50 000. Drugs for ultra-orphan diseases are amongst the most expensive medicines on a cost-per-patient basis. The extremely high prices have prompted initiatives to evaluate cost-effectiveness and cost-utility in EU-member states. The objective of this review was to evaluate the quality of cost-effectiveness and cost-utility studies on ultra-orphan drugs. We searched 2 databases and the reference lists of relevant systematic reviews. Studies reporting on full economic evaluations, or at least aiming at such evaluation, were eligible for inclusion. Quality was assessed with the use of the Consensus on Health Economic Criteria (CHEC)-list. Two-hundred-fifty-one studies were identified. Of these, 16 fitted our inclusion criteria. A study on enzyme replacement and substrate reduction therapies for lysosomal storage disorders did not perform a full economic evaluation due to the high drug costs and the lack of a measurable effect on either clinical or health-related quality of life outcomes. Likewise, a cost-effectiveness analysis of laronidase for mucopolysaccharidosis type 1 was considered unfeasible due to lack of clinical effectiveness data, while in the same study a crude model was used to estimate cost-utility of enzyme replacement therapy (ERT) for Fabry disease. Three additional studies, one on ERT for Fabry disease, one on ERT for Gaucher disease and one on eculizumab for paroxysmal nocturnal haemoglobinuria, used an approach that was too simplistic to lead to a realistic estimate of the incremental cost-effectiveness (ICER) or cost-utility ratio (ICUR). In all other studies (N = 11) more sophisticated pharmacoeconomic models were used to estimate cost-effectiveness and cost-utility of the specific drug, mostly ERT or drugs indicated for pulmonary arterial hypertension (PAH). Seven studies used a Markov-state-transition model. Other models used were patient-level simulation models (N = 3) and decision trees (N = 1). Only 4 studies adopted a societal perspective. All but 2 studies discounted costs and effects appropriately. Drugs for metabolic diseases appeared to be significantly less cost-effective than drugs indicated for PAH, with ICERs ranging from €43 532 (Gaucher disease) to €3 282 252 (Fabry disease). Quality of studies using a Markov-state-transition or patient-level simulation model is in general good with 14–19 points on the CHEC-list. We therefore conclude that economic evaluations of ultra-orphan drugs are feasible if pharmacoeconomic modelling is used. Considering the need for modelling of several disease states and the small patient groups, a Markov-state-transition model seems to be most suitable type of model. However, it should be realised that ultra-orphan drugs will usually not meet the conventional criteria for cost-effectiveness. Nevertheless, ultra-orphan drugs are often reimbursed. Further discussion...

BackgroundNeuropathic pain is one of the key features of (classical) Fabry disease (FD). No randomized clinical trials comparing effectiveness of different pain management strategies have been performed. This review aims to give an overview of existing pain management strategies.MethodsPubMed and Embase were searched up to September 2014 for relevant articles on treatment of neuropathic pain in FD.ResultsSeven-hundred-thirty-one articles were identified of which 26 were included in the analysis. Studies reported on 55 individuals in total, with group-sizes ranging from 1 to 8. Carbamazepine appeared most beneficial: complete pain relief in 5/25, partial relief in 17/25, and no benefit in 3/25 patients. Phenytoin resulted in complete relief in 1/27, partial relief in 12/27 and no benefit in 6/27 patients. In 8 patients a significant reduction in the frequency of pain attacks was described. Gabapentin caused partial relief in 6/7 and no relief in 1/7 patients. Little evidence was reported for SSNRI’s or treatment combinations. Adverse-effects were reported in all treatment strategies.ConclusionsOnly for carbamazepine, phenytoin and gabapentin there is evidence of effectiveness in neuropathic pain due to FD, but comparison of effectiveness between these drugs is lacking. In routine clinical practice adverse-effects may discourage use of carbamazepine and phenytoin in favor of second-generation antiepileptic drugs, but this is currently not supported by clinical evidence. This review suffers greatly from incomplete outcome reports and a predominance of case reports, which emphasizes the need for robust clinical trials and observational cohort studies.

The currently used systemic treatments for GEP-NET patients had low scores according to the NHB-ASCO-F and none could be graded as meaningful clinical beneficial according to the ESMO-MCBS. Despite the low incidence, the heterogeneous patient population and relatively long natural course of NET, future studies on new treatment modalities should aim for high clinical benefit outcomes.

IntroductionAuthorization of orphan medicinal products (OMPs) is often based on studies with several methodological shortcomings. Hence, data are difficult to interpret and efficacy does not always correspond to real-world effectiveness. We investigated to what extent an efficacy-effectiveness gap exists for OMPs for metabolic diseases and set out to explore which factors contribute to it.MethodsWe included all OMPs for rare metabolic diseases authorized in the EU up to 1 January 2016. Efficacy data were obtained from European Public Assessment Reports, relative effectiveness data from the Dutch National Healthcare Institute website, and real-world effectiveness data from literature and interviews with experts and patients. Efficacy and effectiveness were scored as ‘no effect’, ‘unclear’ or ‘good’ based upon a prespecified scoring system.ResultsWe identified 31 authorized OMPs, of which 21 had post-marketing studies available, thus making it possible to score real-world effectiveness. Eight of 21 (38%) OMPs had a ‘good’ real-world effectiveness. The use of a clinical or validated surrogate primary endpoint and a representative study population seemed to be related to good effectiveness in the real world, as were type of marketing authorization, study population and disease prevalence.ConclusionsThis study revealed that less than half of the authorized OMPs are effective in the real world. Since the type of primary endpoint used in the pivotal study seems to be associated with good real-world effectiveness, it is important to agree upon study endpoints through early dialogues among relevant stakeholders.Electronic supplementary materialThe online version of this article (doi:10.1007/s40265-017-0788-z) contains supplementary material, which is available to authorized users.